Pulmonary monitoring, assessment and management

National Guideline Alliance (UK)

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National Guideline Alliance (UK). Cystic Fibrosis: Diagnosis and management. London: National Institute for Health and Care Excellence (NICE); 2017 Oct 25. (NICE Guideline, No. 78.)

9Pulmonary monitoring, assessment and management

9.1. Pulmonary monitoring

Review questions:

1)

What is the value of the following investigative strategies in monitoring the onset of pulmonary disease in people with cystic fibrosis without clinical signs or symptoms of lung disease?

Non-invasive microbiological investigation-induced sputum samples, cough swab, throat swab, and nasopharyngeal aspiration
Invasive microbiological investigation-broncho-alveolar lavage
Lung physiological function tests-Cardiopulmonary exercise testing, Spirometry and Lung Clearance Index (LCI)
Imaging techniques-Chest x-ray and CT scan

2)

What is the value of the following investigative strategies in monitoring evolving pulmonary disease in people with established lung disease?

Non-invasive microbiological investigation-induced sputum samples, cough swab, throat swab, and nasopharyngeal aspiration
Invasive microbiological investigation-broncho-alveolar lavage
Lung physiological function tests-Cardiopulmonary exercise testing, Spirometry and LCI
Imaging techniques-Chest x-ray and CT scan.

3)

What is the added value of imaging and invasive microbiological testing in addition to non-invasive microbiological testing and lung function tests in monitoring the response to treatment following an acute exacerbation?

9.1.1. Introduction

Treatment for cystic fibrosis lung disease is based on the prevention of lung infection and subsequent colonisation by pathogenic organisms, long term maintenance therapies to ensure clinical stability and prevent progressive loss of lung function and treatment of infective exacerbations. It is a condition which requires constant vigilance to monitor disease state with aggressive, early intervention to treat infection.

Infective exacerbations are associated with considerable morbidity and some episodes can lead to permanent reduction in lung function. Treatment response for pulmonary exacerbation is measured by a number of outcome measures, including analysis of noninvasive microbiological specimens, improvement in symptoms, oxygenation, inflammatory markers and pulmonary function. The treatment of an acute exacerbation is closely monitored by cystic fibrosis teams and therapy may be changed depending on the assessment of treatment response.

9.1.2. Description of clinical evidence

The aim of this review was to examine different monitoring strategies for pulmonary disease in people with cystic fibrosis and to determine their impact on improving subsequent intervention and clinical outcomes, therefore the diagnostic accuracy of the different tests was not prioritised for this review. Monitoring techniques were split into 4 categories:

Monitoring technique 1: non-invasive microbiological investigation of respiratory tract samples (including induced sputum samples, cough swabs, throat swabs and nasopharyngeal aspiration);
Monitoring technique 2: invasive microbiological investigation (i.e. bronchoalveolar lavage - BAL);
Monitoring technique 3: pulmonary function tests (including cardiopulmonary exercise testing, spirometry and LCI);
Monitoring technique 4: imaging techniques (including chest X-ray and CT scanning).

The committee considered the effects of monitoring considering three clinical scenarios associated with lung disease and corresponding review questions and protocols were drafted for people with cystic fibrosis:

Protocol 1: without clinical signs or symptoms of lung disease
Protocol 2: with established pulmonary disease
Protocol 3: following an acute pulmonary exacerbation

The committee recognised that those with no pulmonary disease would principally, but not exclusively be young children and that this review would inform investigative strategies to identify the onset of pulmonary disease, as opposed to identifying evolving pulmonary disease in the second population. The committee were interested in comparisons of individual techniques within categories, individual techniques across categories and in combinations of techniques within or across categories. Of particular interest was the effectiveness of imaging techniques in addition to non-invasive microbiological techniques and spirometry.

The committee were specifically interested in the value of adding invasive microbiological investigations and/or imaging techniques to non-invasive microbiological testing and lung function tests to evaluate treatment response in those with an acute pulmonary exacerbation.

We aimed to include systematic reviews, test and treat RCTs and prospective and retrospective observational studies.

For full details see review protocols in Appendix D.

One single literature search was run for the 3 protocols, and 2 studies were included. Neither of these studies absolutely adhered to the clinical scenarios of the protocols.

9.1.2.1. Review 1. Monitoring for pulmonary disease onset in people with cystic fibrosis without clinical signs or symptoms of lung disease

One study (Sanders 2015) was identified for this protocol. The authors used registry data to follow up 60 children who were initially recruited to a RCT of pulmozyme. The authors investigated whether chest CT and pulmonary function test scores (taken at the start and end of the RCT) were associated with the rate of pulmonary exacerbations over the subsequent 10 year period.

9.1.2.2. Review 2. Monitoring for evolving pulmonary disease in people with cystic fibrosis with established lung disease

No studies were identified for this protocol.

9.1.2.3. Review 3. Monitoring for evolving pulmonary disease in people with cystic fibrosis following an acute pulmonary exacerbation

One study (Wainwright 2011) was identified for this protocol. This study was a multicentre RCT (ACFBAL) which recruited 170 participants to determine whether monitoring using BAL to direct therapy for pulmonary exacerbations in the first five years of life reduced P aeruginosa infection and structural lung injury at age 5 years compared with standard management based on clinical features and oropharyngeal culture results.

A summary of the studies included in the reviews is presented in Table 60 and Table 61. See also study selection flow chart in Appendix F, study evidence tables in Appendix G, list of excluded studies in Appendix H, and full GRADE profiles in Appendix J.

9.1.3. Summary of included studies

9.1.3.1. Review 1. Monitoring for pulmonary disease onset in people with cystic fibrosis without clinical signs or symptoms of lung disease

A summary of the studies that were included in this review is presented in Table 60.

9.1.3.2. Review 2. Monitoring for evolving pulmonary disease in people with cystic fibrosis with established lung disease

No studies were identified for this protocol.

9.1.3.3. Review 3. Monitoring for evolving pulmonary disease in people with cystic fibrosis following an acute pulmonary exacerbation

A summary of the studies that were included in this review is presented in Table 61.

9.1.4. Clinical evidence profiles

9.1.4.1. Review 1. Monitoring for pulmonary disease onset in people with cystic fibrosis without clinical signs or symptoms of lung disease

The clinical evidence profiles for this review question are presented in Table 62, Table 63 and Table 64.

9.1.4.2. Review 2. Monitoring for evolving pulmonary disease in people with cystic fibrosis with established lung disease

Not applicable, as no studies were included for this review.

9.1.4.3. Review 3. Monitoring for evolving pulmonary disease in people with cystic fibrosis following an acute pulmonary exacerbation

The clinical evidence profile for this review question is presented in Table 65.

9.1.5. Economic evidence

One economic evaluation relevant to the protocol was identified in the literature search conducted for this guideline. This study was a prospective cost-benefit analysis undertaken on the RCT by Wainwright (2011) (Section 9.1.2.3). A second study has also been included to aid consideration on the frequency of testing for people with established pulmonary disease. Data extraction tables and quality assessments of included studies can be found in Appendix L and M, respectively. Full details of the search and economic article selection flow chart can be found in Appendix E and F, respectively.

This review question was not prioritised for de novo economic modelling. To aid consideration of cost-effectiveness relevant resource and cost use data are presented in Appendix K.

9.1.6. Evidence statements

9.1.6.1. Review 1. Monitoring for pulmonary disease onset in people with cystic fibrosis without clinical signs or symptoms of lung disease

9.1.6.1.1. Monitoring technique 1. Non-invasive microbiological investigation

No evidence was found.

9.1.6.1.2. Monitoring technique 2. Invasive microbiological investigation

No evidence was found.

9.1.6.1.3. Monitoring technique 3. Lung physiological function tests

Lung function

Moderate quality evidence from 1 cohort study with 60 children with cystic fibrosis showed that a 5-point decrease in FEV₁% predicted was associated with a reduction in FEV₁% predicted at 10 years follow-up.

Clearance of the organism from the cultures

No evidence was found for this important outcome.

Pulmonary exacerbations

Moderate quality evidence from 1 cohort study with 60 children with cystic fibrosis showed that a 5-point decrease in FEV₁% predicted was associated with a higher rate of pulmonary exacerbations during the 10-year follow-up period.

Nutritional parameters

No evidence was found for this important outcome.

Quality of life

No evidence was found for this important outcome.

9.1.6.1.4. Monitoring technique 4. Imaging tests

Lung function

Moderate quality evidence from 1 cohort study with 60 children with cystic fibrosis showed that a 1-point increase in Brody chest CT score was associated with a reduction in FEV₁% predicted at 10-year follow-up.

Clearance of the organism from the cultures

No evidence was found for this important outcome.

Pulmonary exacerbations

Moderate quality evidence from 1 cohort study with 60 children with cystic fibrosis showed that a 1-point increase in Brody chest CT score was associated with a higher rate of pulmonary exacerbations during the 10-year follow-up period.

Nutritional parameters

No evidence was found for this important outcome.

Quality of life

No evidence was found for this important outcome.

9.1.6.1.5. Comparison 1. Lung function tests versus imaging tests

Lung function

Moderate quality evidence from 1 cohort study with 60 children with cystic fibrosis showed that there were no differences in the strengths of the association between the Brody chest CT score and FEV₁% predicted in 1999 with FEV₁% predicted in 2009. This result was reported narratively only.

Clearance of the organism from the cultures

No evidence was found for this important outcome.

Pulmonary exacerbations (proxy outcome for time to chronic infection)

Moderate quality evidence from 1 cohort study with 60 children with cystic fibrosis showed that a 1-point difference in the Brody chest CT score was more strongly associated with the rate of pulmonary exacerbations between 1999 and 2009 than a 5% predicted difference in FEV₁% predicted at the time of the chest CT. This result was reported narratively only.

Nutritional parameters

No evidence was found for this important outcome.

Quality of life

No evidence was found for this important outcome.

9.1.6.2. Review 2. Monitoring for evolving pulmonary disease in people with cystic fibrosis with established lung disease

No evidence was found for this review.

9.1.6.3. Review 3. Monitoring for evolving pulmonary disease in people with cystic fibrosis following an acute pulmonary exacerbation

9.1.6.3.1. Monitoring strategy 1. Invasive microbiological investigations and/or imaging techniques in addition to non-invasive microbiological investigations and/or lung function test VERSUS non-invasive microbiological investigations

Comparison 1. Monitoring using bronchoalveolar lavage (BAL) versus standard monitoring

Lung function

Moderate quality evidence from 1 RCT with 157 infants with cystic fibrosis <6 months showed no clinically significant difference between monitoring using BAL and standard monitoring for FEV₁ z scores at 5 years follow-up.

Clearance of the organism from the cultures

Time to chronic infection

No evidence was found for this important outcome

Nutritional parameters

Low to moderate quality evidence from 1 RCT with 157 infants with cystic fibrosis <6 months showed no clinically significant difference in weight, height and BMI (measured as final z-scores) between monitoring using BAL and standard monitoring at 5 years follow-up.

Quality of life

No evidence was found for this important outcome

9.1.6.3.2. Monitoring strategy 2. Invasive microbiological investigations and/or imaging techniques in addition to non-invasive microbiological investigations and/or lung function test VERSUS lung function test

No evidence was found for this strategy.

9.1.6.3.3. Monitoring strategy 3. Invasive microbiological investigations and/or imaging techniques in addition to non-invasive microbiological investigations and/or lung function test VERSUS non-invasive microbiological investigations and lung function test

No evidence was found for this strategy.

9.1.6.4. Economic evidence statements

One cost-benefit analysis (Moodie 2014) on people with cystic fibrosis in Australia and New Zealand found that the additional cost of BAL therapy compared to standard therapy was not offset by reductions in other healthcare expenditure over 5 years. This analysis has minor limitations and is directly applicable given that the type of economic evaluation is unlikely to change the conclusions about cost-effectiveness and all other applicability criteria are met.

One cost-consequence analysis (Etherington 2008) on people with cystic fibrosis in the UK over 6 months, found that the number of routine susceptibility tests conducted on P aeruginosa isolates can be reduced to provide cost savings without adversely affecting clinical outcomes. This analysis will be used as indirect evidence as the frequency of testing was not a comparator included in the protocol. This evidence is characterised by potentially serious limitations, including the before and after type study design and lack of detail regarding the costs included and their sources.

9.1.7. Evidence to recommendations

9.1.7.1. Relative value placed on the outcomes considered

The aim of this review was to examine different monitoring strategies for pulmonary disease in people with cystic fibrosis and determine their impact on improving subsequent intervention and clinical outcomes. The outcomes selected were different for each clinical scenario:

For monitoring for onset of pulmonary disease in people with cystic fibrosis without clinical signs or symptoms of lung disease (review 1), the committee chose lung function and clearance of the organism from the cultures as critical outcomes for decision making. Time to chronic infection, nutritional parameters and quality of life were rated as important. Given that no evidence was found for time to chronic infection, pulmonary exacerbations were considered a proxy outcome.
For monitoring for evolving pulmonary disease in people with cystic fibrosis with established lung disease (review 2), the committee chose lung function and time to next exacerbation as critical outcomes for decision making. Time to chronic infection, mortality, nutritional parameters and quality of life were rated as important
For monitoring for evolving pulmonary disease in people with cystic fibrosis following an acute pulmonary exacerbation (review 3), the committee chose lung function, time to next exacerbation and clearance of the organism as critical outcomes for decision making. Time to chronic infection, inflammatory markers, nutritional parameters and quality of life were rated as important.

9.1.7.2. Consideration of clinical benefits and harms

The committee acknowledged the scarcity of the evidence and, therefore, most of the recommendations were based on their clinical expertise and experience and good practice recommendations.

The committee discussed the recommendations for asymptomatic and symptomatic people to reflect the different scenarios associated with lung disease; people without clinical signs or symptoms of lung disease and people with established lung disease or people presenting an acute pulmonary exacerbation. A distinction was also made between children and adults, were appropriate.

Asymptomatic people

The committee noted that asymptomatic adults should have an annual review including clinical examination, oxygen saturation test, spirometry, chest X-ray, microbiological investigations with sampling and culture of respiratory tract secretions for early asymptomatic infection with cystic fibrosis pathogens and blood testing to include white cell count and markers or aspergillus, including aspergillus serology and serum IgE.

The committee considered annual chest X-rays to be justified due to the low radiation dose, particularly compared with CT scan, and the benefit of comparing serial films, which may pick up changes representing development or progression of lung disease before symptoms develop. This aligned with the CF Trust consensus recommendations that recommends a regular (annual) chest radiograph.

The committee agreed that conducting microbiological tests was also very useful. This was because detection of early infection is of key importance in cystic fibrosis. It ensures that, where indicated, eradication therapy can be instituted promptly to prevent chronic infection. Problematic pathogens may be found even in asymptomatic patients and the committee consider knowledge of infection status essential for infection control purposes.

The committee considered blood tests for aspergillus, specifically IgE and precipitins, necessary to investigate for the presence of allergic broncho-pulmonary aspergillosis (ABPA), a common complication of cystic fibrosis lung disease.

The usefulness of CT scan in this population was also discussed by the committee. The committee agreed that chest x-rays are poorly sensitive for milder lung disease. They argued that the scan is a much more sensitive way of showing bronchiectasis than a plain film from a plain chest radiograph, which can only show bronchiectasis when it is developed. So in asymptomatic children where the lungs are thought to be healthy, a CT scan may find early bronchiectasis allowing escalation of treatment and, therefore, preventing further deterioration. In addition, a CT scan gives a better idea of the structure of the lungs and will show other changes for example, mucus plugging to allow for targeting of physiotherapy. Given the increased dose of radiation exposure associated to CT scans (compared with X-ray, for example), the committee agreed that the chest CT scan for children should be a low-dose scan and a baseline CT scan in asymptomatic children should only be performed when this has not previously been carried out. The committee noted that people with cystic fibrosis may require many CT scans during their life with associated radiation dose. Moreover, modern CT techniques provide high quality long CT at a much lower dose than previously required. Many patients with CF are thin and, therefore, low-dose CT is particularly appropriate. The committee noted that the recommendation to think about a low-dose CT scan is a weak recommendation which indicates that the decision to perform or not perform the low-dose CT scan would be made based on clinical judgement based on individual circumstances.

Finally the committee agreed that lung function testing should also be part of the annual review, due to the usefulness in detecting any deterioration in the lung function.

Symptomatic people

They noted that symptomatic adults should be reviewed at least every 3 months and should have microbiological cultures, spirometry and measurement of oxygen saturation at each encounter. The rationale for recommending these tests at each encounter in those with lung disease is that the objective of the routine reviews (from the lung perspective) is to prevent deterioration in lung function. Obtaining microbiological cultures helps to ensure that if the cause of any such deterioration is an infection, treatment can be tailored accordingly. This aligned with the CF Trust consensus recommendations, which state that frequent (at every clinic visit) microbiological surveillance of respiratory secretions should be undertaken (for example, cough swab, sputum culture and induced sputum). Moreover, the committee agreed that each routine review should include a review of adherence to therapies as many people with cystic fibrosis are on several long term medications and need to perform daily treatments. Treatment adherence is a major determinant of clinical outcomes. The committee noted that lung function testing with spirometry could only be performed in children and young people who can do this.

The committee recommended that for people with cystic fibrosis with lung disease who have symptoms that are concerning them, or their family members or carers, assessments should be considered on an individualised basis. Depending on the assessments that are needed, it can be decided whether to use telemedicine or face-to-face assessments. The committee noted that some people have devices which allow them to measure oxygen saturation, FEV₁, and take respiratory secretion samples at home. Many people would be able to measure weight and length or height at home, and clinical history could be reviewed using telemedicine.

No evidence was found on LCI. The committee noted that LCI can be a useful tool to assess disease progression as it could provide additional respiratory information to spirometry. However, the committee added that LCI is currently in its infancy in the UK. As a result, the committee made recommendations to consider the use of LCI for those clinics that have access to the equipment and ability to interpret the results. To enable stronger recommendations in the future, a research recommendation to assess if LCI is a useful and cost-effective tool for the routine assessment and monitoring of changes in pulmonary status in people with cystic fibrosis was made by the committee.

Additionally, the committee agreed that the annual review should include the same investigations as for asymptomatic adults.

The committee noted that more frequent assessment of symptomatic children may be necessary to ensure resolution of symptoms.

It was noted that, in people who are responding poorly to treatment, and in the absence of identification of pathogens from cough swabs and induced sputum, more invasive procedures including bronchoalveolar lavage (BAL) or CT scanning can be considered.

Although the included study did not show clinically significant differences between the BAL-directed therapy group and the standard group, BAL is still considered the gold standard. The committee discussed that it is likely that children allocated to the standard group did actually receive BAL when they experience an exacerbation, which could explain the lack of differences between both groups.

As evidence was found to suggest correlation between CT score and prognosis, CT may be useful to monitor disease progression. Where CT scores suggest a worsening prognosis, a more aggressive treatment approach may be required to limit or reverse deterioration and improve the prognosis. Based on this, the committee thought doing a low-dose chest CT scan for children with cystic fibrosis could be useful as it helps to monitor disease progression. The committee agreed that the CT scan could detect features that other tests, such as plain chest radiograph, would miss (for example early bronchiectasis).

Acute exacerbations

The committee noted that those with acute exacerbations need to have a separate, defined protocol for monitoring during the exacerbation. As part of this monitoring process, individuals with exacerbations should undergo clinical assessment, microbiological investigations (sputum or cough swab for cystic fibrosis pathogens including selective media) and spirometry.

The committee noted that usually, in practice, a chest X-ray is performed if FEV₁ drops by 10% or more, although treatment of an exacerbation may be provided without reference to an X-ray. The committee, therefore, recommended that performance of X-ray for acute exacerbation should be considered dependent on severity of the exacerbation, symptoms (for example, where there is suspicion of a pneumothorax) or where there is an element of treatment failure. Where new radiological abnormalities are present on X-ray, this should be repeated to confirm resolution following treatment.

The committee noted that during and following an exacerbation, response to treatment should be assessed using spirometry and microbiological investigation, time to next exacerbation and patient reported outcomes.

As for asymptomatic adults, culture of respiratory secretions for early identification of microbial pathogens is important to allow the most appropriate antibiotics to be selected in line with good antibiotic stewardship. An acute exacerbation may be the initial presentation of a newly acquired pathogen so, as for asymptomatic adults, it is important that any new organisms are detected early to allow eradication to be attempted.

They also agreed lung function tests can be useful to assess response to treatment. They noted height is necessary for accurate calculation of spirometric indices and should be confirmed when spirometry is undertaken where not recently been established.

They considered non-invasive oxygen saturation testing (pulse oximetry) to be part of the clinical assessment, justifying the recommendation without specific evidence.

The committee noted that inflammatory markers are helpful to indirectly determine lung damage and monitor response to treatment. As this is not specific to cystic fibrosis, the committee felt it was justified to include reference to this test in this section.

9.1.7.3. Consideration of economic benefits and harm

Spirometry was the cheapest lung function test under consideration and the committee noted that the accuracy of spirometry is demonstrated in both clinical practice and the study by Sanders 2015. For these reasons, the committee agreed spirometry was cost-effective and should continue to be used to monitor for pulmonary disease at each clinic visit.

The committee also considered a place for LCI investigations at the annual review given that the additional respiratory information resulting from a LCI investigation compared to spirometry justifies the additional cost of LCI. However, they noted that LCI is currently in its infancy in the UK and, although it is a promising investigative technique, its application is currently limited to research rather than routine clinical practice.

The committee noted that the intense monitoring schedules proposed during the first year of identification (4-weekly) would put a strain on cystic fibrosis clinics. Moreover, face-to-face contact at a clinic would be burdensome on the person with cystic fibrosis and subject to availability, which may be too late during an exacerbation. For these reasons, the committee advised that visits could be performed outside of the clinic, as either home-visits or telemedicine, where considered appropriate.

The committee acknowledged that a CT scan costs considerably more than a chest X-ray and involves greater exposure to radiation. However, they believed a CT scan would show subtle structural changes in the lungs that would not be evident from a chest X-ray, such as early bronchiectasis. As a result, a CT scan could allow early escalation of treatment to prevent further deterioration that could be more costly to treat. Furthermore, the committee noted that the accuracy of CT scans to predict pulmonary exacerbations was demonstrated in the study by Sanders 2015. For these reasons, the committee concluded they could justify the use of low-dose CT scans as a cost-effective use of NHS resources and made a recommendation to think about doing a low-dose chest CT scan in people who have not had one before.

The committee considered the high cost of BAL and agreed that despite the lack of clinical evidence in favour of BAL, an annual BAL in children would be more informative than several non-invasive investigations throughout the year. The committee also added that BAL is considered as the gold standard test in clinical practice. However, combined with the high cost of BAL, and the potential adverse effects, the committee agreed BAL could only be considered cost-effective in symptomatic people with cystic fibrosis when cheaper and less invasive investigations such as sputum induction had been unsuccessful.

Monitoring for multi-resistant organisms was discussed by the committee and they agreed it would not be a cost-effective use of resources to monitor for those organisms if there was not an effective treatment for the organisms that are identified.

9.1.7.4. Quality of evidence

There was very little evidence available to inform these 3 reviews. Although many studies examined monitoring techniques, only 2 studies were relevant to the protocol and presented clinical outcomes rather than diagnostic outcomes or estimates of correlation between monitoring techniques.

Only 1 prospective cohort study was available to inform the first protocol which focussed on people with cystic fibrosis without clinical signs or symptoms of lung disease. This study included children who had previously been participants in a randomised controlled trial. One of the criteria for inclusion to the trial was having a FVC of 85% predicted or greater. The participants actually had a mean FEV₁ of 99% predicted at the end of the trial, this was similar to the national (United States) average for children without cystic fibrosis. On this basis the study was included to inform the first protocol.

The GRADE quality of this prognostic data was moderate. It was downgraded from high as the adjustment of the rate ratios did not incorporate the potential confounders of concurrent treatment with immunomodulatory and mucolytic agents during the 10 year follow up period.

There was no available evidence that examined the effectiveness of different combinations of monitoring techniques in adults or children without clinical signs or symptoms of lung disease.

Additionally, there was no available evidence that examined the effectiveness of different combinations of monitoring techniques in adults or children with established pulmonary disease, or any prognostic data for this clinical scenario.

The RCT which informed the third protocol did compare monitoring strategies, however, the included population was aged from under 6 months to 5 years. The relevance of the intervention to use BAL to direct therapy is questionable as this would not reflect current clinical practice, the GRADE quality of outcomes was downgraded accordingly. Moreover, the generalisability of the results to adults is questionable.

9.1.7.5. Other considerations

The committee discussed potential equality issues. They noted that young people who live far from a specialist centre may be disadvantaged. However, they agreed no additional recommendations were needed as the use of alternative models care had already extensively been discussed in the service delivery review. See Service configuration.

The committee discussed the need to draft a research recommendation for this topic. They agreed it would be important to evaluate if LCI was a useful tool for routine assessment and monitoring for changes in pulmonary status in people with cystic fibrosis. This is because assessing the severity of lung disease is difficult in younger children, as not all children under 5 years can do spirometry tests and they are not sufficiently sensitive in people with good lung function, where CT scans can show pulmonary status changes before spirometry changes. A simple, sensitive and reproducible measurement such as LCI allows assessment of respiratory status in people with cystic fibrosis and could improve clinical decision-making.

9.1.7.6. Key conclusions

The committee concluded that monitoring for the onset and evolution of pulmonary disease is key to being able to treat early infections.

They agreed that it is important to conduct regular routine reviews with children and adults with cystic fibrosis even if they are asymptomatic, and these reviews should be more frequent in early life. The committee agreed reviews can be conducted more often if necessary based on clinical judgement. During these routine reviews, it is important to carry out a clinical assessment, conduct non-invasive microbiological investigations and pulmonary function tests. They also agreed it is useful to do a chest CT scan for all children before the age of 12 even in the absence of lung disease. Likewise, they agreed it is important to perform a baseline CT scan for cystic fibrosis people diagnosed in adulthood.

With regards to children who are symptomatic, the committee agreed on recommending the use of invasive microbiological investigations, such as BAL, when the cause of the disease cannot be found using non-invasive microbiological tests or if there is no response to treatment.

Finally, the committee also agreed that it is important to monitor the response to treatment during and after a pulmonary exacerbation by assessing whether symptoms have resolved, conducting microbiological investigations and pulmonary function tests.

9.1.8. Recommendations

40.

For people with cystic fibrosis who have clinical evidence of lung disease, base the frequency of routine reviews on their clinical condition but review children and young people at least every 8 weeks and adults at least every 3 months. If appropriate, think about using the review schedules in recommendation 22.

41.

Include the following at each routine review, in relation to pulmonary assessment, for people with cystic fibrosis:

a clinical assessment, including a review of clinical history and medicines adherence, and a physical examination with measurement of weight and length or height
measurement of oxygen saturation
taking respiratory secretion samples for microbiological investigations, using sputum samples if possible, or a cough swab or nasal pharyngeal aspirate (NPA)
lung function testing with spirometry (including forced expiratory volume in 1 second [FEV1], forced vital capacity [FVC], and forced expiratory flow [FEF] 25–75%) in adults, and in children and young people who can do this.

42.

If spirometry is normal at a routine review, consider measuring lung clearance index.

43.

Include the following at each annual review in relation to pulmonary assessment for people with cystic fibrosis:

a clinical assessment, including a review of the clinical history and medicines adherence, and a physical examination, with measurement of weight and length or height
a physiotherapy assessment
measurement of oxygen saturation
a chest X-ray
blood tests, including white cell count, aspergillus serology and serum IgE
taking respiratory secretion samples for microbiological investigations (including non-tuberculous mycobacteria)
lung function testing (for example with spirometry, including FEV₁, FVC, and FEF 25–75%) in adults, and in children and young people who can do this.

44.

Consider measuring lung clearance index at each annual review if spirometry is normal.

45.

For people with cystic fibrosis with lung disease who have symptoms that are concerning them or their family members or carers (as appropriate), consider which of the following may be useful:

review of clinical history
physical examination, including measurement of weight and length or height
measurement of oxygen saturation
taking respiratory secretion samples for microbiological investigations, using sputum samples if possible, or a cough swab or NPA if not
for adults, blood tests to measure white cell count and inflammatory markers such as C-reactive protein
lung function testing, for example with spirometry (including FEV₁, FVC, and FEF 25–75%) in adults, and in children and young people who can do this
lung clearance index for people with normal spirometry results.

Depending on the assessments that are needed, decide whether to provide a remote Telemedicine or face-to-face assessment.

46.

Think about doing a low-dose chest CT scan for children with cystic fibrosis who have not had a chest CT scan before, to detect features that other tests (such as a plain chest X-ray) would miss (for example early bronchiectasis).

47.

Think about doing a chest X-ray for people with cystic fibrosis during or after treatment for an exacerbation of lung disease (taking account of severity), if:

the exacerbation does not respond to treatment or
a chest X-ray before treatment showed new radiological abnormalities.

48.

Monitor the treatment response during and after an exacerbation of lung disease by assessing whether the symptoms and signs have resolved, and as appropriate:

take respiratory secretion samples for microbiological investigations, using sputum samples if possible, or a cough swab or NPA if not
test lung function, for example with spirometry (including FEV₁, FVC and FEF 25–75%) in adults, and in children and young people who can do this
measure oxygen saturation.

49.

Think about using broncho-alveolar lavage to obtain airway samples for microbiological investigation in people with cystic fibrosis if:

they have lung disease that has not responded adequately to treatment and
the cause of the disease cannot be found with non-invasive upper airway respiratory secretion sampling (including sputum induction if appropriate).

9.1.9. Research recommendations

1.: Is lung clearance index a useful and cost-effective tool for the routine assessment and monitoring of changes in pulmonary status in people with cystic fibrosis?

9.2. Airway clearance techniques

Review question: What is the effectiveness of airway clearance techniques in people with cystic fibrosis?

9.2.1. Introduction

The genetic defect in cystic fibrosis results in the dehydration of mucus, causing increased viscidity and resultant difficulty in its clearance from the airways. Assisted airway clearance has, therefore, featured in the treatment routines of people with cystic fibrosis for decades. A variety of techniques have been developed; some require equipment, some rely on the assistance of others and some facilitate independence. The utility of each technique depends upon the degree and extent of the pathophysiology within the lungs.

The role of the specialist cystic fibrosis physiotherapist is to evaluate this pathophysiology and, in collaboration with the person with cystic fibrosis, select the best airway clearance technique that will overcome these challenges. The aim of treatment is not only to improve the removal of bronchopulmonary secretions and reduce the risk of bacterial infection, but to reduce the burden of symptoms such as cough and breathlessness and ultimately slow disease progression. Airway clearance techniques are often employed as part of a wider airway treatment strategy which may also include mucolytic or anti-inflammatory drugs and exercise. As a result, measuring the impact or success of airway clearance techniques alone is not without difficulty.

Airway clearance approaches are individualised and physiologically reasoned and so need to be frequent reviewed and modified by the physiotherapist according to the evolution of lung disease. With the advent of newborn screening and the success of new medical treatments, the person with cystic fibrosis who has little or no lung disease also needs careful consideration. Airway clearance routines for the person with cystic fibrosis and their family or carers can be considered a significant commitment and burden to achieving ‘normal’ life. It is therefore essential that cystic fibrosis teams continue to question what is understood about these frequently used techniques.

9.2.2. Description of clinical evidence

The aim of this review was to examine the effectiveness of airway clearance techniques in people with cystic fibrosis.

The interventions reviewed were: manual physiotherapy techniques (including chest shaking or vibrations, chest percussion), positive expiratory pressure (PEP), active cycle of breathing techniques (ACBT), relaxation or breathing control forced expiration techniques (FET) which includes huffing and breathing control, thoracic expansion exercises, autogenic drainage (AD), oscillating devices (including acapella and flutter, cornet), high frequency chest wall oscillation (e.g. the Vest) and non-invasive ventilation (NIV).

We aimed to compare each airway technique with no intervention, to ascertain effectiveness. In addition, the committee prioritised for inclusion the following comparisons between techniques:

Manual physiotherapy techniques versus oscillating devices (OD)
Manual physiotherapy versus high frequency chest wall oscillation (HFCWO)
Positive expiratory pressure (PEP) versus active cycle of breathing techniques (ACBT)
Positive expiratory pressure (PEP) versus oscillating devices (OD)
Positive expiratory pressure (PEP) versus high frequency chest wall oscillation (HFCWO)
Active cycle breathing technique (ACBT) versus autogenic drainage (AD)
Oscillating device (OD) versus high frequency chest wall oscillation (HFCWO).

We searched for systematic reviews of RCTs and RCTs aimed at assessing the effectiveness of airway clearance techniques in people with cystic fibrosis. Observational studies were not prioritised for inclusion in the review, as there was enough evidence from published randomised trials.

For full details see review protocol in Appendix D.

Six Cochrane systematic reviews (McIlwaine 2015, Morrison 2014, Moran 2013, McKoy 2012, Main 2005, Warnock 2013) and 5 non-Cochrane systematic reviews (Boy 1994, Bradley 2006, Flume 2009, Morgan 2015, Thomas 1995) were identified in our search for potential inclusion. The quality of all reviews was assessed with AMSTAR.

All the Cochrane reviews obtained a total score equal or higher than 10 (out of 11) in the AMSTAR quality checklist and were considered for inclusion. Each Cochrane review was then checked for relevant potential comparisons, as the definitions of the airway clearance techniques differ from the definitions proposed in our protocol.

Four Cochrane reviews were included, as they had relevant comparisons. Where possible, data and quality assessment were extracted from the Cochrane reviews, although the individual studies were retrieved full text for additional information and results.

The Cochrane reviews included were:

McIlwaine (2015) evaluated the effectiveness and acceptability of PEP devices compared to other physiotherapy techniques to improve airway clearance. 4 trials were included from this review (McIlwaine 2013, McIlwaine 2001, Newbold 2005, Tannenbaum 2005), of which 1 (Tannenbaum 2005) was an abstract and only information provided by the Cochrane review was used as the paper could not be retrieved.
Moran (2013) compared the effect of non-invasive ventilation versus no treatment in people with cystic fibrosis. 2 trials were included from this review (Placidi 2006 and Young 2008).
Morrison (2014) evaluated whether oscillatory devices, oral or chest wall were effective for airway clearance and also compared them with other forms of airway clearance for the management of secretions in people with cystic fibrosis. Seven trials were included from this review (Darbee 2005, Grzincich 2008, Padman 1999, Oermann 2001, Homnick 1998, van Winden, Warwick 2004), of which 1 was an abstract (Grzincich 2008)
Warnock (2013) evaluated the effectiveness and acceptability of chest physiotherapy compared to no treatment to improve airway clearance in people with cystic fibrosis. 1 trial was included from this review (Braggion 1995).

Three Cochrane reviews were excluded:

McKoy (2012) evaluated the clinical effectiveness of ACBT with other airway clearance techniques, but it did not include comparisons relevant for this review. The individual studies were also checked for potential inclusion, but none of them met the criteria for inclusion.
Main (2005) compared conventional chest physiotherapy to other airway clearance techniques for cystic fibrosis, but it did not include comparisons relevant for this review. The individual studies were also checked for potential inclusion, and only 1 was considered relevant (Homnick 1998), but it had already been included in another review (Morrison 2014).
Robinson (2010) compared the clinical effectiveness of ACBT with other airway clearance techniques. One trial (Miller 1995) was considered for inclusion, but the intervention consisted in a combination of ACBT and postural drainage.

The quality of the non-Cochrane reviews obtained scores equal to or lower than 6 (out of 11) in the AMSTAR checklist and were therefore excluded. The lists of included studies in these reviews were checked in order to identify other studies that had not been already included, but none of them met the inclusion criteria in our protocol.

No further trials were identified in our search.

The size of the studies ranged from to 8 to 107 people with cystic fibrosis. Four studies included adults (Grzincich, Newbold 2005, Young 2008, Warwick 2004), 2 studies included young people and adults (Braggion 1995, Placidi 2006), 4 studies included children and young people (McIlwaine 2001, Padman 1999, Tannenbaum 2005, van Winden 1998), 4 studies included children, young people and adults (Darbee 2005, Homnick 1998, McIlwaine 2013, Oermann 2001)

One study was conducted in Italy (Braggion 1995), 5 studies in the USA (Darbee 2005, Homnick 1998, Oermann 2001, Padman 1999, Warwick 2004), 2 studies in Australia (Placidi 2006, Young 2008), 3 studies in Canada (McIlwaine 2001, McIlwaine 2013, Newbold 2005), 1 study in the Netherlands (van Winden 1998); the country was not reported in 2 abstracts (Grzincich 2008, Tannenbaum 2005).

The included studies assess the effectiveness and acceptability of airway clearance interventions with the following comparisons:

manual physiotherapy techniques versus oscillating devices – 2 studies (Homnick 1998, Padman 1999)
manual physiotherapy versus high frequency chest wall oscillation (HFCWO) – 1 study (Warwick 2004)
positive expiratory pressure (PEP) versus no airway clearance - 2 studies (Braggion 1995, Placidi 2006)
positive expiratory pressure (PEP) versus oscillating devices – 6 studies (McIlwaine 2001, McIlwaine 2013, Newbold 2005, Padman 1999, Tannenbaum 2005, van Winden 1998)
positive expiratory pressure (PEP) versus high frequency chest wall oscillation (HFCWO) – 4 studies (Braggion 1995, Darbee 2005, Grzincich 2008, McIlwaine 2013)
oscillating device versus high frequency chest wall oscillation (HFCWO) - 1 study (Oermann 2001)
non-invasive ventilation versus no airway clearance technique – 1 study (Young 2008).

Where no evidence for sputum volume was found in the study, sputum weight (both dry and wet) was taken as a proxy outcome for sputum volume.

Evidence from these are summarised in the clinical GRADE evidence profile below (Table 62 Table 69 to Table 75). See also the study selection flow chart in Appendix F, forest plots in Appendix I, study evidence tables in Appendix G and exclusion list in Appendix H.

9.2.3. Summary of included studies

A summary of the studies that were included in this review are presented in Table 68.

9.2.4. Clinical evidence profile

The summary clinical evidence profiles are presented in Table 68 to Table 75.

9.2.5. Economic evidence

One conference abstract identified in the literature search conducted for this guideline was considered relevant to this review question. This paper undertook a cost-consequence analysis to compare positive expiratory pressure (PEP) to high frequency chest wall oscillation (HFCWO) in 107 cystic fibrosis patients in Canada (McIlwaine 2014). They concluded that PEP was less expensive and more effective (dominant) at reducing the number of exacerbations than HFCWO. The methods and results from this analysis are provided in Appendix K.

This review question was not prioritised for de novo economic modelling. To aid consideration of cost-effectiveness, relevant resource and cost use data are presented in Appendix K.

Full details of the search and economic article selection flow chart can be found in Appendix E and F, respectively. Data extraction tables and quality assessments and of included studies can be found in Appendix L and M, respectively.

9.2.6. Evidence statements

9.2.6.1. Comparison 1. Manual physiotherapy versus no airway clearance techniques

No evidence was found for this comparison.

9.2.6.2. Comparison 2. Manual physiotherapy techniques versus oscillating devices

Sputum volume

No evidence was found for this critical outcome.

Patient preference

No evidence was found for this critical outcome.

Pulmonary exacerbations

No evidence was found for this critical outcome.

Pulmonary function tests: FEV₁ and FVC

Very low quality evidence from 1 crossover RCT with 22 children, young people and adults with cystic fibrosis showed no clinically significant difference in FEV₁ percent change from baseline between manual physiotherapy techniques and oscillating device after 8.8 days follow-up.

Very low quality evidence from 1 crossover RCT with 6 children and young people with cystic fibrosis showed no clinically significant difference in FEV₁ percent change from baseline between manual physiotherapy techniques and oscillating device after 1 month follow-up.

Very low quality evidence from 1 crossover RCT with 22 children, young people and adults with cystic fibrosis showed no clinically significant difference in FVC percent change from baseline between manual physiotherapy techniques and oscillating device after 2 week follow-up.

Oxygen saturation

No evidence was found for this important outcome.

Quality of life

No evidence was found for this important outcome.

Hospitalisations

No evidence was found for this important outcome.

9.2.6.3. Comparison 3. Manual physiotherapy versus High Frequency Chest Wall Oscillation

Sputum volume

Low quality evidence from 1 crossover RCT with 12 adults with cystic fibrosis showed no clinically significant difference in sputum dry weight between manual physiotherapy and HFCWO after 1 to 2 week follow-ups.

Low quality evidence from 1 crossover RCT with 12 adults with cystic fibrosis showed no clinically significant difference in sputum wet weight between manual physiotherapy and HFCWO after 1 to 2 week follow-ups.

Patient preference

No evidence was found for this critical outcome.

Pulmonary exacerbations

No evidence was found for this critical outcome.

Pulmonary function tests

No evidence was found for this important outcome.

Oxygen saturation

No evidence was found for this important outcome.

Quality of life

No evidence was found for this important outcome.

Hospitalisations

No evidence was found for this important outcome.

9.2.6.4. Comparison 4. Positive expiratory pressure (PEP) versus no airway clearance technique

Sputum volume

Low quality evidence from 1 crossover RCT with 17 young people and adults with cystic fibrosis showed no clinically significant difference in sputum dry weight between PEP and control after 2 days follow-up.

Moderate quality evidence from 1 crossover RCT with 17 young people and adults with cystic fibrosis showed no clinically significant difference in sputum wet weight between PEP and control after 2 days follow-up.

Patient preference

No evidence was found for this critical outcome.

Pulmonary exacerbations

No evidence was found for this critical outcome.

Pulmonary function tests: FEV₁ and FVC

Very low quality evidence from 1 crossover RCT with 16 young people and adults with cystic fibrosis showed no clinically significant difference in percent predicted FEV₁ between PEP and control after 2 days follow-up.

Low quality evidence from 1 crossover RCT with 17 young people and adults showed no clinically significant difference in FEV₁ (L) between PEP and control after 2 days follow-up.

Very low quality evidence from 1 crossover RCT with 16 young people and adults with cystic fibrosis showed no clinically significant difference in percent predicted FVC between PEP and control after 2 days follow-up.

Low quality evidence from 1 crossover RCT with 17 young people and adults showed no clinically significant difference in FVC between PEP and control after 2 days follow-up.

Oxygen saturation

Moderate quality evidence from 1 crossover RCT with 17 young people and adults showed no clinically significant difference in oxygen saturation between PEP and control after 2 days follow-up.

Quality of life

No evidence was found for this important outcome.

Hospitalisations

No evidence was found for this important outcome.

9.2.6.5. Comparison 5. Positive expiratory pressure (PEP) versus active cycle of breathing techniques (ACBT)

No evidence was found for this comparison.

9.2.6.6. Comparison 6. Positive expiratory pressure (PEP) versus oscillating devices

Sputum volume

No evidence was found for this critical outcome.

Patient preference

Very low quality evidence from 1 parallel RCT with 40 children and young people with cystic fibrosis showed no clinically significant difference in self-withdrawal due to lack of perceived effectiveness between PEP and oscillating device after 1 month follow-up.

Pulmonary exacerbations

Low quality evidence from 1 parallel RCT with 42 adults with cystic fibrosis showed no clinically significant difference in number of hospitalisation for respiratory exacerbations per participant between PEP and oscillating device after 13 months follow-up.

Pulmonary function tests: FEV₁ and FVC

Very low quality evidence from 1 crossover RCT with 6 children and young people with cystic fibrosis showed no clinically significant difference in FEV₁ percent change from baseline between PEP and oscillating device after 2 to 4 week follow-ups.

Low quality evidence from 1 parallel RCT with 30 children and young people with cystic fibrosis showed no clinically significant difference in FEV₁ percent change from baseline between PEP and oscillating device after 6 to 12 months follow-up.

Low quality evidence from 3 parallel RCTs with 160 children, young people and adults with cystic fibrosis showed no clinically significant difference in FEV₁ percent change from baseline between PEP and oscillating device after 1 to 2 years follow-up.

Low quality evidence from 3 RCTs with 160 children, young people and adults with cystic fibrosis showed no clinically significant difference in FVC percent change from baseline between PEP and oscillating device after 1 year follow-up. Moderate inconsistency was observed between the trials, but all of them showed a no clinically significant difference between both treatment groups.

Moderate quality evidence from 1 crossover RCT with 22 children and young people with cystic fibrosis showed no clinically significant difference in percent predicted FVC between PEP and oscillating device after 2 to 4 week follow-ups.

Oxygen saturation

No evidence was found for this important outcome.

Quality of life

High quality evidence from 1 parallel RCT with 107 children, young people and adults with cystic fibrosis showed no clinically significant difference in the physical domain of the CFQ-R questionnaire between PEP and oscillating device after 1 year follow-up.

High quality evidence from 1 parallel RCT with 107 children, young people and adults with cystic fibrosis showed no clinically significant difference in the treatment burden domain of the CFQ-R questionnaire between PEP and oscillating device after 1 year follow-up.

Moderate quality evidence from 1 parallel RCT with 107 children, young people and adults with cystic fibrosis showed no clinically significant difference in the respiratory domain of the CFQ-R questionnaire between PEP and oscillating device after 1 year follow-up.

Hospitalisations

No evidence was found for this important outcome.

9.2.6.7. Comparison 7. Positive expiratory pressure (PEP) versus High Frequency Chest Wall Oscillation (HFCWO)

Sputum volume

Low quality evidence from 1 RCT with 23 adults with cystic fibrosis showed no clinically significant difference in sputum volume between PEP and HFCWO after 1 week follow-up.

Patient preference

No evidence was found for this critical outcome.

Pulmonary exacerbations

Moderate quality evidence from 1 parallel RCT with 91 children, young people and adults with cystic fibrosis showed a clinically significant beneficial effect of PEP compared to HFCWO in number of patients with respiratory exacerbation after 1 year follow-up.

Moderate quality evidence from 1 parallel RCT with 88 children, young people and adults with cystic fibrosis showed a clinically significant beneficial effect of PEP compared to HFCWO in number of patients requiring antibiotics for respiratory exacerbation after 1 year follow-up.

Pulmonary function tests: FEV₁ and FVC

Very low quality evidence from a 2 RCTs with 39 young people and adults with cystic fibrosis showed no clinically significant difference in percent predicted FEV₁ between PEP and HFCWO after 1 week follow-up.

Very low quality evidence from 1 crossover RCT with 15 children, young people and adults with cystic fibrosis showed no clinically significant difference in percent predicted FEV₁ between PEP and HFCWO after 1 to 2 week follow-ups.

Moderate quality evidence from 1 parallel RCT with 88 children, young people and adults with cystic fibrosis showed no clinically significant difference in change from baseline percent predicted FEV₁ between PEP and HFCWO after 1 year follow-up.

Very low quality evidence from 1 crossover RCT with 15 children, young people and adults with cystic fibrosis showed no clinically significant difference in percent predicted FVC between PEP and HFCWO after 1 to 2 week follow-ups.

Moderate quality evidence from a 2 RCTs with 39 young people and adults with cystic fibrosis showed no clinically significant difference in percent predicted FVC between PEP and HFCWO after 1 week follow-up.

Oxygen saturation

No evidence was found for this important outcome.

Quality of life

No evidence was found for this important outcome.

Hospitalisations

No evidence was found for this important outcome.

9.2.6.8. Comparison 8. Active cycle of breathing technique (ACBT) versus no airway clearance technique

No evidence was retrieved for this comparison.

9.2.6.9. Comparison 9. Active cycle breathing technique (ACBT) versus autogenic drainage (AD)

No evidence was retrieved for this comparison.

9.2.6.10. Comparison 10. Autogenic drainage (AD) versus no airway clearance technique

No evidence was retrieved for this comparison.

9.2.6.11. Comparison 11. Oscillating device versus no airway clearance technique

No evidence was retrieved for this comparison.

9.2.6.12. Comparison 12. Oscillating device versus High Frequency Chest Wall Oscillation (HFCWO)

Sputum volume

No evidence was found for this critical outcome.

Patient preference

No evidence was found for this critical outcome.

Pulmonary exacerbations

No evidence was found for this critical outcome.

Pulmonary function tests: FEV₁ and FVC

Moderate quality evidence from 1 crossover RCT with 24 children, young people and adults with cystic fibrosis showed no clinically significant difference in percent predicted FEV₁ between oscillating device and HFCWO after 2 to 4 week follow-ups.

Low quality evidence from 1 crossover RCT with 24 participants showed no clinically significant difference in percent predicted FVC between oscillating device and HFCWO after 2 to 4 week follow-ups.

Oxygen saturation

No evidence was found for this important outcome.

Quality of life

No evidence was found for this important outcome.

Hospitalisations

No evidence was found for this important outcome.

9.2.6.13. Comparison 13. High Frequency Chest Wall Oscillation (HFCWO) versus no clearance technique

No evidence was retrieved for this comparison.

9.2.6.14. Comparison 14. Non-invasive ventilation (NIV) versus no airway clearance technique

Sputum volume

No evidence was found for this critical outcome.

Patient preference

No evidence was found for this critical outcome.

Pulmonary exacerbations

No evidence was found for this critical outcome.

Pulmonary function tests: FEV₁ and FVC

Low quality evidence from 1 crossover RCT with 8 adults with cystic fibrosis showed no clinically significant difference in percent predicted FEV₁ between NIV and control after 6 week follow-up.

Low quality evidence from 1 crossover RCT with 8 adults with cystic fibrosis showed no clinically significant difference in percent predicted FVC between NIV and control after 6 week follow-up.

Oxygen saturation

Moderate quality evidence from 1 crossover RCT with 8 adults with cystic fibrosis showed no clinically significant difference in nocturnal oxygen saturation between NIV and control after 6 week follow-up.

Quality of life

Low quality evidence from 1 crossover RCT with 8 adults with cystic fibrosis showed no clinically significant difference in quality of life chest symptom score using the CF-QOL questionnaire between NIV and control after 6 week follow-up.

Moderate quality evidence from 1 crossover RCT with 8 adults with cystic fibrosis showed no clinically significant difference in quality of life traditional dyspnoea index score using the CFQOL questionnaire between NIV and control after 6 week follow-up.

Hospitalisations

No evidence was found for this important outcome.

9.2.6.15. Economic evidence statements

One cost-benefit analysis on people with cystic fibrosis in Canada found that PEP was less expensive and more effective at reducing exacerbations than HFCWO over 1 year. This analysis is partially applicable with serious limitations, given the limited details reported in the conference abstract.

9.2.7. Evidence to recommendations

9.2.7.1. Relative value placed on the outcomes considered

The aim of this review was to examine the effectiveness of airway clearance techniques in people with cystic fibrosis.

The committee chose sputum volume, pulmonary exacerbations and patient preference as critical outcomes for decision making. Pulmonary function (FEV₁, FVC), oxygen saturation, hospitalisations and quality of life were rated as important outcomes.

9.2.7.2. Consideration of clinical benefits and harms

The committee acknowledged the evidence, but they showed some concerns regarding the quality of the studies and its usefulness to make recommendations. They noted that the studies included in the clinical review had a low number of participants and were conducted over a short time frame. Moreover, none of the studies included children under the age of 6 and several studies excluded patients who were unstable or recovering from an exacerbation. The committee also stressed that RCTs would not reflect clinical practice as techniques are normally individualised because they do not treat the same physiological causes. Given that, the committee noted that it would be difficult for the benefits from an airway clearance technique to be demonstrated in randomised trials.

Based on the review, the committee acknowledged that there was limited evidence either in favour or against the use of routine airway clearance techniques in people with cystic fibrosis. Apart from a clinically significant beneficial effect which favoured the use of PEP over high frequency chest wall oscillation (HFCWO) in the number of pulmonary exacerbations (moderate quality evidence), there were no other clinically significant findings. The committee noted that there was low to moderate quality evidence that showed that using PEP was no better than no airway clearance technique in sputum volume, lung function or oxygen saturation. With regards to the comparisons between different techniques, very low quality evidence showed no clinically significant differences between manual physiotherapy techniques and oscillating devices in lung function. Likewise, very low to high quality evidence showed no clinically significant differences between PEP and oscillatory devices in patient preference, pulmonary exacerbations, lung function, or quality of life.

It was also noted, by the committee, that the effectiveness of airway clearance in other conditions is not generalisable to those with cystic fibrosis as cystic fibrosis is a condition with specific clinical manifestations.

However, the committee discussed that, despite the lack of evidence showing effectiveness, there was a strong rationale (physiological) that airway clearance techniques are useful in children and adults who produce sputum. This is based on the knowledge that in cystic fibrosis the normal mucociliary transport system is impaired and ineffective. Therefore, airway clearance techniques are used to make up for the defects in this system and promote the mobilisation of sputum from the airways to allow expectoration. Due to the dehydrated mucus and airway damage, airway clearance techniques may reduce the risk of infection by assisting the removal of bacteria in the sputum. The committee suggested that the number of trials comparing combinations of airway clearance techniques infers there is underlying knowledge and experience that individual airway clearance techniques are useful.

Moreover, the committee argued that the benefits of airway clearance may not be demonstrated by the amount of sputum produced. In other words, the benefits of airway clearance techniques are not always measurable because the person may just feel better. The committee noted that there are no gold standard outcome measures to evaluate effectiveness of airway clearance techniques. For these reasons the committee agreed not to make a “do not do recommendation” despite the lack of favourable evidence.

The committee also discussed which patients would benefit the most from airway clearance techniques depending on their disease trajectory. The committee noted that paediatric practice has considerably changed in the last few years. Some centres are more comfortable not instigating routine airway clearance with children that are asymptomatic. The focus has been on teaching airway clearance techniques for use when needed, using more structured exercise to promote airflow in the lungs and encouraging close parental assessment of symptoms. It was recognised that some clinicians believe that learning airway clearance techniques at a young age helps to establish a daily routine to carry forward during adulthood. Based on this, the committee agreed it is important to discuss the use of airway clearance techniques with people with cystic fibrosis who do not have clinical evidence of lung disease, and, in the case of children or young people, with their parents or carers (as appropriate) and provide them with training on airway clearance techniques and when to use them. The committee noted that given the lack of evidence of benefit, people without clinical evidence of lung disease (such as CT changes or chronic sputum production) may not have to use airway clearance techniques on a regular basis. However, training on airway clearance techniques should include how to identify the need for performing these techniques. This would allow people with cystic fibrosis to start independently when appropriate rather than delaying the use of these techniques until a health care professional has identified the need.

On the other hand, the committee agreed that when a patient has clinical evidence of lung disease, or has received a treatment that produces sputum, such as mucolytic treatment, performing airway clearance techniques on a regular basis has a strong rationale and is often helpful in relieving symptoms of cough and breathlessness. The committee agreed that there are a number of factors that should be taken into account when choosing an airway clearance technique.

First, they noted it was important to assess the person’s symptoms, including stage of lung disease and current health, and their ability to clear mucus from their lungs. In addition, they highlighted the difficulties of understanding the impact of other treatments and lifestyle choices in people with cystic fibrosis on airway clearance outcomes. They noted it is very important to take into account the individual preferences of the person and their parents or carers, as these may influence adherence.

The committee agreed it is important to assess the effectiveness of the airway clearance technique and choose a different one if needed.

The committee discussed HFCWO, which is becoming more recognised in the UK, at length. This technique is popular among patients in the USA but has a high associated cost. They noted that an increasing number of people with cystic fibrosis and carers are buying HFCWO privately because it is only funded by the NHS in exceptional circumstances, specifically when all other techniques have been exhausted. However, the evidence retrieved for this review did not support the use of HFCWO. No clinically significant differences was found between manual physiotherapy techniques and high frequency chest wall oscillation in sputum volume (low quality evidence). No clinically significant differences were found either between using oscillating devices and HFCWO in lung function (low to moderate quality). Likewise, no clinically significant differences were found between PEP and high frequency chest wall oscillation in sputum volume (low quality evidence) or lung function (very low to moderate). In fact, moderate quality evidence from 2 trials showed that PEP was better at reducing pulmonary exacerbations. Based on this, the committee agreed that, given the current evidence, HFCWO should not be recommended as part of this guideline. However, the committee added that healthcare professionals should consider HFCWO as a last resort in people with cystic fibrosis who have exceptional clinical circumstances. The specialist cystic fibrosis team should decide whether these circumstances apply, and their decision would then be subject to the NHS England policy on Individual Funding Requests. To meet NHS England definition of “exceptional clinical circumstances” the patient must demonstrate that they are both: “Significantly different clinically to the group of patients with the condition in question and at the same stage of progression of the condition” AND “Likely to gain significantly more clinical benefit than others in the group of patients with the condition in question and at the same stage of progression of the condition. Note: Non-clinical factors cannot be taken into account” (NHS England Individual Funding Request Form). In those people, such as those with a neuro-disability, the benefits from other airway clearance techniques may not be achievable given the obstacles to perform them manually. Following this, if HFCWO is the only technique that can maintain or improve their lung function it is an option to consider.

Low to moderate quality evidence from one trial showed no clinically significant beneficial effect of NIV over control in lung function, oxygen saturation and quality of life. Based on their experience and expertise, the committee noted that NIV could be used in people with cystic fibrosis who have moderate or severe lung disease and cannot clear their lungs using standard airway clearance techniques. This is because it is known that NIV unloads the respiratory muscles, therefore, reducing the symptoms associated with respiratory muscle fatigue, in moderate and severe lung disease, such as reduced oxygen and breathlessness.

The committee agreed that NIV can be beneficial as short-term option in moderate disease, when people have difficulty clearing their airways using other clearance techniques, by unloading the respiratory muscles and reducing fatigue.

9.2.7.3. Consideration of economic benefits and harms

Techniques including ACBT, oscillating devices and PEP can be performed at home after an initial visit with a physiotherapist to issue the device and teach the techniques. Therefore, the cost of performing combinations would be similar to single techniques. Moreover, there is no increase in cost if those techniques are performed more frequently as no additional resources are required. In current clinical practice, the person with cystic fibrosis, and their parents or carers, are offered training in airway clearance techniques before there is evidence of lung disease. This early training will prevent the downstream costs from delayed management. Following this, the committee agreed training was relatively cheap to provide and made a recommendation to reinforce best practice, to offer training.

The committee noted that those relatively inexpensive techniques should not be performed if they are ineffective, particularly when the opportunity cost of the person’s time is considered. Performing long, regular periods of airway clearance could reduce adherence to other treatments which could potentially reduce the effects of those treatments. However, the committee agreed that lack of evidence does not mean lack of effect, and hence, lack of cost-effectiveness. Therefore, they made a recommendation to discuss the use of airway clearance techniques.

The committee agreed there was clinical and cost-effectiveness evidence to suggest HFCWO was dominated (more expensive and less effective) by PEP. Subsequently, the committee made a recommendation against its routine use, to prevent a cost ineffective use of NHS resources. However, the committee added that healthcare professionals should consider HFCWO as a last resort in people with cystic fibrosis who have exceptional clinical circumstances, as explained above in the clinical benefits and harms section. However, without knowing the benefits of HFCWO in people with exceptional clinical circumstances, we cannot know if HFCWO will be cost-effective.

Based on their experience and expertise the committee stated that NIV is considered as a cost-effective intervention in clinical practice as it can reduce fatigue (breathlessness) caused by moderate to severe lung disease, unlike cheaper airway clearance techniques.. The committee also agreed that NIV can be beneficial in the short-term, during exacerbations, when people have difficulty clearing their airways using other airway clearance techniques. However, the committee added that the high cost of NIV could not be justified in people with mild disease as any improvements in their outcomes would be negligible and result in a cost-ineffective use of resources.

9.2.7.4. Quality of evidence

The quality of the evidence presented in this report ranged from very low to high as assessed by GRADE. The main reasons that led to downgrading the quality of the evidence were:

For the domain risk of bias, the studies were assigned the same risk of bias as in the Cochrane reviews and were not individually reviewed. The main biases that lead to downgrading the quality of the evidence were selection, attrition, and reporting bias.
Another reason that lead to downgrading the quality of the evidence was the imprecision, as confidence intervals crossed 1 or 2 MIDs. The committee noted that many trials were underpowered to detect a clinically important difference.

No serious issues were found regarding inconsistency (heterogeneity) and the directness of the population (generability of the results).

9.2.7.5. Other considerations

No equality issues were identified by the committee for this review question.

The committee discussed the need to draft a research recommendation for this topic. Since the advent of newborn screening for cystic fibrosis there has been international debate about the level of physiotherapy intervention required from diagnosis to preserve lung health. Some clinical teams opt to teach and recommend daily airway clearance techniques, whereas others use parental respiratory assessment tools with structured exercise. Routine airway clearance from diagnosis places considerable responsibility and time burden on the parents and carers at a time when such techniques are challenging to perform and negotiate with the infant and child. It is important that we fully understand if routine practice is providing benefit to maintain lung health or, in fact, creating unnecessary burden. Future research must seek to understand the impact, not only on long term clinical outcomes, but on the lives of parents, families and carers of infants and children with cystic fibrosis.

9.2.7.6. Key conclusions

The committee concluded that there was limited evidence in favour or against the use of airway clearance techniques in patients with cystic fibrosis. However, there is a strong physiological rationale for airway clearance techniques and they continue to be used routinely in the patient with clinical evidence of lung disease. The use of manual physiotherapy techniques, PEP, ACBT and AD were prioritised by the committee. But they agreed HFCWO should not be recommended due to its cost and the evidence that is inferior to other airway clearance techniques. HFCWO should only be considered as an option of last resort in people with exceptional clinical circumstances. The specialist cystic fibrosis team should decide whether these circumstances apply, and their decision would then be subject to the NHS England policy on Individual Funding Requests. The decision to choose one technique over another would be based on individual factors and the physiological problem or circumstances at the time, rather than one technique being superior to another. Individual preferences should be taken into account when deciding an airway clearance technique as this may impact adherence. NIV could be used in people who are limited by symptoms such as breathlessness and fatigue due to moderate or severe lung disease and cannot clear their lungs using standard airway clearance techniques.

9.2.8. Recommendations

50.

Discuss the use of airway clearance techniques with people with cystic fibrosis who do not have clinical evidence of lung disease and their parents or carers (as appropriate). Provide them with training in airway clearance techniques and explain when to use them.

51.

Offer training in airway clearance techniques to people with cystic fibrosis who have clinical evidence of lung disease and their parents or carers (as appropriate).

52.

When choosing an airway clearance technique for people with cystic fibrosis:

assess their ability to clear mucus from their lungs, and offer an individualised plan to optimise this
take account of their preferences and (if appropriate) those of their parents and carers
take account of any factors that may influence adherence.

53.

Regularly assess the effectiveness of airway clearance techniques, and modify the technique or use a different one if needed.

54.

Do not offer high-frequency chest wall oscillation as an airway clearance technique for people with cystic fibrosis except in exceptional clinical circumstances. The specialist cystic fibrosis team will decide whether these circumstances apply, and their decision would then be subject to the NHS England policy on Individual Funding Requests. Be aware that the evidence shows high-frequency chest wall oscillation is not as effective as other airway clearance techniques.

55.

Consider using non-invasive ventilation in people with cystic fibrosis who have moderate or severe lung disease and cannot clear their lungs using standard airway clearance techniques.

9.2.9. Research recommendations

2.: How effective are daily airway clearance techniques in maintaining lung function in infants and children with cystic fibrosis?

9.3. Mucoactive agents

Review question: What is the effectiveness of mucoactive or mucolytic agents, including dornase alfa, nebulised sodium chloride (isotonic and hypertonic) and mannitol?

9.3.1. Introduction

The underlying lung defects in people with cystic fibrosis leads to an increase in water absorption from the epithelial surface. This results in a reduced airway surface liquid layer and a more viscous mucus layer on the surface of the airways. This mucus accumulates due to reduced clearance and supports the retention of micro-organisms. This, in turn, leads to infection and the destructive inflammatory processes which lead to bronchiectasis.

The primary aim of pulmonary disease management in people with cystic fibrosis is to stabilise, or prevent decline in, pulmonary function and prevent the occurrence of acute pulmonary exacerbations. Therefore, people with cystic fibrosis who have evidence of pulmonary disease commonly employ airway clearance techniques to reduce the burden of viscid mucus and break the destructive cycle of mucus stasis, infection and inflammation.

Mucoactive agents are often employed as adjuncts to airway clearance techniques. These agents change the properties of mucus, through a number of mechanisms, rendering it easier to expectorate: dornase alfa is a recombinant human enzyme which acts by cleaving extracellular DNA (a by-product of neutrophil degeneration) in the mucus; osmotic agents such as mannitol and hypertonic sodium chloride draw water onto the airway surface to rehydrate the airway surface liquid layer; solutions of hypertonic sodium chloride disrupt ionic bonds within the mucus gel.

With a number of mucoactive agents available, this review question aims to determine the effectiveness of mucoactive or mucolytic agents – including dornase alfa, inhaled sodium chloride solutions (both isotonic and hypertonic) and inhaled mannitol – in order to determine their place in the management of cystic fibrosis pulmonary disease.

9.3.2. Description of clinical evidence

The aim of this review was to establish the clinical and cost effectiveness of mucoactive or mucolytic agents in improving airway clearance in children, young people and adults with cystic fibrosis.

The nebulised and inhaled mucoactive and mucolytic agents reviewed were: acetylcysteine, dornase alfa, nebulised sodium chloride (hypertonic and isotonic) and mannitol (only in children and young people up to the age of 18 years as Technology Appraisal (TA) in adults will be included).

NICE TA266 has been published to provide guidance on the use of mannitol dry powder for inhalation for the treatment of cystic fibrosis in adults. The following comparisons were considered:

Mannitol versus placebo
- 2 trials (DPM-CF-301, DPM-CF-302) were included in the TA to assess the effectiveness of mannitol
- another 4 trials were excluded from the TA because of their short duration (DPM-CF-201, DPM-CF-202), population (children only) (DPM-CF-203), and low dose of mannitol and short duration of treatment (Robinson 1999); these trials have been retrieved for potential inclusion in this review.
Mannitol versus other treatments
- no trials were included
  –
  1 trial (Robinson 1999) was identified in the TA for the comparison mannitol versus hypertonic sodium chloride, but was excluded due to low dosage, short treatment duration and small population
  –
  2 trials (CF-301, Jaques 2008) compared mannitol to control (control = low dose mannitol) and 8 trials (Button 1996, Chadwick 1997, Elkins 2006, Eng 1996, Riedler 1996, Robinson 1996, Robinson 1997, Robinson 1999) compared hypertonic sodium chloride to control; however, the Technology Assessment Group (TAG, Riemsma 2011) agreed that the results were not comparable due to the difference in duration (26 weeks versus < 2 weeks).

A report from the National Horizon Scanning Centre (NHSC 2008) was also identified. This report included 4 trials that have been retrieved for assessment.

Systematic reviews of RCTs and RCTs, including cross-over trials were considered for this review. Systematic reviews were assessed for inclusion against the protocol, and if relevant, their quality was assessed using AMSTAR. High-quality systematic reviews were included in our review, and where possible, data was taken directly from the review. Individual studies were also retrieved for completeness and accuracy. Low-quality systematic reviews were excluded from the review, but the list of included studies was checked to identify relevant trials.

Three Cochrane reviews were identified and included in this review:

Yang 2016 evaluated the effectiveness of dornase alfa compared to placebo and other mucoactive or mucolytic agents. Twelve trials were included from this review (Amin 2011; the trial reported in both Ballmann 1998 and Ballmann 2002; Fuchs 1994, Laube 1996, McCoy 1996, Minasian 2010; Quan 2011; Ramsey 1993a; Ranasinha 1993, Shah 1995; the trial reported in Suri 2001, Suri 2002a and Suri 2002b; Wilmott 1996).
Nolan 2015 evaluated the effectiveness and safety of inhaled mannitol in people with cystic fibrosis. Four trials have been included from this review (Aitken 2012, Bilton 2011, Jaques 2008, Minasian 2010). Two of the trials had already been included in the TA report (Aitken 2012, Bilton 2011) and were used to retrieve additional outcomes.
Wark 2010 evaluated the effectiveness of nebulised hypertonic sodium chloride compared to placebo and other mucoactive or mucolytic agents. Three trials have been included from this review (the trial reported in both Ballmann 1998 and Ballmann 2002; Elkins 2006; and the trial reported in Suri 2001, Suri 2002a and Suri 2002b).

Four (non-Cochrane) systematic reviews were also identified (Christopher 1999, Cramer 1996, Duijvestijn 1999, Taylor 200). All of them were excluded due to their low methodological quality, and the list of included studies checked for their potential inclusion.

In addition, 9 trials were identified for inclusion (Amin 2010, Conrad 2015, Dentice 2016, Gupta 2012, Mainz 2016, Ratjen 1985, Rosenfeld 2012, Shah 1996, Skov 2015).

The size of the trials ranged from 14 to 968 participants. Twelve trials included children, young people and adults (Aitken 2012, Bilton 2011, Conrad 2015, Elkins 2006, Fuchs 1994, Jaques 2008, Mainz 2016, McCoy 1996; Ramsey 1993a; Ratjen 1985, Shah 1995a, Wilmott 1996), 1 trial included infants and children (Rosenfeld 2012), 1 trial included children only (Quan 2001), 2 studies included children and young people (Gupta 2012; and the trial reported in Suri 2001, Suri 2002a and Suri 2002b), 3 trials included children and young people and adults aged 18 only (Amin 2010, Amin 2011, Minasian 2010), 2 trials included adults only (Laube 1996, Skov 2015), 3 trials included young people and adults (Dentice 2016, Ranasinha 1993, Shah 1996). The age range was not reported for 1 trial (reported in both Ballmann 1998 and Ballmann 2002 – mean age 13.3).

Five trials were conducted in the United States (Conrad 2015, Fuchs 1994, Laube 1996, McCoy 1996, Wilmott 1996), 3 in the UK (Minasian 2010; the trial reported in Suri 2001, Suri 2002a and Suri 2002b; and Shah 1996), 2 in Canada (Amin 2010, Amin 2011), 2 in Australia (Dentice 2016, Elkins 2006), 1 in India (Gupta 2012), 1 in Denmark (Skov 2015) and 3 in Germany (Mainz 2016, Ratjen 1985; and the trial reported in both Ballmann 1998 and Ballmann 2002). The following 6 studies were conducted in multiple countries: 1 in the United States, Canada, Argentina and Europe (Aitken 2012), 1 in Australia, New Zealand, UK and Ireland (Bilton 2011), 1 in Australia and New Zealand (Jaques 2008), 1 in the United States, Canada and the UK (Shah 1995a), 1 in the United States and Canada (Rosenfeld 2012), 1 in Australia, Belgium, Canada, Denmark, Germany, Ireland, Israel, Netherlands, Norway, Spain, Switzerland and the United States (Quan 2001). For 2 trials the country was not reported (Ramsey 1993a and Ranasinha 1993).

The included studies assessed the effectiveness of mucoactive or mucolytic agents based on the following comparisons:

mannitol versus placebo – 3 trials (Aitken 2012, Bilton 2011, Jaques 2008)
mannitol versus dornase alfa – 1 trial (Minasian 2010)
mannitol plus dornase alfa versus dornase alfa – 1 trial (Minasian 2010)
dornase alfa versus placebo – 10 trials (Amin 2011, Fuchs 1994, Laube 1996, McCoy 1996, Ramsey 1993a, Ranasinha 1993, Quan 2001, Shah 1995, Shah 1996, Wilmott 1996)
dornase alfa versus nebulised sodium chloride – 2 trials (trial reported in both Ballman 1998 and Ballmannn 2002; and trial reported in Suri 2001, Suri 2002a and Suri 2002b)
nebulised sodium chloride (>3% concentration) versus placebo (0.9% to 0.12%) or low concentration (≤3%)
- nebulised sodium chloride (7% concentration) versus placebo (0.9% sodium chloride concentration) – 3 trials (Amin 2010, Elkins 2006, Rosenfeld 2012)
- nebulised sodium chloride (7% concentration) versus placebo (0.12% sodium chloride concentration) – 1 trial (Dentice 2016)
- nebulised sodium chloride (7% concentration) versus low concentration (3%) – 1 trial (Gupta 2016)
- nebulised sodium chloride (6% concentration) versus placebo (0.9% sodium chloride concentration – 1 trial (Mainz 2016)
acetylcysteine versus placebo – 3 trials (Conrad 2015, Ratjen 1985, Skov 2015)

A summary of the studies included in this review are presented in Table 78. See study selection flow chart in Appendix F, study evidence tables in Appendix G, list of excluded studies in Appendix H, forest plots in Appendix I, and full GRADE profiles in Appendix J.

9.3.3. Summary of included studies

A summary of the studies that were included in this review are presented in Table 78.

9.3.4. Clinical evidence profile

The clinical evidence profiles for this review question are presented in Table 79 to Table 85.

9.3.4.1. Mannitol

9.3.4.2. Dornase alfa

9.3.4.3. Nebulised sodium chloride

9.3.4.4. Acetylcysteine

9.3.5. Economic evidence

Six economic evaluations of mucoactive or mucolytic agents to manage cystic fibrosis were identified in the literature search conducted for this guideline. Five of those 6 studies included dornase alfa as an intervention compared with either no dornase alfa or hypertonic sodium chloride, the remaining economic evaluation assessed mannitol (with and without dornase alfa) against best supportive care (control). No economic evaluations were identified that included acetylcysteine. A description of the methods and results of those economics evaluations can be found in Appendix K.

Full details of the search and economic article selection flow chart can be found in Appendix E and F, respectively. Data extraction tables and quality assessments of included studies can be found in Appendix L and M, respectively.

Based on the available evidence, the committee agreed additional economic analysis would be superfluous. Instead, a cost description of the interventions was undertaken in Appendix K.

9.3.6. Evidence statements

9.3.6.1. Mannitol

9.3.6.1.1. Comparison 1.1 Mannitol versus placebo

Lung function: FEV₁

Low quality evidence from 1 cross-over trial with 36 people with cystic fibrosis aged ≥8 years showed no clinically significant difference in the lung function (measured as change in FEV₁ % predicted) between the group of participants receiving mannitol (420 mg twice daily) and those in the control group (non-respirable mannitol <2%) at 2 week follow-up.

Moderate quality evidence from 2 RCTs with 600 people with cystic fibrosis aged ≥6 years showed no clinically significant difference in the lung function (measured as change in FEV₁ % predicted) between the group of participants receiving mannitol (400 mg twice daily) and those in the control group (mannitol 50 mg twice daily) at 2, 4 and 6 months follow-up. Data from these 2 RCTs was also available stratified by age subgroups and is presented below.

Children and young people: Low quality evidence from 2 RCTs with 258 children and young people with cystic fibrosis aged ≥6 years showed no clinically significant difference in the lung function (measured as change in FEV₁ % predicted) between the group of participants receiving mannitol (400 mg twice daily) and those in the control group (mannitol 50 mg twice daily) at 2, 4 and 6 months follow-up.
Adults: Low quality evidence from 2 RCTs with 317 adults with cystic fibrosis showed no clinically significant difference in the lung function (measured as change in FEV1 % predicted) between the group of participants receiving mannitol (400 mg twice daily) and those in the control group (mannitol 50 mg twice daily) at 2 and 4 months follow-up. However low quality evidence from the same studies showed a clinically significant increase in FEV₁ % predicted in the group of adults receiving mannitol compared to the control group at 6 months follow-up.

Time to next exacerbation

Low quality evidence from 2 RCTs with 600 people with cystic fibrosis aged ≥6 years showed no clinically significant difference in the time to first pulmonary exacerbation (protocol defined exacerbation) between the participants receiving mannitol (400 mg twice daily) and those in the control group (mannitol 50 mg twice daily) at 6 months follow-up.

Number of people with protocol defined pulmonary exacerbations (proxy for time to next exacerbation)

Data from the 2 RCTs mentioned under the outcome “time to next exacerbation” did not provide data on time to next exacerbation stratified by age subgroups however data on the proxy outcome “number of people with protocol defined pulmonary exacerbations” was available stratified by age subgroups and is presented below.

Children and young people: Low quality evidence from 2 RCTs with 259 children and young people with cystic fibrosis aged ≥6 years showed no clinically significant difference in the number of participants with protocol defined pulmonary exacerbations between those receiving mannitol (400 mg twice daily) and those in the control group (mannitol 50 mg twice daily) at 6 months follow-up.
Adults: Low quality evidence from 2 RCTs with 341 adults with cystic fibrosis showed no clinically significant difference in the number of participants with protocol defined pulmonary exacerbations between those receiving mannitol (400 mg twice daily) and those in the control group (mannitol 50 mg twice daily) at 6 months follow-up.

Need for additional intravenous antibiotics for pulmonary exacerbation

Very low quality evidence from 2 RCTs with 600 people with cystic fibrosis ≥6 years showed no clinically significant difference in the number of people requiring intravenous antibiotics between the group of participants receiving mannitol (400 mg twice daily) and those in the control group (mannitol 50 mg twice daily) at 6 months follow-up. Moderate heterogeneity was observed between both trials. One trial (n=305) showed no clinically significant differences, whereas the other trial (n=295) showed that there was a clinically significant lower number of people who needed additional intravenous antibiotics in the mannitol group.

Inflammatory markers

No evidence was found for this outcome.

Quality of life

Very low to moderate quality evidence from 2 RCTs with 600 people with cystic fibrosis ≥6 years showed no clinically significant difference in the quality of life (measured with CF-QOL respiratory, vitality, physical, emotion, eating, health, social, body, role, digestion and weight domains) between the participants receiving mannitol (400 mg twice daily) and those in the control group (mannitol 50 mg twice daily) at 4 and 6 months follow-up.

Moderate to high heterogeneity was observed for the respiratory domain at 4 and 6 months, and for the physical, social and role domains at 6 months. In spite of the heterogeneity, both trials showed that the differences between groups were not clinically significant in either trial for the respiratory domain at 4 months, and for the physical and social domains at 6 months.

However, for the respiratory domain, 1 trial (n=278) showed a clinically significant improvement in the control group compared to the mannitol group, whereas the other trial (n=229) showed no clinically significant differences at 6 months follow-up.

Adverse events

Moderate quality evidence from 1 cross-over trial with 36 people with cystic fibrosis aged ≥8 years reported that none of the participants in the intervention group (Mannitol 420 mg twice daily) or the control group (non-respirable mannitol <2%) experienced mild haemoptysis at 2 week follow-up.

Very low quality evidence from the same trial with 36 people with cystic fibrosis aged ≥8 years showed no clinically significant difference in the occurrence of severe haemoptysis between the participants receiving Mannitol (420 mg twice daily) and those in the control group (non-respirable mannitol <2%) at 2 week follow-up.

Moderate quality evidence from 1 trial with 295 people with cystic fibrosis ≥6 years reported that none of the participants in the intervention group (Mannitol 400 mg twice daily) or in the control group (50 mg twice daily) experienced mild bronchospasm at 6 months follow-up.

Moderate quality evidence from the same 1 trial with 295 people with cystic fibrosis ≥6 years reported that 1 participant in the mannitol group experienced moderate bronchospasm, and 1 participant experienced severe bronchospasm in the mannitol group. No events of moderate or severe bronchospasm were observed in the control group at 6 months follow-up. These differences were not clinically significant. Data from this 1 RCT was also available stratified by age subgroups and is presented below.

Children and young people: Moderate quality evidence from 1 RCT with 105 children and young people with cystic fibrosis showed that that none of the participants in the intervention group (Mannitol 400 mg twice daily) or in the control group (50 mg twice daily) experienced bronchospasm at 6 months follow-up.
Adults: Very low quality evidence from 1 RCT with 190 adults with cystic fibrosis showed no clinically significant difference in the occurrence of bronchospasm between the participants receiving mannitol (400 mg twice daily) and those in the control group (mannitol 50 mg twice daily) at 6 months follow-up.

Very low quality evidence from 2 trials with 600 people with cystic fibrosis ≥6 years showed no clinically significant differences in the occurrence of mild, moderate or severe haemoptysis between the participants receiving mannitol (420 mg twice daily) and those in the control group (mannitol 50 mg twice daily) at 6 months follow-up. Data from these 2 RCTs was available stratified by age subgroups and is presented below.

Children and young people: Very low quality evidence from 2 RCTs with 259 children and young people with cystic fibrosis aged ≥6 years showed no clinically significant difference in the occurrence of haemoptysis between the group of participants receiving mannitol (400 mg twice daily) and those in the control group (mannitol 50 mg twice daily) at 6 months follow-up.
Adults: Very low quality evidence from 2 RCTs with 341 adults with cystic fibrosis showed no clinically significant difference in the occurrence of haemoptysis between the group of participants receiving mannitol (400 mg twice daily) and those in the control group (mannitol 50 mg twice daily) at 6 months follow-up.

9.3.6.1.2. Comparison 1.2.1. Mannitol versus dornase alfa

Lung function: FEV₁

Very low quality evidence from 1 cross-over trial with 20 children and young people with cystic fibrosis (mean age 13.2 years) showed no clinically significant difference in the lung function (measured as FEV₁ % change from baseline) between the group of participants receiving mannitol (400 mg twice daily) and the participants receiving dornase alfa (2.5 mg twice daily).

Time to next exacerbation

No evidence was found for this outcome.

Need for additional intravenous antibiotics for pulmonary exacerbation

No evidence was found for this outcome.

Inflammatory markers

No evidence was found for this outcome.

Quality of life

No evidence was found for this outcome.

Adverse events

No evidence was found for this outcome.

9.3.6.1.3. Comparison 1.2.1. Mannitol plus dornase alfa versus dornase alfa

Lung function: FEV₁

Very low quality evidence from 1 cross-over trial with 20 children and young people with cystic fibrosis (mean age 13.2 years) showed no clinically significant difference in the lung function (measured as FEV₁ % change from baseline) between the group of participants receiving a combination of mannitol (400 mg mannitol twice daily) and dornase alfa (2.5 mg twice daily) and the participants receiving dornase alfa alone (2.5 mg twice daily).

Time to next exacerbation

No evidence was found for this outcome.

Need for additional intravenous antibiotics for pulmonary exacerbation

No evidence was found for this outcome.

Inflammatory markers

No evidence was found for this outcome.

Quality of life

No evidence was found for this outcome.

Adverse events

No evidence was found for this outcome.

9.3.6.1.4. Comparison 1.3: Mannitol versus nebulised sodium chloride

No evidence was found for this comparison.

9.3.6.1.5. Comparison 1.4. Mannitol versus acetylcysteine

No evidence was found for this comparison.

9.3.6.2. Dornase alfa

9.3.6.2.1. Comparison 2.1: Dornase alfa versus placebo

Lung function: FEV₁

Very low quality evidence from 1 RCT with 41 people with cystic fibrosis aged >15 years showed a clinically significant improvement in lung function (measured as relative mean % change in FEV₁) in the group of participants receiving dornase alfa (2.5 mg twice daily) compared to those who were receiving placebo at 10 days follow-up.

Very low quality evidence from 4 RCTs with 248 people with cystic fibrosis >5 years showed a clinically significant improvement in lung function (measured as relative mean % change in FEV₁) in the group of participants receiving dornase alfa (2.5 mg once daily or twice daily) compared to those who were receiving placebo at 1 month follow-up. However, a high level of heterogeneity was found. A subgroup analysis showed that that this improvement in lung function was significant in people with moderate lung disease (3 RCTs, n=183, low quality), whereas no differences were found in the group of participants with severe lung disease (1 RCT, n=65, very low quality).

Very low quality evidence from 1 RCT with 80 people with cystic fibrosis and acute pulmonary exacerbation >5 years showed no clinically significant difference in lung function (measured as % mean change in FEV₁) between the group of participants receiving dornase alfa (2.5 mg) and those who were receiving placebo at 1 month follow-up.

Very low quality evidence from 2 RCTs with 319 people with cystic fibrosis >6 years showed a clinically significant improvement in lung function (measured as relative mean % change in FEV₁) in the group of participants receiving dornase alfa (2.5 mg twice daily) compared to those who were receiving placebo at 3 months follow-up.

Low quality evidence from 1 RCT with 647 people with cystic fibrosis >6 years showed a clinically significant improvement in lung function (measured as relative mean % change in FEV₁) in the group of participants receiving dornase alfa (2.5 mg once daily or twice daily) compared to those who were receiving placebo at 6 months follow-up.

Moderate quality evidence from 1 RCT with 410 children with cystic fibrosis aged 6 to 10 years showed no clinically significant difference in lung function (measured as absolute mean % change in FEV₁) between the group of participants receiving dornase alfa (2.5 mg) and those who were receiving placebo at 2 years follow-up.

People experiencing exacerbations (proxy outcome for time to next exacerbation)

Low quality evidence from 1 RCT with 647 people with cystic fibrosis ≥5 years showed no clinically significant difference in the number of people experiencing pulmonary exacerbations between the group of participants receiving dornase alfa (2.5 mg once daily or twice daily) and those who were receiving placebo at 6 months follow-up.

Moderate quality evidence from 1 RCT with 470 children with cystic fibrosis aged 6 to 10 years showed no clinically significant difference in the number of children experiencing pulmonary exacerbations between the group of participants receiving dornase alfa (2.5 mg) and those who were receiving placebo at 6 months follow-up.

Number of days of intravenous antibiotics use (proxy outcome for need for additional intravenous antibiotics for pulmonary exacerbation)

Very low quality evidence from 1 RCT with 320 people with cystic fibrosis ≥7 years showed no clinically significant difference in the number of days of intravenous antibiotic use between the group of participants receiving dornase alfa (2.5 mg once daily or twice daily) and those who were receiving placebo at 3 months follow-up.

Inflammatory markers

No evidence was found for this outcome.

Quality of life

Moderate quality evidence from 1 cross-over RCT with 17 children and young people with cystic fibrosis aged 6 to 18 years showed no clinically significant difference in the quality of life (CFQ-R parents and CFQ-R 14+) between the group of participants receiving dornase alfa (2.5 mg) and those who were receiving placebo at 3 months follow-up.

Adverse events

Very low quality evidence from 2 RCTs with 141 people with cystic fibrosis >5 years showed no clinically significant difference in the occurrence of haemoptysis between the group of participants receiving dornase alfa (2.5 mg) and those who were receiving placebo at 1 month follow-up.

Likewise, very low quality evidence from another RCT with 647 people with cystic fibrosis ≥5 years showed no clinically significant difference in the occurrence of haemoptysis between the group of participants receiving dornase alfa (2.5 mg) and those who were receiving placebo at 6 months follow-up.

Very low quality evidence from 3 RCTs with 233 people with cystic fibrosis >5 years showed a clinically significant higher occurrence of voice alteration in the group of participants receiving dornase alfa (2.5 mg) compared to those who were receiving placebo at 1 month follow-up. Significant heterogeneity was noted between the 2 trials that could be pooled in the meta-analysis. One trial (n=92) noted a harmful effect of dornase alfa, whereas the other did not show any differences. The third trials reported no events in either group.

Likewise, moderate quality evidence from another RCT with 320 children with cystic fibrosis aged 6 to 10 years showed a clinically significant higher occurrence of voice alteration in the group of participants receiving dornase alfa (2.5 mg) compared to those who were receiving placebo at 3 months follow-up.

However, very low quality evidence from 1 RCT with 647 people with cystic fibrosis ≥5 years showed no clinically significant difference in the occurrence of voice alteration between the group of participants receiving dornase alfa (2.5 mg once daily or twice daily) and those who were receiving placebo at 6 months follow-up.

Similarly, low quality evidence from another RCT with 470 children with cystic fibrosis aged 6 to 10 years showed no clinically significant difference in the occurrence of voice alteration between the group of participants receiving dornase alfa (2.5 mg once daily or twice daily) and those who were receiving placebo at 2 years follow-up.

9.3.6.2.2. Comparison 2.2. Dornase alfa versus nebulised sodium chloride - hypertonic or isotonic (NaCL HS or IS)

Lung function: FEV₁

Very low quality evidence from 1 cross-over trial with 48 children with cystic fibrosis (mean age 13.3) showed no clinically significant difference in the lung function (measured as mean % change in FEV₁) between the participants receiving dornase alfa (2.5 mg) and those receiving 5.85% sodium chloride at 3 week follow-up.

Low quality evidence from 1 cross-over trial with 14 people with cystic fibrosis >7 years showed a clinically significant improvement in the lung function (measured as mean % change in FEV₁) in the participants receiving dornase alfa (2.5 mg) compared to those receiving 7% sodium chloride at 3 months follow-up.

Time to next exacerbation

No evidence was found for this outcome.

Number of days of inpatient treatment (proxy outcome for need for additional intravenous antibiotics for pulmonary exacerbation)

Moderate quality evidence from 1 cross-over trial with 14 people with cystic fibrosis >7 years showed no clinically significant difference in the number of days of inpatient treatment between the participants receiving dornase alfa (2.5 mg) and those receiving 7% sodium chloride at 3 months follow-up.

Inflammatory markers

No evidence was found for this outcome.

Quality of life

No evidence was found for this outcome.

Adverse events

No evidence was found for this outcome.

9.3.6.2.3. Comparison 2.3. Dornase alfa versus acetylcysteine

No evidence was found for this comparison.

9.3.6.3. Nebulised sodium chloride: hypertonic or isotonic

9.3.6.3.1. Comparison 3.1. Nebulised sodium chloride (> 3% concentration) versus placebo (0.9%) or low-concentration (≤ 3%)

Lung function: FEV₁ %

Moderate quality evidence from 1 RCT with 132 adults with cystic fibrosis showed a clinically significant higher likelihood of regaining pre-exacerbation FEV₁% predicted in the group of participants receiving 7% sodium chloride compared to those who were receiving 3% sodium chloride at hospital discharge.

Moderate quality evidence from 1 RCT with 30 children and young people with cystic fibrosis aged 6 to 16 years showed a clinically significant decrease in the lung function (measured as % change in FEV₁) between the group of participants receiving 7% sodium chloride compared to those who were receiving 3% sodium chloride at 2 week follow-up.

Very low quality evidence from 2 RCTs with 93 people with cystic fibrosis aged ≥6 years showed no clinically significant difference in lung function (measured as % change in FEV₁) between the group of participants receiving 6 to 7% sodium chloride compared to those who were receiving 3% sodium chloride at 4 week follow-up. Significant heterogeneity was observed between both trials. The larger trial (n=123) showed no clinically significant difference between both groups, whereas the smallest trial (n=30) showed a clinical significant difference in favour of low-dose concentration.

Moderate quality evidence from 1 RCT with 148 people with cystic fibrosis ≥6 years showed no clinically significant difference in the lung function (measured as % change in FEV₁) between the group of participants receiving 7% sodium chloride and those who were receiving 0.9% sodium chloride at 12, 36 and 48 week follow-ups.

Moderate quality evidence from 1 RCT with 140 people with cystic fibrosis ≥5 years showed a clinically significant improvement in the lung function (measured as % change in FEV₁) in the group of participants receiving 7% sodium chloride compared to those who were receiving 0.9% sodium chloride at 24 week follow-up.

Time to next exacerbation

Moderate quality evidence from 2 RCTs with 453 infants, children, young people and adults with cystic fibrosis showed no clinically significant difference in the time to first pulmonary exacerbation between the group of participants receiving 7% sodium chloride and those who were receiving <3% sodium chloride at 48 week follow-up.

Need for additional intravenous antibiotics for pulmonary exacerbation

High quality evidence from 1 RCT with 321 children with cystic fibrosis ≤6 years showed a clinically significant increase in the number of days of treatment 7% sodium chloride -dose NaCl (7% HS) compared to those who were receiving 0.9% sodium chloride at 48 week follow-up.

Inflammatory markers

No evidence was found for this outcome.

Quality of life

Moderate to high quality evidence from 1 RCT with 132 adults with cystic fibrosis showed no clinically significant difference in the quality of life (measured with CF-QOL physical, burden, health and respiratory domains) between the group of participants receiving 7% sodium chloride and those who were receiving 3% sodium chloride at hospital discharge and at 7 week follow-up.

Low to moderate quality evidence from 1 cross-over trial with 20 children and young people with cystic fibrosis aged 6 to 18 years showed no clinically significant difference in the quality of life (measured with CFQ-R 14+ or CFQ-R parent respiratory domain) between the group of participants receiving 7% sodium chloride and those who were receiving 0.9% sodium chloride at 4 week follow-up.

High quality evidence from 1 RCT with 67 people with cystic fibrosis ≥6 years showed no clinically significant difference in the quality of life (measured as change in CFQ-R parents) between the group of participants receiving 7% sodium chloride and those who were receiving 0.9% sodium chloride at 48 week follow-up.

Moderate quality evidence from 1 RCT with 92 people with cystic fibrosis ≥6 years showed a clinically significant beneficial effect in the quality of life (measured as change in CFQ-R 14+) in the group of participants receiving 7% sodium chloride compared to those who were receiving 0.9% sodium chloride at 48 week follow-up.

Moderate quality evidence from 1 RCT with 321 children with cystic fibrosis ≤6 years showed no clinically difference in the quality of life (measured as change in CFQ-R respiratory) between the group of participants receiving 7% sodium chloride compared and those who were receiving 0.9% sodium chloride at 48 week follow-up.

Adverse events

No evidence was found for this outcome.

9.3.6.3.2. Comparison 3.2. Nebulised sodium chloride versus acetylcysteine

No evidence was found for this comparison.

9.3.6.4. Acetylcysteine

9.3.6.4.1. Comparison 4. Acetylcysteine versus placebo

Lung function: FEV₁

Very low quality evidence from 1 RCT with 21 adults with cystic fibrosis showed no clinically significant difference in the lung function (measured as change in FEV₁ % predicted) between the participants receiving acetylcysteine (2400 mg per day) and those receiving placebo at 4 week follow-up

Low quality evidence from 1 RCT with 22 children and young people with cystic fibrosis aged 6 to 21 years showed no clinically significant difference in the lung function (measured as change in FEV₁ % predicted) between the participants receiving acetylcysteine (200 mg × 3 times per day) and those receiving placebo at 12 week follow-up.

Similarly, moderate quality evidence from 1 RCT with 70 people with cystic fibrosis >9 years showed no clinically significant difference in the lung function (measured as change in FEV₁ % predicted) between the participants receiving acetylcysteine (900mg/3 times per day) and those receiving placebo at 24 week follow-up.

Time to next exacerbation

No evidence was found for this outcome.

Incidence of exacerbations (proxy outcome for need for additional intravenous antibiotics for pulmonary exacerbation)

Low quality evidence from 1 RCT with 70 people with cystic fibrosis >9 years showed no clinically significant difference in the incidence of pulmonary exacerbations between the participants receiving acetylcysteine (900mg/3 times per day) and those receiving placebo at 24 week follow-up.

Inflammatory markers

High quality evidence from 1 RCT with 70 people with cystic fibrosis >9 years showed no significant difference in the inflammatory markers (measured as sputum IL-8 log10) between the participants receiving acetylcysteine (900mg/3 times per day) and those receiving placebo at 24 week follow-up. The uncertainty for this outcome could not be calculated.

Quality of life

Low quality evidence from 1 RCT with 70 people with cystic fibrosis >9 years showed no clinically significant difference in the quality of life (measured with CFQ-R respiratory domain) between the participants receiving acetylcysteine (900mg/3 times per day) and those receiving placebo at 24 week follow-up.

Adverse events

No evidence was found for this outcome.

9.3.6.5. Economic evidence statements

One cost-benefit analysis (Menzin 1996) undertaken in the UK, on people with cystic fibrosis, found that daily dornase alfa may reduce the cost of respiratory tract infection related care compared to placebo, over 24 weeks. This analysis is partially applicable as clinical effectiveness data was taken from an old US trial that may reflect outdated practices and practices that may not be generalisable to the UK. The evidence was also associated with very serious limitations including the omission of dornase alfa in their costs.

One cost-effectiveness analysis (Christopher 1999) undertaken in the UK, on people with cystic fibrosis, using a lifetime horizon, found that the cost per life year gained for daily dornase alfa compared to placebo was £52,550 for all participants and £16,110 for the subgroup of participants with FEV1≤70%. This analysis is partially applicable with very serious limitations, namely as clinical effectiveness data was taken from an old US trial that may reflect outdated practices and practices that may not be generalisable to the UK.

One cost-benefit analysis (McIntyre 1996) undertaken in the UK, on people with cystic fibrosis, using a lifetime horizon, found that the cost per life year gained for daily dornase alfa compared to placebo could range from £10,311 to £45,234. This analysis is partially applicable with very serious limitations, namely as clinical effectiveness data was taken from an old US trial that may reflect outdated practices and practices that may not be generalisable to the UK.

One cost-benefit analysis (Suri 2002) on people with cystic fibrosis in the UK, over 12 weeks, found that daily dornase alfa was more effective than hypertonic saline, but significantly increased health care costs. Administering dornase alfa on alternate days, rather than daily, was as effective, with a potential for cost savings. This analysis is partially applicable with minor limitations.

One cost-effectiveness analysis (Grieve 2003) on people with cystic fibrosis in the UK found that the cost per 1% gain in FEV1% over 12 weeks, for daily dornase alpha compared to hypertonic saline was £110; for daily dornase alfa compared to alternate day dornase alfa £214 and for alternate day dornase alfa compared to hypertonic saline £89. This analysis has minor limitations and is directly applicable given that the type of economic evaluation is unlikely to change the conclusions about cost-effectiveness and all other applicability criteria are met.

One cost-utility analysis (NICE TA266) on people with cystic fibrosis in the UK using a lifetime horizon, found that the ICER for mannitol compared to best supportive care was £41,074 and for mannitol plus dornase alfa compared to best supportive care plus dornase alfa £47,095. Amendments to the original analysis found that mannitol plus dornase alfa compared dornase alfa plus best supportive care for people with cystic fibrosis using dornase alfa (i.e. mannitol as add-on therapy) produced an ICER of £80,098. For mannitol compared to best supportive care for people with cystic fibrosis who are ineligible, intolerant or inadequately responsive to rhDNase (i.e. mannitol as second-line therapy) the ICER was £29,883. This analysis is directly applicable. The initial analysis is associated with serious limitations as both comparisons use clinical effectiveness data taken from the whole adult population, irrespective of dornase alfa use which underestimates the effectiveness of dornase alfa use.

9.3.7. Evidence to recommendations

9.3.7.1. Relative value placed on the outcomes considered

The aim of this review was to establish the clinical and cost effectiveness of mucoactive or mucolytic agents in improving airway clearance in children, young people and adults with cystic fibrosis.

The committee identified lung function (FEV₁% predicted), time to pulmonary exacerbation and the need for intravenous antibiotics for pulmonary exacerbation as critical outcomes for this evidence review. Where no evidence was found for time to pulmonary exacerbation, the number of people experiencing a pulmonary exacerbation was taken as a proxy outcome. Inflammatory markers, quality of life and adverse events were rated as important outcomes.

9.3.7.2. Consideration of clinical benefits and harms

The committee discussed whether a mucoactive or mucolytic agent should be prescribed to everyone who has cystic fibrosis. However, taking into account the potential adverse effects, as well as the inconvenience and the cost of treatment, it was agreed not to recommend it to everyone. Instead, the committee agreed that it should be offered to people with cystic fibrosis who have clinical evidence of lung disease based on radiological imaging or lung function testing.

The committee reviewed the evidence comparing dornase alfa to placebo, which shows significant differences in FEV₁ in favour of dornase alfa at 1, 3, 6 and 24 month follow-ups, but also a lack of significant differences in FEV₁ in people with severe lung disease at 1 month follow-up.

The committee discussed the evidence comparing nebulised sodium chloride with control (0.9%) or low-concentration (< 3%). After reviewing the conflicting evidence comparing 7% sodium chloride to 0.9% sodium chloride, the committee relied on their expertise and experience to recommend hypertonic sodium chloride instead of isotonic sodium chloride. The committee also reviewed the evidence comparing 7% sodium chloride to 3% sodium chloride. A moderate quality RCT found a clinically significant improvement in FEV₁ in the group of participants receiving 7% sodium chloride compared to those who were receiving 3% sodium chloride at 2 and 4 week follow-ups. It was discussed whether a specific concentration of hypertonic sodium chloride should be specified in the recommendations. The committee concluded that it was appropriate not to mention a specific concentration because the highest concentration tolerable for the individual patient should be used (to maximum 7%).

The committee reviewed the evidence comparing acetylcysteine to placebo. Very low to moderate quality evidence showed no clinically significant differences in FEV₁ between acetylcysteine and placebo at 4, 12 and 24 week follow-ups. Likewise, low quality evidence showed no differences in need for additional intravenous antibiotics for pulmonary exacerbation at 24 week follow-up. No clinically significant differences were found in inflammatory markers or quality of life either. The committee also noted that acetylcysteine was not commonly used in clinical practice because of the unpleasant smell and taste. Moreover, acetylcysteine needs to be taken up to 4 times a day, so overall it is less tolerable and more burdensome than other mucoactive agents. Based on this, the committee agreed not to make a recommendation in favour of acetylcysteine.

The committee was aware of the NICE TA266 that provides guidance on the use of mannitol dry powder for inhalation for the treatment of cystic fibrosis in adults. Therefore data on mannitol was stratified by age to allow the committee to consider the evidence on children and young people separately from the evidence on adults. The committee discussed the recommendations from NICE TA266 and agreed that mannitol could be recommended as an option in adults who cannot use dornase alfa because of ineligibility, intolerance or inadequate response, and in those whose lung function is rapidly declining (FEV₁ decline greater than 2% annually) for whom other osmotic agents are not considered appropriate. They agreed that people currently receiving mannitol whose cystic fibrosis does not meet the cited criteria should be able to continue treatment until they, and their clinician, consider it appropriate to stop. Therefore, the committee adopted these recommendations from NICE TA266.

The committee discussed the use of mannitol in children and young people. Overall the evidence did not show mannitol to have significant clinical benefit nor harm. The committee noted that mannitol is rarely used in clinical practice in children and young people. They were aware of issues of poor tolerability and difficulties with the inhaler device in children and young people. The committee agreed that mannitol may be an option for children and young people when rhDNase and hypertonic sodium chloride have failed or are not tolerated and so made a recommendation to this effect.

The committee reviewed the evidence comparing nebulised dornase alfa to hypertonic sodium chloride, which showed significant differences in FEV₁ in favour of dornase alfa at 3 month follow-up but not at 3 week follow-up. The evidence was low or very low quality. Due to the limited evidence, the committee relied on their expertise and experience to guide their decision as to whether dornase alfa or hypertonic sodium chloride should be the first-line treatment. On balance, they agreed that dornase alfa was more effective and tolerable, and insufficient evidence was presented to change currently accepted practice. Therefore, the committee recommended dornase alfa as first choice treatment and hypertonic sodium chloride as second choice treatment.

The committee recommended using hypertonic sodium chloride (alone or in combination with dornase alfa) if there is an inadequate response to dornase alfa, based on clinical assessment or lung function testing. The committee noted that treatment should be tailored to the individual, taking into account their previous experience of mucoactive agents and any previously demonstrated efficacy.

The committee discussed whether separate recommendations on dornase alfa and hypertonic sodium chloride were needed for different age groups. However, they concluded that the choice of mucoactive agent would not differ based on age group in current practice and noted that some studies did not present data disaggregated by age subgroups.

No evidence was found for children under 5 years in the evidence review. The committee noted that dornase alfa is not licensed for this age group, however, it is current practice to prescribe dornase alfa to children under 5.

9.3.7.3. Consideration of economic benefits and harms

The economic evidence found that dornase alfa was more expensive and more effective than placebo. Although those subjective measures of cost-effectiveness cannot be compared to NICE’s threshold, the committee concluded that the evidence did not infer dornase alfa was cost-ineffective in order to warrant a change in current clinical practice. Furthermore, the clinical evidence showed clinically significant improvements in participants receiving dornase alfa compared to those receiving placebo, providing evidence that the benefits of dornase alfa could justify the costs. The committee also added that there is some evidence that early use of dornase alfa is associated with better survival rates. Therefore, despite the high acquisition cost of dornase alfa, the committee believed, based on the evidence, their knowledge and expertise, that a recommendation in favour of dornase alfa as the first-line treatment would be a cost-effective use of resources.

In light of the economic evidence from Suri 2002 and Grieve 2003, the committee agreed that substantial cost savings could be made by reducing dornase alfa from once daily (current practice in England) to alternate day use. However, the committee noted that the trial by Suri 2002 aimed to identify a change in FEV₁% and was not powered to measure a change in exacerbations, which have a greater treatment cost and impact on health-related quality of life. The committee noted that alternate day use is encouraged in Wales based on the findings in those studies, but agreed that additional research was needed to justify a deviation to the licensed dose.

For these reasons, the committee agreed that a research recommendation should be made to analyse the clinical and cost-effectiveness of once daily dornase alfa compared to alternate day dornase alfa. To acknowledge this uncertainty, the committee did not state whether dornase alfa should be offered daily or on alternate days in their recommendation, given that potential cost savings from alternate day use should not be discouraged, where they are considered effective.

It was noted that a high proportion of the participants in the trial by Suri 2002 were already receiving dornase alfa at enrolment. When questioned if hypertonic sodium chloride should be used as a first-line treatment, the committee stated that dornase alfa and hypertonic sodium chloride have different mechanisms of action and there was clinical and cost-effective evidence to suggest that the former should be targeted first. The committee also highlighted that the unpleasant taste and experience of hypertonic saline can lead to poor adherence, subsequently reducing the potential benefits of treatment.

However, the committee agreed that when dornase alfa begins to stabilise respiratory symptoms, there was a role for hypertonic sodium chloride as an add-on, or second-line therapy to dornase alfa, to improve their symptoms, before more costly treatment (mannitol) is considered. The committee stated higher concentrations of hypertonic sodium chloride are more effective than lower concentrations; although higher concentrations are less well tolerated. Given the unit cost of hypertonic sodium chloride (£0.45 per 4ml, NHS Electronic Drug Tariff November 2016) is equivalent regardless of concentration (7%, 6% or 3%) the committee wanted to recommend the highest tolerable concentration, before mannitol is considered.

When presented with the HTA on mannitol (NICE TA266) in adults, the committee acknowledged that the appraisal committee did not find mannitol to be cost-effective as addon therapy to dornase alfa in all adults with cystic fibrosis. However, the committee accepted the population identified by the appraisal committee (adults with cystic fibrosis for whom hypertonic saline is not considered appropriate, who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase and whose lung function is rapidly declining) as a cost-effective use of resources. Following this, the committee agreed a recommendation in favour of dornase alfa as first-line therapy and hypertonic as the subsequent add-on, or second line therapy, would reflect the sequence of treatments inferred from the HTA.

The committee noted that the cost-effectiveness of mucoactive agents would not differ between children and adults, referring to the clinical evidence did not find any important differences between age groups. However, given that the HTA (NICE TA266) on mannitol was explicitly for adults, the committee agreed a recommendation in children and young people should be considered to prevent potentially cost-ineffective practices from a relatively expensive treatment. Subsequently, the committee noted there was no significant clinical evidence in favour of mannitol over control in children and young people with cystic fibrosis. Combined with the committee’s experience that mannitol is poorly tolerated and unlikely to provide additional benefits compared to nebulised treatments such as hypertonic saline that are cheaper and easier to administer, the committee concluded that mannitol would only be considered as a cost-effective option in children and young people when all other options have failed. As a result, the committee included a recommendation to consider mannitol in children and young people when other options provide an inadequate response or are not tolerated, to reflect current practice.

The committee advised that unlike dornase alfa, acetylcysteine is not as well tolerated and is more burdensome to take which may reduce its effects. Moreover, despite the low acquisition cost of acetylcysteine, the clinical evidence review found no significant benefits compared to placebo to make a recommendation in favour of acetylcysteine. As a result, the committee agreed that the use of acetylcysteine would depend on clinical judgement and did not make a recommendation on its use.

Following the review of the clinical and economic evidence, the committee concluded that additional economic analysis in this area would have limited value to influence their recommendations given that current practice, inferred largely by NICE TA266, was followed. Following this, the committee iterated the importance of a research recommendation to identify the most clinical and cost effectiveness dose of dornase alfa in people with cystic fibrosis.

9.3.7.4. Quality of evidence

The quality of the evidence presented in this report ranged from very low to high as assessed by GRADE. The main reasons that led to downgrading the quality of the evidence were:

For the domain risk of bias, the studies were assigned the same risk of bias as in the Cochrane reviews and were not individually reviewed. The main biases that lead to downgrading the quality of the evidence were selection, attrition, and reporting bias.
Another reason that lead to downgrading the quality of the evidence was the imprecision, as confidence intervals crossed 1 or 2 clinical or default MIDs.
High heterogeneity was also a reason to downgrade the quality of the evidence. The committee noted some studies were underpowered to detect differences between groups.

With regards to indirectness, the committee noted that the participants in the trials comparing mannitol versus placebo, mannitol versus dornase alfa and mannitol + dornase alfa versus dornase alfa alone had undergone a tolerance test at screening. Those who failed were not entered in the studies and this limits the generalisability of the results to the general cystic fibrosis population. No serious issues were found regarding the directness of the population or intervention for the other comparisons.

9.3.7.5. Other considerations

No equality issues were identified by the committee for this review question.

The committee agreed to draft a research recommendation for this topic. They noted the trial by Suri 2002 (comparing daily dornase alfa, alternate day dornase alfa and hypertonic saline) was underpowered to detect a difference in the number of exacerbations. They discussed that reducing the dose, for example from once daily to alternate day dornase alfa, would reduce the burden of treatment and potentially increase adherence. In addition, substantial cost savings are also anticipated.

In certain circumstances medicines are prescribed outside their licensed indications (off-label use) to children and young people because the clinical need cannot be met by licensed medicines, for example, for an indication not specified in the marketing authorisation, or administration of a different dose. At the time of publication (October 2017), rhDNase did not have a UK marketing authorisation for use in children with cystic fibrosis for this indication. However, the Standing Committee on Medicines has issued a policy statement on the use of unlicensed medicines and the use of licensed medicines for unlicensed indications in children and young people. This states clearly that such use is necessary in paediatric practice and that doctors are legally allowed to prescribe medicines outside their licensed indications where there are no suitable alternatives and where use is justified by a responsible body of professional opinion.

It was noted that in the management of chronic infections a smaller pack size of drug may be available to assess the initial effects of the treatment (test dose), so as to minimise the potential for waste. Where a test pack is not available, the manufacturer may be able to offer alternative solutions to prevent waste in the event of a failed test dose. Without this test pack healthcare professionals may need to open a month’s treatment to assess the effects and tolerance in each patient. However, the aim to reduce pharmacy waste is not exclusive to cystic fibrosis and should be considered as good practice in all disease areas.

The role of CFTR modulators were not included in the scope as current clinical practice in this area was considered to be consistent and effective, relative to the other areas under consideration. For completeness, a recommendation referring to the NICE technology appraisal on lumacaftor–ivacaftor for treating cystic fibrosis homozygous for the F508del mutation was added.

9.3.7.6. Key conclusions

The committee concluded that a mucoactive agent should be given to everyone who has respiratory symptoms or other evidence of lung disease. They agreed rhDNase should be recommended as first-line treatment and hypertonic sodium chloride as second-line treatment. The guideline should recommend hypertonic sodium chloride instead of isotonic sodium chloride, but should not mention the concentration of hypertonic sodium chloride. They agreed that Mannitol dry powder should be recommended to adults that fulfil the criteria outlined by the HTA (NICE TA266) and should be considered as third line treatment only for children and young people if inadequate response or intolerability to rhDNase and hypertonic sodium chloride.

9.3.8. Recommendations

56.

Offer a mucoactive agent to people with cystic fibrosis who have clinical evidence of lung disease.

57.

Offer rhDNase (dornase alfa; recombinant human deoxyribonuclease)¹ as the first choice of mucoactive agent.

58.

If clinical evaluation or lung function testing indicates an inadequate response to rhDNase, consider both rhDNase² and hypertonic sodium chloride or hypertonic sodium chloride alone.

59.

Consider mannitol dry powder for inhalation³ for children and young people who cannot use rhDNase and hypertonic sodium chloride because of ineligibility, intolerance or inadequate response.

60.

Mannitol dry powder for inhalation is recommended as an option for treating cystic fibrosis in adults:

who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase and
whose lung function is rapidly declining (forced expiratory volume in 1 second [FEV1] decline greater than 2% annually) and
for whom other osmotic agents are not considered appropriate.

[This recommendation is from Mannitol dry powder for inhalation for treating cystic fibrosis (NICE technology appraisal 266).]

61.

People currently receiving mannitol whose cystic fibrosis does not meet the criteria in recommendation 56 should be able to continue treatment until they and their clinician consider it appropriate to stop.

[This recommendation is from Mannitol dry powder for inhalation for treating cystic fibrosis (NICE technology appraisal 266).]

62.

For guidance on using lumacaftor–ivacaftor, see the NICE technology appraisal on lumacaftor–ivacaftor for treating cystic fibrosis homozygous for the F508del mutation.

9.3.9. Research recommendations

3.: What is the most clinically and cost-effective dose of rhDNase (dornase alfa; recombinant human deoxyribonuclease) for people with cystic fibrosis?

9.4. Pulmonary Infection

Pulmonary infection is the cause of much of the morbidity and mortality associated with cystic fibrosis.

Antimicrobial treatment strategies aim to prevent acquisition of infection, eradicate early infection and suppress chronic respiratory infections where chronic infection ensues from organisms with known or suspected pathogenicity. There is a low threshold to treat respiratory infection. To minimise the risk of antimicrobial resistance, treatment is guided and informed by known or expected microbiological results, based on local surveillance data where necessary.

Chronic infection with P aeruginosa and B cepacia complex leads to a worsening clinical picture, a reduction in respiratory function, more hospital admissions and increased treatment costs. Prompt and aggressive treatment of these organisms is therefore imperative for first and recurrent isolates following a period free from infection.

The scope of these review questions is to review the evidence in people with cystic fibrosis for the prevention of S aureus infection and the treatment of respiratory exacerbations and chronic infection caused by S aureus, P aeruginosa, B cepacia complex and Aspergillus species.

This chapter will also review evidence for the use of antifungal treatments. The use of antifungal agents is increasing in the management of cystic fibrosis with recognition that fungi such as Aspergillus spp may lead to infection as well as a damaging immune response associated with allergic bronchopulmonary aspergillosis.

Other organisms such as Achromobacter xylosoxidans and Stenotrophomonas maltophilia are encountered in people with cystic fibrosis. These have a relatively lower prevalence and are beyond the scope of this current guideline.

9.4.1. Prophylaxis

Review question: What is the effectiveness of long-term antimicrobial prophylaxis to prevent pulmonary bacterial colonisation with S aureus in people with CF?

9.4.1.1. Description of clinical evidence

The aim of this review was to compare the clinical and cost effectiveness of various antimicrobials given as long-term prophylaxis (for more than 3 months) against bacterial infection in people with cystic fibrosis.

We searched for systematic reviews of RCTs and RCTs aimed at assessing the effectiveness of long-term antimicrobial prophylaxis to prevent pulmonary bacterial infection with S aureus in people with cystic fibrosis. Cross-over trials were not considered for inclusion, as this study design does not allow evaluation of the effects of prophylaxis on long-term outcomes measures.

For full details see review protocol in Appendix D.

Two systematic reviews were identified for potential inclusion in this review (McCaffery 1999, Smyth 2014).

One systematic review (McCaffery 1999) was finally excluded as the quality was assessed as low according to AMSTAR checklist (score of 5 out of 11). The individual studies included in this review were checked for potential inclusion.

One Cochrane systematic review (Smyth 2014) was included as the quality was assessed as high according to AMSTAR checklist (score of 10 out of 11). This systematic review included 4 RCTs (Chatfield 1991, Schlesinger 1984, Stutman 2002, Weaver 1994, Beardsmore 1995). One study (Schlesinger 1984) was excluded from our review as it included treatments that were not specified in the evidence review protocol and it did not report on any outcomes of interest.

The data and risk of bias assessment from the systematic review were used where possible. The individual studies were also retrieved full copy for completeness. Data for other outcomes of interests included in the protocol, but not included in the Cochrane SR, was directly extracted from the individual studies.

No further studies were identified in our search.

With regards to the population, the studies included in the Cochrane review included infants or small children (under 2 years) with confirmed cystic fibrosis.

The trials compared the effectiveness of long-term prophylactic antibiotic treatment with placebo and treatment “as required”. The treatments evaluated included continuous oral Flucloxacillin and continuous oral Cephalexin.

In relation to the outcomes, evidence was found for number of children who S aureus was identified at least once; lung function, measured as FEV₁, minor adverse events and identification of P aeruginosa. Where no evidence was retrieved for time to next pulmonary exacerbation, number of children experiencing a pulmonary exacerbations and number of children requiring hospitalisation due to infection was taken as a proxy outcome.

No results were identified for time to identification of S aureus, major adverse events and emergence of the resistant organisms.

Evidence from these are summarised in the clinical GRADE evidence profile below (Table 89 and Table 90). See also the study selection flow chart in Appendix F, forest plots in Appendix I, study evidence tables in Appendix G and exclusion list in Appendix H.

9.4.1.2. Summary of included studies

A summary of the studies that were included in this review are presented in Table 88.

9.4.1.3. Clinical evidence profile

The summary clinical evidence profiles for this review question are presented in Table 89 and Table 90.

9.4.1.4. Economic evidence

No economic evaluations of prophylaxis treatment were identified in the literature search conducted for this guideline. Full details of the search and economic article selection flow chart can be found in Appendix E and F, respectively.

This review question was not prioritised for de novo economic modelling. To aid consideration of cost-effectiveness relevant resource and cost use data are presented in Appendix K.

9.4.1.5. Evidence statements

9.4.1.5.1. Comparison 1. Continuous oral Flucloxacillin versus antibiotics ‘as required’

Time to identification of the pathogen (S aureus) in sputum culture

No evidence was found for this critical outcome.

Number of positive pathogen cultures (S aureus) identified

Very low quality evidence from 1 RCT with 96 infants with cystic fibrosis showed no clinically significant difference in the number of children in whom S aureus was identified between the group who were receiving continuous oral Flucloxacillin prophylaxis and the group who were receiving antibiotics ‘as required’ during the first year of follow-up.

Low quality evidence from 2 RCTs with 149 infants with cystic fibrosis showed that there was a clinically significant lower number of children in whom S aureus was identified in the group who were receiving continuous oral Flucloxacillin prophylaxis compared to the group who were receiving antibiotics ‘as required’ during the first 2 years of follow-up.

Very low quality evidence from 1 RCT with 119 infants with cystic fibrosis showed that there was a clinically significant lower number of children in whom S aureus was identified between the group who were receiving continuous oral Flucloxacillin prophylaxis and the group who were receiving antibiotics ‘as required’ during the first 3 years of follow-up.

Lung function

No evidence was found for this important outcome.

Pulmonary exacerbation

Very low quality evidence from 2 RCTs with 124 infants with cystic fibrosis showed no clinically significant difference in the number of annual hospital admissions due to pulmonary exacerbations between the children who were receiving continuous oral Flucloxacillin prophylaxis and the children who were receiving antibiotics ‘as required’ during the 3 years follow-up.

Quality of life

No evidence was found for this important outcome.

Minor adverse events

No evidence was found for this important outcome.

Major adverse events

No evidence was found for this important outcome.

Identification of P aeruginosa

Very low quality evidence from 1 RCT with 95 infants with cystic fibrosis showed no clinically significant difference in the number of children in whom P aeruginosa was identified between the group who were receiving continuous oral Flucloxacillin prophylaxis and the group who were receiving antibiotics ‘as required’ during the first year of follow-up.

Very low quality evidence from 2 RCTs with 149 infants with cystic fibrosis showed no clinically significant difference in the number of children in whom P aeruginosa was identified between the group who were receiving continuous oral Flucloxacillin prophylaxis and the group who were receiving antibiotics ‘as required’ during the first 2 years of follow-up.

Very low quality evidence from 1 RCT with 120 infants with cystic fibrosis showed no clinically significant difference in the number of children in whom P aeruginosa was identified between the group who were receiving continuous oral Flucloxacillin prophylaxis and the group who were receiving antibiotics ‘as required’ during the first 3 years of follow-up.

Adherence to treatment

No evidence was found for this important outcome.

Emergence of resistant organisms

No evidence was found for this important outcome.

9.4.1.5.2. Comparison 2. Continuous oral Cephalexin versus antibiotics ‘as required’

Time to identification of the pathogen (S aureus) in sputum culture

No evidence was found for this critical outcome.

Number of positive pathogen cultures (S aureus) identified

Moderate quality evidence from 1 RCT with 152 children with cystic fibrosis < 2 years (n=152) showed that there was a clinically significant lower number of children in whom S aureus was identified in the group who were receiving continuous oral Cephalexin prophylaxis compared to the group who were receiving antibiotics ‘as required’ during the first year of follow-up.

Moderate quality evidence from 1 RCT (n=166) showed that there was a clinically significant lower number of children in whom S aureus was identified in the group who were receiving continuous oral Cephalexin prophylaxis compared to the group who were receiving antibiotics ‘as required’ during the first 2 years of follow-up.

Moderate quality evidence from 1 RCT (n=141) showed that there was a clinically significant lower number of children in whom S aureus was identified in the group who were receiving continuous oral Cephalexin prophylaxis compared to the group who were receiving antibiotics ‘as required’ during the first 3 years of follow-up.

Moderate quality evidence from 1 RCT (n=127) showed that there was a clinically significant lower number of children in whom S aureus was identified in the group who were receiving continuous oral Cephalexin prophylaxis compared to the group who were receiving antibiotics ‘as required’ during the first 4 years of follow-up.

Low quality evidence from 1 RCT (n=98) showed that there was a clinically significant lower number of children in whom S aureus was identified in the group who were receiving continuous oral Cephalexin prophylaxis compared to the group who were receiving antibiotics ‘as required’ during the first 5 years of follow-up.

Low quality evidence from 1 RCT (n=43) showed that there was a clinically significant lower number of children in whom S aureus was identified in the group who were receiving continuous oral Cephalexin prophylaxis compared to the group who were receiving antibiotics ‘as required’ during the 6 years of follow-up.

Lung function: FEV₁

Very low quality evidence from 1 RCT (n=119) showed no clinically significant difference in lung function, measured as FEV₁, between the children who were receiving continuous oral Cephalexin prophylaxis and the children who were receiving antibiotics ‘as required’ at 6 years follow-up.

Pulmonary exacerbation

Very low quality evidence from 1 RCT (n=119) showed no clinically significant difference in the percentage of pulmonary exacerbations between the children who were receiving continuous oral Cephalexin prophylaxis and the children who were receiving antibiotics ‘as required’ during the six years follow-up.

Very low quality evidence from 1 RCT (n=119) showed no clinically significant difference in the number of annual hospital admissions due to pulmonary exacerbations between the children who were receiving continuous oral Cephalexin prophylaxis and the children who were receiving antibiotics ‘as required’ during the 6 years follow-up.

Quality of life

No evidence was found for this important outcome.

Minor adverse events

Moderate quality evidence from 1 RCT (n=119) showed no clinically significant difference in the report of generalised rash, nappy rash and stool frequency between the children who were receiving continuous oral Cephalexin prophylaxis and the children who were receiving antibiotics ‘as required’ during the 6 year study duration.

Major adverse events

No evidence was found for this important outcome.

Identification of P aeruginosa

Very low quality evidence from 1 RCT (n=152) showed no clinically significant difference in the number of children in whom P aeruginosa was identified between the group who were receiving continuous oral Cephalexin prophylaxis and the group who were receiving antibiotics ‘as required’ during the first year of follow-up.

Low quality evidence from 1 RCT (n=166) showed no clinically significant difference in the number of children in whom P aeruginosa was identified between the group who were receiving continuous oral Cephalexin prophylaxis and the group who were receiving antibiotics ‘as required’ during the first 2 years of follow-up.

Very low quality evidence from 1 RCT (n=141) showed no clinically significant difference in the number of children in whom P aeruginosa was identified between the group who were receiving continuous oral Cephalexin prophylaxis and the group who were receiving antibiotics ‘as required’ during the first 3 years of follow-up.

Low quality evidence from 1 RCT (n=127) showed no clinically significant difference in the number of children in whom P aeruginosa was identified between the group who were receiving continuous oral Cephalexin prophylaxis and the group who were receiving antibiotics ‘as required’ during the first 4 years of follow-up.

Very low quality evidence from 1 RCT (n=98) showed no clinically significant difference in the number of children in whom P aeruginosa was identified between the group who were receiving continuous oral Cephalexin prophylaxis and the group who were receiving antibiotics ‘as required’ during the first 5 years of follow-up.

Very low quality evidence from 1 RCT (n=43) showed no clinically significant difference in the number of children in whom P aeruginosa was identified between the group who were receiving continuous oral Cephalexin prophylaxis and the group who were receiving antibiotics ‘as required’ during the 6 years of follow-up.

Adherence to treatment

Moderate quality evidence from 1 RCT (n=119) showed a higher level of adherence to treatment in the group of children who were receiving continuous oral Cephalexin prophylaxis (85% vs. 80%). The uncertainty around this could not be calculated.

Emergence of resistant organisms

No evidence was found for this important outcome.

9.4.1.5.3. Economic evidence statements

No evidence on cost-effectiveness in people with cystic fibrosis was available for this review.

9.4.1.6. Evidence to recommendations

9.4.1.6.1. Relative value placed on the outcomes considered

The committee identified time to identification of the pathogen (S aureus) in respiratory samples, the time to the next pulmonary exacerbation and the development of P aeruginosa infection as critical outcomes for this evidence review. If there was no evidence for time to next pulmonary exacerbation, the number of people with cystic fibrosis experiencing a pulmonary exacerbations and number of people with cystic fibrosis being admitted to hospital with to pulmonary exacerbations were taken as alternative proxy outcomes.

In addition to the critical outcomes, lung function (measured by FEV₁ or LCI), evidence of inflammation on CT scanning (in children under 5 years of age), quality of life, adherence to treatment (or patient preference), adverse events and the emergence of resistant organisms were considered important outcomes.

9.4.1.6.2. Consideration of clinical benefits and harms

The committee noted that it is accepted that S aureus can cause serious lung disease in cystic fibrosis. The isolation of S aureus from respiratory samples means that the respiratory tract is colonised or infected with this pathogen. This can lead to pulmonary inflammation and progressive lung disease.

The committee noted that the evidence showed that anti-staphylococcal prophylaxis with an antimicrobial agent (either flucloxacillin or cephalexin) led to a decreased number of children in whom S aureus was isolated. The quality of the evidence for this outcome ranged from very low to moderate. Despite the fact that the evidence did not show this was associated with clinical benefit, there being no improvement in lung function or reduction in exacerbations in children given prophylaxis compared with those who were not, the reduction in S aureus was, nevertheless, a critically important outcome. Overall, the evidence did not reveal the occurrence of adverse events with prophylaxis.

The committee were concerned about the theoretical possibility that long-term antimicrobial prophylaxis for S aureus might be associated with an increased risk infection with P aeruginosa. Although the evidence did not demonstrate this, the committee noted that the quality of the evidence for this outcome ranged from very low to low. The committee observed that, given the widespread expert consensus that this risk is a concern, they agreed that it could be mitigated by recommending that flucloxacillin be used rather than cephalexin. The fact that cephalosporins are broad spectrum is postulated to be the reason why an increase in pseudomonas isolation may be seen, but this is not known with certainty. Recommending flucloxacillin rather than a cephalosporin was in keeping with current practice. The committee discussed what age to recommend anti-staphylococcal prophylaxis until. The committee noted that a beneficial effect (decreased number of children in whom S aureus was isolated) was observed for the comparison oral flucloxacillin versus placebo + antibiotic “as required” at 2 and 3 years of follow-up. Therefore, the committee recommended to offer flucloxacillin up to age 3. The committee noted that the same beneficial effect was observed for the comparison between another anti-staphylococcal agent (oral cephalexin) versus placebo + antibiotic “as required” at each subsequent year of follow-up up to 6 years of follow-up. Although this evidence was on an anti-staphylococcal agent, there was no direct evidence on flucloxacillin after 3 years of follow-up. Therefore the committee decided to only make a weak recommendation to “consider” continuing flucloxacillin up to 6 years of age.

The committee noted that for children who are allergic to penicillins, an alternative oral anti-staphylococcal agent should be considered.

9.4.1.6.3. Consideration of economic benefits and harms

The committee believed, based on their knowledge and experience, that colonisation with S aureus was likely to be associated with an increased risk of pulmonary disease and a worse prognosis compared to no colonisation. The clinical benefits of prophylaxis, although not demonstrated by the available evidence, might well be important and, if so, prophylaxis is likely to be cost-effective.

In contrast to current recommendations in the USA, the committee did not think there were grounds to advise the non-use of prophylaxis. This was based on the low cost of prophylaxis treatment and the potentially serious consequences of S aureus pulmonary infection that would outweigh the cost of prophylaxis.

The committee believed cephalexin and flucloxacillin were similar in terms of efficacy, but noted that cephalexin is a broader spectrum antibiotic that could increase the risk of P aeruginosa infection. For this reason, the committee agreed that using the more expensive flucloxacillin would be a cost-effective choice because it is a narrower spectrum antibiotic, thus reducing the expected cost of a P aeruginosa infection.

The committee noted that the cost of flucloxacillin varied substantially according to the preparation used, with oral solutions costing more than capsules (NHS Electronic Drug Tariff November 2016: 250mg/5ml oral solution sugar free, £1.32/5ml versus 250mg capsules, £0.05). Prophylaxis in infants would require the use of oral solutions and the committee believed that sugar free solutions were preferable although more expensive. However, once children were old enough to take capsule preparations they believed these should be used if they are cheaper and equally effective.

The committee recognised that long-term prophylaxis could be burdensome for the person with cystic fibrosis and their parents or carers. This is particularly the case when products are unpalatable and because the need for medications for cystic fibrosis increase with age. Moreover, long-term use of flucloxacillin would be costly at approximately £67 per month (costed on a BNF recommended dose of 125 mg twice daily: 125mg/5ml oral solution sugar free; basic price, £21.97; quantity 100ml). For this reason, the committee made a recommendation to offer prophylaxis treatment up to the age of 3 years, and to consider continuing up to the age of 6 years as there was no evidence it provided benefit beyond this age, to justify the cost and burden of treatment beyond this time. The committee added that this could reduce resource use in this area, if children who are receiving prophylactic treatment over the age of 6, discontinue treatment following the recommendation.

9.4.1.6.4. Quality of evidence

Two of the studies included in the Cochrane review (Smyth 2014) compared oral flucloxacillin versus antibiotics as required. The quality of the evidence was moderate to very low quality as assessed by GRADE. The main reasons that lead to downgrading the quality of the evidence were the moderate risk of bias found in the studies and the levels of imprecision.

One study included in the Cochrane review (Smyth 2014) compared oral cephalexin versus antibiotics as required. The quality of the evidence was moderate to very low quality as assessed by GRADE. The main reason for downgrading the quality of the evidence was the large number of losses to follow-up. It is known that the participants who leave the study do normally differ to those who remain, therefore, the results have to be interpreted with caution. The outcome about adherence to treatment was reported narratively only.

9.4.1.6.5. Other considerations

In the absence of strong evidence in favour of the use of antimicrobial prophylaxis to prevent pulmonary bacterial colonisation with S aureus, the committee agreed that other aspects were to be considered when deciding whether to start treatment or not. The preferences of the parents were discussed. It was acknowledged that some parents want their children to take anti-staphylococcal treatment; whereas, others are more reluctant as they cannot see a clear benefit of having treatment. The committee agreed that it was important to discuss prophylaxis with the parents and a recommendation was made to this effect.

Patient tolerance of prophylaxis was discussed by the committee. As mentioned above, clinical practice in the UK is to favour the use of flucloxacillin, but alternatives (for example cephalexin) can be considered if there are significant side effects.

An important concern raised by the committee was the duration of treatment. Currently there is considerable variation in clinical practice. It was noted that although there is a common view that prophylaxis should continue until the age of 3 (as suggested by the CF Trust), in many cases it is continued beyond that age. The study included in the review followed children up to the age of 6. There was no conclusive evidence that there was continuing benefit of prophylaxis treatment up to this age. But it was the consensus view of the committee that continuing up to age 6 was a reasonable duration of treatment. Given the lack of evidence comparing different lengths of prophylaxis treatment, and the concerns raised by patients and parents alike, the committee concluded that this should be a priority for research. However, they agreed not to draft a research recommendation as there is an ongoing trial that will address this issue (Cystic Fibrosis Trust CF START).

At the time of publication (October 2017), flucloxacillin did not have a UK marketing authorisation for use in people with cystic fibrosis for this indication. However, there are clinical situations in which the off-label use of a medicine may be judged by the prescriber to be in the best clinical interests of the patient. As a result, the committee agreed they could recommend the off-label use of flucloxacillin because the clinical need cannot be met by a licensed product and there is sufficient evidence or experience of using the medicine to demonstrate its safety and efficacy to support this.

No equality issues were identified by the committee for this review question.

9.4.1.6.6. Key conclusions

The committee agreed to recommend anti-staphylococcal prophylaxis for children with cystic fibrosis up to age 3, and consider continuing up to 6 years of age. The committee agreed that the potential benefits and disadvantages of treatment should be discussed with parents or carers before starting anti-staphylococcal prophylaxis. Flucloxacillin should be the first choice given that cephalexin may be associated with a higher rate of P aeruginosa growth or isolation.

9.4.2. Acute

Review question: What is the effectiveness of antimicrobial treatment for acute pulmonary infection or those with an exacerbation in children and adults with cystic fibrosis?

9.4.2.1. Description of clinical evidence

The aim of this review was to compare the clinical and cost effectiveness of different antimicrobial regimens in achieving clinical resolution of acute pulmonary infection or exacerbation in children and adults with cystic fibrosis.

We looked for studies that included children and adults with cystic fibrosis who presented with clinical manifestations suggesting development of an acute pulmonary infection or those with an exacerbation and who are already known to have a positive sputum or airway culture for one of the following pathogens at entry to the trial:

S aureus
P aeruginosa
B cepacia complex
Haemophilus influenzae
Nontuberculous mycobacteria (Mycobacterium avium complex and Mycobacterium abscessus).
We also looked for studies that included children and adults with cystic fibrosis who present with clinical manifestations suggesting development of an acute pulmonary infection or those with an exacerbation without an identified pathogen at trial entry.

Pulmonary exacerbation was defined as:

Fuchs definition (original form (4/16 symptoms leading to IV antibiotic treatment) or modified form (4/16 symptoms leading to any change in antibiotic therapy).
or
European Cystic Fibrosis Society Consensus definition: “need for additional antibiotic treatment as indicated by a recent change in at least 2 of 6 defined symptoms”.

However, the definition of pulmonary exacerbation used in the study was also accepted.

Additionally, acute infection was defined as a person with cystic fibrosis who is found, on routine microbiological investigation, to have a significant respiratory pathogen (newly identified infection).

We searched for systematic reviews of RCTs and RCTs. Systematic reviews were assessed for inclusion against the protocol, and if relevant, their quality was assessed using AMSTAR. High-quality systematic reviews were included in our review, and where possible, data and quality assessment was taken directly from the review. Individual studies were also retrieved for completeness and accuracy, and were also checked for additional outcomes of interest. Low-quality SR were excluded from our review, but the list of included studies was checked to identify relevant trials.

For full details see review protocol in Appendix D.

The results are presented separately for each pathogen.

9.4.2.1.1. P aeruginosa

The interventions that were included in the protocol for the treatment of infection with or exacerbation due to P aeruginosa were: Ciprofloxacin (oral), Aztreonam (inhaled or IV), Ceftazidime (IV), Meropenem (IV), Piperacillin-Tazobactam (IV), Fosfomycin (IV), Ticarcillin-Clavulanate (IV), Aztreonam (inhaled or IV), Chloramphenicol (oral). For first infection only we also considered sequencing antibiotics: Ciprofloxacin (oral) then either Colistin or Tobramycin (inhaled).

Four Cochrane systematic reviews were identified in the search (Elphick 2016, Hurley 2015, Hewer 2014, Remmington 2016).

Two reviews were included:

Hurley (2015) evaluated if intravenous antibiotics for the treatment of pulmonary exacerbations in people with CYSTIC FIBROSIS improve short- and long-term clinical outcomes. 13 randomised control trials (RCTs) from this Cochrane review were included (Blumer 2005; Conway 1997; De Boeck 1989, Elborn 1992; Gold 1985; Macystis fibrosisarlane 1985; Master 2001; McCarty 1988; Richard 1997; Salh 1992; Schaad 1987; Schaad 1989; Wesley 1988). The outcome ‘eradication of pathogen’ was not included in this Cochrane review. Each paper was checked for this outcome and 2 RCTs (Richard 1997 and Schaad 1989) were included.
Langton (2014) evaluated whether antibiotic treatment of early P aeruginosa infection in children and adults with CYSTIC FIBROSIS alters clinical and microbiological outcomes. Two RCTs from this Cochrane review were included (Proesmans 2013, Taccetti 2012). These RCTs aimed to eradicate acute infection (first positive isolate of P aeruginosa).

Two reviews were excluded.

Elphick (2016): no additional RCTs were included from this Cochrane review.
Remmington (2016): no additional RCTs were included from this Cochrane review.

No additional relevant trials were identified in our search.

The 13 included studies from the Hurley (2015) Cochrane systematic review evaluated the effectiveness of intravenous antibiotics for the treatment of pulmonary exacerbations based on the following comparisons:
Comparison 1. Single IV agents compared
- Ceftazidime versus Aztreonam (Elborn 1992, Salh 1992)
Comparison 2. Single IV antibiotic (with placebo) versus combination IV antibiotic
- Tobramycin+placebo versus tobramycin+ceftazidime (Master 2001)
- Tobramycin+placebo versus piperacillin + tobramycin (Macystis fibrosisarlane 1985)
Comparison 3. Single IV antibiotic versus combination IV antibiotic
- Piperacillin versus piperacillin+tobramycin (McCarty 1988)
- Ceftazidime versus tobramycin + ticarcillin (Gold 1985, Wesley 1988)
- Ceftazidime versus tobramycin + piperacillin (De Boeck 1989)
- Colistin versus colistin + another anti-pseudomonal antibiotic (Conway 1997)
Comparison 4. Combination IV antibiotics versus combination IV antibiotics
- Aztreonam+IV amikacin versus IV ceftazidime+IV amikacin (Schaad 1989)
- IV meropenem + IV tobramycin versus IV ceftazidime + IV tobramycin (Blumer 2005)
Comparison 5. Combination of two IV antibiotics + inhaled antibiotic versus 2 IV antibiotics without inhaled antibiotic
- IV ceftazidime + IV amikacin versus IV ceftazidime + IV amikacin + inhaled amikacin (Schaad 1987)
Comparison 6. Combination of IV ceftazidime + IV tobramycin versus oral ciprofloxacin (Richard 1997)
The 2 included studies from the Langton (2014) Cochane systematic review evaluated the effectiveness of antibiotic treatment for acute infection with the first positive isolate of P aeruginosa based on the following comparisons:
Comparison 7. Oral ciprofloxacin + inhaled colistin versus inhaled tobramycin (Proesmans 2013)
Comparison 8. Inhaled colistin + oral ciprofloxacin versus inhaled tobramycin + oral ciprofloxacin (Taccetti 2012)
The size of studies ranged from 19 to 223 participants with cystis fibrosis. Five studies included children, young people and adults (Blumer 2005, Macystis fibrosisarlane 1985, Schaad 1987, Schaad 1989, Taccetti 2012), 1 study included adults only (Conway 1997), 3 studies included young people and adults (Elborn 1992, Gold 1985, Salh 1992), 4 studies included children and young people (McCarty 1988, Proesmans 2013, Richard 1997, Wesley 1988), 2 studies did not report the age range (De Boeck 1989, Master 2001).
Three studies were conducted in the UK (Conway 1997, Elborn 1992, Salh 1992), 2 in the USA (Blumer 2005, McCarty 1988), 2 in Belgium (De Boeck 1989, Proesmans 2013), 1 in Canada (Gold 1985), 2 in Australia (Macystis fibrosisarlane 1985, Master 2001), 3 in Switzerland (Richard 1997, Schaad 1987, Schaad 1989), 1 in New Zealand (Wesley 1988), 1 in Italy (Taccetti 2012).

9.4.2.1.2. S aureus

The interventions that were included in the protocol for the treatment of infection with or exacerbation due to S aureus were: Flucloxacillin (oral or IV), Cotrimoxazole (oral or IV), Doxycycline (oral) (not for under 12’s) and Cefradrine (oral).

One Cochrane systematic review was identified for inclusion (Lo 2015). This review examined interventions for eradicating methicillin-resistant S aureus, however no published RCTs were identified.

An additional Cochrane systematic review (Southern 2012) on the use of macrolide antibiotics was assessed. The RCTs included in this review have comparisons of placebo and different dosages. As these comparisons are not included in our protocol, no RCTs from this Cochrane review were included.

No relevant trials were identified in our search.

9.4.2.1.3. B cepacia complex

The interventions that were included in the protocol for the treatment of infection with or exacerbation due B Cepacia Complex were: Cotrimoxazole (oral or IV), Meropenem (IV or inhaled), Ceftazidime (IV or inhaled), Temocillicin (oral or IV), Imipenem (oral or IV), Trimethoprim (oral or IV) and Tobramycin (oral or IV).

Two Cochrane systematic reviews were identified for inclusion. One Cochrane review examined eradication of B Cepacia Complex (Regan 2016) and another Cochrane review examined treatment of exacerbations in people with B Cepacia Complex (Horsley 2016). Neither of these Cochrane reviews included any RCTs.

No relevant trials were identified in our search.

9.4.2.1.4. H influenzae

The interventions that were included in the protocol for the treatment of infection with or exacerbation due to H influenzae were: Co-amoxiclav (oral or IV), Cefuroxime (IV), Cefaclor, Cefixime, Doxycycline (>12 years), and Macrolide (clarithromycin/azithromycin).

No relevant systematic reviews or trials were identified in our search.

9.4.2.1.5. Nontuberculous mycobacteria

We considered Mycobacterium Avium Complex and Mycobacterium Abscessus.

The interventions that were included in the protocol for the treatment of infection with or exacerbation due to M. Avium Complex were: Clarithromycin (oral), Azithromycin (oral), Rifampicin (oral), Ethambutol (oral) and Amikacin (inhaled and potentially IV).

The interventions that were included in the protocol for the treatment of infection with or exacerbation due to M. Abscessus were: Cefoxitin (IV), Clarithromycin (IV), Amikacin (IV and inhaled), Meropenem (IV and inhaled), Tigecycline, Co-trimoxazole (oral), Moxifloxacin (oral), Ciprofloxain (oral), Doxycycline/minocycline (tetratcyclines) (oral), Linezolid (oral) and Clofazimine (oral).

A Cochrane SR was identified in the search (Waters 2016). This review aimed to compare antibiotic treatment versus non-antibiotic treatment, or different combinations of antibiotics, for non-tuberculous mycobacteria lung infection in people with CYSTIS FIBROSIS. No trials were identified for inclusion in this review.

No relevant trials were identified in our search.

9.4.2.1.6. No identified pathogen

The interventions that were included in the protocol for the treatment of infection with or exacerbation without an identified pathogen at trial entry were any of the above.

No relevant systematic reviews or trials were identified in our search.

Evidence from these are summarised in the clinical GRADE evidence profile below (Table 65–Table 103). See also the study selection flow chart in Appendix F, forest plots in Appendix I, study evidence tables in Appendix G and exclusion list in Appendix H.

9.4.2.2. Summary of included studies

A summary of the studies that were included in this review are presented in Table 91 to Table 95.

9.4.2.2.1. P aeruginosa

9.4.2.2.2. S aureus

9.4.2.2.3. B cepacia complex

9.4.2.2.4. Non-tuberculous mycobacteria

9.4.2.2.5. Non-identified pathogen

No studies were identified for inclusion.

9.4.2.3. Clinical evidence profile

The clinical evidence profiles for the review question addressing antimicrobials for pulmonary exacerbation are presented in Table 65 - Table 101. The clinical evidence profiles for the review question addressing antimicrobials for acute exacerbations are presented in Table 102 and Table 103.

9.4.2.3.1. P aeruginosa

Antimicrobials for pulmonary exacerbations due to P aeruginosa

Antimicrobials for acute infection with P aeruginosa

9.4.2.3.2. S aureus

No studies were identified for inclusion.

9.4.2.3.3. B cepacia complex

No studies were identified for inclusion.

9.4.2.3.4. Non-tuberculous mycobacteria

No studies were identified for inclusion.

9.4.2.3.5. Non-identified pathogen

No studies were identified for inclusion.

9.4.2.4. Economic evidence

No economic evaluations of interventions relevant to acute antimicrobial treatment were identified in the literature search conducted for this guideline. Full details of the search and economic article selection flow chart can be found in Appendix E and F, respectively.

This review question was not prioritised for de novo economic modelling. Instead additional economic analysis has been undertaken on chronic antimicrobial treatment as this was considered to have a larger impact on resources and current clinical practice.

To aid their recommendations, the committee requested a cost description on antimicrobials to manage acute pulmonary infection with P aeruginosa. Unlike the other pathogens under consideration, P Aeruginosa was considered to be one of the most prevalent pathogens that require urgent treatment.

Antimicrobials to manage pulmonary infection with P aeruginosa include ceftazidime, meropenem and imipenem amongst others. But for these antimicrobials, several brands are available resulting in a variety of acquisition costs. As outlined in NICE’s Guide to the methods of technology appraisal 2013, the reduced price should be used in the reference-case analysis to best reflect the price relevant to the NHS. For this reason the lowest cost brand is presented in Table 104. Basic prices are taken from the NHS Electronic Drug Tariff November 2016, unless otherwise stated.

9.4.2.5. Evidence statements

9.4.2.5.1. P aeruginosa

Antimicrobial treatment for pulmonary exacerbations due to P aeruginosa

Comparison 1. Single IV agents compared for pulmonary exacerbations with P aeruginosa

Lung function: FEV₁

Low quality evidence from 2 RCTs with 46 young people and adults with cystic fibrosis experiencing a pulmonary exacerbation with P aeruginosa showed no clinically significant difference in absolute change of FEV₁ litres between the participants receiving 2 week courses of both ceftazidime (2g 3/day or 8g/day in 4 doses) and those receiving aztreonam (2g 3/day or 8g/day in 4 doses) at 2 week follow-up. Moderate inconsistency was observed between both trials, but both trials showed no differences between groups. In addition, the difference in the absolute change in FEV₁ litres was minimal in both groups.

Eradication

No evidence was found for this critical outcome.

Resolution of infection/exacerbation or measure of treatment failure (e.g. need for additional antibiotics)

No evidence was found for this important outcome.

Duration of the acute episode

No evidence was found for this important outcome.

Quality of life

No evidence was found for this important outcome.

Mortality

No evidence was found for this important outcome.

Adverse events

No evidence was found for this important outcome.

Comparison 2. Single IV antibiotic (with placebo) versus combination IV antibiotic for pulmonary exacerbations with P aeruginosa

Lung function: FEV₁

Low quality evidence from 1 RCT with 98 young people with cystic fibrosis experiencing a pulmonary exacerbation with P aeruginosa showed no clinically significant difference in FEV₁ % predicted (absolute change) between the participants who received a 10 day course of IV tobramycin (9mg/kg 3× daily) with placebo and those who received a 10 day course of IV ceftazidime (50mg/kg/dose 3× daily and IV tobramycin 3mg/kg 3× daily) at 10 days follow-up.

Very low quality evidence from 1 RCT with 18 young people with cystic fibrosis with P aeruginosa in sputum admitted to hospital for worsening respiratory status showed no clinically significant difference in FEV₁ % predicted (relative change) between the participants who received a 2 week course of both tobramycin with placebo (5% dextrose 4-hourly) and piperacillin at both 50mg/kg 4-hourly and 100mg/kg 8-hourly at 2 week follow-up. All participants received tobramycin 2.5mg/kg 3× daily, oral flucloxacillin 25 mg/kg/day in 4 doses and oral probenecid (suggested to increase antibiotic concentrations) at 250 - 500mg 3× daily.

Adverse events

Low quality evidence from 1 RCT with 18 young people with cystic fibrosis with P aeruginosa in sputum admitted to hospital for worsening respiratory status showed no clinically significant difference in sensitivity reactions between the participants who received a 2-week course of tobramycin with placebo (5% dextrose 4-hourly) and those who received a 2-week course of all regimens of piperacillin (both 50 mg/kg 4-hourly and 100 mg/kg 8-hourly) at 2 week follow-up. All participants received tobramycin 2.5 mg/kg 3× daily, oral flucloxacillin 25 mg/kg/day in 4 doses and oral probenecid (suggested to increase antibiotic concentrations) at 250 - 500 mg 3× daily.

Very low quality evidence from 1 RCT with 18 young people with cystic fibrosis with P aeruginosa in sputum admitted to hospital for worsening respiratory status showed no clinically significant difference in number of hospital admissions due to tinnitus between the participants who received a 10 day course of both tobramycin (9 mg/kg 3× daily) with placebo and those who received ceftazidime (50 mg/kg/dose 3× daily and IV tobramycin 3 mg/kg 3× daily) at 2 week follow-up.

Very low quality evidence from 1 RCT with 44 young people with cystic fibrosis experiencing an exacerbation with P aeruginosa showed no clinically significant difference in serum or creatinine levels between the participants who received a 10 day course of both tobramycin (9 mg/kg 3× daily) with placebo and those who received ceftazidime (50 mg/kg/dose 3× daily and IV tobramycin 3 mg/kg 3× daily) at 2 week follow-up.

However, moderate quality evidence from the same trial showed a clinically significant lower levels of NAG in the participants who received a 10 day course of tobramycin (9 mg/kg 3× daily) with placebo compared with who received a 10 day course combination of IV ceftazidime (50 mg/kg/dose 3× daily) and IV tobramycin (3 mg/kg 3× daily) at 2 week follow-up.

Comparison 3. Single IV antibiotic versus combination IV antibiotic for pulmonary exacerbations with P aeruginosa

Lung function: FEV₁

Low quality evidence from 1 RCT with 30 young people with cystic fibrosis experiencing an acute exacerbation due to P aeruginosa showed a clinically significant beneficial effect of a 10–14 day course of combination ticarcillin (300 mg/kg/day in 4 doses) and tobramycin (10 mg/kg/day in 3 doses) in FEV₁ % relative change compared with a 10–14 day course ceftazidime (200 mg/kg/day in 4 doses) at 2 week follow-up.

Low quality evidence from 1 RCT with 71 adults with cystic fibrosis experiencing a pulmonary exacerbation with P aeruginosa showed a clinically significant beneficial effect of a 12 day course of a combination of colistin (2 MU 3× daily) and a second anti-pseudomonal antibiotic in FEV₁ (ml) absolute change compared with colistin (2 MU 3× daily) alone at 12 days follow-up.

Very low quality evidence from 1 RCT with 21 young people with cystic fibrosis experiencing a pulmonary exacerbation with P aeruginosa showed no clinically significant difference in FEV₁ % predicted (absolute change) between a 2 week course of ceftazidime 50 mg/kg 3× daily and a combination of piperacillin (75 mg/kg 4× daily) and tobramycin (10 mg/kg/day in 3 doses) at 2 week follow-up.

Eradication

Low quality evidence from 1 RCT with 38 children with cystic fibrosis showed a clinically significant beneficial effect of combination of piperacillin (600 mg/kg/day) and (tobramycin 8 - 10 mg/kg/day) in eradicating P aeruginosa compared with piperacillin alone (600 mg/kg/day).

Resolution of infection/exacerbation or measure of treatment failure (e.g. need for additional antibiotics)

Very low quality evidence from 1 RCT with 19 children with cystic fibrosis admitted to hospital for treatment of a pulmonary exacerbation with P aeruginosa showed no clinically significant difference in time to readmission (months) between a 2 week course of ceftazidime (50 mg/kg 3× daily) and a 2 week course combination piperacillin (75 mg/kg 4× daily) and tobramycin (10 mg/kg/day in 3 doses) at 3 months follow-up.

Very low quality evidence from 1 RCT with 22 children and young people with cystic fibrosis and severe chest infection treated for an exacerbation with P aeruginosa showed no clinically significant difference in number of admissions to hospital requiring IV antibiotics or mortality between a 2 week course of ceftazidime (150 mg/kg/day) and a 2 week course of combination tobramycin (7.5 mg/kg/day) and ticarcillin (300 mg/kg/day) at 3 months follow-up.

Duration of the acute episode

No evidence was found for this important outcome.

Quality of life

No evidence was found for this important outcome.

Mortality

Low quality evidence from 1 RCT with 21 young people with cystic fibrosis experiencing a pulmonary exacerbation with P aeruginosa showed no clinically significant difference in mortality between a 2 week course of ceftazidime 50 mg/kg 3× daily and 2 week course combination piperacillin (75 mg/kg 4× daily) and tobramycin (10 mg/kg/day in 3 doses) at 4 months follow-up.

Low quality evidence from 1 RCT with 71 adults with cystic fibrosis experiencing a pulmonary exacerbation with P aeruginosa showed no clinically significant difference in mortality between a 12 day course of a combination of colistin (2 MU 3× daily) and a second anti-pseudomonal antibiotic in FEV₁ (ml) absolute change compared with 12 day course colistin (2 MU 3× daily) alone at 12 week follow-up.

Adverse events

Very low quality evidence from 2 RCTs with 52 children and young people with cystic fibrosis experiencing an exacerbation due to P aeruginosa showed no clinically significant difference in liver transaminase enzyme elevation between a 10–14 day course of ceftazidime and combination ticarcillin and tobramycin.

Low quality evidence from 1 RCT with 71 adults with cystic fibrosis experiencing a pulmonary exacerbation with P aeruginosa showed no clinically significant difference in neurological adverse effects between a 12 day course colistin (2 MU 3× daily) alone and a 12 day course combination of colistin (2 MU 3× daily) and a second anti-pseudomonal antibiotic at 12 days follow-up.

Very low quality evidence from 1 RCT with 17 children with cystic fibrosis admitted for treatment of pulmonary exacerbations showed no clinically significant difference in rash and fever between a 10 day course of piperacillin alone (600 mg/kg/day) and a 10 day course combination piperacillin (600 mg/kg/day) and tobramycin (8 - 10 mg/kg/day) at 10 days follow-up.

Very low quality from 1 RCT with 30 young people with cystic fibrosis and P aeruginosa infection (34 treatment observations) showed no clinically significant difference in proteinuria between a 10–14 day course of ceftazidime (200 mg/kg/day in 4 doses) and combination ticarcillin (300 mg/kg/day in 4 doses) and 10–14 day course tobramycin (10 mg/kg/day in 3 doses) in FEV₁ % relative change compared with ceftazidime.

Low and very low quality evidence from 1 RCT with 71 adults with cystic fibrosis experiencing a pulmonary exacerbation with P aeruginosa showed no clinically significant difference in change in blood urea (mmol/L) and change in serum creatine (mol/L) between a 12 day course of a combination of colistin (2 MU 3× daily) and a 12 day course second anti-pseudomonal antibiotic and colistin (2 MU 3× daily) alone at 12 days follow-up.

Comparison 4. Combination IV antibiotics versus combination IV antibiotics for pulmonary exacerbations with P aeruginosa

Lung function: FEV₁

Low quality evidence from 1 RCT including observations for 49 courses of IV combination therapy (≈42 people with cystic fibrosis aged 3 to 24 years admitted to hospital due to a pulmonary exacerbation with P aeruginosa) showed no clinically significant difference in FEV₁ % predicted (absolute change) between a 2 week course of combination of aztreonam (300 mg/kg/day in 4 doses) and amikacin (36 mg/kg/day in 3 doses) and a 2 week course combination of ceftazidime (300 mg/kg/day in 4 doses) and amikacin (36 mg/kg/day in 3 doses) at 2 week follow-up.

Very low to low quality evidence from 1 RCT with 97 people with cystic fibrosis ≥5 years treated for pulmonary exacerbation showed no clinically significant difference in both FEV₁ % predicted absolute change and relative change between a 2 week course of combination of meropenem (40 mg/kg up to a maximum dose of 2 g) and tobramycin and a 2 week course combination of ceftazidime (50 mg/kg) and tobramycin. Tobramycin dose adjusted to give a peak serum concentration of>= 8 µg/mL and trough concentration of < 2 µg/mL.

Eradication

Very low quality evidence from 1 RCT including observations for 49 courses of IV combination therapy (≈42 people with cystic fibrosis aged 3 to 24 years admitted to hospital due to a pulmonary exacerbation with P aeruginosa) showed no clinically significant difference in eradication of P aeruginosa between a 2 week course of combination of aztreonam (300 mg/kg/day in 4 doses) and amikacin (36 mg/kg/day in 3 doses) and a 2 week course combination of ceftazidime (300 mg/kg/day in 4 doses) and amikacin (36 mg/kg/day in 3 doses) at 2 week follow-up.

Resolution of infection/exacerbation or measure of treatment failure (e.g. need for additional antibiotics)

No evidence was found for this important outcome.

Duration of the acute episode

No evidence was found for this important outcome.

Quality of life

No evidence was found for this important outcome.

Mortality

No evidence was found for this important outcome.

Adverse events

Very low quality evidence from 1 RCT including observations for 56 courses of IV combination therapy (≈42 people with cystic fibrosis aged 3 to 24 years admitted to hospital due to a pulmonary exacerbation with P aeruginosa) showed no clinically significant difference in rash, liver transaminase levels and thrombocytopenia between a 2 week course of combination of aztreonam (300 mg/kg/day in 4 doses) and amikacin (36 mg/kg/day in 3 doses) compared with a 2 week course of combination of ceftazidime (300 mg/kg/day in 4 doses) and amikacin (36 mg/kg/day in 3 doses) at 2 week follow-up.

Comparison 5. Combination of 2 IV antibiotics + inhaled antibiotic versus combination of 2 IV antibiotics without inhaled antibiotic for pulmonary exacerbations with P aeruginosa

Lung function

No evidence was found for this critical outcome.

Eradication of pathogen

Moderate quality evidence from 1 RCT including observations for 84 courses of treatment (≈62 people with cystic fibrosis aged 3 to 24 years admitted to hospital due to a pulmonary exacerbation with P aeruginosa) showed a clinically significant beneficial effect of a 15 day course of IV ceftazidime (250 mg/kg/day in 4 doses) and IV amikacin (33 mg/kg/day in 3 doses) and nebulised amikacin (100 mg 2× daily) compared with a 15 day course IV ceftazidime and IV amikacin without nebulised amikacin at 15 days follow-up.

Duration of the acute episode

No evidence was found for this important outcome.

Quality of life

No evidence was found for this important outcome.

Mortality

No evidence was found for this important outcome.

Adverse events

Very low quality evidence from 1 RCT with including observations for 54 courses of treatment (≈62 people with cystic fibrosis aged 3 to 24 years admitted to hospital due to a pulmonary exacerbation with P aeruginosa) found no clinically significant difference in raised liver transaminases between a 15 day course of IV ceftazidime (250 mg/kg/day in 4 doses) and IV amikacin (33 mg/kg/day in 3 doses) and nebulised amikacin (100 mg 2× daily) compared with IV ceftazidime and IV amikacin without nebulised amikacin.

Comparison 6. Combination IV antibiotics versus oral antibiotics for pulmonary exacerbations with P aeruginosa

Lung function

No evidence was found for this critical outcome.

Eradication of pathogen

Moderate quality evidence from 1 RCT with 89 children with cystic fibrosis and P aeruginosa infection showed a clinically significant beneficial effect of a 2 week course of combination of IV ceftazidime (50 mg/kg 3× daily) and a 2 week IV tobramycin (3 mg/kg 3× daily) in eradicating P aeruginosa compared with oral ciprofloxacin (15 mg/kg 2× daily) at 2 week follow-up.

Duration of the acute episode

No evidence was found for this important outcome.

Quality of life

No evidence was found for this important outcome.

Mortality

No evidence was found for this important outcome.

Adverse events

Very low quality evidence from 1 RCT with 108 children with cystic fibrosis and P aeruginosa infection showed no difference in treatment-related adverse events between a 2 week course of combination IV ceftazidime (50 mg/kg 3× daily) and IV tobramycin (3 mg/kg 3× daily) and oral ciprofloxacin (15 mg/kg 2× daily).

Antimicrobial treatment for acute infection with P aeruginosa

Comparison 7. Oral ciprofloxacin and inhaled colistin versus inhaled tobramycin for acute infection with P aeruginosa

Lung function

No evidence was found for this critical outcome.

Eradication of pathogen

No evidence was found for this critical outcome.

Time to next pulmonary exacerbation

No evidence was found for this important outcome.

Resolution of infection/exacerbation or measure of treatment failure

No evidence was found for this important outcome.

Quality of life

No evidence was found for this important outcome.

Adverse events

Very low quality evidence from 1 RCT with 58 children with cystic fibrosis with new isolation of P aeruginosa showed no clinically significant difference in adverse events (severe cough) between a 3 month course of combination inhaled colistin (2 MU 2× daily) and oral ciprofloxacin (10 mg/kg 3× daily) compared with a 3 month course of inhaled tobramycin (300 mg 2× daily for 28 days) at 3 months follow-up.

Comparison 8. Inhaled colistin and oral ciprofloxacin versus inhaled tobramycin and oral ciprofloxacin for acute infection with P aeruginosa

Lung function: FEV₁

Very low quality evidence from 1 RCT with 128 people with cystic fibrosis >1 year with first ever or new P aeruginosa infection showed no clinically significant difference in FEV₁ % predicted (relative change) between a 28 day course of combination colistin (2× daily inhalation of 2 MU) and ciprofloxacin (2× daily of 15 mg/kg/dose) compared with a 28 day course combination of tobramycin inhaled solution (300 mg 2× daily) and ciprofloxacin (2× daily doses of 15 mg/kg/dose) at 54 days follow-up.

Eradication of pathogen

No evidence was found for this critical outcome.

Time to next pulmonary exacerbation

No evidence was found reporting this important outcome.

Resolution of infection/exacerbation or measure of treatment failure

Very low quality evidence from 1 RCT with 128 people with cystic fibrosis >1 year with first ever or new P aeruginosa infection showed no clinically significant difference in discontinuation due to lack of compliance between a 28 day course of combination colistin (2× daily inhalation of 2 MU) and ciprofloxacin (2× daily of 15 mg/kg/dose) compared with a 28 day course of combination of tobramycin inhaled solution (300 mg 2× daily) and ciprofloxacin (2× daily doses of 15 mg/kg/dose) at 28 days follow-up.

Very low quality evidence from 1 RCT with 128 people with cystic fibrosis >1 year with first ever or new P aeruginosa infection showed no clinically significant difference in pulmonary exacerbation during early eradication treatment leading to treatment failure between a 28 day course of combination colistin (2× daily inhalation of 2 MU) and ciprofloxacin (2× daily of 15 mg/kg/dose) compared with a 28 day course combination of tobramycin inhaled solution (300 mg 2× daily) and ciprofloxacin (2× daily doses of 15 mg/kg/dose) at 28 days follow-up.

Quality of life (QOL)

No evidence was found for this important outcome.

Adverse events

Very low quality evidence from 1 RCT with 128 people with cystic fibrosis >1 year with first ever or new P aeruginosa infection showed no clinically significant difference in adverse events (vomiting, photosensitivity, wheeze) between a 28 day course of combination colistin (2× daily inhalation of 2 MU) and ciprofloxacin (2× daily of 15 mg/kg/dose) compared with a 28 day course combination of tobramycin inhaled solution (300 mg 2× daily) and ciprofloxacin (2× daily doses of 15 mg/kg/dose) at 28 days follow-up.

9.4.2.5.2. S aureus

No evidence was found.

9.4.2.5.3. B cepacia complex

No evidence was found.

9.4.2.5.4. H influenzae

No evidence was found.

9.4.2.5.5. Nontuberculous mycobacteria

No evidence was found.

9.4.2.5.6. Non-identified pathogen

No evidence was found.

9.4.2.5.7. Economic evidence statements

No evidence on cost-effectiveness in people with cystic fibrosis was available for this review.

9.4.2.6. Evidence to recommendations

9.4.2.6.1. Relative value placed on the outcomes considered

The committee chose eradication of specific pathogens, where present, and improvement in lung function measured using either FEV₁ or the lung clearance index (LCI) as critical outcomes for decision making for both acute infection and pulmonary exacerbation.

In addition they chose the following as important outcomes: resolution of exacerbation or measures of treatment failure (for example, the need for additional antibiotics), duration of the episode, quality of life, adverse events and mortality for pulmonary exacerbations. For acute pulmonary infection, the important outcomes were: time to next acute infection, resolution of infection or measure of treatment failure (for example, the need for additional antibiotics), quality of life and adverse events.

9.4.2.6.2. Consideration of clinical benefits and harms

The committee discussed the recommendations for each pathogen separately.

P aeruginosa

The committee acknowledged the evidence presented to them and discussed it in the light of their clinical expertise and experience.

The committee discussed 2 different scenarios: acute infection and pulmonary exacerbation.

If a person with cystic fibrosis develops a new infection with P aeruginosa (meaning a positive respiratory secretion sample culture where previous cultures in the recent past have been negative) the committee agreed antibiotic treatment is needed. They emphasised early treatment of P aeruginosa infection is very important as it is recognised chronic infection with this pathogen has a negative impact in the quality of life.

The committee noted the management will differ depending on the severity of the symptoms.

If the person is clinically well, the committee suggested it should be treated in order to try to eradicate it using a combination of systemic antibiotics, oral or intravenous, with an inhaled antibiotic. They discussed the use, for example, of oral ciprofloxacin combined with inhaled colistin or nebulised tobramycin. The recommendation to treat this group was based on the committee’s recognition that P aeruginosa is an important pathogen in cystic fibrosis. In their expert opinion intensive treatment with systemic and inhaled antibiotics should improve the chances of eradication. The committee made this recommendation based on their clinical experience as the available evidence was scarce and of very low quality and, therefore, not very useful in making recommendations.

If the person is clinically unwell, for example with new respiratory symptoms and signs or a worsening of existing respiratory symptoms and signs, the approach might be different. The committee recommended that, in that situation, the initial therapy should consist of a course of intravenous antibiotics with an inhaled antibiotic. They discussed, for example, the use of 2 anti-pseudomonal antibiotics, such as ceftazidime and tobramycin, given intravenously together with the inhaled antibiotic. This recommendation is based on moderate quality evidence that showed participants who received an inhaled antibiotic in addition to a combination of 2 intravenous antibiotics were less likely to be admitted to hospital due to a pulmonary exacerbation.

In both groups, based on the consensus of the committee, they advised giving extended treatment in order to try to increase the likelihood of eradication.

In the event that eradication was unsuccessful, the committee agreed that prolonged treatment with an inhaled antibiotic should be given to try and supress it. They recommendations using colistimethate as the first-line choice for this inhalation therapy. Please see antimicrobial treatment for the management of chronic P aeruginosa.

For the management of pulmonary exacerbations due to P aeruginosa in people who are chronically infected with pseudomonas, the committee agreed to recommend oral or intravenous antibiotics, depending on the severity of the illness. The intravenous treatment should consist in a combination of 2 agents, as supported by the evidence included in this review. The committee noted that low quality evidence showed a clinically significant beneficial effect in lung function and in eradication of the organism with a combination of 2 intravenous antibiotics compared to a single antibiotic. In addition, the evidence showed no clinically significant difference in the occurrence of adverse events.

Finally, the committee recommended that if people with chronic P aeruginosa infection suffer from repeated pulmonary exacerbations, consideration should be given to altering the antibiotic regimen used at intervals in order to reduce the possibility of non-response due to emergence of resistance. This should take account of the individual’s pseudomonas antibiotic sensitivity testing. This recommendation was based on the consensus of the committee.

S aureus

No evidence was found for the treatment of S aureus, therefore, recommendations were based on committee’s clinical expertise.

The committee discussed 2 possible scenarios, depending on whether the child is on prophylaxis treatment.

The committee recognised that a potential reason for emergence of S aureus infection was non-adherence to the prophylaxis regimen, so they advised this should be reviewed with parents and carers. They also advised that following treatment-dose anti-staphylococcal antibiotics, the prophylaxis should be reinstated even if treatment was unsuccessful as they believed that suppression of the infection was likely to be clinically beneficial.

If a child is not on prophylaxis against S aureus, and is then found to have developed an infection with this pathogen, the committee recommended oral antibiotic treatment if they are well. They discussed flucloxacillin, co-amoxiclav or doxycycline as potentially useful antibiotic choices for people over 12 years. If, however, they are unwell (for example, with symptoms such as cough), and have evidence of pulmonary disease (for example, reduced lung function based on testing), then either oral or intravenous antibiotic treatment, depending on disease severity, is recommended. The antibiotic used should be broad spectrum to take account of the possibility that S aureus might not be the cause of the illness, but the treatment should include anti-S aureus cover.

The committee agreed that for people with new evidence of MRSA respiratory infection (with or without pulmonary exacerbation), specialist microbiological advice should give guidance on treatment to eradicate it.

B cepacia complex

No evidence was found for the treatment of B cepacia complex, therefore recommendations were based on committee’s clinical expertise.

The committee agreed that if a person develops a new infection with B cepacia complex, an attempt should be made to eradicate the infection with antibiotic therapy whether or not the person was unwell with the infection. They considered that specialist advice should be sought on this treatment. They suggested a combination of 2 or 3 appropriate intravenous antibiotics would usually be given. Examples of intravenous antibiotics that might be advised included, but are not limited to, ceftazidime, meropenem, amikacin and temocillin in addition to specialist advice on the exact regimen was required. The committee noted that it is important to treat new B cepacia complex infections effectively as chronic infection can cause a deterioration in lung function and, in some people, an overwhelming, and even fatal, infection called ‘cepacia syndrome’ may occur. Persistent isolation of B cepacia complex may also adversely impact on a persons’ eligibility for transplantation. The committee noted that treating new infections with B cepacia complex is common practice in adult CF centres.

The committee also discussed the case of people with chronic B cepacia complex infection despite attempts at eradication. They did not recommend treatment for those with chronic B cepacia complex who are clinically well. They noted that B cepacia complex is very resistant to most treatments once established, therefore, treatment is unlikely to work. However, if they became unwell with a pulmonary exacerbation, the committee recommended that specialist advice be sought regarding the use of oral or intravenous antibiotics. They discussed that this would usually be with a course of intravenous antibiotics, although oral antibiotics might also be used for a less severe exacerbation.

H influenzae

No evidence was found for the treatment of H influenzae, therefore recommendations were based on committee’s clinical expertise.

The committee agreed it is important to treat H influenzae in order to prevent chronic infection with this pathogen. This is because although there might not be detectable evidence of disease due to it, the belief is that it will cause lung damage and so should be eradicated. They discussed 2 possible scenarios if a person develops an infection.

If the person is clinically well (asymptomatic), the committee recommended giving an oral antibiotic agent. If the person is clinically unwell (for example, with cough or reduced lung function), they recommended the use of an oral or intravenous antibiotic treatment depending on the severity of the illness.

These recommendations are consistent with clinical practice and with the CF Trust recommendations (CF Consensus document: antibiotic treatment for Cystic Fibrosis, 2009).

Nontuberculous mycobacteria

No evidence was found for the treatment of nontuberculous mycobacteria (NTM), therefore, recommendations were based on committee’s clinical knowledge and expertise. The committee noted that treatment is complex and guidelines are evolving. There is still uncertainty about the best approach to treatment.

The committee emphasised the importance of confirming the presence on nontuberculous mycobacteria by repeating respiratory secretion cultures. This is because nontuberculous mycobacteria are often just sporadic commensal organisms, that is, they just come and go without causing disease. Therefore, the first step when this pathogen is found is to ensure that it persists before actually considering whether it is causing disease. This diagnostic issue was also raised by the CF Trust Consensus document on antibiotic treatment for cystic fibrosis (CF Consensus document: antibiotic treatment for Cystic Fibrosis, 2009).

The committee noted, in a person with respiratory disease who is found to be NTM positive, it was not always easy to determine whether or not the infection was contributing to the disease. Therefore, they recommended that a chest CT scan should be performed because it may show changes that would clarify the role of nontuberculous mycobacteria in the disease.

The committee recommended that a discussion should take place with the person affected and, if appropriate, with parents or carers about the uncertain benefits of therapy aimed at eradication of nontuberculous mycobacteria. They should discuss that, when considering a decision to treat, it is important to be aware of the potential toxicities associated with the drugs used. Potential toxic effects included vomiting, nephrotoxicity and ototoxicity. This is particularly pertinent for people who are positive for nontuberculous mycobacteria but clinically well, where the benefits are less certain.

The committee recommended that consideration be given to treatment for those who are positive for nontuberculous mycobacterium respiratory infection and who have a chest CT scan showing changes consistent with it and who are unwell with pulmonary disease, despite optimisation of other treatment. The recommendation made by the committee to treat based on clinical grounds is consistent with the CF Trust recommendations (CF Consensus document: antibiotic treatment for Cystic Fibrosis, 2009).

The committee recognised that evidence regarding the optimal antibiotic regimen and duration of treatment was lacking. The committee discussed the fact that the approaches to treating M avium complex and M abscessus differ. Currently, treatment for M avium typically includes a combination of 3 oral anti-mycobacterial agents including a macrolide and rifampicin and ethambutol. Current eradication treatment for M abscessus is more intensive and may include repeated courses of triple antibiotic therapy administered intravenously, together with a combination or oral and inhaled antibiotics. Antibiotics used include, but are not limited to, cefoxitin, tigecycline, amikacin, carbapenems and macrolides. They recommended that specialist microbiological advice be sought on which antibiotics to use and on duration of treatment. The committee noted that there was existing consensus guidance on the management of non-tuberculous mycobacteria in an article by Floto, R. A., Olivier, K. N., Saiman, L., et al. (2016) titled “US Cystic Fibrosis Foundation and European Cystic Fibrosis Society consensus recommendations for the management of non-tuberculous mycobacteria in individuals with cystic fibrosis”.

Non-identified pathogen

No evidence was found for the treatment of unidentified infections, therefore recommendations were based on committee’s clinical expertise.

The committee agreed that if a person presents with clinical manifestations suggesting the development of an acute pulmonary infection, or an exacerbation without an identified pathogen, it would be appropriate to treat with a broad-spectrum antibiotic while continuing to collect respiratory secretion samples. The choice of oral or IV treatment will depend on the severity of the symptoms.

Treatment should be modified once the pathogen causing the infection or the exacerbation is identified.

9.4.2.6.3. Consideration of economic benefits and harms

The clinical evidence review demonstrated that the benefits of combination antibiotics to treat exacerbations due to P aeruginosa could justify their additional cost relative to single antibiotics. For example, clinically significant beneficial effects in lung function were found for combination IV antibiotics compared to single IV antibiotics. Clinically significant benefits in eradication were found for the more intensive regimen, specifically combination IV antibiotics compared to single antibiotic therapy, 2 IV antibiotics plus an inhaled antibiotic compared to IV antibiotics without an inhaled antibiotic and combination IV antibiotics compared to oral antibiotics.

No evidence was found for the other pathogens listed in the protocol, thus the committee made recommendations to reflect current clinical practice and resource use as they considered this to be a cost-effective use of resources.

The specific antibiotics administered in the trials were of less importance to the committee as antibiotics received by a person with cystic fibrosis to treat an acute infection, or exacerbation, need to be varied in accordance with cultures, sensitivities and local resistance patterns of isolated pathogens. Consequently, the committee stated it would be inappropriate to recommend specific antibiotics or a number of antibiotics as this would limit the variation in antibiotics used by healthcare professionals and, subsequently, the effectiveness and cost-effectiveness of the antibiotic over time. Instead, the committee were interested in the combination and preparation of antibiotics that were administered to infer which regimens were cost-effective.

When the same number of different combinations of antibiotics, of the same preparation (for example, two IV antibiotics vs. a different combination of two IV antibiotics) were compared, no significant difference was demonstrated for any of the proposed outcomes. However, the committee iterated that no significance difference does not infer that there was no clinical change, pre versus post treatment, as the trials included a comparator that was an antimicrobial agent that would be expected to issue a treatment effect.

In light of the findings from the clinical evidence review and their own clinical experience, the committee wanted to recommend 2 antibiotics in different classes and consider changing regimens over time when treating exacerbations associated with P aeruginosa. The committee added, when discussing cost implications, that ceftazidime is used more often and is less expensive than aztreonam and meropenem.

The committee agreed IV antibiotics are generally more expensive than oral preparations for many reasons regardless of the active agent, including their purchase price and, in some cases, sterile production and healthcare professional administration. Additionally, they are more invasive and have a greater potential for associated adverse effects. Consequently, the committee recommended that, where appropriate, if the person is clinically well (asymptomatic), treatment with an oral agent should be considered; whereas if the person is clinically unwell (for example presents with cough or reduced lung function) the use of an appropriate oral or IV antibiotic could also be considered depending on the severity of symptoms.

The committee noted that the experience of each clinic to manage the range of pathogens people with cystic fibrosis can become infected with can be variable. Moreover, given the limited evidence on the most effective way to treat acute infections, the committee agreed that the cost of obtaining specialist advice on how to manage rarer, and potentially detrimental pathogens such as MRSA, B cepacia complex and non-tuberculous mycobacteria, would be offset by the potential downstream costs from inappropriate management. Therefore, to ensure the most effective antibiotic regimens are utilised, the committee made recommendations to seek specialist microbiological advice on which antibiotics to use and on the duration of treatment.

The committee were reluctant to recommend “no treatment” in people with cystic who have a pulmonary disease exacerbation and no clear cause (based on recent respiratory secretion samples) as the lack of evidence should not infer lack of effect. Given that the expected downstream costs from an untreated infection would outweigh the cost of treatment, the committee agreed a broad-spectrum antibiotic should be offered.

9.4.2.6.4. Quality of evidence

P aeruginosa

The quality of the evidence was rated as very low to moderate as assessed by GRADE for the antimicrobial treatment due to pulmonary exacerbations with P aeruginosa, and very low for the antimicrobial treatment of acute infections with P aeruginosa. No high quality evidence was found. The main reasons that led to downgrading the quality of the evidence were:

For the domain risk of bias, the studies were assigned the same risk of bias as in the Cochrane reviews and were not individually reviewed. The main biases that lead to downgrading the quality of the evidence were attrition bias and lack of blinding.
Another reason that lead to downgrading the quality of the evidence was imprecision as confidence intervals crossed 1 or 2 MIDs.

No serious issues were found regarding the directness of the population or the interventions.

S aureus

Not applicable, as no evidence was found for this pathogen.

B cepacia complex

Not applicable, as no evidence was found for this pathogen.

Non-tuberculous mycobacteria

Not applicable, as no evidence was found for this pathogen.

Non-identified pathogen

Not applicable, as no evidence was found for this pathogen.

9.4.2.6.5. Other considerations

No equality issues were identified by the committee for this review question.

The committee agreed a research recommendation should not be prioritised for this topic. They noted there is sufficient evidence available on the management of acute exacerbations with P aeruginosa. They also noted studies on the management of acute infection with other pathogens are difficult to conduct. Recommendations are consistent with clinical practice and new research is unlikely to lead to significant changes.

9.4.2.6.6. Key conclusions

The committee concluded that:

People with cystic fibrosis who present with a new infection with P aeruginosa should be treated with a combination of oral or IV antibiotics together with inhaled antibiotics, regardless of whether the person is symptomatic or not. A follow-up antibiotic treatment could be considered with the aim to eradicate the pathogen.
People with cystic fibrosis who present with an acute exacerbation due to P aeruginosa should be treated with a combination of oral or IV antibiotics, depending on the severity of the illness. Agents should be changed over time.
Children with cystic fibrosis who are on prophylactic treatment and present with a new infection with S aureus should start treatment-dose anti-staphylococcal antibiotics.
People with cystic fibrosis who are not on prophylactic treatment and present with a new infection with S aureus and are clinically well may require treatment with an oral anti-staphylococcal antibiotic.
People with cystic fibrosis who are not on prophylactic treatment and present with a new infection with S aureus and are clinically unwell may require treatment with an additional oral or intravenous anti-staphylococcal antibiotic.
For people who have new evidence of MRSA respiratory infection (with or without pulmonary exacerbation), specialist microbiological advice should be sought on treatment to eradicate it.
People with cystic fibrosis who present with a new infection with B cepacia complex should be given a combination of IV antibiotics, regardless of whether they are symptomatic or not.
People with cystic fibrosis who present with an acute exacerbation due to B cepacia complex should be treated with appropriate oral or IV antibiotics, depending on the severity of the illness.
People with cystic fibrosis who present with a new infection with H influenzae should be treated with appropriate oral or IV antibiotics, depending on the severity of the symptoms.
People with cystic fibrosis who present with a new infection where non-tuberculous mycobacteria is suspected should have the diagnosis confirmed prior to commencing treatment. Combination anti-mycobacterial treatment should be considered. Specialist microbiologist advice should be sought.
People with cystic fibrosis who present with an acute exacerbation due to non-tuberculous mycobacteria should be treated with appropriate oral or IV antibiotics, depending on the severity of the illness.
People with cystic fibrosis who present with an exacerbation without a known pathogen should be treated with an oral or IV broad-spectrum antibiotic. Treatment should be changed accordingly, once the pathogen has been identified.

9.4.3. Chronic

Review question: What is the effectiveness of antimicrobial regimens in suppressing chronic pulmonary infection in children and adults with cystic fibrosis with any of the following pathogens: P aeruginosa, B cepacia Complex, S aureus and Aspergillus Fumigatus?

9.4.3.1. Description of clinical evidence

The aim of this review was to determine the clinical and cost-effectiveness of different antimicrobial treatment regimens to suppress chronic pulmonary infection in children and adults with cystic fibrosis and one of the following pathogens:

P aeruginosa
S aureus
B cepacia complex
A fumigatus

We searched for systematic reviews of RCTs and RCTs, including cross-over trials. Systematic reviews were assessed for inclusion against the protocol, and if relevant, their quality was assessed using AMSTAR. High-quality systematic reviews were included in our review, and where possible, data and quality assessment was taken directly from the review. Individual studies were also retrieved for completeness and accuracy, and were checked for additional outcomes of interest. Low-quality systematic reviews were excluded from our review, but their lists of included studies were checked to identify relevant trials.

For full details see review protocol in Appendix D.

The results are presented separately for each pathogen.

9.4.3.1.1. P Aeruginosa

The interventions that were included in the protocol for the treatment of chronic infection with P aeruginosa were Aztreonam lysine (inhaled, nebulised), Azithromycin (oral, antibiotic-dose only), Ciprofloxacin (oral), Colistimethate sodium (dry powderfor inhalation, nebulised), Fosfomycin (inhaled) and Tobramycin (dry powder for inhalation, nebulised).

One NICE TA report 276 (Tappenden 2013) has been published to provide guidance on the treatment of chronic P Aeruginosa. This systematic review evaluated the effectiveness and cost-effectiveness of Colistimethate sodium dry powder inhalation and Tobramycin dry powder inhalation for the treatment of chronic P Aeruginosa lung infection in people with cystic fibrosis over the age of 6 years. Three trials were included in the review (COLO/DPI/02/05, COLO/DPI/02/06, Konstan 2011a/EAGER trial).

Four Cochrane systematic reviews were identified in the search.

Two reviews were included:
- Remmington (2016) evaluated the effectiveness of oral anti-pseudomonal antibiotics for cystic fibrosis. One trial was included from this review (Sheldon 1993).
- Ryan (2011) evaluated the effectiveness of inhaled antibiotics for long-term therapy in cystic fibrosis. Eight trials were included from this review (Chuchalin 2007, Hodson 2002, Jensen 1987, Lenoir 2007, McCoy 2008, Murphy 2004, Ramsay 1993, Ramsey 1999).
Two reviews were excluded:
- Elphick (2016) evaluated the effectiveness of single versus combination IV antibiotic therapy for treating people with cystic fibrosis. One trial included people with cystic fibrosis and chronic infection with P Aeruginosa, but it was not included in the review as it evaluated the effectiveness of Ceftazidime, a treatment that was not prioritised by the committee in the evidence review protocol.
- Southern (2012) evaluated the effectiveness and safety of macrolide antibiotics. All the included studies used low dose azithromycin, lower than the therapeutic range for antimicrobial action, and they were not relevant for this review.

Seven further systematic reviews were identified. Six of them (Cai 2011, Carr 2004, Florescu 2009, Littlewood 2012, Maiz 2013 and Mukhopadhyay 1996) were assessed as low quality according to AMSTAR and were, therefore, excluded from our review. The included papers were checked for inclusion. Utteley (2013) was excluded as it reported the same data as the TA report.

In addition, 8 primary studies have also been identified (Assael 2013, Flume 2016, Galeva 2013, Konstan 2011/EVOLVE trial, Retsch-Bogart 2009, Schuster 2013, Trapnell 2012, Wainwright 2011).

The size of the studies ranged between 16 and 520 people. Thirteen studies included children, young people and adults (Assael 2013, Chuchalin 2007, COLO/DPI/02/05, COLO/DPI/02/06, Flume 2016, Galeva 2013, Jensen 1987, Konstan 2011/EVOLVE trial, Konstan 2011a/EAGER trial, Lenoir 2007, McCoy 2008, Retsch-Bogart 2009, Schuster 2013), 2 studies included children and young people (Murphy 2004, Wainwright 2011), 1 included young people and adults (Hodson 2002), 3 studies included adults only (Ramsey 1999, Sheldon 1993, Trapnell 2012). 1 study (Ramsey 1993) did not report the age range, the mean age was 17.7 years.

Two studies were conducted in the UK (COLO/DPI/02/05, Hodson 2002), 6 in the USA (Flume 2016, Murphy 2004, Retsch-Bogart 2009, Ramsey 1993, Ramsey 1999, Trapnell 2012), 1 in Canada (Sheldon 1993), 1 in Denmark (Jensen 1987), 10 studies in multiple countries; 1 in the EU, Russia and Ukraine (COLO/DPI/02/06), 1 in Europe and the United States (Assael 2013), 1 in Hungary, Poland and Russia (Chuchalin 2007), 1 in Bulgaria, Estonia, Latvia, Lithuania, Romania, Russia, Egypt, and India (Galeva 2013), 1 in Bulgaria, Lithuania, Serbia, Argentina, Brazil, Chile, Mexico and the United States (Konstan 2011/EVOLVE trial), 1 in 15 unspecified countries (Konstan 2011a/EAGER trial), 1 in France, Italy, Moldova, Ukraine (Lenoir 2007), 1 in Australia, Canada, New Zealand and the United States (McCoy 2008), 1 in Europe (Schuster 2013), 1 in Australia and the United States (Wainwright 2011).

The included studies evaluated their effectiveness based on the following comparisons.

Aztreonam lysine vs placebo – 3 studies (McCoy 2009, Retsch-Bogart 2009, Wainwright 2011)
Ciprofloxacin vs placebo – 1 study (Sheldon 1993)
Colistin vs placebo – 1 study (Jensen 1987)
Colistin inhalation powder vs colistin inhalation solution – 1 study (COLO/DPI/02/05)
Colistin vs tobramycin – 3 studies (Hodson 2002, COLO/DPI/02/06, Schuster 2013)
Tobramycin vs placebo – 6 studies (Chuchalin 2007, Galeva 2013, Konstan 2011/EVOLVE trial, Lenoir 2007, Ramsey 1993, Ramsey 1999)
Tobramycin inhalation powder vs tobramycin inhalation solution – 1 study (Konstan 2011a/EAGER trial)
Tobramycin vs Aztreonam lysine – 1 study (Assael 2013)
Fosfomycin + tobramycin vs placebo – 1 study (Trapnell 2012)
Tobramycin + azithromycin vs tobramycin alone (Flume 2016)
Continuous alternating therapy vs intermittent treatment: aztreonam lysine + tobramycin or placebo + tobramycin (Flume 2016)

A report from the National Horizon Scanning Centre (NHSC 2010) was also identified. This report included 5 trials that have been retrieved for assessment.

The presentation of evidence synthesis will be divided in 2 parts based on the type of analysis which was used to produce these syntheses:

A network meta-analysis was conducted for the treatment of chronic P Aeruginosa. It included the critical outcomes listed in the protocol: lung function (FEV₁) and number of people with ≥ 1 exacerbations. The results for these will be provided at a later stage.
Pairwise comparisons have been performed for the rest of the outcomes included in the review protocol and are presented in this review.

9.4.3.1.2. S Aureus

The interventions that were included in the protocol for the treatment of chronic infection with S aureus were Cefradine (oral), Cotrimoxazole (oral), Doxycycline (oral) and Flucloxacillin (oral).

One Cochrane review (Lo 2015) was identified for potential inclusion. This review aimed to evaluate the effectiveness of antimicrobial treatment regimens to eradicate methicillin-resistant S aureus (MRSA) in people with cystic fibrosis and all disease severities. No trials were identified for inclusion. The list of excluded studies was also checked. None of the 48 excluded studies were relevant.

No other trials relevant trials were identified in our search.

9.4.3.1.3. B Cepacia Complex

The interventions that were included in the protocol for the treatment of chronic infection with B cepacia complex were Ceftazidime (inhaled, nebulised), Cotrimoxazole (oral), Imipenem (inhaled, nebulised), Meropenem (inhaled, nebulised), and Trimethoprim (oral).

One Cochrane review (Ryan 2011) was identified for potential inclusion. This review included trials that evaluated the effectiveness of inhaled antibiotics for long-term therapy in cystic fibrosis and included one cross-over trial that looked at people with cystic fibrosis infected with B cepacia. This study was not considered for inclusion in our review as it assessed the effectiveness of inhaled Taurolidine, an intervention that is not routinely used in clinical practice.

No other trials relevant trials were identified in our search.

9.4.3.1.4. A Fumigatus

The interventions that were included in the protocol for the treatment of chronic infection with A fumigatus were Amphotericin (inhaled, nebulised), Itraconazole (oral), Posaconaizole (oral) and Voriconazole (oral).

One Cochrane review (Elphick 2014) was identified for potential inclusion. This review evaluated the effectiveness of antifungal interventions for the treatment of allergic bronchopulmonary aspergillosis (ABPA) in people with cystic fibrosis. No trials were identified for inclusion. The list of excluded studies was also checked. One study (Aaron 2012) had already been identified in our search and it is included in the review, and the other three studies were not relevant (due to study design or intervention evaluated). This RCT included 35 people with cystic fibrosis over the age of 6 years, and chronically colonised with A fumigatus. It was conducted in Canada. It compared the effectiveness of oral Itraconazole versus placebo for a 24-week treatment period. In relation to the outcomes, it included lung function, pulmonary exacerbations, quality of life and adverse events.

9.4.3.2. Summary of included studies

A summary of the studies that were included in this review are presented in Table 105 to Table 107.

9.4.3.3. Clinical evidence profile

The clinical evidence profiles for this review question are presented separately for each pathogen.

9.4.3.3.1. P aeruginosa

Results from the NMA and pairwise comparisons are presented separately in this section.

9.4.3.3.2. Clinical evidence profile for NMA outcomes (FEV₁ % predicted and number of participants experiencing at least one pulmonary exacerbation)

As treatment effects were found to vary over time, NMAs were conducted separately for short (4–10 weeks) and long (>10 weeks) of treatment.

FEV₁ % Predicted

Nine studies of 7 treatments tested in 1346 participants were included in the review. Due to very high unexplained heterogeneity between studies, it was felt that the studies should not be meta-analysed. Therefore the studies have been evaluated individually, and are reported without pooled effects (section 9.4.3.4).

Number of patients experiencing at least one pulmonary exacerbation – Short-term treatment (4–10 weeks)

Three studies of 354 participants were included in the network of 4 interventions (placebo, aztreonam lysine (nebulised), tobramycin (nebulised), tobramycin plus fosfomycin (nebulised)) (Figure 6). The evidence for this analysis was of low quality. For all three studies the risk of bias was unclear.

Table 108 presents the results of the conventional pair-wise meta-analyses (head to head comparisons) (upper-right section of table), together with the results computed by the NMA for every possible treatment comparison (lower-left section of table). Both results are presented as odds ratios (95% CrI). These results were derived from a fixed effects model (see Appendix N – Model Fit).

There was considerable uncertainty throughout the network. Aztreonam lysine was found to be significantly more effective than placebo and tobramycin (nebulised) at reducing the odds of experiencing at least one exacerbation. No other significant effects were found. Inconsistency could not be assessed as there were no closed loops of treatments.

In this analysis, aztreonam lysine was found to have the highest probability (88.30%) of being the best treatment to reduce the odds of experiencing at least one exacerbation, followed by tobramycin plus fosfomycin (nebulised) (10.00%) (Table 109).

Number of patients experiencing at least one pulmonary exacerbation – Long-term treatment (>10 weeks)

Six studies of 1,749 participants were included in the network of 6 interventions (placebo, aztreonam lysine (nebulised), tobramycin (nebulised), no treatment, tobramycin (powder), 28 days aztreonam lysine (nebulised) alternating with 28 days tobramycin (nebulised) (Figure 7) The evidence for this analysis was of moderate quality. Two studies were at high risk of bias and for the other 4 studies the risk of bias was unclear.

Table 111 presents the results of the conventional pair-wise meta-analyses (head to head comparisons) (upper-right section of table), together with the results computed by the NMA for every possible treatment comparison (lower-left section of table). Both results are presented as odds ratios (95% CrI). These results were derived from a fixed effects model (see Appendix G – Model Fit).

Inconsistency could not be assessed as there were no closed loops of treatments.

In this analysis, aztreonam lysine was found to have the highest probability (85.01%) of being the best treatment to reduce the odds of experiencing at least one exacerbation, followed by the combination treatment (14.83%) (Table 112).

9.4.3.4. Clinical evidence profile for non-NMA outcomes

The summary clinical evidence profiles for this review question are presented in Table 114 to Table 123.

9.4.3.4.1. S Aureus

No relevant studies were identified.

9.4.3.4.2. B cepacia complex

No relevant studies were identified.

9.4.3.4.3. A fumigatus

The clinical evidence profile for the antimicrobial treatment of chronic infection with A fumigatus is presented in Table 65.

9.4.3.5. Economic evidence

Four economic evaluations of antimicrobial agents to suppress chronic infection with P aeruginosa were identified in the literature search conducted for this guideline. The methods and results of those studies are described in Appendix K. Full details of the search and economic article selection flow chart can be found in Appendix E and F, respectively. Data extraction tables and quality assessments of included studies can be found in Appendix L and M, respectively.

This area was prioritised for de novo economic modelling; consequently, a cost-utility model was developed. Due to study heterogeneity, it was considered inappropriate to undertake one reliable, fully incremental analysis; hence, 4 comparisons within the model were developed. The model uses a lifetime horizon based on the assumption that antimicrobials to supress P aeruginosa are given on a long-term basis.

The model takes the form of a state transition model to estimate transitions between 3 lung function (FEV₁% predicted) strata. Transition probabilities between the 3 FEV₁% strata and the probability of experiencing an exacerbation each cycle were taken from the clinical evidence review. A post lung transplant health state was also included in the model to reflect the clinical pathway.

A series of scenario analyses were undertaken in order to test how sensitive the results were to uncertainty in individual parameters. The methods used to construct the model and the results of all analyses are reported in Appendix K.

Manufacturers of antimicrobials included in the model have agreed Patient Access Schemes (PAS) with the Department of Health to reduce the cost of their drug, to subsequently increase cost-effectiveness. To account for these discounts on the drug acquisition cost, there is an option in the model to apply them. For completeness, the committee applied those discounts in the model, to reassess their cost-effectiveness. Table 125 below provides the base case result using list prices and PAS prices over a lifetime horizon.

9.4.3.6. Evidence statements

9.4.3.6.1. Antimicrobial regimens for the treatment of chronic P Aeruginosa

Aztreonam lysine

Comparison 1: Aztreonam lysine versus placebo

Lung function: FEV₁

Moderate quality evidence from 1 RCT with 157 people with cystic fibrosis and chronic P aeruginosa infection ≥ 6 years showed a clinically significant improvement in lung function (measured as relative change in FEV₁% predicted) in the group of participants receiving Aztreonam lysine (75 mg/day) compared to those in the placebo group at 28 days follow-up.

Number of people with exacerbations

NMA outcome

Time to next exacerbation

No evidence was found for this critical outcome.

Suppression of the organism

High quality evidence from two RCTs with 321 people with cystic fibrosis and chronic P aeruginosa infection ≥ 6 years showed no clinically significant difference in the suppression of P aeruginosa (measured as change in sputum density log 10 CFU/G) between the participants who were receiving Aztreonam lysine (75 mg/day) and those who were receiving placebo at 4 week follow-up.

Nutritional status: weight

High quality evidence from one RCT with 164 people with cystic fibrosis and chronic P aeruginosa infection ≥ 6 years showed difference clinically significant improvement in the nutritional status (measured as % weight change in kg) between the participants who were receiving Aztreonam lysine (75 mg/day) compared to those who were receiving placebo at 4 week follow-up.

Quality of life

Very low to high quality evidence from two RCTs with 321 people with cystic fibrosis and chronic P aeruginosa infection ≥ 6 years showed a clinically significant beneficial effect of Aztreonam lysine (75 mg/day) in the following domains of quality of life: eating and vitality (measured with the CFQ-R questionnaire) compared to placebo, at 4 week follow-up. However, very low to moderate quality evidence from the same trials showed no clinically difference in the following domains of quality of life: body image, digestion, eating, emotional functioning, physical functioning, respiratory symptoms, role/school, social functioning, treatment burden and weight ((measured with the CFQ-R questionnaire) between both groups.

Moderate to high unexplained heterogeneity was found for the following domains: eating, emotional functioning, health perceptions, physical functioning, respiratory symptoms, role or school, treatment burden and vitality.

Mild adverse events

Low quality evidence from 1 RCT with 164 people with cystic fibrosis and chronic P aeruginosa infection ≥ 6 years showed no clinically significant difference in the occurrence of chest discomfort between the participants who were receiving Aztreonam lysine (75 mg/day) and those who were receiving placebo at 4 week follow-up.

Low quality evidence from 3 RCTs with 532 people with cystic fibrosis and chronic P aeruginosa infection ≥ 6 years showed no clinically significant difference in the occurrence of cough between the participants who were receiving Aztreonam lysine (75 mg/day) and those who were receiving placebo at 4 week follow-up.

Very low quality evidence from 2 RCTs with 321 people with cystic fibrosis and chronic P aeruginosa infection ≥ 6 years showed no clinically significant difference in the occurrence of headache between the participants who were receiving Aztreonam lysine (75 mg/day) and those who were receiving placebo at 4 week follow-up. Significant unexplained heterogeneity was found between both trials, although both showed no clinically significant differences between both treatment groups.

Serious adverse events

Low quality evidence from 1 RCT with 164 people with cystic fibrosis and chronic P aeruginosa infection ≥ 6 years showed no clinically significant difference in the occurrence of dyspnoea between the participants who were receiving Aztreonam lysine (75 mg/day) and those who were receiving placebo at 4 week follow-up.

Low quality evidence from 2 RCTs with 375 people with cystic fibrosis and chronic P aeruginosa infection ≥ 6 years showed no clinically significant difference in the occurrence of haemoptysis between the participants who were receiving Aztreonam lysine (75 mg/day) and those who were receiving placebo at 4 week follow-up.

Mortality

High quality evidence from 1 RCT with 211 people with cystic fibrosis and chronic P aeruginosa infection > 7 years showed that there were no deaths in either group (Aztreonam lysine 75 mg/day or placebo) at 4 week follow-up.

Emergence of resistant organisms

Low to moderate quality evidence from 1 RCT with 155 people with cystic fibrosis and chronic P aeruginosa infection ≥ 6 years showed no clinically significant difference in the number of people in whom S aureus, S maltophilia or A xylosoxidans was persistently isolated between the participants who were receiving Aztreonam lysine (75 mg/day) and those who were receiving placebo at 42 day follow-up.

High quality evidence from 1 RCT with 155 people with cystic fibrosis and chronic P aeruginosa infection ≥ 6 years showed that B Cepacia was not isolated in the participants of either group (Aztreonam lysine 75 mg/day or placebo) at 42 days follow-up.

9.4.3.6.2. Azithromycin (high-dose only)

No evidence was found for this treatment.

9.4.3.6.3. Ciprofloxacin (oral)

Comparison 2: Ciprofloxacin versus placebo

Lung function

No evidence was found for this critical outcome.

Number of people with exacerbations

NMA outcome.

Time to next exacerbation

No evidence was found for this critical outcome.

Suppression of the organism

No evidence was found for this important outcome.

Nutritional status: weight

Very low quality evidence from 1 RCT with 40 adults with cystic fibrosis and chronic P aeruginosa infection showed no clinically significant difference in weight (kg) between the participants who were receiving Ciprofloxacin (500 mg. for 10 days/every 3 months) and those who were receiving placebo at 12 months follow-up.

Quality of life

No evidence was found for this important outcome.

Mild adverse events

Very low quality evidence from 1 RCT with 40 adults with cystic fibrosis and chronic P aeruginosa infection showed no clinically significant difference in the occurrence of gastrointestinal adverse events between the participants who were receiving Ciprofloxacin (500 mg. for 10 days/every 3 months) and those who were receiving placebo at 12 months follow-up.

Serious adverse events

No evidence was found for this important outcome.

Mortality

Low quality evidence from 1 RCT with 40 adults with cystic fibrosis and chronic P aeruginosa infection showed no clinically significant difference in the mortality rate between the participants who were receiving Ciprofloxacin (500 mg. for 10 days/every 3 months) and those who were receiving placebo at 12 months follow-up.

Emergence of resistant organisms

Very low quality evidence from 1 RCT with 40 adults with cystic fibrosis and chronic P aeruginosa infection showed no clinically significant difference in the number of people in whom resistant strains of P aeruginosa were isolated between the participants who were receiving Ciprofloxacin (500 mg. for 10 days/every 3 months) and those who were receiving placebo at 12 months follow-up.

Very low quality evidence from 1 RCT with 40 adults with cystic fibrosis and chronic P aeruginosa infection showed no clinically significant difference in the number of people in whom resistant strains of S aureus were isolated between the participants who were receiving Ciprofloxacin (500 mg. for 10 days/every 3 months) and those who were receiving placebo at 12 months follow-up.

9.4.3.6.4. Colistimethate sodium (dry powder, inhaled)

Comparison 3.1: Colistin versus placebo

Lung function: FEV₁

Low quality evidence from 1 RTC with 29 people with cystic fibrosis and chronic P aeruginosa infection >7 years showed no clinically significant difference in lung function (measure as change in FEV₁ % predicted) between the participants receiving colistin (1 million units, twice daily for 3 months) and those receiving placebo at 3 months follow-up.

Number of people with exacerbations

NMA outcome

Time to next exacerbation

No evidence was found for this critical outcome.

Suppression of the organism

Moderate quality evidence from 1 RCT with 40 people with cystic fibrosis and chronic P aeruginosa infection >7 years showed that P aeruginosa was not eradicated of the sputum of any patient (Colistin solution 1 million units, twice daily for 3 months or placebo) during the 3 month trial.

Nutritional status

No evidence was found for this important outcome.

Quality of life

No evidence was found for this important outcome.

Mild adverse events

No evidence was found for this important outcome.

Serious adverse events

No evidence was found for this important outcome.

Mortality

No evidence was found for this important outcome.

Emergence of resistant organisms

Moderate quality evidence from 1 RCT with 40 people with cystic fibrosis and chronic P aeruginosa infection >7 years reported that none of the patients in either group (Colistin solution 1 million units, twice daily for 3 months or placebo) were infected with other colistin-resistant microorganisms (Ps. Cepacia, Serratia marcesens, Preteus mirabilis, Gram-positive organisms or fungi) during the 3 month trial.

Moderate quality evidence from 1 RCT with 40 people with cystic fibrosis and chronic P aeruginosa infection >7 years reported that resistance to colistin was not developed in any patient (Colistin solution 1 million units, twice daily for 3 months or placebo) during the 3 month trial.

Moderate quality evidence from 1 RCT with 40 people with cystic fibrosis and chronic P aeruginosa infection >7 years reported no change in resistant pattern to other commonly used anti-pseudomonas treatments in any patient (Colistin solution 1 million units, twice daily for 3 months or placebo) during the 3 month trial.

Comparison 3.2: Colistin DPI versus colistin nebulised

Lung function: FEV₁

Very low quality evidence from 1 RCT with 31 people with cystic fibrosis and chronic P aeruginosa infection ≥8 years showed no clinically significant difference in lung function (measured as % mean change in FEV₁ % predicted) between the participants who were receiving Colistin DPI (125 mg/twice daily) and those receiving Colistin inhalation solution (2 MU/twice daily) at 4 week follow-up.

Number of people with exacerbations

NMA outcome

Time to next exacerbation

No evidence was found for this critical outcome.

Suppression of the organism

No evidence was found for this important outcome.

Nutritional status

No evidence was found for this important outcome.

Quality of life

No evidence was found for this important outcome.

Mild adverse events

Very low quality evidence from 1 RCT with 31 people with cystic fibrosis and chronic P aeruginosa infection ≥8 years showed no clinically significant difference in the occurrence of chest discomfort, cough and vomiting between the participants who were receiving Colistin DPI (125 mg/twice daily) and those receiving Colistin inhalation solution (2 MU/twice daily) at 8 week follow-up.

Serious adverse events

Very low quality evidence from 1 RCT with 31 people with cystic fibrosis and chronic P aeruginosa infection ≥8 years showed no clinically significant difference in the occurrence of dyspnoea between the participants who were receiving Colistin DPI (125 mg/twice daily) and those receiving Colistin inhalation solution (2 MU/twice daily) at 8 week follow-up.

Mortality

No evidence was found for this important outcome.

Emergence of resistant organisms

No evidence was found for this important outcome.

Comparison 3.3: Colistin versus Tobramycin

Lung function: FEV₁

Very low quality evidence from 1 RCT with 109 people with cystic fibrosis and chronic P aeruginosa infection > 7 years showed no clinically significant difference in lung function (measured as mean % change in FEV₁ % predicted) between the participants receiving Colistin (COLI neb 1MU/3 ml. twice daily) and those who were receiving Tobramycin (TOBI neb 300 mg/5ml twice daily) at 1 to 3 months follow-up.

Low quality evidence from 1 RCT with 374 people with cystic fibrosis and chronic P aeruginosa infection ≥ 6 years showed no clinically significant difference in lung function (measured as mean % change in FEV₁ % predicted) between the participants receiving Colistin (COLI DPI 120 mg. twice daily) and those who were receiving Tobramycin (TOBI neb 300 mg/5ml twice daily) at 4 and 12 week follow-up.

Low quality evidence from 2 RCTs with 658 people with cystic fibrosis and chronic P aeruginosa infection ≥ 6 years showed no clinically significant difference in lung function (measured as mean % change in FEV₁ % predicted) between the participants receiving Colistin and those who were receiving Tobramycin (COLI neb 1MU/3 ml. twice daily versus TOBI neb 300 mg/5ml twice daily and COLI DPI 120 mg. twice daily versus TOBI neb 300 mg/5ml twice daily) at 24 week follow-up.

Number of people with exacerbations

NMA outcome

Time to next exacerbation

Very low quality evidence from 1 RCT with 374 people with cystic fibrosis and chronic P aeruginosa infection ≥ 6 years showed no clinically significant difference in the time to next pulmonary exacerbation (measured as mean time to first additional anti-pseudomonal treatment) between the participants receiving Colistin (COLI DPI 120 mg. twice daily) and those who were receiving Tobramycin (TOBI neb 300 mg/5ml twice daily) during the 24 weeks duration of the trial.

Suppression of the organism

Low quality evidence from 1 RCT with 79 people with cystic fibrosis and chronic P aeruginosa infection > 7 years showed no clinically significant difference in the suppression of P aeruginosa (measured as change in sputum PA density log10 CFU/ml) between the participants receiving Colistin (COLI neb 1MU/3 ml. twice daily) and those who were receiving Tobramycin (TOBI neb 300 mg/5ml twice daily) at 4 week follow-up.

Nutritional status

Low quality evidence from 1 RCT with 374 people with cystic fibrosis and chronic P aeruginosa infection ≥ 6 years showed no clinically significant difference in the BMI change between the participants receiving Colistin (COLI DPI 120 mg. twice daily) and those who were receiving Tobramycin (TOBI neb 300 mg/5ml twice daily) at 24 week follow-up.

Quality of life

Moderate quality evidence from 1 RCT with 374 people with cystic fibrosis and chronic P aeruginosa infection ≥ 6 years showed no difference in change in quality of life (measured with the individual domains of the CFQ-R questionnaire) between the participants receiving Colistin (COLI DPI 120 mg. twice daily) and those who were receiving Tobramycin (TOBI neb 300 mg/5ml twice daily) at 24 week follow-up. The uncertainty for this outcome could not be calculated.

Mild adverse events

Very low quality evidence from 1 RCT with 115 people with cystic fibrosis and chronic P aeruginosa infection >7 years showed no clinically significant difference in the occurrence of sputum changes, pharyngitis or cough between the participants receiving Colistin (COLI neb 1MU/3 ml. twice daily) and those who were receiving Tobramycin (TOBI neb 300 mg/5ml twice daily) at 4 week follow-up.

Very low quality evidence from 1 RCT with 374 people with cystic fibrosis and chronic P aeruginosa infection ≥ 6 years showed no clinically significant difference in the occurrence of productive cough, chest discomfort or vomiting between the participants receiving Colistin (COLI DPI 120 mg. twice daily) and those who were receiving Tobramycin (TOBI neb 300 mg/5ml twice daily) at 24 week follow-up.

Serious adverse events

Very low quality evidence from 1 RCT with 115 people with cystic fibrosis and chronic P aeruginosa infection >7 years showed no clinically significant difference in the number of participants who experienced more than 1 serious adverse event between the participants receiving Colistin (COLI neb 1MU/3 ml. twice daily) and those who were receiving Tobramycin (TOBI neb 300 mg/5ml twice daily) at 4 week follow-up.

Very low quality evidence from 1 RCT with 115 people with cystic fibrosis and chronic P aeruginosa infection >7 years showed no clinically significant difference in the occurrence of dyspnoea between the participants receiving Colistin (COLI neb 1MU/3 ml. twice daily) and those who were receiving Tobramycin (TOBI neb 300 mg/5ml twice daily) at 4 week follow-up.

Moderate evidence from 1 RCT with 374 people with cystic fibrosis and chronic P aeruginosa infection ≥ 6 years showed a clinically significant higher number of people withdrawn from the study due to a serious adverse effect in the group of participants receiving Colistin (COLI DPI 120 mg. twice daily) compared to those who were receiving Tobramycin (TOBI neb 300 mg/5ml twice daily) at 24 week follow-up.

Very quality evidence from 1 RCT with 374 people with cystic fibrosis and chronic P aeruginosa infection ≥ 6 years showed no clinically significant difference in the occurrence of dyspnoea or haemoptysis between the participants receiving Colistin (COLI DPI 120 mg. twice daily) and those who were receiving Tobramycin (TOBI neb 300 mg/5ml twice daily) at 24 week follow-up.

Mortality

No evidence was found for this outcome.

Emergence of resistant organisms

Low quality evidence from 1 RCT with 115 people with cystic fibrosis and chronic P aeruginosa infection >7 years reported that none of the patients in either treatment group (COLI neb 1MU/3 ml. twice daily and TOBI neb 300 mg/5ml twice daily) developed highly tobramycin-resistant P aeruginosa at 24 week follow-up.

9.4.3.7. Fosfomycin (inhaled)

No evidence was found for this treatment.

9.4.3.8. Tobramycin (dry powder, inhaled)

Comparison 4.1: Tobramycin versus placebo

Lung function: FEV₁

Low quality evidence from 4 RCTs with 516 children, young people and adults with cystic fibrosis and chronic P aeruginosa infection showed a clinically significant improvement in lung function (measured as mean % change in FEV₁ % predicted) in the group of participants who were receiving tobramycin (TOBI DPI 112 mg daily, TOBI nebulised 300 mg or 600 mg daily) compared to those who were receiving placebo at 1 to 3 months follow-up. Moderate heterogeneity was found between the trials. Three trials showed a clinically significant improvement in the tobramycin group, whereas 1 trial showed no differences.

Number of people with exacerbations

NMA outcome

Time to next exacerbation

No evidence was found for this outcome.

Suppression of the organism

High quality evidence from 3 RCTs with 357 people with cystic fibrosis and chronic P aeruginosa infection ≥ 6 years showed a clinically significant higher number of people in whom P aeruginosa was eradicated (measured as negative culture) in the group of participants receiving Tobramycin (TOBI neb 300 mg or TOBI DPI 112 mg daily) compared to those who were receiving placebo at 4 week follow-up. Low heterogeneity was observed between the 3 trials, but all of them were consistent in showing a beneficial effect of tobramycin compared to placebo.

High quality evidence from 1 RCT with 242 people with cystic fibrosis and chronic P aeruginosa infection ≥ 6 years showed a clinically significant higher number of people in whom P aeruginosa was eradicated (measured as negative culture) in the group of participants receiving Tobramycin (TOBI neb 300 mg daily) compared to those who were receiving placebo at 20 week follow-up. However, moderate quality evidence from the same trial showed no clinically significant difference in the eradication of P aeruginosa 8, and 24 week follow-ups.

Moderate quality evidence from 1 RCT with 59 people with cystic fibrosis and chronic P aeruginosa infection ≥ 6 years showed no clinically significant difference in the eradication of P aeruginosa (measured as negative culture) between the participants receiving Tobramycin (TOBI neb 300 mg daily) and those who were receiving placebo at 6 week follow-up.

Moderate quality evidence from 1 RCT with 55 people with cystic fibrosis and chronic P aeruginosa infection ≥ 6 years showed a clinically significant decrease in P aeruginosa sputum density (log10 CFU/ml) in the group of participants receiving Tobramycin (TOBI DPI 112 mg daily) compared to those who were receiving placebo at 4 week follow-up.

Likewise, low quality evidence from another RCT with 95 people with cystic fibrosis and chronic P aeruginosa infection > 6 years showed a clinically significant decrease in P aeruginosa mucoid and non-mucoid sputum density (log10 CFU/ml) in the group of participants receiving tobramycin (TOBI DPI 112 mg) compared to those who were receiving placebo at 4 week follow-up.

Nutritional status: weight

High quality evidence from 1 RCT with 59 people with cystic fibrosis and chronic P aeruginosa infection ≥ 6 years showed no clinically significant difference in weight (kg) between the participants receiving Tobramycin (TOBI neb 300 mg daily) and those who were receiving placebo at 12 week follow-up.

Likewise, moderate quality evidence from another RCT with 245 people with cystic fibrosis and chronic P aeruginosa infection ≥ 6 years showed no clinically significant difference in weight (kg) between the participants receiving Tobramycin (TOBI neb 300 mg daily) and those who were receiving placebo at 24 week follow-up.

Quality of life

No evidence was found for this outcome.

Mild adverse events

Very low quality evidence from 2 RCTs with 150 people with cystic fibrosis and chronic P aeruginosa infection ≥ 6 years showed a clinically significant lower occurrence of mild adverse events in the group of participants receiving Tobramycin (TOBI DPI 112 mg daily) compared to those who were receiving placebo at 4 week follow-up.

However, low quality evidence from 1 RCT with 245 people with cystic fibrosis and chronic P aeruginosa infection ≥ 6 years showed no clinically significant difference in the occurrence of minor adverse events between the participants receiving Tobramycin (TOBI neb 300 mg daily) and those who were receiving placebo at 24 week follow-up.

Low quality evidence from 1 RCT with 55 people with cystic fibrosis and chronic P aeruginosa infection ≥ 6 years showed no clinically significant difference in the occurrence of auditory impairment between the participants receiving tobramycin (TOBI DPI 112 mg) and those who were receiving placebo at 4 week follow-up. In addition,

Moreover, high quality evidence from 1 RCT with 300 people with cystic fibrosis and chronic P aeruginosa infection ≥ 6 years showed no cases of auditory impairment in either group (TOBI neb 300 mg daily or placebo) at 24 week follow-up. No cases were identified either at 42 week follow-up (n=71).

Moderate quality evidence from 1 RCT with 520 people with cystic fibrosis and chronic P aeruginosa infection ≥ 6 years showed a clinically significant higher occurrence of tinnitus in the group of participants receiving Tobramycin (TOBI neb 300 mg daily) compared to those who were receiving placebo at 24 week follow-up.

Very low quality evidence from 2 RCTs with 150 people with cystic fibrosis and chronic P aeruginosa infection ≥ 6 years showed no clinically significant difference in the occurrence of cough between the participants receiving tobramycin (TOBI DPI 112 mg) and those who were receiving placebo at 4 week follow-up. High unexplained heterogeneity was found between both trials, although both of them showed no clinically significant differences between both groups.

Moderate quality evidence from 1 RCT with 300 people with cystic fibrosis and chronic P aeruginosa infection ≥ 6 years no clinically significant difference in the occurrence of tinnitus between the participants receiving tobramycin (TOBI neb 300 mg daily) and those who were receiving placebo 24 week follow-up.

Very low quality evidence from 1 RCT with 95 people with cystic fibrosis and chronic P aeruginosa infection ≥ 6 years showed no clinically significant difference in the occurrence of headaches between the participants receiving tobramycin (TOBI DPI 112 mg) and those who were receiving placebo 4 week follow-up.

Very low quality evidence from 2 RCTs with 150 people with cystic fibrosis and chronic P aeruginosa infection ≥ 6 years showed no clinically significant difference in the occurrence of serious adverse events between the participants receiving tobramycin (TOBI DPI 112 mg) and those who were receiving placebo at 4 week follow-up.

However, high quality evidence from 1 RCT with 246 people with cystic fibrosis and chronic P aeruginosa infection ≥ 6 years showed a clinically significant lower occurrence of serious adverse events in the group of participants receiving Tobramycin (TOBI neb 300 mg daily) compared to those who were receiving placebo at 24 week follow-up.

Very low quality evidence from 1 RCT with 95 people with cystic fibrosis and chronic P aeruginosa infection ≥ 6 years showed no clinically significant difference in the occurrence of haemoptysis between the participants receiving tobramycin (TOBI DPI 112 mg) and those who were receiving placebo 4 week follow-up.

Likewise, moderate quality evidence from one RCT with 520 people with cystic fibrosis and chronic P aeruginosa infection ≥ 6 years showed no clinically significant difference in the occurrence haemoptysis between the participants receiving Tobramycin (TOBI neb 300 mg daily) and those who were receiving placebo at 24 week follow-up.

Low quality evidence from 1 RCT with 520 people with cystic fibrosis and chronic P aeruginosa infection ≥ 6 years showed no clinically significant difference in the occurrence pneumothorax between the participants receiving Tobramycin (TOBI neb 300 mg daily) and those who were receiving placebo at 24 week follow-up.

Mortality

Low quality evidence from 1 RCT with 95 people with cystic fibrosis and chronic P aeruginosa infection ≥ 6 years showed no clinically significant difference in mortality between the participants receiving tobramycin (TOBI DPI 112 mg) and those who were receiving placebo 4 week follow-up.

Likewise, moderate quality evidence from two RTCs with 839 people with cystic fibrosis and chronic P aeruginosa infection ≥ 6 years showed no clinically significant difference in the mortality rate between the participants receiving Tobramycin (TOBI neb 300 mg daily) and those who were receiving placebo at 24 week follow-up.

Emergence of resistant organisms

Very low quality evidence from 2 RCTs with 672 people with cystic fibrosis and chronic P aeruginosa infection ≥ 6 years showed no clinically significant difference in the number of participants in whom tobramycin–resistant P aeruginosa was isolated between the group of participants receiving Tobramycin (TOBI neb 300 mg daily) and those who were receiving placebo at 24 week follow-up. Significant unexplained heterogeneity was found between both trials, with 1 of them showing a clinically significant harmful effect of tobramycin, and the other trial showing no differences between both groups.

High quality evidence from 1 RCT with 520 people with cystic fibrosis and chronic P aeruginosa infection ≥ 6 years showed that drug-resistant B Cepacia was not isolated in the participants of either group (TOBI neb 300 mg daily or placebo) at 24 week follow-up

Low quality evidence from 1 RCT with 520 people with cystic fibrosis and chronic P aeruginosa infection ≥ 6 years showed that drug-resistant B Cepacia was not isolated in the participants of either group (TOBI neb 300 mg daily or placebo) at 24 week follow-up

Low quality evidence from 1 RCT with 520 people with cystic fibrosis and chronic P aeruginosa infection ≥ 6 years showed no clinically significant difference in the frequency of new isolates of drug-resistant A xylosoxidans between the participants who were receiving Tobramycin (TOBI neb 300 mg daily) and those who were receiving placebo at 24 week follow-up.

High quality evidence from 1 RCT with 389 people with cystic fibrosis and chronic P aeruginosa infection ≥ 6 years showed a clinically significant lower number of patients in whom new isolates of drug–resistant Aspergillus was isolated in the group of participants receiving Tobramycin (TOBI neb 300 mg daily) compared to those who were receiving placebo at 24 week follow-up.

Comparison 4.2: Tobramycin DPI versus tobramycin nebulised

Lung function: FEV₁

Low quality evidence from 1 RCT with 517 people with cystic fibrosis and chronic P aeruginosa infection ≥6 years showed no clinically significant difference in lung function (measured as % mean change in FEV₁% predicted) between the participants receiving tobramycin DPI (112 mg/twice daily) and those receiving tobramycin inhalation solution (300 mg/5ml twice daily) at 4, 20 and 24 week follow-up.

Number of people with exacerbations

NMA outcome

Time to next exacerbation

No evidence was found for this critical outcome.

Suppression of the organism

Low to moderate quality evidence from 1 RCT with 517 people with cystic fibrosis and chronic P aeruginosa infection ≥6 years showed no clinically significant difference in change in sputum density (measured as log10 CFU) in the group of participants receiving tobramycin DPI (112 mg/twice daily) compared with those receiving tobramycin inhalation solution (300 mg/5ml twice daily) at 4 and at 20 week follow-up.

Nutritional status

No evidence was found for this important outcome.

Quality of life

No evidence was found for this important outcome.

Mild adverse events

Moderate quality evidence from 1 RCT with 517 people with cystic fibrosis and chronic P aeruginosa infection ≥6 years showed no clinically significant difference in the occurrence of mild adverse events (any) between the participants receiving tobramycin DPI (112 mg/twice daily) and those receiving tobramycin inhalation solution (300 mg/5ml twice daily) at 24 week follow-up.

Very low quality evidence from 1 RCT with 517 people with cystic fibrosis and chronic P aeruginosa infection ≥6 years showed no clinically significant difference in the occurrence of productive cough, headache or vomiting between the participants receiving tobramycin DPI (112 mg/twice daily) and those receiving tobramycin inhalation solution (300 mg/5ml twice daily) at 24 week follow-up.

Serious adverse events

Low quality evidence from 1 RCT with 517 people with cystic fibrosis and chronic P aeruginosa infection ≥6 years no clinically significant difference in the occurrence of serious adverse events (any) in the group of participants receiving tobramycin DPI (112 mg/twice daily) compared with those receiving tobramycin inhalation solution (300 mg/5ml twice daily) at 24 week follow-up.

Very low quality evidence from 1 RCT with 517 people with cystic fibrosis and chronic P aeruginosa infection ≥6 years showed no clinically significant difference in the occurrence of dyspnoea and haemoptysis between the participants receiving tobramycin DPI (112 mg/twice daily) and those receiving tobramycin inhalation solution (300 mg/5ml twice daily) at 24 week follow-up.

Mortality

No evidence was found for this important outcome.

Emergence of resistant organisms

No evidence was found for this important outcome.

Comparison 4.3: Tobramycin versus Aztreonam lysine

Lung function: FEV₁

Moderate quality evidence from 1 RCT with 268 people with cystic fibrosis and chronic P aeruginosa infection ≥ 6 years showed no clinically significant difference in lung function (measured as % change in FEV₁ % predicted) between the group of patients receiving tobramycin inhalation solution (300 mg/twice daily) and the patients receiving aztreonam lysine (75g/3-times daily) at 3 months follow-up.

Number of people with exacerbations

NMA outcome

Time to next exacerbation

No evidence was found for this critical outcome.

Suppression of the organism

Low quality evidence from 1 RCT with 194 people with cystic fibrosis and chronic P aeruginosa infection ≥6 years showed no clinically significant difference in the change of sputum density (measured as log10 CFU) between the group of patients receiving Tobramycin inhalation solution (300 mg/twice daily) and the patients receiving Aztreonam lysine (75g/3-times daily) at 20 week follow-up.

Nutritional status: weight

Low quality evidence from 1 RCT with 268 people with cystic fibrosis and chronic P aeruginosa infection ≥6 years showed no clinically significant difference in the percentage of weight change (kg) between the group of patients receiving Tobramycin inhalation solution (300 mg/twice daily) and the patients receiving Aztreonam lysine (75g/3-times daily) at 24 week follow-up.

Quality of life

Low quality evidence from 1 RCT with 261 people with cystic fibrosis and chronic P aeruginosa infection ≥ 6 years showed a clinically significant decrease in quality of life (measured as change from baseline in the CFQ-R questionnaire respiratory domain) in the group of participants receiving tobramycin inhalation solution (300 mg/twice daily) compared to those receiving Aztreonam lysine (75g/3-times daily) at 20 week follow-up.

Mild adverse events

Very low to low quality evidence with 268 people with cystic fibrosis and chronic P aeruginosa infection ≥ 6 years showed no clinically significant difference in the occurrence of chest discomfort, cough, headache and vomiting between the group of patients receiving Tobramycin inhalation solution (300 mg/twice daily) and the patients receiving Aztreonam lysine (75g/3-times daily) at 3 months follow-up.

Serious adverse events

Low quality evidence with 268 people with cystic fibrosis and chronic P aeruginosa infection ≥6 years showed no clinically significant difference in the occurrence of dyspnoea and haemoptysis between the group of patients receiving Tobramycin inhalation solution (300 mg/twice daily) and the patients receiving Aztreonam lysine (75g/3-times daily) at 3 months follow-up.

Mortality

No evidence was found for this outcome.

Emergence of resistant organisms

No evidence was found for this outcome.

Comparison 5. Combination of fosfomycin + tobramycin versus placebo

Lung function: FEV₁

Moderate quality evidence from 1 RCT with 70 adults with cystic fibrosis and chronic P aeruginosa infection showed a clinically significant improvement in lung function (measured as relative change in FEV₁ % predicted) in the group of participants receiving combination of fosfomycin and tobramycin (80/20 mg) compared to those receiving placebo at 4 week follow-up.

Likewise, low quality evidence from the same trial (N=73) showed a clinically significant improvement in lung function (measured as relative change in FEV₁ % predicted) in the group of participants receiving combination of fosfomycin and tobramycin (160/40 mg) compared to those receiving placebo at 4 week follow-up.

Number of people with exacerbations

NMA outcome

Time to next exacerbation

No evidence was found for this critical outcome.

Suppression of the organism

Low quality evidence from 1 RCT with 70 adults with cystic fibrosis and chronic P aeruginosa infection showed a clinically significant decrease in sputum P aeruginosa density (log10 CFU/g) in the group of participants receiving combination of fosfomycin and tobramycin (80/20 mg) compared to those receiving placebo at 4 week follow-up.

However, low quality evidence from the same trial (N=73) showed no clinically significant difference between a combination of fosfomycin and tobramycin (160/40 mg) and placebo at 4 week follow-up.

Nutritional status

No evidence was found for this important outcome.

Quality of life

No evidence was found for this important outcome.

Mild adverse events

No evidence was found for this important outcome.

Serious adverse events

No evidence was found for this important outcome.

Mortality

No evidence was found for this important outcome.

Emergence of resistant organisms

No evidence was found for this important outcome.

Comparison 6. Continuous alternating therapy versus intermittent treatment: aztreonam lysine + tobramycin or placebo + tobramycin

Lung function: FEV₁

Moderate quality evidence from 1 RCT with 88 people with cystic fibrosis and chronic P aeruginosa infection ≥ 6 years showed no clinically significant difference in lung function (measure as % change in FEV₁ % predicted) between the participants receiving continuous alternating therapy (tobramycin inhalation solution 300 mg daily for 28 days, followed by aztreonam lysine) and those on an intermittent regimen (tobramycin inhalation solution 300 mg daily for 28 days, followed by placebo) at 20 week follow-up. Values at 4, 12 and 20 weeks were averaged.

Number of people with exacerbations

NMA outcome

Time to next exacerbation

Low quality evidence from 1 RCT with 88 people with cystic fibrosis and chronic P aeruginosa infection ≥ 6 years showed no clinically significant difference in time to next exacerbation between the participants receiving continuous alternating therapy (tobramycin inhalation solution 300 mg daily for 28 days, followed by aztreonam lysine) and those on an intermittent regimen (tobramycin inhalation solution 300 mg daily for 28 days, followed by placebo).

Suppression of the organism

No evidence was found for this important outcome.

Nutritional status

No evidence was found for this important outcome.

Quality of life

Low quality evidence from 1 RCT with 88 people with cystic fibrosis and chronic P aeruginosa infection ≥ 6 years showed no clinically significant difference in quality of life (measured with the CFQ-R questionnaire) between the participants receiving continuous alternating therapy (tobramycin inhalation solution 300 mg daily for 28 days, followed by aztreonam lysine) and those on an intermittent regimen (tobramycin inhalation solution 300 mg daily for 28 days, followed by placebo) at 20 week follow-up. Values at 4, 12 and 20 weeks were averaged.

Mild adverse events

Low quality evidence from 1 RCT with 88 people with cystic fibrosis and chronic P aeruginosa infection ≥ 6 years showed a clinically significant increase in the occurrence of cough in the group of participants receiving continuous alternating therapy (tobramycin inhalation solution 300 mg daily for 28 days, followed by aztreonam lysine) compared to those on an intermittent regimen (tobramycin inhalation solution 300 mg daily for 28 days, followed by placebo) at 3 months follow-up.

Serious adverse events

Low quality evidence from 1 RCT with 88 people with cystic fibrosis and chronic P aeruginosa infection ≥ 6 years showed no clinically significant difference in the occurrence of dyspnoea between the participants receiving continuous alternating therapy (tobramycin inhalation solution 300 mg daily for 28 days, followed by aztreonam) and those on an intermittent regimen (tobramycin inhalation solution 300 mg daily for 28 days, followed by placebo) at 3 months follow-up.

Very low quality evidence from 1 RCT with 88 people with cystic fibrosis and chronic P aeruginosa infection ≥ 6 years showed a clinically significant increase in the occurrence of serious adverse events (no treatment related) in the group of participants receiving continuous alternating therapy (tobramycin inhalation solution 300 mg daily for 28 days, followed by aztreonam lysine) compared to those on an intermittent regimen (tobramycin inhalation solution 300 mg daily for 28 days, followed by placebo) at 3 months follow-up.

Mortality

No evidence was found for this important outcome.

Emergence of resistant organisms

No evidence was found for this important outcome.

9.4.3.8.1. Antimicrobial regimens for the treatment of chronic S aureus

Cefradine (oral)

No evidence was found for this treatment.

Cotrimoxazole (oral)

No evidence was found for this treatment.

Doxycycline (oral)

No evidence was found for this treatment.

Flucloxacillin (oral)

No evidence was found for this treatment.

9.4.3.8.2. Antimicrobial regimens for the treatment of chronic B cepacia complex

Ceftazidime (inhaled)

No evidence was found for this treatment.

Cotrimoxazole (oral)

No evidence was found for this treatment.

Imipenem (oral)

No evidence was found for this treatment.

Meropenem (inhaled)

No evidence was found for this treatment.

Trimethoprim (oral)

No evidence was found for this treatment.

9.4.3.8.3. Antimicrobial regimens for the treatment of chronic A fumigatus

Amphotericin (inhaled)

No evidence was found for this treatment.

Itraconazole (oral)

Comparison 7: Itraconazole versus placebo

Lung function: FEV₁

Very low quality evidence from 1 RCT with 35 people with cystic fibrosis and chronically colonised with A fumigatus ≥ 6 years showed no clinically significant difference in lung function (measured as percentage change in FEV₁ predicted from baseline) between the participants who were receiving oral Itraconazole (5mg/kg once or twice daily) and those who were receiving placebo after 24 or 48 week follow-up.

Exacerbations

Very low quality evidence from 1 RCT with 35 people with cystic fibrosis and chronically colonised with A fumigatus ≥ 6 years showed no clinically significant difference in the time to next exacerbation between the participants who were receiving oral Itraconazole (5mg/kg once or twice daily) and those who were receiving placebo.

Very low quality evidence from 1 RCT with 35 people with cystic fibrosis and chronically colonised with A fumigatus ≥ 6 years showed no clinically significant difference in the number of patients requiring oral or IV antibiotics due to a pulmonary exacerbation between the participants who were receiving oral Itraconazole (5mg/kg once or twice daily) and those who were receiving placebo after 24 or 48 week follow-up.

Very low quality evidence from 1 RCT with 35 people with cystic fibrosis and chronically colonised with A fumigatus ≥ 6 years showed no clinically significant difference in the number of patients admitted to hospital due to a pulmonary exacerbation between the participants who were receiving oral Itraconazole (5mg/kg once or twice daily) and those who were receiving placebo after 24 or 48 week follow-ups.

Suppression of the organism

No evidence was found for this important outcome.

Nutritional status

No evidence was found for this important outcome.

Quality of life

Very low quality evidence from 1 RCT with 35 people with cystic fibrosis and chronically colonised with A fumigatus ≥ 6 years showed no differences in quality of life (measured as change in CFQ-R total score and respiratory domain) between the participants who were receiving oral Itraconazole (5mg/kg once or twice daily) and those who were receiving placebo after the 24-week treatment duration. The uncertainty around this outcome could not be calculated.

Mild adverse events

Very low evidence from one RCT with 35 people with cystic fibrosis and chronically colonised with A fumigatus ≥ 6 years showed no clinically significant difference in the occurrence of minor adverse events (including: increased dyspnoea, rash, hyperglycaemia, flu-like illness, diarrhoea and conjunctivitis) between the participants who were receiving oral Itraconazole (5mg/kg once or twice daily) and those who were receiving placebo during the 24-week treatment duration.

Serious adverse events

Very low quality evidence from one RCT with 35 people with cystic fibrosis and chronically colonised with A fumigatus ≥ 6 years showed no clinically significant difference in the occurrence of major adverse events (including: haemoptysis and spontaneous pneumothorax) between the participants who were receiving oral Itraconazole (5mg/kg once or twice daily) and those who were receiving placebo during the 24-week treatment duration.

Mortality

No evidence was found for this important outcome.

Emergence of resistant organisms

No evidence was found for this important outcome.

Posaconazole (oral)

No evidence was found for this treatment.

Voriconazole (oral)

No evidence was found for this treatment.

9.4.3.8.4. Economic evidence statements

One cost-benefit analysis (Iles 2003) on people with cystic fibrosis in the UK, compared 12 months before nebulised tobramycin use with 12 months during nebulised tobramycin use. They found that the introduction of nebulised tobramycin reduced the cost of hospital attendances and parenteral antibiotics, but did not offset the cost of nebulised tobramycin. This analysis is directly applicable given that the type of economic evaluation is unlikely to change the conclusions about cost-effectiveness and all other applicability criteria are met. The evidence is associated with serious limitations from the before and after type study used to inform the analysis.

One cost-utility analysis (Tappenden 2013) on people with cystic fibrosis in the UK, found that if colistimethate sodium dry powder is priced lower than that of nebulised tobramycin the ICER lies in the south-west quadrant of the cost-effectiveness plane reflecting a QALY loss and cost savings for colistimethate sodium dry powder compared with nebulised tobramycin. However, if colistimethate sodium dry powder is priced higher than that of nebulised tobramycin the incremental cost is positive, and colistimethate sodium dry powder is dominated by nebulised tobramycin. The lifetime horizon and ‘within-trial’ analysis resulted in smaller incremental differences in both costs and QALYs, but led to the same conclusions. This analysis is directly applicable with minor limitations.

One cost-utility analysis (Tappenden 2014) on people with cystic fibrosis in the UK, over a lifetime horizon, found that using list prices, nebulised tobramycin dominated colistimethate sound dry powder and tobramycin dry powder has an ICER of £123,563 compared to nebulised tobramycin. When the revised patient access scheme discount was applied to colistimethate sodium dry powder, nebulised tobramycin was more expensive and less effective with an ICER of £288,563. When the revised patient access scheme discount was applied to tobramycin dry powder, it dominated nebulised tobramycin. This analysis is directly applicable with minor limitations.

One cost-utility analysis (Schecter 2015) on people with cystic fibrosis in the US, found that aztreonam dominated nebulised tobramycin over a 3 year time horizon. This analysis is partially applicable, due to the US third party payer perspective taken. The evidence is associated with serious limitations, including the potential conflict of interest and lack of detail in their methods.

The economic model developed for this review, found that nebulised colistimethate sodium, nebulised tobramycin and tobramycin dry powder were not cost-effective compared to placebo in the base case (list prices). Tobramycin dry powder was also dominated (more expensive and less effective) by the treatments in this comparison.

The economic model developed for this review, found that nebulised tobramycin is not cost-effective compared to nebulised colistimethate sodium, in the base case (list prices), with an ICER of £602,472.

The economic model developed for this review, found that nebulised tobramycin dominated (more effective and less expensive) colistimethate sodium dry powder, in the base case (list prices).

The economic model developed for this review, found that nebulised aztreonam is not cost-effective compared to nebulised tobramycin, in the base case (list prices), with an ICER of £34,348. The combination treatment (28 days aztreonam lysine alternating with 28 days nebulised tobramycin) was also dominated (more expensive and less effective) by aztreonam lysine in this comparison.

9.4.3.9. Evidence to recommendations

9.4.3.9.1. Relative value placed on the outcomes considered

The aim of this review was to determine the clinical and cost-effectiveness of different antimicrobial treatment regimens to suppress chronic pulmonary infection in people with cystic fibrosis.

The committee identified lung function and time to next pulmonary exacerbation as critical outcomes for this evidence review. Where no evidence was found for time to next pulmonary exacerbation, number of people experiencing a pulmonary exacerbation and number of hospital admissions due to a pulmonary exacerbation were taken as proxy outcomes. Suppression of the organism, nutritional status, quality of life, adverse events and emergence of resistant organisms were rated as important outcomes.

9.4.3.9.2. Consideration of clinical benefits and harms

The committee discussed the recommendations for each pathogen separately.

Chronic P Aeruginosa

The committee discussed the results from the network meta-analysis. They noted that it was not possible to conduct network meta-analysis for the critical outcome FEV₁ due to high unexplained heterogeneity.

The results from the NMA suggested that Aztreonam lysine was more effective than placebo or tobramycin at reducing the odds of experiencing a pulmonary exacerbation. This result has to be treated with caution as there was considerable uncertainty in the network.

The committee also discussed the results from the review, conventional pair-wise meta-analysis. They first reviewed the evidence comparing treatments against placebo.

With regards to colistin, the evidence showed that inhaled colistin was no better than placebo with regards to lung function. The committee noted this evidence was of low quality and came from a small single trial. Moderate quality evidence showed that inhaled colistin was not associated with the emergence of resistant organisms when compared to placebo. They looked at the evidence comparing different routes of administration. Very low quality evidence from one trial showed no differences between colistin DPI and inhaled colistin in lung function and in the occurrence of adverse events.

The committee discussed the evidence comparing tobramycin and placebo. They noted tobramycin was associated with a clinically significant improvement in lung function at 1 to 3 months. However, moderate heterogeneity was found between trials therefore, they agreed this result should be interpreted with caution. With regards to suppressing the organisms, the evidence showed contradicting results. High quality evidence showed that tobramycin was better than placebo at suppressing the organism (measured as having a negative culture) at 4 and 20 week follow-ups. In addition, low to moderate quality evidence showed a clinically significant reduction in sputum density at 4 week follow-ups. However, moderate quality evidence showed no clinically significant difference in the eradication of P aeruginosa 6, 8, and 24 week follow-ups. The evidence regarding side effects was not conclusive either, but tobramycin was associated with an increased risk in the occurrence of mild adverse events including tinnitus. They looked at the evidence comparing different routes of administration. They noted there were no clinically significant differences between tobramycin DPI and inhaled tobramycin in lung function, change in sputum density or adverse events. The quality of the evidence range from very low to moderate.

With regards to ciprofloxacin, the committee noted there was no evidence for the critical outcome lung function. No differences were found in weight.

They noted there was moderate quality evidence showing that aztreonam lysine was better than placebo for lung function, weight and quality of life. In addition, no clinically significant differences were found in the occurrence of adverse events or in the emergence of resistant organisms.

The committee also reviewed the evidence comparing colistin and tobramycin. Very low to low quality evidence showed no clinically significant differences in lung function at 4, 12 and 24 weeks. Likewise, very low quality evidence showed no differences in time to next additional anti-pseudomonal treatment. With regards to the important outcomes, no clinically significant differences were found for suppression of the organism (measured as change in sputum density), weight, quality of life, adverse events and emergence of resistant organisms. The quality of the evidence ranged from very low to moderate.

The committee reviewed the evidence comparing tobramycin and aztreonam. Moderate quality evidence showed no clinically significant differences in lung function at 3 month follow-up. Low quality evidence showed no differences in change in sputum density or quality of life at 20 week follow-ups, and in weight at 24 weeks. Finally, no differences were found in the occurrence of adverse events at 3 months.

The committee noted the combination of fosfomycin and high low-dose tobramycin was found to be significantly better than placebo in lung function at 4 week follow-up. This evidence came from a single trial and was rated as of low to moderate quality. Low quality evidence from the same trial showed a clinically significant decrease in sputum density in the group receiving low-dose tobramycin, but this different was not clinically significant in the high-dose group.

Finally the committee discussed the compassion between continuous alternating therapy with tobramycin followed by aztreonam and intermittent treatment with tobramycin followed by placebo. The evidence showed no differences between both treatment regimens in lung function (moderate quality), time to next exacerbation (low quality) and quality of life (low quality) at 20 weeks. However, they noted the risk of adverse events was higher in the participants in the continuous alternating therapy group.

The committee noted no evidence was found for high-dose azithromycin and fosfomycin.

The findings of the clinical evidence were discussed in the light of the economic evidence. In addition, the committee discussed the current recommendations from the NICE TA report 276 (Tappenden 2013) that looked at colistin and tobramycin for the treatment of chronic P aeruginosa in people with cystic fibrosis over the age of 6 years.

As recommended in the NICE TA report 276 the committee agreed that colistin should be used as first-line treatment and can be given as dry powder for inhalation to those people who cannot tolerate it in its nebulised form. This recommendation is consistent with clinical practice and the CF Trust consensus recommendations.

The committee discussed whether aztreonam lysine or tobramycin should be given as second line treatment in case clinical deterioration occurs despite regular colistin. Clinical deterioration was considered to be an increase in the number of exacerbations or a decline in pulmonary function (determined by spirometry). In line with NICE TA report 276, the committee agreed to recommend either aztreonam lysine, nebulised tobramycin or tobramycin dry powder (see the section on economic benefits and harms). This is because although they noted the NMA suggested aztreonam was better than placebo or tobramycin, there was lots of uncertainty regarding the results. In addition, the available direct evidence comparing aztreonam lysine and tobramycin did not favour either treatment.

The committee discussed their understanding that the effect of an antimicrobial may diminish over time with repeated exposure. This may account for improvements seen in clinical trials with new agents in treatment-naïve populations. Therefore, it would be appropriate to change between agents in line with an individual’s response.

The committee noted that adherence to treatment can be a relevant issue and should be considered when prescribing treatment.

The committee noted that in practice, combinations of inhaled antimicrobials may be prescribed on alternate cycles, for example, colistin alternating with tobramycin or aztreonam lysine or tobramycin alternating with aztreonam lysine. However, in the absence of evidence, they did not write a recommendation.

The committee noted that other inhaled antimicrobials were in development but did not form part of this review as the data was not available when the review was undertaken (for example, levofloxacin inhalation solution). The omission of levofloxacin from the recommendations does not reflect a decision not to recommend it but rather the fact that it was not included in this review.

Chronic S aureus

No evidence was found for the treatment of chronic S aureus, therefore, recommendations were based on committee’s clinical expertise. They noted the Cochrane review is empty.

The committee made separate recommendations for MSSA and MRSA. This is because MRSA treatment is more complex than MSSA treatment.

The committee’s consensus was that long term oral antibiotic treatment to suppress MSSA could be justified whether the person is unwell or not, because this is a recognised and important pulmonary pathogen in children and adults. Supressing it might be expected to reduce the risk of progressive lung disease and of acute exacerbations caused by this infection. The choice of treatment would depend on disease severity.

With regards to MRSA, the committee agreed that there is no need to routinely give antibiotic treatment to suppress infection in people with chronic MRSA who are stable. They noted it is important to explain the risks and benefits of treatment to the person with cystic fibrosis and their families. However, they agreed that if S aureus is repeatedly isolated from a patient’s respiratory samples and the lung function is deteriorating a course of antibiotics could be considered. This is because MRSA can be fatal in people who are unwell.

The committee acknowledged the infection control guideline (CG 139) and agreed that many of the principles are also applicable to people with cystic fibrosis.

Chronic B cepacia complex

No evidence was found for the treatment of B cepacia complex, therefore, recommendations were based on committee’s clinical expertise. The committee noted that only a small number of people are infected with B cepacia complex, and most published studies are anecdotal reports.

The committee agreed that there is a strong emphasis in cross-infection prevention to avoid the spread of B cepacia complex between people with cystic fibrosis. However, they noted there is variability in the way people are treated.

Given that there is no evidence to support giving antibiotics to people with chronic B cepacia complex who are stable, the committee noted that it is important to discuss the possible risks of treating the infection, such as drug toxicity, with the person with cystic fibrosis and their family members or carers.

The committee agreed treatment could be considered for people with chronic B cepacia complex who are experiencing an exacerbation or whose lung function is deteriorating.

The committee noted the used of inhaled antibiotics can be considered. However, they agreed it is important to seek specialist microbiological advice on which antibiotic to use as healthcare professionals may have limited experience dealing with B cepacia complex.

Finally, the committee agreed treatment should be stopped if no benefit is observed.

Chronic A fumigatus

The committee acknowledged the evidence was scarce and of poor quality. They noted therapeutic azole levels were not achieved in many participants. Therefore, recommendations were mainly based on the committee’s clinical knowledge and experience.

The committee agreed that, in people who are stable, there is no need to treat with antifungal agents to suppress infection. This is because it is known that chronic aspergillus colonisation can exist without associated deterioration in lung function. Treatment of this organism can be difficult and is associated with adverse events.

The committee discussed that, in people who are chronically infected with A fumigatus and deteriorating without an obvious explanation, a trial with an antifungal agent can be considered. They agreed to recommend a trial with an antifungal agent because this pathogen could be the cause of the deterioration in the lung function. They noted that their first-line choice was itraconazole but that therapeutic levels of this agent are particularly difficult to achieve and it may be necessary to change to another antifungal such as voriconazole or posaconazole. Regardless, the choice of the antifungal agent should take in vitro sensitivities into account to ensure the optimal drug is used. They acknowledged that advice may be sought from a specialist microbiologist to inform choice. Finally, they highlighted that clinical response should be appropriately assessed and that treatment could be stopped or modified if no benefit was observed.

The committee acknowledge that it was important to distinguish between those who have respiratory symptoms due to infection with aspergillus and those who have clinical manifestations due to allergic sensitisation to aspergillus. For people with cystic fibrosis who have elevated aspergillus serology (aspergillus-specific IgG and/or IgE), declining pulmonary function and whose pulmonary treatment is optimised, the committee agreed that clinicians should think about treating allergic bronchopulmonary aspergillosis (ABPA) or other aspergillus airway disease, especially if a chest x-ray or CT scan shows consistent changes.

9.4.3.9.3. Consideration of economic benefits and harms

Antimicrobial regimens for the treatment of chronic P aeruginosa

The committee agreed that the use of a lifetime horizon in the economic model was appropriate. However, they acknowledged the limitation of extrapolating short-term trial results over a lifetime horizon. The committee noted that the model did not reflect the current treatment pathway where some people switch their treatment or receive a combination of treatments. However, the committee agreed that there was no clinical effectiveness data available on treatment switching or combinations to inform the model beyond the trial by Flume 2016. As a result, the committee considered the “with-in” trial analysis that did not extrapolate data to a lifetime horizon to address those limitations. The committee noted that trial participants were not treatment naïve which may underestimate the benefits and cost-effectiveness of those treatments in a naïve population.

The committee considered the impact of treatment adherence on cost-effectiveness, as cost-effectiveness may be overestimated beyond a trial setting, if the same benefits are not achieved. The committee advised that colistimethate sodium has a lower adherence than tobramycin because it requires more time and effort to administer. On the other hand, the committee also believed colistimethate tasted better than tobramycin which may increase adherence to colistimethate compared to tobramycin, especially in children. As a result, there are issues in both directions that could cancel out with little influence on the model. The committee added that people with cystic fibrosis may be more likely to adhere to a dry powder inhalation treatment than a nebulised treatment in view of the speed and convenience of drug delivery. However, newer nebulisers with quicker delivery time, such as the PARI eFlow jet nebuliser and I-neb, are increasing in use. For these reasons, it remains unclear whether dry powder inhalers would reduce treatment burden compared to newer quicker nebulisers.

It is current practice to offer people infected with chronic P aeruginosa antimicrobial treatment to prevent deterioration in their lung function. Despite this, the committee discussed how the benefits of antimicrobial treatment may not outweigh their costs. As a result, the committee questioned if current practice should be changed based on the economic model that found a small decrease in effectiveness for a large cost saving. Following this, the committee acknowledged that current NICE HTA recommendations state nebulised colistimethate sodium should be offered as a first-line option. However, the sources of evidence considered in NICE TA276 did not compare nebulised colistimethate sodium to “no treatment” which, again, questions if nebulised colistimethate sodium should be recommended.

If “no treatment” cannot be accepted as an option, the committee agreed that nebulised colistimethate sodium would be the most cost-effective antimicrobial and tobramycin dry powder would be the least as it was dominated (less effective and more expensive) by the other options in the economic model.

The committee agreed that it was reasonable to assume the exacerbation rate for nebulised colistimethate sodium was equal to nebulised tobramycin in the absence of data. The committee also agreed that given the current clinical pathway, they would have liked to have seen effectiveness evidence comparing nebulised colistimethate sodium, colistimethate dry powder and “no treatment”, especially as this evidence was not available during the submission of evidence in NICE TA276. To reduce this uncertainty, the committee considered a research recommendation to assess the clinical and cost-effectiveness of those options. However, the committee acknowledged a trial with a placebo arm would be unlikely to be approved.

The committee highlighted that current practice for inhaled therapies in cystic fibrosis follows the Clinical Commissioning Policy by NHS England who propose aztreonam lysine as a third line treatment following tobramycin. However, this recommendation is based primarily on cost and not cost-effectiveness that assesses if the additional benefit from aztreonam lysine outweigh its additional cost. Moreover, the cost-effectiveness of aztreonam lysine compared to nebulised tobramycin was published during the development of this guideline by Schechter 2015. Consequently, the comparison between nebulised tobramycin and aztreonam lysine was of greatest interest to the committee.

They agreed that the analysis by Schechter 2015 was favoured towards aztreonam lysine for several reasons. For example, the analysis included a much higher cost to manage an exacerbation (potentially as the analysis took a US third party perspective) and used a high drug acquisition cost for nebulised tobramycin than aztreonam lysine, influencing aztreonam lysine’s “dominant” result. Furthermore, participants included in the trial by Assael 2013 were not naïve to tobramycin, potentially with less to scope to benefit from tobramycin compared to aztreonam lysine.

However, the clinical evidence review also favoured aztreonam lysine over the other treatments under consideration. Based on the results from the economic model that was developed to reflect UK clinical practice, the committee agreed that aztreonam lysine could displace nebulised tobramycin as many of the analyses explored provided an ICER below NICE’s upper threshold for cost-effectiveness. However, given current NICE HTA recommendations, the committee agreed they could not recommend aztreonam lysine as the sole second-line option following colistimethate sodium. As a result, the committee prioritised a recommendation to consider aztreonam lysine or tobramycin when the person with a chronic infection is clinically deteriorating, despite regular inhaled colistimethate sodium.

The committee continued to discuss the combination treatment (28 days aztreonam lysine alternating with 28 days nebulised tobramycin) that was dominated by aztreonam lysine in the model. Given that a combination treatment incurs a continuous drug cost and demonstrated clinical effectiveness above nebulised tobramycin and below aztreonam lysine, the result was considered to accurately represent the available evidence. However, the committee vocalised their concerns that the RCTs identified in the clinical evidence review were flawed as they were often underpowered and included participants who were not treatment naive. The committee agreed a research recommendation was needed to demonstrate the clinical and cost effectiveness of combination treatments, but acknowledged that such a study would be impossible to conduct as the number of eligible participants would lead to another underpowered study. Overall, the committee acknowledged the limitations of the available evidence and agreed not to make a recommendation regarding combination treatments, as they believed clinical practice was clinically effective and cost-effective.

Antimicrobial regimens for the treatment of A fumigatus, S aureus and B cepacia complex

The committee advised that people with cystic fibrosis who have a stable chronic infection with A fumigatus, S aureus or B cepacia complex, and leave hospital untreated, feel anxious. To reduce their anxiety, the committee agreed that clinicians should inform their patients that there is no evidence on the effectiveness of suppressive antimicrobial treatment with the aim to reduce the number of people who insist on receiving treatment that is potentially cost-ineffective.

The committee advised that people who are chronically infected with S aureus are given flucloxacillin in UK clinical practice. They noted there is some variation when the treatment is initiated and stopped with regards to the severity of their symptoms. The committee acknowledged the higher price of oral solutions compared to capsules (NHS Electronic Drug Tariff September 2016: flucloxacillin 500mg capsules; £2.22/28 capsules, £0.08/500mg vs. flucloxacillin 250mg/5ml oral solution sugar free; £27.24/100ml, £2.72/500mg/10ml) and agreed that people who are chronically infected would be given the cheaper capsule preparation as they are unlikely to have swallowing difficulties at the age of chronic infection. Based on a dose of 4g/day, the cost of flucloxacillin in capsule form would be less than £1/day. Despite such low acquisition costs, the committee agreed that they should not be prescribed if they do not benefit the person with the chronic infection, especially as cystic fibrosis is a multi-system disorder associated with complex daily regimens. As a result, the committee concluded that antibiotics to suppress chronic MRSA should only be considered in people who are deteriorating, but not in people who have a stable chronic infection, as the cost and burden of treatment is likely to outweigh the benefits of treatment. Conversely, treatment should be considered to suppress chronic MSSA in people with stable pulmonary status given that the expected downstream costs associated with an unmanaged infection would outweigh the cost and burden of suppressive therapy.

The committee advised that the long-term use of drugs used to suppress B cepacia complex can have adverse effects associated with additional treatment costs and quality of life decrements. Consequently, the committee did not want to recommend the use of those drugs in people who are chronically infected and stable, adding that reducing their treatment burden may subsequently promote adherence to their existing regimens and outweigh the benefits of suppressive treatment. However, the committee agreed that people who are deteriorating should consider a trial of chronic suppressive treatment with an inhaled antibiotic. The committee also stated that clinicians should observe someone’s response to treatment to ensure the cost of treatment is justified by suppression of the infection and to discontinue their treatment when they suspect the expected cost to exceed the expected benefit.

The committee advised that the first-line treatment for people who are chronically infected with A fumigatus is itraconazole. The committee discussed the clinical evidence that found no significant difference between itraconazole and usual care and concluded that the study was low quality with an undefined population. The committee also noted that the antimicrobials used to supress A fumigatus are relatively expensive compared to those used to suppress B cepacia complex and S aureus. As a result, the committee concluded that treatment in people who are deteriorating should take a stepwise approach, starting with the cheapest treatment (NHS Electronic Drug Tariff September 2016: itraconazole 100mg capsules; £3.42/15 capsules, £0.23/100mg). Based on a dose of 200mg twice daily, the cost of itraconazole in capsule from would be less than £1/day. Similarly to a stable chronic infection with B cepacia complex or S aureus, the committee agreed that people who have a stable chronic infection with A fumigatus should not be given routine antimicrobials treatment in an to attempt to suppress the chronic infection.

Overall, cost data has little use without associated benefits. Therefore, while the cost of long-term suppressive antimicrobial treatment could be significant, without knowing the benefits of treatment we cannot know if they will be cost-effective. Therefore a research recommendation to assess the clinical effectiveness of suppressive antimicrobial treatment in people chronically infected with S aureus, B cepacia complex or A fumigatus will assess if the benefits can justify the costs in order to reduce current uncertainty in this area.

9.4.3.9.4. Quality of evidence

P aeruginosa

The quality of the evidence ranged from very low to high as assessed by GRADE. For the domain risk of bias, the studies were assigned the same risk of bias as in the Cochrane reviews and were not individually reviewed.

The main reasons that lead to downgrading the quality of the evidence was the risk of bias, many of the studies were open trials and there were issues in relation to data reporting, randomisation and allocation concealment.

Another reason that lead to downgrading the quality of the evidence was imprecision, as confidence intervals crossed 1 or 2 clinical or default MIDs.

No issues where identified in relation to the directness of the population.

S aureus

Not applicable, as no evidence was found for this pathogen.

B Cepacia Complex

Not applicable, as no evidence was found for this pathogen.

A fumigatus

One study was found for the treatment of chronic A fumigatus. The evidence was considered low to very low quality as assessed by GRADE. The main reasons that lead to downgrading the quality of the evidence were the moderate risk of bias found in the study and the levels of imprecision. The evidence was downgraded further because the committee noted therapeutic dosages were not achieved in 2 out of 3 of the participants.

9.4.3.9.5. Other considerations

No equality issues were identified by the committee for this review question.

The committee agreed a research recommendation should not be prioritised for this topic. There is sufficient evidence to inform the management of chronic P aeruginosa. Studies on the management of S aureus, B cepacia complex, and A fumigatus are difficult to conduct.

In certain circumstances medicines are prescribed outside their licensed indications (off-label use) to children and young people because the clinical need cannot be met by licensed medicines; for example, for an indication not specified in the marketing authorisation, or administration of a different dose. At the time of publication (October 2017), colistimethate sodium DPI, nebulised tobramycin, tobramycin DPI and nebulised aztreonam did not have a UK marketing authorisation for use in children with cystic fibrosis for this indication. However, the Standing Committee on Medicines has issued a policy statement on the use of unlicensed medicines and the use of licensed medicines for unlicensed indications in children and young people. This states clearly that such use is necessary in paediatric practice and that doctors are legally allowed to prescribe medicines outside their licensed indications where there are no suitable alternatives and where use is justified by a responsible body of professional opinion.

9.4.3.9.6. Key conclusions

The guideline committee concluded that the recommendations from the NICE TA report 276 (Tappenden 2013) are current. They agreed colistin should be the first-line treatment for the management of chronic P aeruginosa. Aztreonam lysine or tobramycin can be given if the person continues to deteriorate. Although they noted aztreonam lysine has shown to be more cost-effective. The committee agreed there is no need to routinely give treatment to people who are chronically infected with S aureus or A fumigatus. Treatment should be considered if clinical deterioration is observed and the response to treatment should be assessed. Moreover, they noted that there is no evidence to support using antibiotics to suppress chronic B cepacia complex infection in people who have stable pulmonary status. The committee also agreed it is important discuss with the person with cystic fibrosis and the families about the benefits and harms of giving treatment.

9.4.4. Recommendations

S aureus

63.

Offer flucloxacillin⁴ as antibiotic prophylaxis against respiratory Staphylococcus aureus infection for children with cystic fibrosis from the point of diagnosis up to age 3, and consider continuing up to 6 years of age. Before starting flucloxacillin, discuss the uncertainties and possible adverse effects with their parents or carers (as appropriate). For children who are allergic to penicillins, consider an alternative oral anti-Staphylococcus aureus agent.

64.

For children who are taking antibiotic prophylaxis and have a respiratory sample culture that is positive for Staphylococcus aureus:

review prophylaxis adherence and help the child’s parents or carers (as appropriate) with any difficulties they are having
start treatment-dose anti-Staphylococcus aureus antibiotics
restart prophylaxis after treatment, even if treatment has not been successful.

65.

For people who are not taking prophylaxis and have a new Staphylococcus aureus infection (that is, previous respiratory sample cultures did not show Staphylococcus aureus infection):

if they are clinically well, consider an oral anti-Staphylococcus aureus agent
if they are clinically unwell and have pulmonary disease, consider oral or intravenous (depending on infection severity) broad-spectrum antibiotics that include an anti-Staphylococcus aureus agent.

66.

Consider a long-term antibiotic to suppress chronic methicillin-sensitive Staphylococcus aureus (MSSA) respiratory infection in people whose pulmonary disease is stable.

67.

For people with chronic MSSA respiratory infection who become clinically unwell with pulmonary disease, consider oral or intravenous broad-spectrum antibiotics (depending on infection severity) that include an anti-Staphylococcus aureus agent.

68.

For people with new evidence of methicillin-resistant Staphylococcus aureus (MRSA) respiratory infection (with or without pulmonary exacerbation), seek specialist microbiological advice on treatment.

69.

Do not routinely use antibiotics to suppress chronic MRSA in people with stable pulmonary disease.

70.

If a person with cystic fibrosis and chronic MRSA respiratory infection becomes unwell with a pulmonary exacerbation or shows a decline in pulmonary function, seek specialist microbiological advice.

71.

For guidance on preventing the spread of infection, refer to the NICE guideline on healthcare-associated infections.

P aeruginosa

72.

If a person with cystic fibrosis develops a new Pseudomonas aeruginosa infection (that is, recent respiratory secretion sample cultures showed no infection):

if they are clinically well:
- commence eradication therapy with a course of oral or intravenous antibiotics, together with an inhaled antibiotic
- follow this with an extended course of oral and inhaled antibiotics
if they are clinically unwell:
- commence eradication therapy with a course of intravenous antibiotics together with an inhaled antibiotic
- follow this with an extended course of oral and inhaled antibiotics.

73.

If eradication treatment is not successful despite treatment as recommended in 2, offer sustained treatment with an inhaled antibiotic. Consider nebulised colistimethate sodium as first-line treatment. (See recommendation 6 on using colistimethate dry powder for inhalation).

74.

Depending on infection severity, use either an oral antibiotic or a combination of 2 intravenous antibiotics of different classes for people:

who have chronic Pseudomonas aeruginosa infection (when treatment has not eradicated the infection) and
who become clinically unwell with a pulmonary disease exacerbation.

75.

If a person with chronic Pseudomonas aeruginosa infection repeatedly becomes clinically unwell with pulmonary disease exacerbations, consider changing the antibiotic regimens used to treat exacerbations.

76.

Colistimethate sodium dry powder for inhalation (DPI) is recommended as an option for treating chronic pulmonary infection caused by Pseudomonas aeruginosa in people with cystic fibrosis only if:

they would clinically benefit from continued colistimethate sodium but do not tolerate it in its nebulised form and thus tobramycin therapy would otherwise be considered and
the manufacturer provides colistimethate sodium DPI with the discount agreed as part of the patient access scheme to primary, secondary and tertiary care in the NHS.

[This recommendation is from Colistimethate sodium and tobramycin dry powders for inhalation for treating pseudomonas lung infection in cystic fibrosis (NICE technology appraisal 276)]

77.

For people with chronic Pseudomonas aeruginosa infection who are clinically deteriorating despite regular inhaled colistimethate sodium, consider nebulised aztreonam, nebulised tobramycin, or tobramycin DPI (see recommendation 78 on using tobramycin DPI)⁵.

78.

Tobramycin DPI is recommended as an option for treating chronic pulmonary infection caused by Pseudomonas aeruginosa in people with cystic fibrosis only if:

nebulised tobramycin is considered an appropriate treatment, that is, when colistimethate sodium is contraindicated, is not tolerated or has not produced an adequate clinical response and
the manufacturer provides tobramycin DPI with the discount agreed as part of the patient access scheme to primary, secondary and tertiary care in the NHS.

[This recommendation is from Colistimethate sodium and tobramycin dry powders for inhalation for treating pseudomonas lung infection in cystic fibrosis (NICE technology appraisal 276)]

79.: People currently using tobramycin DPI or colistimethate sodium DPI that is not recommended according to recommendations 76 or 78 should be able to continue treatment until they and their clinician consider it appropriate to stop. For children and young people this decision should be made jointly by the clinician, the child or young person and their parents or carers.

[This recommendation is from Colistimethate sodium and tobramycin dry powders for inhalation for treating pseudomonas lung infection in cystic fibrosis (NICE technology appraisal 276)]

Burkholderia cepacia complex

80.

For people with cystic fibrosis who develop a new Burkholderia cepacia complex infection (that is, recent respiratory sample cultures showed no Burkholderia cepacia infection):

whether they are clinically well or not, give antibiotic eradication therapy using a combination of intravenous antibiotics
seek specialist microbiological advice on the choice of antibiotics to use.

81.

Be aware that there is no evidence to support using antibiotics to suppress chronic Burkholderia cepacia complex infection in people with cystic fibrosis who have stable pulmonary status. Discuss the possible risks (for example drug toxicity) of treating the infection with the person and their family members or carers (as appropriate).

82.

For people with cystic fibrosis who have chronic Burkholderia cepacia complex infection (when treatment has not eradicated the infection) and who become clinically unwell with a pulmonary disease exacerbation:

give a combination of oral or intravenous antibiotics
seek specialist microbiological advice on which antibiotics to use.

83.

For people with cystic fibrosis who have chronic Burkholderia cepacia complex infection and declining pulmonary status:

consider sustained treatment with an inhaled antibiotic to suppress the infection
seek specialist microbiological advice on which antibiotic to use
stop this treatment if there is no observed benefit.

H influenzae

84.: For people with cystic fibrosis who develop a Haemophilus influenzae infection (diagnosed by a positive respiratory sample culture) but do not have clinical evidence of pulmonary infection, treat with an appropriate oral antibiotic.
85.: For people with cystic fibrosis who develop a Haemophilus influenzae infection (diagnosed by a positive respiratory sample culture) and are unwell with clinical evidence of pulmonary infection, treat with an appropriate antibiotic, given orally or intravenously depending on the severity of the illness.

Non tuberculous mycobacteria

86.

For people with cystic fibrosis who are clinically well but whose airway secretions are persistently positive for non-tuberculous mycobacteria, discuss with them and their family members or carers (as appropriate):

the clinical uncertainties about non-tuberculous mycobacterial infection and
the possible benefits and risks (for example, drug toxicity) of treating it.

87.

If a person with cystic fibrosis has a respiratory sample test positive for new nontuberculous mycobacteria infection, repeat the test for confirmation.

88.

If repeat testing confirms persistent non-tuberculous mycobacteria, do a chest CT scan to look for changes consistent with non-tuberculous mycobacteria disease.

89.

Consider non-tuberculous mycobacterial therapy aimed at eradication for people with cystic fibrosis:

whose airway secretions persistently test positive for non-tuberculous mycobacteria and
who are clinically unwell with pulmonary disease, or who have a chest CT scan showing changes consistent with non-tuberculous mycobacteria disease and
whose pulmonary disease has not responded to other recommended treatments.

Seek specialist microbiological advice on which antibiotics to use and on the duration of treatment.

A fumigatus complex

90.

Do not routinely use antifungal agents to suppress chronic Aspergillus fumigatus complex respiratory infection (diagnosed by persistently positive respiratory secretion sample cultures) in people with cystic fibrosis and stable pulmonary status.

91.

For people with cystic fibrosis with chronic Aspergillus fumigatus complex respiratory infection and declining pulmonary status:

consider sustained treatment with an antifungal agent to suppress the infection
seek specialist microbiological advice on which antifungal agent to use
stop treatment or change to a different agent if there is no benefit.

92.

For people with cystic fibrosis with elevated aspergillus serology (aspergillus-specific IgG and/or IgE) and declining pulmonary function despite optimised pulmonary treatment, think about treating for allergic bronchopulmonary aspergillosis or other aspergillus airway disease, especially if there are consistent chest X-ray or CT scan changes.

Unidentified Infections

93.

For people with cystic fibrosis who have a pulmonary disease exacerbation and no clear cause (based on recent respiratory secretion sample cultures):

use an oral or intravenous (depending on the exacerbation severity) broad-spectrum antibiotic
continue collecting respiratory secretion samples, and change treatments if a pathogen is identified and a more appropriate treatment is available.

9.5. Immunomodulatory agents

Review question: What is the effectiveness of immunomodulatory agents in the management of lung disease?

9.5.1. Introduction

Progressive pulmonary disease is the primary cause of morbidity and mortality in adults with cystic fibrosis (CF). The decrease in lung function associated with chronic infection by a variety of organisms has been related to the severity of pulmonary inflammation.

In cystic fibrosis the cystic fibrosis transmembrane conductance regulator (CFTR) is defective. This results in alterations in the way airway epithelial cells direct the inflammatory response in the airways. Defects in CFTR are associated with increased production of pro-inflammatory mediators, including IL-8, which is a potent neutrophil attractor. As a result a large number of these inflammation-causing cells are directed to the airways causing high levels of inflammation and damage. These neutrophils are the primary effector cells responsible for the pathological manifestations of cystic fibrosis lung disease. Additionally, deficiencies in molecules regulating the immune response, such as IL-10, likely contribute to the generation of the excessive and persistent inflammatory response.

Therapies which reduce pulmonary inflammation may prove to be clinically efficacious and so reduce the damage caused by persistent infection and improve patient outcomes.

9.5.2. Description of clinical evidence

The aim of this review was to determine the clinical and cost effectiveness of immunomodulatory agents in children and young people and adults with cystic fibrosis.

We aimed to look at different immunomodulatory treatments, including inhaled corticosteroids, oral and IV corticosteroids, macrolide antibiotics, NSAIDs and monoclonal antibodies, compared to placebo or other immunomodulatory treatment.

Use of Azithromycin in an antimicrobial dose (greater than 250 mg 3 times a week or 500 mg 3 times a week for body weight over 40kg) was excluded from this evidence review and considered in the evidence review on antimicrobials for acute pulmonary infections.

We searched for systematic reviews of RCTs and RCTs assessing the effectiveness of immunomodulatory agents in people with cystic fibrosis.

For full details see review protocol in Appendix D.

Five Cochrane systematic reviews were identified in the search (Balfour-Lynn 2016, Cheng 2015, Jat 2013, Lands 2016, Southern 2012).

Four reviews were included in this evidence review. Where possible, data and risk of bias assessment was extracted directly from the Cochrane systematic reviews. Individual studies were retrieved for completeness and accuracy, and were also checked for additional outcomes of interest.

Balfour-Lynn 2016 evaluated the effectiveness of inhaled corticosteroids compared to placebo or standard treatment. 3 RCTs on Fluticasone use were included from this review (Balfour-Lynn 1997, Balfour-Lynn 2006, De Boeck 2007).
Cheng 2015 evaluated the effectiveness of oral corticosteroids compared to placebo or existing conventional therapy. 3 RCTs were included from this review: 2 trials examined use of Prednisone (Eigen 1995 and Auerbach 1985) and 1 trial examined use of Prednisolone (Greally 1994).
Lands 2016 evaluated the effectiveness of oral NSAIDs compared to placebo or existing therapy. 3 RCTs were included from this review: 2 trials on use of ibuprofen (Konstan 1995 and Lands 2007) and 1 trial on piroxicam (Sordelli 1994).
Southern 2012 evaluated the effectiveness of macrolide antibiotics compared to placebo, other antibiotic class, or other macrolide. 5 RCTs on Azithromycin were included from this review (Clement 2006, Equi 2002, Saiman 2003, Saiman 2010, Wolter 2002).

An additional Cochrane review (Jat 2015) evaluated the effectiveness of anti-IgE therapy for allergic bronchopulmonary aspergillosis in people with cystic fibrosis. The review reported on 1 clinical trial (Novartis 2008) of Omalizumab which terminated early. This clinical trial (Novartis 2008) was not included as the adverse events reported were not listed in the review protocol.

In addition, 1 observational study (Lai 2000) on the use of Prednisone and 1 RCT on the use of clarithromycin (Robinson 2012) were identified for inclusion in this evidence review.

No evidence was identified which reported on IV methylprednisolone use.

The presentation of evidence synthesis was divided in two parts based on the type of analysis which was used to produce these syntheses:

Two outcomes, the forced expiratory volume in 1 second (FEV₁) % predicted and the rate of pulmonary exacerbations, were considered for network meta-analysis (NMA). These were each split into short (1–10 months) and long-term (>10 months) treatment. Ten studies were included in the NMAs for FEV₁ % predicted and eight studies were included in the NMAs for rate of pulmonary exacerbations (see Section 1.1.2.1) Pairwise comparisons were performed for the rest of the outcomes included in the review protocol. Ten RCTs were included from the Cochrane systematic reviews for the outcomes of nutritional status, time to next pulmonary exacerbation, adverse effects and quality of life.

If a study did not report standardised height or weight scores (such as BMI, z scores or standard deviation scores), the absolute value (in centimetres or kilograms) was included. Standard deviation scores reported were compared to a population of children without cystic fibrosis.
The size of the studies ranged between 23 and 285 people with cystic fibrosis. Two studies included children (Auerbach 1985, De Boeck 2007), 8 studies included children and young people (Balfour-Lynn 1997, Clement 2006, Eigen 1995, Equi 2002, Greally 1994, Lai 2000, Lands 2007, Saiman 2010), 1 study included young people and adults (Wolter 2002), 5 studies included children, young people and adults (Balfour-Lynn 2006, Konstan 1995, Robinson 2012, Saiman 2003, Sordelli 1994).
Three studies were conducted in the UK (Balfour-Lynn 1997, Balfour-Lynn 2006, Equi 2002), 6 in the USA (Auerbach 1985, Eigen 1995, Konstan 1995, Lai 2000, Saiman 2003, Saiman 2010), 1 in Belgium (De Boeck 2007), 1 in France (Clement 2006),1 in Ireland (Greally 1994), 1 in Canada (Lands 2007), 1 in Argentina (Sordelli 1994), 1 in Australia (Wolter 2002), 1 in the USA and Australia (Robinson 2012).

A summary of the studies included in this review is presented in Table 159. See study selection flow chart in Appendix F, study evidence tables in Appendix G, list of excluded studies in Appendix H, forest plots in Appendix I, and full GRADE profiles in Appendix J.

9.5.3. Summary of included studies

A summary of the included studies is presented in Table 126.

9.5.4. Clinical evidence profile

9.5.4.1. Clinical evidence profile for NMA outcomes (FEV₁ % predicted and rate of pulmonary exacerbations)

As treatment effects were found to vary over time, NMAs were conducted separately for short (1–10 months) and long (>10 months) of treatment.

9.5.4.1.1. FEV₁ % Predicted – Short-term (1–10 month) treatment

Six studies of 735 participants were included in the network of three classes of interventions – placebo, macrolide antibiotics (azithromycin, clarithromycin), inhaled corticosteroids (fluticasone) (Figure 8). The evidence was of moderate quality. Four studies were at low risk of bias and for the 2 other studies the risk of bias was unclear.

Table 127 presents the results of the conventional pair-wise meta-analyses (head to head comparisons) (upper-right section of table), together with the results computed by the NMA for every possible treatment comparison (lower-left section of table). Both results are presented as mean differences (95% CrI). These results were derived from a fixed effects model (Appendix N).

Macrolide antibiotics were found to have a clinically significant improvement versus placebo for limiting the decline in FEV₁ % predicted for people with cystic fibrosis treated for 1–10 months (Figure 9). Inhaled corticosteroids were not found to have a clinically significant effect on FEV₁ % predicted compared with placebo. Macrolide antibiotics were also not found to have a clinically significant effect over inhaled corticosteroids for short-term treatment. Incoherence could not be assessed as there were no closed loops of treatments.

In this analysis, macrolide antibiotics were found to have the highest probability (91.21%) of being the best treatment to improve/limit the decline in FEV₁ % predicted among interventions with a duration of 1–10 months (Table 128).

9.5.4.1.2. FEV₁ % Predicted - Long-term (>10 month) treatment

Five studies of 511 participants were included in the network of four classes of interventions – placebo, NSAIDs (ibuprofen), macrolide antibiotics (azithromycin), inhaled corticosteroids (fluticasone), and oral corticosteroids (prednisolone) (Figure 10). The evidence was of low quality. Two studies were at low risk of bias and for the other three studies the risk of bias was unclear.

Table 130 presents the results of the conventional pair-wise meta-analyses (head to head comparisons) (upper-right section of table), together with the results computed by the NMA for every possible treatment comparison (lower-left section of table). Both results are presented as mean differences (95% CrI). These results were derived from a fixed effects model (Appendix N).

NSAIDs and oral corticosteroids were found to have a clinically significant improvement versus placebo for limiting the decline in FEV₁ % predicted for people with cystic fibrosis for >10 months of treatment (Figure 11). Long-term macrolide antibiotic treatment was not found to have a clinically significant effect on FEV₁ % predicted compared with placebo. There may be a clinically significant improvement of long-term oral corticosteroid treatment versus long-term macrolide antibiotic treatment, though there was insufficient evidence to confirm this. Incoherence could not be assessed as there were no closed loops of treatments.

In this analysis, long-term NSAID treatment was found to have the highest probability (65.2%) of being the best treatment to improve/limit the decline in FEV₁ %, followed by long-term oral corticosteroid treatment (12.9%) (Table 131).

9.5.4.1.3. Rate of pulmonary exacerbations - Short-term (1–10 month) treatment

Three studies of 226 participants were included in the network of 2 classes of interventions – placebo and macrolide antibiotics (azithromycin, clarithromycin) (Figure 12). The evidence for this analysis was of moderate quality. One study was at low risk of bias and for the other 2 studies the risk of bias was unclear.

As there was only evidence on 2 classes of short-term treatments to reduce the rate of pulmonary exacerbations no NMA was performed for this outcome.

Very low quality evidence showed no clinically significant difference in the rate of exacerbations after short-term treatment between macrolide antibiotics and placebo (see Appendix N). This result was derived from a random effects pairwise analysis.

9.5.4.1.4. Rate of pulmonary exacerbations - Long-term (>10 month) treatment

Three studies of 321 participants were included in the network of four classes of interventions – placebo, macrolide antibiotics (azithromycin), inhaled corticosteroids (fluticasone), and oral corticosteroids (prednisolone) (Figure 13). The evidence was of low quality. One study was at low risk of bias and for the other 2 the risk of bias was unclear.

Table 134 presents the results of the conventional pair-wise meta-analyses (head to head comparisons) (upper-right section of table), together with the results computed by the NMA for every possible treatment comparison (lower-left section of table). Both results are presented as mean differences (95% CrI). These results were derived from a fixed effects model (Appendix N).

There was considerable uncertainty throughout the network. No clinically significant differences were found between any of the treatments in the network. Incoherence could not be assessed as there were no closed loops of treatments.

In this analysis, long-term macrolide antibiotic treatment was found to have the highest probability (56.8%) of being the best treatment to reduce the rate of exacerbations, followed by long-term oral corticosteroid treatment (25.5%) (Table 135).

One study (Sordelli 1994) that provided information on NSAID efficacy was a candidate for inclusion into the network. However, as the NSAID used in the study (piroxicam) was considered to have potentially severe side effects and as the study was at high risk of bias (trial was unblinded and neither randomisation nor allocation methods were sufficiently described) it was not included in the final network.

As this was the only study providing information on NSAIDs, the results of the network were highly sensitive to it. Inclusion of this study did not affect estimates for other classes in the network, but provided an estimate for NSAID efficacy. This quality of evidence for this new network worsened from low to very low quality, with NSAIDs having the highest probability (61.2%) of being the best treatment, followed by macrolide antibiotics (24.7%). Further results of this sensitivity analysis are reported in Appendix N.

9.5.4.2. Clinical evidence profile for non-NMA outcomes (nutritional status, time to next pulmonary exacerbation, adverse events and quality of life)

The summary clinical evidence profile tables are presented in Table 137 - Table 140.

9.5.5. Economic evidence

No economic evaluations of immunomodulatory agents were identified in the literature search conducted for this guideline. Full details of the search and economic article selection flow chart can be found in Appendix E and F, respectively.

This area was prioritised for de novo economic modelling; consequently, a cost-utility model was developed. The model uses a lifetime horizon based on the assumption that immunomodulatory agents are given on a long-term basis.

The model takes the form of a state transition model to estimate transitions between 3 lung function (FEV₁% predicted) strata. Transition probabilities between the three FEV₁% strata and the number of exacerbations experienced each cycle were taken from the NMA.

Treatment related adverse effects and post lung transplant health states were also included in the model to reflect the clinical pathway.

A series of deterministic sensitivity analyses were undertaken in order to test how sensitive the results were to uncertainty in individual parameters. Probabilistic sensitivity analysis was also conducted in the model to take account of the simultaneous effect of uncertainty relating to model parameter values. The methods used to construct the model and the results of all analyses are reported in Appendix K. Table 141 below presents the results from the base-case, where it is clear azithromycin dominates the alternatives as it is most the effective and least expensive option.

9.5.6. Evidence statements

9.5.6.1. Evidence statements for NMA outcomes (FEV₁ % predicted and rate of pulmonary exacerbations)

See section 9.5.4.1.

9.5.6.2. Evidence statements for non-NMA outcomes (nutritional status, time to next pulmonary exacerbation, adverse events and quality of life)

9.5.6.2.1. Corticosteroids

Inhaled Beclometasone

No evidence was found for this treatment.

Inhaled Budesonide

No evidence was found for this treatment.

Inhaled Fluticasone

Comparison 1. Fluticasone versus placebo

Time to next exacerbation

Low quality evidence from 1 RCT with 171 children, young people and adults with cystic fibrosis showed no clinically significant difference in the time to next exacerbation between fluticasone and placebo at 6 months follow-up.

Nutritional status

No evidence was found for this important outcome.

Quality of life

No evidence was found for this important outcome.

Adverse effects

Moderate quality evidence from 1 RCT with 30 children with cystic fibrosis showed no clinically significant difference in growth measured by change in height standard deviation score between fluticasone and placebo over 12 months follow-up.

Moderate quality evidence from 1 RCT with 80 people with cystic fibrosis showed no clinically significant difference in growth measured by change in height measured by centimetres between fluticasone and placebo over 8 months follow-up.

Mortality

No evidence was found for this important outcome.

9.5.6.2.2. Corticosteroids

IV Methylprednisolone

No evidence was found for this treatment.

Oral Prednisone/Prednisolone

Comparison 2. Prednisone/prednisolone versus placebo

Time to next exacerbation

No evidence was found for this critical outcome.

Nutritional status: weight and height

Very low quality evidence from 1 RCT with 25 children and young people with cystic fibrosis showed no clinically significant difference in weight measured in kilograms between 2 mg/kg prednisolone and placebo at 12 week follow-ups.

Low quality evidence from 1 observational study with 55 young people (males) with cystic fibrosis showed no clinically significant difference in weight measured in kilograms between 1 mg/kg prednisolone and placebo at the age of 18.

Moderate quality evidence from 1 observational study with 52 young people (males) with cystic fibrosis showed a clinically significant harmful effect of 2 mg/kg prednisolone in weight measured in kilograms compared to placebo at the age of 18.

Very low quality evidence from 1 observational study with 43 young people (females) with cystic fibrosis showed no clinically significant difference in weight measured in kilograms between 1 mg/kg prednisolone and placebo at the age of 18.

Very low quality evidence from 1 observational study with 46 young people (females) with cystic fibrosis showed no clinically significant difference in weight measured in kilograms between 2 mg/kg prednisolone and placebo at the age of 18.

Very low quality evidence from 1 observational study with 52 young people (males) with cystic fibrosis showed a clinically significant harmful effect of 1 mg/kg prednisolone in height measured in centimetres compared to placebo at the age of 18.

Very low quality evidence from 1 observational study with 52 young people (males) with cystic fibrosis showed a clinically significant harmful effect of 2 mg/kg prednisolone in height measured in centimetres compared to placebo at the age of 18.

Very low quality evidence from 1 observational study with 43 young people (females) with cystic fibrosis showed no clinically significant difference in height measured in centimetres between 1 mg/kg prednisolone and placebo at the age of 18.

Very low quality evidence from 1 observational study with 46 young people (females) with cystic fibrosis showed no clinically significant difference in height measured in centimetres between 2 mg/kg prednisolone and placebo at the age of 18.

Quality of life

No evidence was found for this important outcome.

Adverse effects

Very low quality evidence from 1 RCT with 190 children with cystic fibrosis showed no clinically significant difference in cataracts, diabetes mellitus, glycosuria and hyperglycaemia between 1 mg/kg prednisone and placebo at 4 years follow-up.

Very low quality evidence from 1 RCT with 190 children with cystic fibrosis showed no clinically significant difference in cataracts and diabetes mellitus between 2 mg/kg prednisone and placebo at 3 years follow-up.

Low quality evidence from 1 RCT with 190 children with cystic fibrosis showed no clinically significant difference in glycosuria between 2 mg/kg prednisone and placebo at 3 years follow-up.

Low quality evidence from 1 RCT with 190 children with cystic fibrosis showed a clinically significant harmful effect of 2 mg/kg prednisone compared with placebo for hyperglycaemia at 3 years follow-up.

Mortality

Low quality evidence with 45 children with cystic fibrosis showed no clinically significant difference in mortality between 2mg/kg prednisone and placebo at 4 years follow-up.

9.5.6.2.3. Macrolide antibiotics

Azithromycin

Comparison 3. Azithromycin versus placebo

Time to next exacerbation

High quality evidence from 2 RCT with 445 children and young people with cystic fibrosis showed a clinically significant beneficial effect of azithromycin in the time to next exacerbation compared to placebo at 6 months follow-up.

High quality evidence from 1 RCT with 82 children and young people with cystic fibrosis showed a clinically significant beneficial effect of azithromycin in the time to next exacerbation compared to placebo at 12 months follow-up.

Nutritional status: BMI and weight

Moderate quality evidence from 1 RCT with 82 children and young people with cystic fibrosis showed no clinically significant difference in change in BMI z score from baseline between azithromycin and placebo at 12 months follow-up.

Moderate quality evidence from 2 RCTs with 440 people with cystic fibrosis > 6 years showed a clinically significant beneficial effect of azithromycin in weight change measured in kilograms compared to placebo at 24 week follow-up.

Quality of life

High quality evidence from 1 RCT with 177 people with cystic fibrosis > 6 years showed no clinically significant difference in change in quality of life (measure with CFQ-R total score, and CFQ-R physical, psychosocial and body image domains) between azithromycin and placebo at 6 months follow-up.

Adverse effects

Low quality evidence from 1 RCT with 185 people with cystic fibrosis > 6 years showed no clinically significant difference in hearing impairment and tinnitus between azithromycin and placebo at 6 months follow-up.

Mortality

No evidence was found for this important outcome.

9.5.6.2.4. NSAIDs

Ibuprofen

Comparison 4. Ibuprofen versus placebo

Time to next exacerbation

No evidence was found for this critical outcome.

Nutritional status: weight

Low quality evidence from 1 RCT with 84 people with cystic fibrosis aged 5 to 39 years showed a clinically significant beneficial effect of ibuprofen in annual rate of change in percent ideal body weight compared to placebo at 4 years follow-up. However, this clinically beneficial significant effect was seen in children under 13 years only (n=49). Very low quality evidence from this study showed no clinically significant difference in change in percent ideal body weight in people with cystic fibrosis over 13 years (n=35) at 4 years follow-up.

Quality of life

No evidence was found for this important outcome.

Adverse effects

Low quality evidence from 1 RCT with 142 children with cystic fibrosis showed no clinically significant difference in increase of abdominal pain between ibuprofen and placebo at 2 years follow-up.

Very low quality evidence from 1 RCT with 84 children, young people and adults with cystic fibrosis showed no clinically significant difference in increase of abdominal pain between ibuprofen and placebo at 4 years follow-up.

Low quality evidence from 1 RCT with 142 children with cystic fibrosis showed no clinically significant difference in abdominal bleeding between ibuprofen and placebo at 2 years follow-up.

Mortality

No evidence was found for this important outcome.

9.5.6.3. Monoclonal antibody

Omalizumab

No evidence was found for this treatment.

9.5.6.4. Economic evidence statements

No evidence on cost-effectiveness in people with cystic fibrosis was available for this review.

The economic model found that azithromycin dominated (more effective and less expensive) the remaining treatments in the model (NSAIDs, oral corticosteroids, inhaled corticosteroids and “no treatment”). This result was also found in the extensive deterministic and probabilistic sensitivity analysis that were undertaken.

9.5.7. Evidence to recommendations

9.5.7.1. Relative value placed on the outcomes considered

The aim of this review was to determine the clinical and cost effectiveness of immunomodulatory agents in reducing pulmonary inflammation in children, young people and adults with cystic fibrosis.

The guideline committee identified FEV₁% predicted, time to next exacerbation and adverse events (particularly growth retardation in children) as critical outcomes for decision making. Quality of life, nutritional status and mortality were rated as important outcomes.

9.5.7.2. Consideration of clinical benefits and harms

The committee discussed the results of the evidence and their experience in clinical practice.

The committee discussed the NMA results that found azithromycin had the best probability of reducing exacerbations and one of the worst for improving lung function. Based on their clinical experience, the committee agreed azithromycin can reduce exacerbations, but may not necessarily improve lung function. They highlighted, however, that there is no evidence that supports a direct link between lung function and clinical exacerbations and the critical outcome is to reduce the number of pulmonary exacerbations. They noted azithromycin does not have such a problematic interaction profile compared to other alternative immunomodulatory agents. They also noted azithromycin is usually offered as first-line in current practice and they agreed to recommend it to people who are suffering a clinical deterioration (as assessed by lung function) and to those who present recurrent pulmonary exacerbations. They suggested that due to its pharmacokinetic profile, it can be administered 3 times per week, rather than daily. The committee discussed the duration of treatment as, in practice, it tends to be used for longer than the duration in studies. It was agreed that treatment should be reviewed periodically to assess response.

The committee agreed that oral corticosteroids can be considered if clinical deterioration continues despite treatment with azithromycin, where all other treatments have been maximised.

The committee noted there was less evidence on fluticasone than the other treatments in the NMA. It was tested in only 12 patients suggesting that more research on fluticasone is needed to increase the confidence in the results. They noted that in practice, fluticasone does not improve lung function to the extent the NMA inferred. In the absence of evidence-base and empirical evidence to support its use, they agreed to not recommend the use of inhaled corticosteroids.

The committee also noted the lack of evidence for omalizumab and that this is limited to case reports.

The committee acknowledged ibuprofen showed a beneficial effect in terms of lung function and nutritional status. However, they were reluctant to recommend it widely due to the high dose and therapeutic drug monitoring required (which is not universally available), its adverse effects profile and potential interaction with other drugs. Although the studies did not show significant adverse events for ibuprofen, they emphasised longer follow-up trials are needed to assess this. Moreover, none of the studies reported on renal function, which is known to be negatively affected by long-term ibuprofen use. The committee noted ibuprofen is not currently routinely used in clinical practice for the management of cystic fibrosis in the UK. Nevertheless, they agreed not to write a “do not do” recommendation, as they acknowledged ibuprofen may be suitable for some people (for example when azithromycin is not deemed appropriate).

The committee agreed it is important to assess tolerability and adverse effects in addition to efficacy when making decisions about treatment.

9.5.7.3. Consideration of economic benefits and harms

The committee stated that it was crucial the adverse effects of treatment were taken into consideration when making their recommendations as they may outweigh the benefits related to lung function and exacerbations the agents can provide. As a result, the economic modelling was used by the committee as one of many ways to assess those trade-offs.

NMAs were undertaken for this review question. This allowed the treatments identified in the review to be compared to a single comparator and enable the economic model to perform a fully incremental analysis that compares all treatments simultaneously in order to identify the most cost-effective treatment. However, in the network, there were a lot of indirect comparisons coming from a small number of head-to-head trials and, for most comparisons where direct evidence was available, it came from a single trial. Consequently, the NMAs were not over-interpreted by the committee when making their recommendations.

From their clinical experience, azithromycin can reduce exacerbations, but not necessarily improve lung function. Based on this, the committee accepted the results from the NMA that found azithromycin to have the best probability of reducing exacerbations and one of the worst for improving lung function.

On the other hand, the committee did not agree fluticasone improves lung function to the extent the NMA inferred. Following this, the committee noted that there was less evidence on fluticasone than the other treatments in the NMA, suggesting that more evidence on fluticasone was needed to increase their confidence in the results. The committee also questioned the inclusion of fluticasone in the economic model as it was no longer used as an immunomodulatory agent in clinical practice. Subsequently, the committee recognised that the model provided sufficient evidence not to recommend fluticasone as an immunomodulatory agent, as it was dominated (more expensive and less effective) by its comparators in all analyses explored.

Conversely, the committee agreed that azithromycin should be offered as the first-line treatment given that it dominated (less expensive and more effective) all alternatives in the model and had the highest probability of being the most cost-effective agent in probabilistic analysis. The committee also noted that azithromycin is the first-line treatment in current clinical practice, particularly as it has a relatively small interactions profile.

The committee advised that ibuprofen and oral corticosteroids were associated with more serious treatment-related adverse effects in clinical practice than azithromycin. For this reason, the committee agreed that those agents would not be considered cost-effective compared to azithromycin as they would be dominated (more expensive and less effective). However, the committee agreed they could not recommend against those agents if azithromycin was no longer effective or contraindicated, given that clinical uncertainty was not completely removed by the economic model. One reason for this was the absence of exacerbation data for ibuprofen and the resulting ICER in the south-west quadrant (less expensive and less effective) for ibuprofen compared to “no treatment” when the exacerbation rates were equivalent. Given that there was evidence from the review that ibuprofen improved lung function, and clinical experience from the committee that immunomodulatory benefits were demonstrated by ibuprofen, the committee concluded they could not recommend against the use of ibuprofen.

Following this, the committee noted that mucolytic use would be optimised if azithromycin was no longer effective before a second line immunodulatory agent is considered. The committee added that NSAIDs are rarely used as immunomodulatory agents in clinical practice and concluded that a recommendation in favour of oral prednisolone would be appropriate following no beneficial effect from azithromycin and mucolytics. This was supported by the economic model that found oral prednisolone to dominate NSAIDs and “no treatment”, or, in other words, that oral prednisolone provides greater benefits at a lower cost. A recommendation was considered by the committee to regularly review the effectiveness, tolerability and side effects of immunomodulatory agents in order to lead to more timely identification to reduce the downstream costs to manage those events. However, the recommendation was subsequently removed as the committee agreed that treatment-related adverse effects should be monitored as part of good practice.

Overall, the results from the NMAs and subsequently, the model, were generally considered to be in line with UK practice, which is why the committee’s recommendations broadly follow those results. Committee consensus and current UK practice played a large part in informing their strong recommendations where the evidence was weaker.

9.5.7.4. Quality of evidence

The quality of the evidence presented in this report ranged from very low to high as assessed by GRADE. The main reasons that led to downgrading the quality of the evidence were:

For the domain risk of bias, the studies were assigned the same risk of bias as in the Cochrane reviews and were not individually reviewed. The main biases that led to downgrading the quality of the evidence were selection process, lack of blinding, inadequate concealment, attrition and reporting bias.
Another reason that led to downgrading the quality of the evidence was the imprecision, as confidence intervals crossed 1 or 2 MIDs. The committee noted that some trials were underpowered to detect a clinically important difference.

For the rate of exacerbations after short-term treatment inconsistency (heterogeneity) was found to be very serious and is likely to be due to substantial clinical heterogeneity in the clinical history of patients that cannot be captured from the study reports. For other outcomes no serious inconsistency was found as most outcomes were reported by single studies, though clinical heterogeneity may still have been an issue. This can lead to issues when comparing treatments across different trials.

No issues were identified regarding the directness of the population (generalisability of the results).

9.5.7.5. Other considerations

No equality issues were identified by the committee for this review question.

The committee agreed a research recommendation was not needed as research is unlikely to change clinical practice. In addition, the committee were aware that there are large ongoing trials in this area.

9.5.7.6. Key conclusions

The committee concluded that azithromycin should be offered as long term treatment to people with cystic fibrosis who are deteriorating or having pulmonary exacerbations. The response to treatment should be assessed periodically and treatment may be stopped if there is no evidence of clinical benefit. Oral corticosteroids or NSIADs may be a suitable alternative, but it is important to assess tolerability and side effects regularly. The use of inhaled corticosteroids should not be considered as immunomodulatory treatment.

9.5.8. Recommendations

94.: For people with cystic fibrosis and deteriorating lung function or repeated pulmonary exacerbations, offer long-term treatment with azithromycin at an immunomodulatory dose⁶.
95.: For people who have continued deterioration in lung function, or continuing pulmonary exacerbations while receiving long-term treatment with azithromycin, stop azithromycin and consider oral corticosteroids.
96.: Do not offer inhaled corticosteroids as an immunomodulatory treatment for cystic fibrosis.

Footnotes

1: At the time of publication (October 2017), rhDNase did not have a UK marketing authorisation for use in children under 5 years of age with cystic fibrosis. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council’s Prescribing guidance: prescribing unlicensed medicines for further information.
2: At the time of publication (October 2017), rhDNase did not have a UK marketing authorisation for use in children under 5 years of age with cystic fibrosis for this indication. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council’s Prescribing guidance: prescribing unlicensed medicines for further information
3: At the time of publication (October 2017), rhDNase did not have a UK marketing authorisation for use in children with cystic fibrosis for this indication. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council’s Prescribing guidance: prescribing unlicensed medicines for further information
4: At the time of publication (October 2017), flucloxacillin did not have a UK marketing authorisation for use in people with cystic fibrosis for this indication. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council’s Prescribing guidance: prescribing unlicensed medicines for further information.
5: At the time of publication (October 2017), Colistimethate sodium DPI, nebulised tobramycin, tobramycin DPI and nebulised aztreonam nebulised aztreonam and nebulised tobramycin did not have a UK marketing authorisation for use in children under 6 did with cystic fibrosis for this indication. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council’s Prescribing guidance: prescribing unlicensed medicines for further information.
6: At the time of publication (October 2017), azithromycin did not have a UK marketing authorisation for this indication. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council’s Prescribing guidance: prescribing unlicensed medicines for further information.

Figures

Figure 6Network for number of patients experiencing at least one exacerbation with short-term (4–10 weeks) treatment

Source/Note: Size of nodes are proportional to the number of patients in the network treated with a particular intervention. Thickness of connecting lines are proportional to the number of studies comparing two interventions.

Figure 7Network for number of patients experiencing at least one exacerbation with long-term (>10 weeks) treatment

Figure 8. Network for FEV1 % predicted short-term treatment.

Figure 8Network for FEV₁ % predicted short-term treatment

Note: Size of nodes are proportional to the number of patients in the network treated with a particular intervention. Thickness of connecting lines are proportional to the number of studies comparing two interventions.

Figure 9. Forest plot showing mean differences (with their 95% CrI) of NMA estimates for each intervention versus placebo for FEV1 % predicted with short-term treatment.

Figure 9Forest plot showing mean differences (with their 95% CrI) of NMA estimates for each intervention versus placebo for FEV₁ % predicted with short-term treatment

Note: Vertical dashed line shows the line of no effect

Figure 10. Network for FEV1 % predicted long-term treatment.

Figure 10Network for FEV₁ % predicted long-term treatment

Figure 11. Forest plot showing mean differences (with their 95% CrI) of NMA estimates for each intervention versus placebo for FEV1 % predicted with long-term treatment.

Figure 11Forest plot showing mean differences (with their 95% CrI) of NMA estimates for each intervention versus placebo for FEV₁ % predicted with long-term treatment

Note: Vertical dashed line shows the line of no effect

Figure 12Network for rate of pulmonary exacerbations short-term treatment

Figure 13Network for rate of pulmonary exacerbations long-term treatment

Figure 14Forest plot showing rate ratio (with their 95% CrI) of NMA estimates for each intervention versus placebo for the rate of exacerbations with long-term treatment

Note: Vertical dashed line shows the line of no effect

Tables

Table 60Summary of included studies

Study

Intervention/Comparison

Population

Outcomes

Comments

Sanders 2015
(USA)
Cohort study

Chest CT (Brody score)

Baseline data: For this study the authors used data obtained at the baseline and at end of the PEIT study (1997–1999)
Follow-up data: Data from the time of chest CT in 1999 through 2009 were obtained from the CFFPR and linked to the original chest CT data

FEV₁% predicted

PFTs were obtained on the same day as the chest CT

N=60 children with CF who participated in the PEIT trial
Age: 6 to 10 years

Pulmonary exacerbations
(proxy outcome for time to next exacerbation)^*
(pulmonary exacerbation defined as hospitalizations treated with IV AB and/or if the “pulmonary exacerbation” box was checked in the CFFPR form
FEV₁% predicted^**

No adjustments for the confounder of concurrent treatment with immunomodulatory and/or mucolytic agents

: BAL: bronchoalveolar lavage; CFFPR: cystic fibrosis Foundation Patient Registry; MD: mean difference; SD: standard deviation
*: multivariate Poisson model adjusted for sex, genotype, and FEV₁ and mucoid P aeruginosa status at the time of the chest CT
**: multivariate linear regression model adjusted for sex, genotype, and FEV₁ and mucoid P aeruginosa status at the time of the chest CT

Table 61Summary of included studies

Study	Intervention/Comparison	Population	Outcomes	Comments
Wainwright 2011 (Australia & New Zealand) Multicentre RCT	Standard monitoring group Used clinical features and oropharyngeal cultures to direct therapy. BAL monitoring group standard monitoring + BAL performed before 6 months when well, when hospitalised for exacerbations, if P aeruginosa cultured from oropharyngeal specimen and following P aeruginosa eradication therapy. Culture results from the BAL fluid informed treatment decisions	N=168 infants with CF <6 months Mean age (SD): 3.6 (1.6) months Standard therapy: n=84 BAL therapy: n=86 Children were followed until age 5 years	FEV₁ z scores Weight z scores Height z scores BMI z scores	Indirectness: intervention in BAL monitoring group does not reflect that of current clinical practice

: BAL: bronchoalveolar lavage; CFFPR: cystic fibrosis Foundation Patient Registry; MD: mean difference; SD: standard deviation

Table 62Summary clinical evidence profile: Monitoring technique 3. Lung physiological function tests (FEV₁% predicted at baseline) for prognosis of pulmonary exacerbations and FEV₁ percent predicted at 10 years

Prognostic factors	Included studies	Study design	Setting	n	Result (adjRR, MD)	Quality	Notes
Pulmonary exacerbations (defined as hospitalizations treated with IV AB), 10 year follow-up
FEV₁ % predicted, 5-point decrease	1 (Sanders 2015)	Cohort study	CF centres in Europe	60	adjRR: 1.19 (95% CI: 1.10 - 1.30)	Moderate¹	Multiple Poisson model adjusted for sex, genotype, FEV₁ and mucoid P aeruginosa status at time of chest CT. p value = < 0.001
Difference in FEV₁ % predicted
FEV₁ % predicted, 5-point decrease	1 (Sanders 2015)	Cohort study	CF centres in Europe	60	MD: −4.47 (95% CI: −6.48 to - 2.76)	Moderate¹	Multiple linear model adjusted for sex, genotype, FEV₁ and mucoid P aeruginosa status at time of chest CT. p value = < 0.001

: Abbreviations: adjRR: adjusted rate ratio; CF: cystic fibrosis; CI: confidence interval; CT: computerised tomography; FEV₁: forced expiratory volume in 1 second; MD: mean difference adjRR: adjusted rate ratio 1 The quality of the evidence was downgraded by 1 due to no adjustments for the confounder of concurrent treatment with immunomodulatory and/or mucolytic agents.

Table 63Summary clinical evidence profile: Monitoring technique 4. Chest CT scan for prognosis of pulmonary exacerbations and FEV₁% predicted at 10 years

Prognostic factors	Included studies	Study design	Setting	n	Result (adjRR, MD)	Quality	Notes
Pulmonary exacerbations (defined as hospitalizations treated with IV AB), 10 year follow-up
Brody chest CT score, 1-point increase	1 (Sanders 2015)	Cohort study	CF centres in Europe	60	adjRR: 1.39 (95% CI: 1.15 - 1.67)	Moderate¹	Multiple Poisson model adjusted for sex, genotype, FEV₁ and mucoid P aeruginosa status at time of chest CT. p value = < 0.001
Difference in FEV₁ % predicted, 10 year follow-up
Brody chest CT score, 1-point increase	1 (Sanders 2015)	Cohort study	CF centres in Europe	60	MD: - 4.76 (95% CI: −7.80 to - 1.72)	Moderate¹	Multiple linear model adjusted for sex, genotype, FEV₁ and mucoid P aeruginosa status at time of chest CT. p value = 0.003

: Abbreviations: adjRR: adjusted rate ratio; CF: cystic fibrosis; CI: confidence interval; CT: computerised tomography; FEV₁: forced expiratory volume in 1 second; MD: mean difference
1: The quality of the evidence was downgraded by 1 due to no adjustments for the confounder of concurrent treatment with immunomodulatory and/or mucolytic agents

Table 64Summary clinical evidence profile: Comparison 1. FEV₁% predicted versus chest CT scan for prognosis of pulmonary exacerbations and FEV₁% predicted at 10 years

Comparison 1. FEV₁% predicted versus chest CT scan for prognosis of pulmonary exacerbations and FEV₁% predicted at 10 years
Outcomes	Illustrative comparative risks* (95% CI)		Difference between tests p-value	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	FEV₁% predicted, 5% decrease	Brody chest CT score, 1-point decrease	Difference between tests p-value	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
Pulmonary exacerbations, defined as hospitalization treated with IV AB Follow-up: 10 years	adjRR = 1.19 (95% CI: 1.10 - 1.30)²	adjRR = 1.39 (95% CI: 1.15 - 1.67)²	RR = 0.86*, p-value =0.037 By ChiSquare test2	60 (Sanders 2015)	⊕⊕⊕⊝ moderate¹	Multiple Poisson model adjusted for sex, genotype, FEV₁ and mucoid P aeruginosa status at time of chest CT.
Change/decline in FEV₁% predicted Follow-up: 10 years	Mean difference: −4.47 (95% CI: −6.48 to 2.76)	Mean difference: - 4.76 (95% CI: −7.80 to - 1.72)	MD: 0.29*, p-value = 0.4 By F test²	60 (Sanders 2015)	⊕⊕⊕⊝ moderate¹	Multiple linear model adjusted for sex, genotype, FEV₁ and mucoid P aeruginosa status at time of chest CT.

*: The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
: Abbreviations: AB: antibiotics; adjRR: adjusted rate ratio; CI: confidence interval; FEV₁: forced expiratory volume in 1 second; IV: intravenous; MD: mean difference
*: Calculated by NGA technical team
: adjRR: adjusted rate ratio
1: The quality of the evidence was downgraded by 1 due to no adjustments for the confounder of concurrent treatment with immunomodulatory and/or mucolytic agents
2: This result was reported narratively only

Table 65Summary clinical evidence profile: Comparison 1. BAL monitoring versus standard monitoring

Comparison 1. BAL monitoring versus standard monitoring
Outcomes	Illustrative comparative risks^* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Standard monitoring risk	BAL monitoring	Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
FEV₁ z score Better indicated by higher values Follow-up: 5 years	The mean FEV₁ in the control group was −0.41	The mean FEV₁ in the intervention group was 0.15 lower (0.58 lower to 0.28 higher)		157 (Wainwright 2011)	⊕⊕⊕⊝ moderate¹
Clearance of P aeruginosa following 1 or 2 courses of eradication therapy Better indicated by higher values Follow up: 5 years	907 per 1000	970 per 1000 (871 to 1000)	RR 1.07 (0.96 to 1.2)	82 (Wainwright 2011)	⊕⊕⊕⊝ moderate¹
Weight z scores Better indicated by higher values Follow-up: 5 years	The mean weight in the control group was −0.21	The mean weight in the intervention group was 0.06 higher (0.21 lower to 0.32 higher)		157 (Wainwright 2011)	⊕⊕⊝⊝ low¹^,²
Height z scores Better indicated by higher values Follow-up: 5 years	The mean height in the control group was −0.19	The mean height in the intervention group was 0.06 higher (0.23 to 0.35 lower)		157 (Wainwright 2011)	⊕⊕⊕⊝ moderate¹
BMI z scores, BMI calculated as weight in kg divided by height in meters squared. Better indicated by higher values Follow-up: 5 years	The mean BMI in the control group was 0.01	The mean BMI in the intervention group was 0.02 higher (0.25 lower to 0.3 higher)		157 (Wainwright 2011)	⊕⊕⊕⊝ moderate¹

*: The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
: Abbreviations: BAL: bronchoalveolar lavage; BMI: body mass index; FEV₁: forced expiratory volume in 1 second; MD: mean difference; RR: risk ratio
1: The quality of the evidence was downgraded by 1 due to serious indirectness as intervention in BAL monitoring group does not reflect that of current clinical practice.
2: The quality of the evidence was downgraded by 1 due to serious imprecision as 95% CI crossed 1 default MID.

Table 66Research recommendation rationale

Research question	Is lung clearance index a useful and cost-effective tool for the routine assessment and monitoring of changes in pulmonary status in people with cystic fibrosis?
Why this is needed
Importance to ‘patients’ or the population	LCI measured by multiple-breath washout (MBW) is a more sensitive test of impaired lung function compared to FEV₁, particularly in those with relatively normal pulmonary function. It may be a tool to help decisions on early intervention with treatment in children and adults with cystic fibrosis.
Relevance to NICE guidance	Validation of this tool for clinical care could change some recommendations for disease monitoring and treatment intervention. This is of particular relevance in pre-school children where FEV₁ is not reliably performed. High: the research is essential to inform future updates of key recommendations in the guideline
Relevance to the NHS	If validated and adopted training in Physiology labs and new equipment would be required. In pre-school children it may identify those who require increased intervention, and those who potentially need less regular monitoring and less aggressive therapy. Targeted treatment may potentially have cost savings.
National priorities	No document identified
Current evidence base	FEV₁ measurements are difficult to perform in preschool infants. FEV₁ measurements often do not become abnormal until significant lung disease is established.
Equality	This test is of particular relevance to preschool children.
Feasibility	The proposed research can be carried out within a realistic timescale and at an acceptable cost. There are no ethical or technical issues.
Other comments	None

Table 67Research recommendation statements

Criterion	Explanation
Population	Children with cystic fibrosis, up to 6 years old (pre-school children)
Intervention	LCI, measure by multiple breath washout (MBW) testing at regular intervals
Comparators	Alternative lung function test: FEV₁ (measured by spirometry)
Outcomes	Change in lung function Quality of life as measured by a validated tool, such as CF-QOL or CFQ-R) Nutritional parameters (BMI, weight/height) Time to chronic infection Resource use Unit costs
Study design	RCT or cluster RCT
Timeframe	Within 2 years

Table 68Summary of included studies

Study	Intervention/Co mparison	Population	Outcomes	Comments
Cochrane systematic reviews
McIlwaine 2015 Cochrane SR	Positive Expiratory Pressure (PEP) vs High Frequency Chest Wall Oscillation (HFCWO) (McIlwaine 2013) Positive expiratory pressure (PEP) vs oscillating device (McIlwaine 2001, Newbold 2005, Tannenbaum 2005)	People with CF of any age with any degree of disease severity. People with CF post-lung transplant were excluded.	PEP vs HFCWO Sputum weight (dry and wet) PEP vs oscillating device: Patient preference (self-withdrawal due to lack of effectiveness) Hospitalisations for respiratory exacerbation Number of participants experiencing respiratory exacerbations Lung function Quality of life Not reported: Oxygen saturation
Moran 2013 Cochrane SR	Overnight noninvasive ventilation (NIV) vs no airway clearance technique (room air) (Young 2008) Positive Expiratory Pressure (PEP) mask vs no airway clearance (directed cough) (Placidi 2006)*	People with CF of any age with any type of acute and chronic respiratory failure.	NIV vs no airway clearance technique: Lung function Oxygen saturation (nocturnal) Quality of life PEP vs no airway clearance technique: Sputum weight Lung function Oxygen saturation Not reported: Patient preference Pulmonary exacerbations Hospitalisations	*Comparison not in Cochrane SR; comparison made by the NGA technical team using data from controls in comparisons included in Cochrane SR.
Morrison 2014 Cochrane SR	Positive Expiratory Pressure (PEP) vs High Frequency Chest Wall Oscillation (HFCWO) (Braggion 1995, Derbee 2005, Grzincich 2008) Positive expiratory pressure (PEP) vs oscillating device (flutter) (Padman 1999, van Winden 1998) Oscillating device vs High Frequency Chest Wall Oscillation (Oermann 2001) Manual physiotherapy techniques vs oscillating devices (flutter) (Homnick 1998, Padman 1999) Manual physiotherapy vs High Frequency Chest Wall Oscillation (Warwick 2004)	Children, young people and adults with CF with any degree of disease severity.	PEP vs HFCWO: Sputum volume Lung function PEP vs oscillating device: Lung function Oscillating device vs HFCWO: Lung function Manual techniques vs HFCWO: Sputum weight. Manual techniques vs oscillating device: Lung function Not reported: Patient preference Pulmonary exacerbations Hospitalisations Oxygen saturation (nocturnal) Quality of life
Warnock 2013 Cochrane SR	Positive expiratory pressure (PEP) mask vs no airway clearance technique (Braggion 1995)	People with CF of any age.	PEP vs control: lung function test Not reported: Expectorated secretions Sputum volume Patient preference Pulmonary exacerbations Hospitalisations Oxygen saturation (nocturnal) Quality of life
Primary studies included in the Cochrane SR
Braggion 1995 (Italy) RCT, crossover design	Intervention 1: Positive expiratory pressure (PEP) 50-minute session (unclear if this included 15 mins of nebulisation) Intervention 2: High Frequency Chest Wall Oscillation (HFCWO) 50-minute session (unclear if this included 15 mins of nebulisation) Control: no airway clearance	N=16 young people and adults with CF Mean age (SD): 20.3 (4) years. Age range: 15 to 27	FEV₁ % predicted FVC % predicted	Included in Morrison 2014 SR and in Warnock 2013 SR 15 minutes of saline nebulised prior to treatment. 2 treatments per day for 2 days, then rest 1 day. Next intervention for 2 days, then rest 1 day. Then the final intervention.
Darbee 2005 (USA) RCT, crossover design	Intervention 1: Positive expiratory pressure (PEP) mask 30-minute sessions Intervention 2: High Frequency Chest Wall Oscillation (HFCWO) 30-minute sessions	N=15 children, young people and adults with CF Age ≥7 years. Mean (SD) age: 17.5 (4.2) Participants were admitted to hospital for acute exacerbation. All participants performed HFCWO 1 - 3 times daily as outpatients before admission, but none had performed PEP	FEV₁ % predicted FVC % predicted	Included in Morrison 2014 SR Both treatments were alternated within 48 hours of hospital admission and then reversed prior to discharge.
Grzincich 2008 (Country not reported) RCT, unclear if crossover design	Intervention 1: Positive expiratory pressure (PEP) 30-minute sessions Intervention 2: High Frequency Chest Wall Oscillation (HFCWO) 30-minute sessions	N=23 adults with CF Mean age: 25 years. People hospitalized for an exacerbation	Sputum volume	Included in Morrison 2014 SR Interventions and control implemented during the first 3 days of hospitalisation for an exacerbation Abstract only
Homnick 1998 (USA) RCT, crossover design	Intervention 1. Manual physiotherapy 30-minute sessions, 4 times daily during hospitalisation Intervention 2. Oscillating device (flutter) 15-minute sessions, 4 times daily during hospitalisation	N=22 children, young people and adults with CF (33 hospitalisations) Mean (range) age: 12 (7 to 44)	% change from baseline in FEV₁ % change from baseline in FVC	Included in Morrison 2014 SR
McIlwaine 2001 (Canada) RCT, parallel design	Intervention 1. Positive expiratory pressure (PEP) mask 20-minute sessions twice daily for 1 year Intervention 2. Oscillating device (flutter) Sessions of ≥15 minutes twice daily for 1 year	N=40 children and young people with CF Age range: 7 to 17 Intervention 1: n=20 Intervention 2: n=20 Participants were excluded if they had been hospitalised within the past month for a pulmonary exacerbation, or if they were not stable on clinical evaluation, chest radiograph or pulmonary function	Patient preference: self-withdrawal due to lack of perceived effectiveness FEV₁ (% change from baseline) FVC (% change from baseline)	Included in McIlwaine 2015 SR
McIlwaine 2013 (Canada) Multi-centre RCT, parallel design	Intervention 1: Positive expiratory pressure (PEP) mask 6 cycles; treatment for 1 year Intervention 2: High Frequency Chest Wall Oscillation (HFCWO) 6 sets of 5-minute cycles; treatment for 1 year	N=107 children, young people and adults with CF from 12 CF centres. PEP: n=51 HFCWO: n=56 Age range: 6 to 47 years. FEV₁>40% predicted Participants were excluded if they had been hospitalised within the past month for a pulmonary exacerbation, or if they were not stable on clinical evaluation, chest radiograph or pulmonary function.	FEV₁ (% change from baseline) FVC (% change from baseline) QoL (CFQ-R: physical domain, treatment burden, respiratory domain)	Included in McIlwaine 2015 SR On entering the study, participants performed a 2-month washout period before being allocated to an intervention
Newbold 2005 (Canada) RCT, parallel design	Intervention 1: Positive expiratory pressure (PEP) mask 20-minute session, twice daily for 13 months Intervention 2: Oscillating device (flutter) Duration approx. 20 minutes, twice daily for 13 months	N=42 adults with CF PEP: n=21. Mean (SD) age: 28 (8.1) Flutter: n=21. Mean (SD) age: 31 (8.7) Participants were excluded if they had been hospitalised within the past month for a pulmonary exacerbation, had changed their medication within the past month, or did not have a daily cough or daily sputum	FEV₁ (% change from baseline) FVC (% change from baseline) Hospitalizations for respiratory exacerbations	Included in McIlwaine 2015 SR
Oermann 2001 (USA) RCT, crossover design	Intervention 1: Oscillating device (flutter). Number of times per day not reported Intervention 2: High Frequency Chest Wall Oscillation. Number of times per day not reported.	N=29 children, young people and adults with CF Mean (range) age: 23 (9 to 39) Baseline FVC range: 50 to 80 % predicted Clinically stable for 1 month prior to enrolment.	FEV₁ % predicted FVC % predicted	Included in Morrison 2014 SR 5 participants withdrew (4 exited due to illness and 1 due to noncompliance with clinic visits) 4 weeks in each arm, 2-week lead-in/wash out periods during which time they resumed their normal routine therapies which were not outlined
Padman 1999 (USA) RCT, crossover design	Intervention 1: Manual chest physiotherapy Intervention 2: Positive expiratory pressure (PEP) mask 15-minute sessions, 3 times per day for 1 month Intervention 3: Oscillating device (flutter) 15-minute sessions, 3 times per day for 1 month	N=15 children and young people with CF were randomized, 6 completed the study. Age range: 5 to 17 Participants were clinically stable and able to perform respiratory function tests; no hospitalisations in the month prior to the study	% change from baseline in FEV₁	Included in Morrison 2014 SR 5 participants excluded due to hospital admission for acute exacerbation, 4 withdrew (no reason given)
Placidi 2006 (Australia) RCT, crossover design	Intervention: Positive expiratory pressure (PEP) mask Control: no airway clearance technique (directed cough)	N= 17 young people and adults with CF Age: >15 years. Mean (SD) age: 28 (7) People had severe lung disease and were admitted for pulmonary exacerbation.	Sputum dry weight Sputum wet weight Lung function - FEV₁ Lung function - FVC Oxygen saturation - Spo2 %	Included in Moran 2013 SR Follow-up: mean 2 days
Tannenbaum 2005 (Country not reported) RCT, parallel design	Intervention 1: Positive expiratory pressure (PEP) mask Intervention 2: oscillating device (cornet)	N = 30 children and young people with CF Age range: 6 to 15 years	% change from baseline FEV₁	Included in McIlwaine 2015 SR Information was provided from 3 abstracts, no further information obtained
Young 2008 (Australia) RCT, crossover design	Intervention: Overnight noninvasive ventilation for 6 weeks Control: No airway clearance technique (room air) for 6 weeks	N=8 adults with CF Mean (SD) age: 37 (8) years Participants with moderate lung disease.	FEV₁ % predicted FVC % predicted Oxygen saturation (nocturnal) (%) Quality of life: CF QOL chest symptom score; CF QOL traditional dyspnoea index score	Included in Moran 2013 SR 2-week washout period
van Winden 1998 (The Netherlands) RCT, crossover design	Intervention 1: Positive expiratory pressure (PEP) mask Twice daily Intervention 2: Oscillating device (flutter) Twice daily	N=22 children and young people with CF Mean age (range): 12 years (7 to 17). People were clinically stable for 2 weeks before the study	FEV₁ % predicted FVC % predicted	Included in Morrison 2014 SR 2 weeks in each arm, 1 week wash-in and wash-out period
Warwick 2004 (USA) RCT, crossover design	Intervention 1: Manual physiotherapy. 10 hand positions Duration: approximately 45 to 50 minutes daily for 4 weeks Intervention 2: High Frequency Chest Compression Duration: approximately 36 to 50 minutes daily for 4 weeks	N=12 adults with CF Age mean (range): 29.1 (19 to 50) Consistent sputum producers; all volunteers with no illness within 6 weeks of study	Sputum weight (dry) Sputum weight (wet)	Included in Morrison 2014 SR All treatments preceded by nebulisers.

: CF: cystic fibrosis, HFCWO: high frequency chest wall oscillation; PEP: positive expiratory pressure; SR: systematic review

Table 69Summary clinical evidence profile: Comparison 2. Manual physiotherapy versus oscillating devices

Comparison 2. Manual physiotherapy compared to oscillating device for CF
Outcomes	Illustrative comparative risks^* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Assumed risk	Corresponding risk	Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Oscillating device (OD)	Manual physiotherapy
Lung function Measured as FEV₁ % change from baseline Scale from: 0 to 100 Follow-up: mean 8.8 days	The mean % change from baseline in FEV₁ in the OD group was 43.7	The mean % change from baseline in FEV₁ in the manual physiotherapy groups was 7.9 lower (31.04 lower to 15.24 higher)		22 (Homnick 1998)	⊕⊝⊝⊝ very low¹^,²
Lung function Measured as FEV₁ % change from baseline Scale from: 0 to 100 Follow-up: mean 1 months	The mean % change from baseline in FEV₁ in the OD group was 3.66	The mean % change from baseline in FEV₁ in the manual physiotherapy groups was 2.59 higher (6.3 lower to 11.48 higher)		6 (Padman 1999)	⊕⊝⊝⊝ very low³^,⁴
Lung Function - FVC % change from baseline Scale from: 0 to 100 Follow-up: mean 2 weeks	The mean % change from baseline in FVC in the OD group was 27.2	The mean % change from baseline in FVC in the manual physiotherapy group was 2.9 higher (14.21 lower to 20.01 higher)		22 (Homnick 1998)	⊕⊝⊝⊝ very low¹^,⁴

*: The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
: Abbreviations: CI: confidence interval; FEV₁: forced expiratory volume in 1 second; FVC: forced vital capacity; MD: mean difference
1: The quality of the evidence downgraded by 2 due to selection bias and attrition bias
2: The quality of the evidence was downgraded by 1 due to serious imprecision as 95% CI crossed 1 default MID
3: The quality of the evidence was downgraded by 2 due to attrition bias and reporting bias.
4: The quality of the evidence was downgraded by 2 due to very serious imprecision as 95% CI crossed 2 default MIDs

Table 70Summary clinical evidence profile: Comparison 3. Manual physiotherapy versus high frequency chest wall oscillation

Comparison 3. Manual physiotherapy techniques compared to high frequency chest oscillation therapy for CF
Outcomes	Illustrative comparative risks^* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Assumed risk	Corresponding risk	Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	High frequency chest oscillation therapy (HFCWO)	Manual physiotherapy
Sputum weight (dry) (grams) Follow-up: 1–2 weeks	The mean sputum weight (dry) in the HFCWO groups was 0.57	The mean sputum weight (dry) in the manual physiotherapy groups was 0.13 lower (0.42 lower to 0.16 higher)		12 (Warwick 2004)	⊕⊕⊝⊝ low¹^,²
Sputum weight (wet) (grams) Follow-up: 1–2 weeks	The mean sputum weight (wet) in the HFCWO groups was 13.56	The mean sputum weight (wet) in the manual physiotherapy groups was 4.04 lower (10.77 lower to 2.69 higher)		12 (Warwick 2004)	⊕⊕⊝⊝ low¹^,²

*: The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
: Abbreviations: CI: confidence interval; FEV₁: forced expiratory volume in 1 second; HFCWO: high frequency chest wall oscillation; MD: mean difference
1: The quality of the evidence was downgraded by 1 due to lack of blinding.
2: The quality of the evidence was downgraded by 1 due to serious imprecision as 95% CI crossed a default MID

Table 71Summary clinical evidence profile: Comparison 4. Positive expiratory pressure (PEP) versus no airway clearance technique

Comparison 4. Positive expiratory pressure (PEP) compared to no airway clearance technique for CF
Outcomes	Illustrative comparative risks^* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Assumed risk	Corresponding risk	Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	No airway clearance technique	Positive expiratory pressure (PEP)
Sputum dry weight (grams) Follow-up: mean 2 days	The mean sputum dry weight in the control groups was 0.97	The mean sputum dry weight in the PEP groups was 0.03 lower (0.48 lower to 0.42 higher)		17 (Placidi 2006)	⊕⊕⊝⊝ low¹
Sputum wet weight (grams) Follow-up: mean 2 days	The mean sputum wet weight in the control groups was 13.98	The mean sputum wet weight in the PEP groups was 1.8 higher (1.72 lower to 5.32 higher)		17 (Placidi 2006)	⊕⊕⊕⊝ moderate²
Lung function - FEV₁ % predicted Scale from: 0 to 100 Follow-up: mean 2 days	The mean FEV₁% predicted in the control groups was 60.3	The mean FEV₁% predicted in the PEP groups was 2.1 higher (11.73 lower to 15.93 higher)		16 (Braggion 1995)	⊕⊝⊝⊝ very low³^,⁴
Lung function - FEV₁ (litres) Follow-up: mean 2 days	The mean FEV₁ (litres) in the control groups was 0.99	The mean FEV₁ (litres) in the PEP groups was 0.01 higher (0.18 lower to 0.2 higher)		17 (Placidi 2006)	⊕⊕⊝⊝ low¹
Lung Function FVC % predicted Scale from: 0 to 100 Follow-up: mean 2 days	The mean FVC % predicted in the control groups was 81.6 % predicted	The mean FVC % predicted in the PEP groups was 1.2 higher (12.88 lower to 15.28 higher)		16 (Braggion 1995)	⊕⊝⊝⊝ very low¹^,³
Lung function - FVC (litres Follow-up: mean 2 days	The mean FVC (litres) in the control groups was 1.96	The FVC in the PEP groups was 0.05 higher (0.35 lower to 0.45 higher)		17 (Placidi 2006)	⊕⊕⊝⊝ low¹
Oxygen saturation - Spo2 % Scale from: 0 to 100 Follow-up: mean 2 days	The mean oxygen saturation (spo2) in the control groups was 94.6	The mean oxygen saturation (spo2) in the PEP groups was 0.3 higher (0.58 lower to 1.18 higher)		17 (Placidi 2006)	⊕⊕⊕⊝ moderate²

*: The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
: Abbreviations: CI: confidence interval; FEV₁: forced expiratory volume in 1 second; FVC: forced vital capacity; MD: mean difference; SpO2: peripheral capillary oxygen saturation
1: The quality of the evidence was downgraded by 2 due to very serious imprecision as 95% CI crossed 2 default MIDs
2: The quality of the evidence was downgraded by 1 due to serious imprecision as 95% CI crossed a default MID
3: The quality of the evidence was downgraded by 2 due to lack of blinding, attrition bias and reporting bias
4: The quality of the evidence was downgraded by 2 due to very serious imprecision as 95% CI crossed 2 clinical MIDs

Table 72Summary clinical evidence profile: Comparison 6. Positive expiratory pressure (PEP) versus oscillating devices

Comparison 6. Positive expiratory pressure (PEP) compared to oscillating device for CF
Outcomes	Illustrative comparative risks^* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Assumed risk	Corresponding risk	Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	oscillating device (OD)	Positive expiratory pressure (PEP)
Patient preference: self-withdrawal due to lack of perceived effectiveness Follow-up: mean 1 years	250 per 1000	22 per 1000 (2 to 385)	RR 0.09 (0.01 to 1.54)	40 (McIlwaine 2001)	⊕⊝⊝⊝ very low¹^,²
Hospitalizations for respiratory exacerbations number per participant Follow-up: mean 13 months	The mean number of hospitalizations for respiratory exacerbations in the OD group was 0.7 per participant	The mean hospitalizations for respiratory exacerbations in the PEP groups was 0.4 lower (0.92 lower to 0.12 higher)		42 (Newbold 2005)	⊕⊕⊝⊝ low³^,⁴
Lung function - FEV₁ % change from baseline Scale from: 0 to 100 Follow-up: 2–4 weeks	The mean % change from baseline in FEV₁ in the OD group was 3.66	The mean % change from baseline in FEV₁ in the PEP groups was 4.08 higher (4.66 lower to 12.82 higher)		6 (Padman 1999)	⊕⊝⊝⊝ very low⁴^,⁵
Lung function - FEV₁ % change from baseline Scale from: 0 to 100 Follow-up: mean 6–12 months	The mean % change from baseline in FEV₁ in the OD groups was −10.95	The mean % change from baseline in FEV₁ in the PEP groups was 9.71 higher (2.12 lower to 21.54 higher)		30 (McIlwaine 2001)	⊕⊕⊝⊝ low¹^,⁴
Lung function - FEV₁ % change from baseline Scale from: 0 to 100 Follow-up: 1–2 years	The mean % change from baseline in FEV₁ in the OD groups was 2.78	The mean % change from baseline in FEV₁ in the PEP groups was 2.82 lower (6.36 lower to 0.72 higher)		160 (McIlwaine 2013, Newbold 2005, Tannenbaum 2005)	⊕⊕⊝⊝ low⁴^,⁶
Lung function - FVC % change from baseline Scale from: 0 to 100 Follow-up: mean 1 years	The mean % change from baseline in FVC in the OD groups was −0.07	The mean % change from baseline in FVC in the PEP groups was 0.44 lower (6.66 lower to 5.78 higher)		160 (McIlwaine 2001, McIlwaine 2013, Newbold 2005)	⊕⊕⊝⊝ low⁶^,⁷
Lung function - FVC (% predicted) Scale from: 0 to 100 Follow-up: 2–4 weeks	The mean FVC % predicted in the OD groups was 99 % predicted	The mean FVC % predicted in the PEP groups was 2 lower (4.09 lower to 0.09 higher)		22 (van Winden 1998)	⊕⊕⊕⊝ moderate⁴
QOL – CFQ-R: physical domain Scale from: 0 to 100 Follow-up: mean 1 years	The mean CFQ-R - physical domain in the OD groups was −3.04	The mean CFQ-R - physical domain in the PEP groups was 2.2 higher (1.32 lower to 5.72 higher)		107 (McIlwaine 2013)	⊕⊕⊕⊕ high⁸
QOL – CFQ-R: treatment burden Scale from: 0 to 100 Follow-up: mean 1 years	The mean QOL-CFQ-R: treatment burden in the OD groups was −3.6	The mean QOL – CFQ-R: treatment burden in the PEP groups was 1.05 higher (6.35 lower to 8.45 higher)		107 (McIlwaine 2013)	⊕⊕⊕⊕ high⁸
QOL – CFQ-R: respiratory domain Scale from: 0 to 100 Follow-up: mean 1 years	The mean CFQ-R - respiratory domain in the OD groups was 0.19	The mean CFQ-R - respiratory domain in the PEP groups was 2.79 higher (3.68 lower to 9.26 higher)		107 (McIlwaine 2013)	⊕⊕⊕⊝ moderate⁸^,⁹

*: The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
: Abbreviations: CI: confidence interval; CFQ-R: cystic fibrosis questionnaire revised; FEV1: forced expiratory volume in 1 second; FVC: forced vital capacity; MD: mean difference; OD: oscillating device; PEP: positive expiratory pressure; RR: risk ratio
1: The quality of the evidence was downgraded by 1 due to reporting bias.
2: The quality of the evidence was downgraded by 2 due to very serious imprecision as 95% CI crossed 2 default MIDs
3: The quality of the evidence was downgraded by 1 due to differences in baseline characteristics (pulmonary function values) between both groups.
4: The quality of the evidence was downgraded by 1 due to serious imprecision as 95% CI crossed a default MID
5: The quality of the evidence was downgraded by 2 due to attrition bias and reporting bias.
6: Taking into account weighting in a meta-analysis and the likely contribution from each component, the quality of the evidence was downgraded by 1 due differences in baseline participant characteristics.
7: The quality of the evidence was downgraded by 1 due to serious heterogeneity (I-squared inconsistency statistic of 69%) and no plausible explanation was found with sensitivity analysis.
8: Clinical MID=8.5 was used to assess imprecision because the CFQ-R questionnaire (Quittner et al. 2009) was used
9: The quality of the evidence was downgraded by 1 as 95% CI crossed 1 clinical MID

Table 73Summary clinical evidence profile: Comparison 7. Positive expiratory pressure (PEP) versus High Frequency Chest Wall Oscillation (HFCWO)

Comparison 7. Positive expiratory pressure (PEP) compared to high frequency chest wall oscillation (HFCWO) for CF
Outcomes	Illustrative comparative risks^* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Assumed risk	Corresponding risk	Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	High frequency oscillation therapy (HFCWO)	Positive expiratory pressure (PEP)
Sputum volume (ml) Follow-up: mean 1 weeks	The mean sputum volume in the HFCWO groups was 6.7	The mean sputum volume in the PEP groups was 1.8 higher (3 lower to 6.6 higher)		23 (Grzincich 2008)	⊕⊕⊝⊝ low¹^,²
Respiratory exacerbations: number of patients Follow-up: mean 1 years	833 per 1000	608 per 1000 (458 to 792)	RR 0.73 (0.55 to 0.95)	91 (McIlwaine 2013)	⊕⊕⊕⊝ moderate²
Pulmonary exacerbations (patients requiring antibiotics) Follow-up: mean 1 years	870 per 1000	615 per 1000 (348 to 824)	RR 0.71 (0.55 to 0.93)	88 (McIlwaine 2013)	⊕⊕⊕⊝ moderate²
Lung function - FEV₁ % predicted Scale from: 0 to 100 Follow-up: 1 weeks	The mean FEV₁ % predicted in the HFCWO groups was 64.8	The mean FEV₁ % predicted in the PEP groups was 0.67 higher (8.04 lower to 9.38 higher)		39 (Braggion 1995; Grzincich 2008)	⊕⊝⊝⊝ very low³^,⁴
Lung Function - FEV₁ % predicted Scale from: 0 to 100 Follow-up: 1–2 weeks	The mean FEV₁ % predicted in the HFCWO groups was 69	The mean FEV₁ % predicted in the PEP groups was 3 lower (20.54 lower to 14.54 higher)		15 (Darbee 2005)	⊕⊝⊝⊝ very low⁴^,⁵
Lung function - FEV₁ change from baseline in FEV₁ % predicted Scale from: 0 to 100 Follow-up: 1 years	The mean change in FEV₁ % predicted in the HFCWO groups was 9.4	The mean change in FEV₁ % predicted in the PEP groups was 3.59 lower (9.29 lower to 2.11 higher)		88 (McIlwaine 2013)	⊕⊕⊕⊝ moderate⁶
FVC % predicted Scale from: 0 to 100 Follow-up: 1–2 weeks	The mean FVC % predicted in the HFCWO groups was 83	The mean FVC in the PEP groups was 3 lower (16.6 lower to 10.6 higher)		15 (Darbee 2005)	⊕⊝⊝⊝ very low⁵^,⁷
FVC % predicted Scale from: 0 to 100 Follow-up: 1 weeks	The mean FVC % predicted in the HFCWO groups was 86.4	The mean FVC % predicted in the PEP groups was 0.66 higher (7.4 lower to 8.71 higher)		39 (Braggion 1995, Grzincich 2008)	⊕⊕⊕⊝ moderate³
Lung function - FVC change from baseline in % predicted Scale from: 0 to 100 Follow-up: 1 years	The mean change in FVC % predicted in the HFCWO groups was 11.39	The mean change in FVC % predicted in the PEP groups was 5 lower (10.3 lower to 0.3 higher)		88 (McIlwaine 2013)	⊕⊕⊕⊝ moderate²

*: The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
: Abbreviations: CI: confidence interval; FEV₁: forced expiratory volume in 1 second; FVC: forced vital capacity; HFCWO: high frequency chest wall oscillation; MD: mean difference; PEP: positive expiratory pressure; RR: risk ratio
1: The quality of the evidence was downgraded by 1 as risk of bias could not be fully assessed from abstract paper which did not discuss method in detail.
2: The quality of the evidence was downgraded by 1 due to serious imprecision as 95% CI crossed a default MID.
3: Taking into account weighting in a meta-analysis and the likely contribution from each component, the quality of the evidence was downgraded by 1 as risk of bias could not be fully assessed from abstract paper which did not discuss method in detail.
4: The quality of the evidence was downgraded by 2 due to very serious imprecision as 95% CI crossed 2 clinical MIDs.
5: The quality of the evidence was downgraded by 1 due to selection bias.
6: The quality of the evidence was downgraded by 1 due to serious imprecision as 95% CI crossed a clinical MID
7: The quality of the evidence was downgraded by 2 due to very serious imprecision as 95% CI crossed 2 default MIDs

Table 74Summary clinical evidence profile: Comparison 12. Oscillating device versus High Frequency Chest Wall Oscillation (HFCWO)

Comparison 12. Oscillating device compared to high frequency chest wall oscillation for CF
Outcomes	Illustrative comparative risks^* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Assumed risk	Corresponding risk	Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	High frequency chest wall oscillation (HFCWO)	Oscillating device (OD)
Lung function - FEV₁ % predicted Follow-up: 2–4 weeks	The mean FEV₁ % predicted in the HFCWO groups was 56.5	The mean FEV₁ % predicted in the OD groups was 1.6 lower (3.44 lower to 0.24 higher)		24 (Oermann 2001)	⊕⊕⊕⊝ moderate¹
Lung function - FVC % predicted Follow-up: 2–4 weeks	The mean FVC % predicted in the HFCWO groups was 74	The mean FVC% predicted in the OD groups was 1.4 lower (3.07 lower to 0.27 higher)		24 (Oermann 2001)	⊕⊕⊝⊝ low¹^,²

*: The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
: Abbreviations: CI: confidence interval; FEV₁: forced expiratory volume in 1 second; FVC: forced vital capacity; HFCWO: high frequency chest wall oscillation; MD: mean difference; OD: oscillating device
1: The quality of the evidence was downgraded by 1 due to reporting bias.
2: The quality of the evidence was downgraded by 1 due to serious imprecision as 95% CI crossed a default MID.

Table 75Summary clinical evidence profile: Comparison 14. Non-invasive ventilation (NIV) versus no airway clearance technique

Comparison 14. Non-invasive ventilation (NIV) compared to no airway clearance technique for CF
Outcomes	Illustrative comparative risks^* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Assumed risk	Corresponding risk	Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	No airway clearance technique	Non-invasive ventilation (NIV)
Lung function - FEV₁ % predicted Scale from: 0 to 100 Follow-up: 6 weeks	The mean FEV₁ % predicted in the control groups was 32	The mean FEV₁ % predicted in the NIV groups was 1 higher (8.62 lower to 10.62 higher)		8 (Young 2008)	⊕⊕⊝⊝ low¹
Lung function - FVC % predicted Scale from: 0 to 100 Follow-up: 6 weeks	The mean FVC % predicted in the control groups was 54	The FVC% predicted in the NIV groups was 4 higher (10.3 lower to 18.3 higher)		8 (Young 2008)	⊕⊕⊝⊝ low²
Oxygen saturation (nocturnal) % Scale from: 0 to 100 Follow-up: 6 weeks	The mean oxygen saturation (%) (nocturnal) in the control groups was 89	The mean oxygen saturation (nocturnal) (%) in the NIV groups was 3 higher (1.12 lower to 7.12 higher)		8 (Young 2008)	⊕⊕⊕⊝ moderate³
Quality of life - CF QOL chest symptom score Scale from: 0 to 100 Follow-up: 6 weeks	The mean CFQOL chest symptom score in the control groups was 64	The mean CF-QOL chest symptom score in the NIV groups was 7 higher (11.73 lower to 25.73 higher)		8 (Young 2008)	⊕⊕⊝⊝ low¹^,⁴
Quality of life - CF QOL traditional dyspnoea index score Scale from: 0 to 100 Follow-up: 6 weeks	The mean CFQOL traditional dyspnoea index score in the control groups was −1.9	The mean CF-QOL traditional dyspnoea index score in the NIV groups was 2.9 higher (0.71 to 5.09 higher)		8 (Young 2008)	⊕⊕⊕⊝ moderate⁴^,⁵

*: The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
: Abbreviations: CI: confidence interval; FEV₁: forced expiratory volume in 1 second; FVC: forced vital capacity; MD: mean difference; NIV: non-invasive ventilation
1: The quality of the evidence was downgraded by 2 due to very serious imprecision as 95% CI crossed 2 clinical MIDs
2: The quality of the evidence was downgraded by 2 due to very serious imprecision as 95% CI crossed 2 default MIDs
3: The quality of the evidence was downgraded by 1 due to serious imprecision as 95% CI crossed 1 default MID
4: Clinical MID=5 was used to assess imprecision for quality of life because the CF QOL questionnaire (Gee et al. 2000) was used
5: The quality of the evidence was downgraded by 1 due to serious imprecision as 95% CI crossed 1 clinical MID

Table 76Research Recommendation justification

Research question	How effective are daily airway clearance techniques in maintaining lung function in infants and children with cystic fibrosis?
Why this is needed
Importance to ‘patients’ or the population	Performing daily airway clearance techniques places considerable responsibility and time burden on parents and carers at a time when such techniques are challenging to perform and negotiate with the infant and child with cystic fibrosis. It is essential that parents, carers and people with CF are reassured that this level of input is based on proven clinical benefit. Parent, carers and people with CF frequently report in the literature that daily airway clearance routines are difficult to adhere to and incorporate into daily life. If routine airway clearance is not deemed necessary until a certain time point, this could have a significant impact on the quality of life of parents, carers and people with CF.
Relevance to NICE guidance	High: With this evidence, definitive recommendations could be made regarding ‘routine’ vs ‘when required’ use of airway clearance techniques – at present there is varied clinical practice throughout the UK
Relevance to the NHS	CF services need to be able to direct and plan the physiotherapy input to people with CF and their families/carers to ensure that the resources are placed where there is proven clinical benefit rather than basing service delivery on historical behaviours. Further evidence in this area will eliminate the need to provide an intervention ‘just in case’ it preserves lung health but in fact physiotherapists will be able to use the evidence to target the right patients with the right intervention based on evidence of the likelihood of improved health outcomes. There will be a financial advantage if less airway clearance devices are required in the future due to a reduction in routine airway clearance approaches in the UK. There may be a small financial disadvantage if more airway clearance devices are required if routine airway clearance is proven from diagnosis to benefit health outcomes. There is unlikely to be any change in the physiotherapy input required as interventions will continue to include exercise guidance, advice on assessment/monitoring of lung health and teaching of airway clearance techniques for when they are required.
National priorities	This research question is similar to one of the top 10 research priorities published by the James Lind Alliance in January 2017 – ‘Can exercise replace chest physiotherapy for people with CF’ The comparative group to ‘routine airway clearance’ is likely to include structured exercise so could help answer the above question for infants and children.
Current evidence base	The current evidence base includes mostly small, short term studies with limited methodological rigour and are unable to draw conclusions regarding the long-term impact of airway clearance techniques on lung health in people with CF. Most of the studies include people with respiratory symptoms and established lung disease and therefore it is also not possible to apply this knowledge to the asymptomatic person without evidence of lung disease. The current evidence base compares the different types of airway clearance techniques but has yet to answer the question whether airway clearance as an intervention provides any long term clinical benefit to lung health either in the symptomatic or indeed the asymptomatic person with CF.
Equality	CF centres across the UK have different approaches to routine airway clearance – further evidence will help direct care and potentially improve equity of access of evidence based physiotherapy interventions.
Feasibility	The research could be carried out within a realistic timescale and with realistic funding
Other comments	None

Table 77Research Recommendation Statements

Criterion	Explanation
Population	Infants and children with a diagnosis of cystic fibrosis – to be confirmed by specified criteria
Intervention	Daily airway clearance techniques
Comparators	Airway clearance techniques only when specified criteria met. For example, based on: - Disease severity - Asymptomatic/symptomatic
Outcomes	Expectorated secretions (mucus, sputum, phlegm) Sputum volume Hospitalisations, change in frequency Pulmonary exacerbations, change in frequency Lung function (FEV₁, FVC) o forced vital capacity (FVC) Oxygen saturation measured by pulse or transcutaneous oximetry Quality of Life (using a validated tool, such CFQ-R or CF-QOL) Patient preference Resource use Unit costs
Study design	Multicentre RCT
Timeframe	2–6 years

Table 78Summary of included studies

Study	Intervention/Comparison	Population	Outcomes	Comments
NICE Technology Appraisal
NICE Technical Appraisal (TA Mannitol 2012)	Comparison 1: Mannitol versus placebo CF-301 CF-302 Comparison 2: Mannitol versus other treatments No studies were included.	Adults with CF.	Comparison 1: Mannitol versus placebo Change in FEV₁ Reduction in pulmonary exacerbations Reduction of AB and hospitalization days Quality of life Safety Comparison 2: Mannitol versus other treatments n/a	CF-301: Bilton 2011 CF-302: Aitken 2012 This TA was reviewed in Riemsma et al., Mannitol dry powder for inhalation for the treatment of cystic fibrosis. Klejnen Systematic Reviews Ltd., 2011
Cochrane systematic reviews
Yang 2016 Cochrane SR	Comparison 1: Dornase Alfa versus placebo Amin 2011 Ballmann 1998 and Ballmann 2002 Fuchs 1994 Laube 1996 McCoy 1996 Minasian 2010 Quan 2001 Ramsey 1993a Ranasinha 1993 Shah 1995a Wilmott 1996 (non-NMA) Comparison 2: Dornase alfa versus hypertonic sodium chloride Suri 2001, Suri 2002 and Suri 2002a	Children and adults with CF (diagnosed clinically and by sweat or genetic testing) and with all stages of lung disease were included.	Comparison 1: Dornase Alfa versus placebo FEV₁ change People experiencing exacerbations Use of antibiotics Adverse events Change in quality of life Comparison 2: Dornase alfa versus hypertonic sodium chloride FEV₁ change Quality of life Days of inpatient treatment	AMSTAR: 10/11
Nolan 2015 Cochrane SR	Comparison 1: Mannitol versus placebo Aitken 2012 Bilten 2011 Comparison 2: Mannitol versus Dornase Alfa Minasian 2010 Comparison 3: Mannitol + Dornase Alfa versus Dornase Alfa Jaques 2008	Children and adults with CF (diagnosed clinically and by sweat or genetic testing) and including all degrees of disease severity.	Comparison 1: Mannitol versus placebo FEV₁ ml, % predicted Pulmonary exacerbations Time to first pulmonary exacerbation Number of patients needing AB/hospitalisation HRQOL – 11 domains Adverse events Comparison 2: Mannitol versus Dornase Alfa FEV₁% change Comparison 3: Mannitol + Dornase Alfa versus Dornase Alfa FEV₁% change	AMSTAR: 11/11
Wark 2010 Cochrane SR	Comparison 1: Nebulised hypertonic sodium chloride versus isotonic sodium chloride Elkins 2006 Comparison 2: hypertonic sodium chloride versus dornase alfa (dornase alfa) Ballmann 1998 and Ballmann 2002 Suri 2001, Suri 2002a and Suri 2002b	Children and adults with CF (diagnosed clinically and by sweat or genetic testing) and including all degrees of disease severity.	Comparison 1: Nebulised hypertonic sodium chloride versus isotonic sodium chloride FEV₁ Inflammatory markers Quality of life Hospital admissions Adverse events Comparison 2: hypertonic sodium chloride versus dornase alfa (dornase alfa) FEV₁ Quality of life Hospital admissions	AMSTAR: 9/11 The update for this review was not yet published when we carried out our review. Cochrane kindly provided us with a copy of the update. We concluded that the relevant studies included in the update were also included in Wark 2010.
Individual studies included in the TA or the Cochrane SR
CF-301: Bilton 2011 (Australia, New Zealand, UK, Ireland) Multi-centre RCT, parallel design	Intervention: Inhaled dry powder mannitol, 400 mg BD for 26 weeks Comparison: Subtherapeutic mannitol (mannitol 50 mg)	N=295 people with CF were randomized Mean (SD) age: 23 (11.3) years. Age ≥6 years. Participants were clinically stable at start of study.	Change in FEV₁ % predicted Time to first protocol defined pulmonary exacerbation Number of patients needing additional IV antibiotics Change in quality of life (HRQOL – CFQOL) Adverse events: bronchospasm (mild, moderate and severe) haemoptysis (mild, moderate and severe)	In NICE TA on Mannitol & in Cochrane SR Nolan 2015 Participants receiving hypertonic saline were excluded. High dropout rate, however sensitivity analysis showed a consistent treatment effect with no change to conclusions.
CF-302: Aitken 2012 (USA, Canada, Argentina, Europe) Multi-centre RCT, parallel design	Intervention: Inhaled dry mannitol, 400 mg BD for 26 weeks Comparison: Subtherapeutic mannitol (mannitol 50 mg)	N= 305 people with CF from 53 sites were randomized Mean age: 20 years. Age range: 6 to 53. Participants were clinically stable at start of study.	Change in FEV₁ % predicted Time to first protocol defined pulmonary exacerbation Number of patients needing additional IV antibiotics Change in quality of life (HRQOL – CFQOL) Adverse events: haemoptysis (mild, moderate and severe)	In NICE TA on Mannitol & in Cochrane SR Nolan 2015 Participants receiving hypertonic saline were excluded. High dropout rate, however sensitivity analysis showed a consistent treatment effect with no change to conclusions.
Amin 2011 (Canada) RCT, crossover design	Intervention: Dornase alfa, 2.5 mg OD for 4 weeks intervention/comparison, 4-week washout period Comparison: Placebo	N=19 people with CF were randomized. Age range: 6 to 18years Baseline FEV₁ ≥ 80% predicted	Change in FEV₁ % predicted Change in quality of life (measured with CFQ-R questionnaires)	In Cochrane SR Yang 2016 Data only reported on 17 people who completed the trial.
Ballmann 1998 and Ballmann 2002 (Germany) RCT, crossover design	Intervention 1: Nebulization of 2.5 mg dornase alfa OD 3 weeks intervention, 3-week washout period Intervention 2: Nebulization of 10 ml 5.85% sodium chloride OD	N=14 people with CF Mean age: 13.3. Age range not reported. With mild to moderate pulmonary involvement.	% change in FEV₁	In Wark 2010 and Yang 2016 Withdrawals were not discussed within the paper. Both interventions preceded by 2 puffs salbutamol via a spacer
Elkins 2006 (Australia) RCT, parallel design	Intervention: 7% sodium chloride BD 48 weeks Comparison: 0.9% sodium chloride BD	N=164 people with CF from 16 hospitals were randomized. Age ≥6 years Participants were in clinically stable condition.	% change in FEV₁ Change in quality of life (measured with CFQ-R questionnaires)	In Wark 2010 2 people were excluded from the analysis: 1 person in each group voluntarily withdrew before first dose. 17 people were lost to follow-up. 15 people stopped inhalation but continued visits.
Fuchs 1994 (USA) RCT, parallel design	Intervention: Nebulized dornase alfa 2.5 mg OD or BD 24 weeks Comparison: Placebo	N= 968 people with CF were randomized. Age: Over 5. FVC: > 40% predicted Clinically stable	Relative mean % change in FEV₁ Number of people experiencing exacerbations Adverse events: haemoptysis, voice alteration	In Cochrane SR Yang 2016 25 people withdrew from the study, 8 in the placebo group and once-daily group and 9 in the twicedaily group. All participants were included in the analysis.
Jaques 2008 (Australia and New Zealand) Multi-centre RCT, crossover design	Intervention: Inhaled dry powder mannitol 420mg BD for 2-weeks, 2week washout period Comparison: Non-respirable Mannitol	39 people with CF from 7 sites were randomized. Mean (range) age: 19.1 (range 8 to 48) years Participants were clinically stable at start of study	Change in FEV₁ % predicted Adverse events: haemoptysis (mild and severe)	In Cochrane SR Nolan 2015 No hypertonic saline within 2 weeks of start of study. 4 withdrawals.
Laube 1996 (USA) RCT, parallel design	Intervention: 2.5 mg nebulized dornase alfa BD for 6 days Comparison: placebo	N= 20 adults with CF Age: Over 18 With stable stage CF. FVC: 35%-75% predicted No withdrawals.	Relative mean % change in FEV₁ (overall and for subgroup with moderate disease)	In Cochrane SR Yang 2016 There were no withdrawals.
McCoy 1996 (USA) RCT, parallel design	Intervention: Nebulized dornase alfa 2.5 mg OD for 12 weeks Comparison: Placebo	N= 320 people with CF Age: 7 to 57 FVC: < 40% predicted.	Relative mean % change in FEV₁ Number of days of IV antibiotic use Adverse events: voice alteration	In Cochrane SR Yang 2016 40 participants withdrew from the trial.
Minasian 2010 (UK) RCT, crossover design	Intervention1: Mannitol 400mg BD Intervention 2: Dornase alfa alone: 2.5 mg BD Intervention 3: Mannitol (as above) plus dornase alfa (dose unclear) For 12 weeks	N=28 people with CF randomised Mean (SD) age: 13.3 (2.24) years. Age for eligibility was between 8 and 18 years. Participants were clinically stable at start of study. Currently receiving dornase alfa or having an FEV₁ >40% and <70% predicted (and therefore eligible to receive dornase alfa).	FEV₁ % change from baseline	In Cochrane SR Nolan 2015 and Cochrane SR Yang 2016 Participants using hypertonic saline were excluded. 45 were recruited but only 28 were randomised. 8 participants withdrew.
Quan 2001 (Australia, Belgium, Canada, Denmark, Germany, Ireland, Israel, Netherlands, Norway, Spain, Switzerland and the United States) Multi-centre RCT, parallel design	Intervention: 2.5 mg dornase alfa OD for 96 weeks Comparison: Placebo	N=474 children with CF randomized from 49 centres Age: 6 to 10 (mean age 8.4) FVC>85% predicted	Absolute mean % change in FEV₁ Number of people experiencing exacerbations Adverse events: voice alteration	In Cochrane SR Yang 2016 410 completed the study. 60 participants withdrew from the study. The ITT population was 470.
Ramsey 1993a (Country not reported) RCT, parallel design	Intervention: Nebulized dornase alfa 0.6 mg, 2.5 mg or 10 mg BD for 10 days Comparison: placebo	N= 181 people with CF Age: 8 to 65 Stable stage CF FVC>= 40% predicted	Relative mean % change in FEV₁ (overall results and subgroup analysis for people with moderate disease severity) Adverse events: voice alteration	In Cochrane SR Yang 2016 No withdrawals.
Ranasinha 1993 (Country not reported) RCT, parallel design	Intervention: Nebulized dornase alfa 2.5 mg BD for 10 days Comparison: placebo	N= 71 people with CF Age range: 16 to 55 All participants had stable disease FVC > 40% predicted	Relative mean % change in FEV₁ (overall results and subgroup analysis for people with moderate disease severity) Adverse events: haemoptysis, voice alteration	In Cochrane SR Yang 2016
Shah 1995a (USA, Canada, UK) Multi-centre RCT, parallel design	Intervention: 2.5 mg nebulised dornase alfa BD for 14 days Comparison: Placebo	N: 70 people with CF randomized from 3 sites. Age: ≥5 years Severe (FVC < 40% predicted) lung disease	Relative mean % change in FEV₁ (Overall results and subgroup analysis for people with severe disease) Adverse events: haemoptysis, voice alteration	In Cochrane SR Yang 2016 5 dropouts (2 died, 2 withdrew consent, 1 had a heart lung transplant)
Suri 2001, Suri 2002a and Suri 2002b (UK) RCT, crossover design	Intervention 1: 2.5 mg dornase alfa OD; Intervention 2: alternate day 2.5 mg dornase alfa; Intervention 3: 5 mL 7%hypertonic saline BD 12-week treatment periods with a 2-week washout period between each period	N= 48 children and young people with CF were randomised. Age range: 7.3 to 17.	Mean % change in FEV₁ Number of days of inpatient treatment	In Wark 2010 and Yang 2016 45 completed first treatment period, 44 completed the second treatment period and 40 completed the third treatment period.
Wilmott 1996 (USA) RCT, parallel design	Intervention: Dornase alfa 2.5 mg nebulised BD over 15 days Comparison: Placebo	N= 80 people with CF from 11 CF centres Age: Over 5 Admitted to hospital for at least 1 night for treatment of a chest exacerbation (protocol defined) with FVC > 35% predicted Participants in both groups had a moderate clinical degree of dyspnoea.	Mean % change in FEV₁	In Cochrane SR Yang 2016 No withdrawals mentioned in the paper
Additional primary studies
Amin 2010 (Canada) RCT, crossover design	Intervention: 7% sodium chloride BD for 4 weeks, 4-week washout period Comparison: 0.9% sodium chloride	N=20 people with CF randomized. Mean (SD) age: 10.5 (3.1). Age range for eligibility: 6 to 18 years. Baseline FEV₁% predicted ≥80%	Quality of life (Measured with CFQ-R questionnaire)	1 person was excluded from the analysis.
Conrad 2015 (USA) RCT, parallel design	Intervention: Acetylcysteine 3 times daily for 24 weeks Comparison: Placebo	N0=70 people with CF were randomized. Age range: 9 to 59 years. Stable mildmoderate lung disease; FEV predicted	Change in FEV₁ Change in sputum IL-8 (log10) Incidence of pulmonary exacerbations Quality of life (Measured with CFQ-R)	6 in the acetylcysteine group and 2 in the placebo group were withdrawn or lost to follow-up. Of these, 1 in the placebo group was excluded from the analysis.
Dentice 2016 (Australia) RCT, parallel design	Intervention: 7% sodium chloride 4ml 3 times daily throughout hospital admission Control: 0.12% sodium chloride Both groups received usual care.	N=132 people with CF admitted for management of a pulmonary exacerbation. Mean age (SD), range: Intervention: 28 (9), 17 to 62 years Control: 27 (9), 18 to 63 years	Failed to regain preexacerbation FEV₁% predicted Change in quality of life Time to first pulmonary exacerbation	All participants were included in the analysis related to relevant outcomes. On average, hospital admission lasted 12 days in intervention group and 13 in control group
Gupta 2012 (India) RCT, parallel design	Intervention: 7% sodium chloride BD for 28 days (high dose) Comparison: 3% sodium chloride	N=31 children and young people with CF were randomized. Age range: 6 to 16 years Able to perform reproducible pulmonary function test was among inclusion criteria. No inclusion criteria relating to severity of lung disease.	% change in FEV₁	30 people completed the study and were included in the analysis.
Mainz 2016 (Germany) RCT, crossover design	Intervention: 6% sodium chloride OD for 28 days, 28-day washout period Comparison: 0.9% sodium chloride	N=69 people with CF with chronic rhinosinusitis Age ≥6 years. Mean age (SD): 22.8 (12).	FEV₁ % predicted	5 people were excluded from the analysis.
Ratjen 1985 (Germany) RCT, parallel design	Intervention: Acetylcysteine 3 times daily for 12 weeks Comparison: Placebo	N=21 people with CF were included in the analysis. Mean (range) age: 13.9 (6 to 21) People with mild to moderate lung disease.	Change in FEV₁	Total N in the study was 36 people who were randomized to 3 interventions (1 not relevant to this review). There were 4 withdrawals out of 36 people; 1 in placebo group, 3 unclear.
Rosenfeld 2012 (USA and Canada) Multicentre RCT, parallel design	Intervention: 7% sodium chloride BD for 48 weeks Comparison: 0.9% sodium chloride	N=321 infants and children with CF were randomized. Age: < 6 years	Time to first pulmonary exacerbation Number of days of treatment for a pulmonary exacerbation Change in quality of life (Measured with CFQ-R)	29 withdrew (15 in intervention group and 14 in comparison group) but everyone was included in the analysis.
Shah 1996 (UK) RCT, parallel design	Intervention 1: 2.5 mg dornase alfa bd BD for 10 days Placebo: 150 mmol sodium chloride, 1.5 mmol calcium chloride	N: 71 people with CF randomized. Age: >15 years Stable condition prior for 14 days prior to enrolment	Relative mean % change in FEV₁	30 people were excluded from the analysis due to inadequate sputum samples.
Skov 2015 (Denmark) Open trial, parallel design	Intervention: Acetylcysteine 2400 mg/day for 4 weeks Comparison: Placebo	N=21 people with CF n=11 in the NAC group and n=10 in the placebo group Median age: 39 years (range 25 to 61)	Change in FEV₁ % predicted	There were 2 withdrawals, 1 in the intervention and 1 in the placebo group.

: Abbreviations: BD: twice daily; CF: cystic fibrosis; FEV: forced expiratory volume; N: number; OD: once daily; RCT: randomised controlled trial; SR: systematic review

Table 79Summary clinical evidence profile: Comparison 1.1. Mannitol versus placebo

Comparison 1.1. Mannitol versus placebo
Outcomes	Illustrative comparative risks^* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Assumed risk	Corresponding risk	Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Placebo	Mannitol
FEV₁ % predicted (repeated measures, change from baseline) Range of scores: 0 to 100 Follow-up: 2 weeks	Not reported	The mean FEV₁ % predicted (repeated measures, change from baseline) in the mannitol groups was 3.95 higher (0.96 to 6.94 higher)		36 (Jaques 2008)¹	⊕⊕⊝⊝ low²^,³
FEV₁ % predicted (repeated measures, change from baseline) Range of scores: 0 to 100 Follow-up: 2 months	Not reported	The mean FEV₁ % predicted (repeated measures, change from baseline) in the mannitol groups was 2.98 higher (1.04 to 4.92 higher)		600 (Aitken 2012, Bilton 2011)	⊕⊕⊕⊝ moderate²
FEV₁ % predicted (repeated measures, change from baseline) Range of scores: 0 to 100 Follow-up: 4 months	Not reported	The mean FEV₁ % predicted (repeated measures, change from baseline) in the mannitol groups was 3.26 higher (1.16 to 5.35 higher)		600 (Aitken 2012, Bilton 2011)	⊕⊕⊝⊝ low²^,³
FEV₁ % predicted (repeated measures, change from baseline) Range of scores: 0 to 100 Follow-up: 6 months	Not reported	The mean FEV₁ % predicted (repeated measures, change from baseline) in the mannitol groups was 3.89 higher (1.69 to 6.08 higher)		600 (Aitken 2012, Bilton 2011)	⊕⊕⊝⊝ low²^,³
FEV₁ % predicted in children and young people (repeated measures, change from baseline) Range of scores: 0 to 100 Follow-up: 2 months	Not reported	The mean FEV₁ % predicted (repeated measures, change from baseline) in the mannitol groups was 2.64 higher (0.73 lower to 6.02 higher)		258 (Aitken 2012, Bilton 2011)	⊕⊕⊝⊝ low²^,³
FEV₁ % predicted in children and young people (repeated measures, change from baseline) Range of scores: 0 to 100 Follow-up: 4 months	Not reported	The mean FEV₁ % predicted (repeated measures, change from baseline) in the mannitol groups was 1.34 higher (2.42 lower to 5.10 higher)		258 (Aitken 2012, Bilton 2011)	⊕⊕⊝⊝ low²^,³
FEV₁ % predicted in children and young people (repeated measures, change from baseline) Range of scores: 0 to 100 Follow-up: 6 months	Not reported	The mean FEV₁ % predicted (repeated measures, change from baseline) in the mannitol groups was 3.03 higher (0.78 lower to 6.84 higher)		258 (Aitken 2012, Bilton 2011)	⊕⊕⊝⊝ low²^,³
FEV₁ % predicted in adults (repeated measures, change from baseline) Range of scores: 0 to 100 Follow-up: 2 months	Not reported	The mean FEV₁ % predicted (repeated measures, change from baseline) in the mannitol groups was 3.72 higher (0.82 to 6.64 higher)		317 (Aitken 2012, Bilton 2011)	⊕⊕⊝⊝ low²^,³
FEV₁ % predicted in adults (repeated measures, change from baseline) Range of scores: 0 to 100 Follow-up: 4 months	Not reported	The mean FEV₁ % predicted (repeated measures, change from baseline) in the mannitol groups was 4.23 higher (0.98 to 7.48 higher)		317 (Aitken 2012, Bilton 2011)	⊕⊕⊝⊝ low²^,³
FEV₁ % predicted in adults (repeated measures, change from baseline) Range of scores: 0 to 100 Follow-up: 6 months	Not reported	The mean FEV₁ % predicted (repeated measures, change from baseline) in the mannitol groups was 5.74 higher (2.36 to 9.13 higher)		317 (Aitken 2012, Bilton 2011)	⊕⊕⊝⊝ low²^,³
Time to first protocol defined pulmonary exacerbation Follow-up: 6 months	Not reported	Not reported	HR 0.7 (0.48 to 1.02)	600 (Aitken 2012, Bilton 2011)	⊕⊕⊝⊝ low²^,⁴
Number of children and young people with protocol defined exacerbations (proxy for time to next exacerbation) Follow-up: 6 months	Not calculable (events per group not reported)	Not calculable (events per group not reported)	RR 0.62 (0.35 to 1.09)	259 (Aitken 2012, Bilton 2011)	⊕⊕⊝⊝ low²^,⁵
Number of adults with protocol defined exacerbations (proxy for time to next exacerbation) Follow-up: 6 months	Not calculable (events per group not reported)	Not calculable (events per group not reported)	RR 0.76 (0.52 to 1.13)	341 (Aitken 2012, Bilton 2011)	⊕⊕⊝⊝ low²^,⁵
Number of patients needing additional IV antibiotics Follow-up: 6 months	Study population		RR 0.81 (0.7 to 0.95)	600 (Aitken 2012, Bilton 2011)	⊕⊝⊝⊝ very low²^,⁵^,⁶
	561 per 1000	454 per 1000 (392 to 533)
	Moderate
	560 per 1000	454 per 1000 (392 to 532)
Quality of life - CFQOL respiratory domain (change from baseline) Range of scores: 0 to 100 Follow-up: 4 months	The mean change in CFQOL respiratory in the placebo group was 3.8 in 1 study, 0.1 in the other study	The mean change in CFQOL respiratory domain in the mannitol groups was 1.54 lower (4.69 lower to 1.61 higher)		507 (Aitken 2012, Bilton 2011)	⊕⊝⊝⊝ very low²^,³^,⁷
Quality of life – CFQOL respiratory domain (change from baseline) Range of scores: 0 to 100 Follow-up: 6 months	The mean change in CFQOL respiratory in the placebo group was 5.6 in 1 study, −2.5 in the other study	The mean change in CFQOL respiratory in the mannitol groups was 0.99 lower (4.5 lower to 2.52 higher)		465 (Aitken 2012, Bilton 2011)	⊕⊝⊝⊝ very low²^,⁸^,⁹
Quality of life - CFQOL vitality domain (change from baseline) Range of scores: 0 to 100 Follow-up: 4 months	The mean change in CFQOL vitality in the placebo group was −5.4 in 1 study, −3.5 in the other study	The mean change in CFQOL vitality in the mannitol groups was 3.42 higher (0.21 lower to 7.04 higher)		361 (Aitken 2012, Bilton 2011)	⊕⊕⊝⊝ low²^,³
Quality of life - CFQOL vitality domain (change from baseline) Range of scores: 0 to 100 Follow-up: 6 months	The mean change in CFQOL change in CFQOL vitality in the placebo group was −4.2 in 1 study, −5.1 in the other study	The mean change in CFQOL vitality in the mannitol groups was 4.84 higher (0.86 to 8.82 higher)		325 (Aitken 2012, Bilton 2011)	⊕⊕⊝⊝ low²^,³
Quality of life - CFQOL physical domain (change from baseline) Range of scores: 0 to 100 Follow-up: 4 months	The mean change in CFQOL physical in the placebo group was 2.3 in 1 study, −1.5 in the other study	The mean change in CFQOL physical in the mannitol groups was 1.8 lower (4.72 lower to 1.11 higher)		505 (Aitken 2012, Bilton 2011)	⊕⊕⊕⊝ moderate²
Quality of life - CFQOL physical domain (change from baseline) Range of scores: 0 to 100 Follow-up: 6 months	The mean change in CFQOL physical in the placebo group was 1.1 in 1 study, −4.7 in the other study	The mean change in CFQOL physical in the mannitol groups was 0.52 higher (2.75 lower to 3.79 higher)		465 (Aitken 2012, Bilton 2011)	⊕⊝⊝⊝ very low²^,⁹^,¹⁰
Quality of life - CFQOL emotion domain (change from baseline) Range of scores: 0 to 100 Follow-up: 4 months	The mean change in CFQOL emotion in the placebo group was 2.9 in 1 study, −0.1 in the other study	The mean change in CFQOL emotion in the mannitol groups was 2.11 lower (4.56 lower to 0.34 higher)		506 (Aitken 2012, Bilton 2011)	⊕⊕⊕⊝ moderate²
Quality of life - CFQOL emotion domain (change from baseline) Range of scores: 0 to 100 Follow-up: 6 months	The mean change in CFQOL emotion in the placebo group was 2.1 in 1 study, 0.5 in the other study	The mean change in CFQOL emotion in the mannitol groups was 1.27 lower (3.74 lower to 1.2 higher)		465 (Aitken 2012, Bilton 2011)	⊕⊕⊕⊝ moderate²
Quality of life - CFQOL eating domain (change from baseline) Range of scores: 0 to 100 Follow-up: 4 months	The mean change in CFQOL eating in the placebo group was −3.3 in 1 study, 0.6 in the other study	The mean change in CFQOL eating in the mannitol groups was 0.81 higher (1.96 lower to 3.58 higher)		505 (Aitken 2012, Bilton 2011)	⊕⊕⊕⊝ moderate²
Quality of life - CFQOL eating domain (change from baseline) Range of scores: 0 to 100 Follow-up: 6 months	The mean change in CFQOL eating in the placebo group was −1.4 in 1 study, 1.9 in the other study	The mean change in CFQOL eating in the mannitol groups was 0.68 higher (2.29 lower to 3.65 higher)		466 (Aitken 2012, Bilton 2011)	⊕⊕⊕⊝ moderate²
Quality of life - CFQOL health domain (change from baseline) Range of scores: 0 to 100 Follow-up: 4 months	The mean change in CFQOL health in the placebo group was −1 in 1 study, 2.3 in the other study	The mean change in CFQOL health in the mannitol groups was 0.43 lower (4.18 lower to 3.32 higher)		360 (Aitken 2012, Bilton 2011)	⊕⊕⊕⊝ moderate²
Quality of life - CFQOL health domain (change from baseline) Range of scores: 0 to 100 Follow-up: 6 months	The mean change in CFQOL health in the placebo group was −0.9 in 1 study, 1.1 in the other study	The mean change in CFQOL health in the mannitol groups was 0.21 lower (4.14 lower to 3.72 higher)		325 (Aitken 2012, Bilton 2011)	⊕⊕⊕⊝ moderate²
Quality of life - CFQOL social domain (change from baseline) Range of scores: 0 to 100 Follow-up: 4 months	The mean change in CFQOL social in the placebo group was 0.2 in 1 study, −0.8 in the other study	The mean change in CFQOL social (change from baseline) in the mannitol groups was 1.2 lower (3.7 lower to 1.3 higher)		504 (Aitken 2012, Bilton 2011)	⊕⊕⊕⊝ moderate²
Quality of life - CFQOL social domain (change from baseline) Range of scores: 0 to 100 Follow-up: 6 months	The mean change in CFQOL social in the placebo group was 0.9 in 1 study, −0.7 in the other study	The mean change in CFQOL social in the mannitol groups was 1.47 lower (4.25 lower to 1.32 higher)		465 (Aitken 2012, Bilton 2011)	⊕⊝⊝⊝ very low²^,³^,¹¹
Quality of life - CFQOL body domain (change from baseline) Range of scores: 0 to 100 Follow-up: 4 months	The mean change in CFQOL body in the placebo group was 1.5 in 1 study, 1.6 in the other study	The mean change in CFQOL body in the mannitol groups was 3.1 lower (6.49 lower to 0.29 higher)		500 (Aitken 2012, Bilton 2011)	⊕⊕⊝⊝ low²^,³
Quality of life - CFQOL body domain (change from baseline) Range of scores: 0 to 100 Follow-up: 6 months	The mean change in CFQOL body in the placebo group was 2.9 in 1 study, 1.8 in the other study	The mean change in CFQOL body in the mannitol groups was 1.19 lower (4.51 lower to 2.13 higher)		461 (Aitken 2012, Bilton 2011)	⊕⊕⊕⊝ moderate²
Quality of life - CFQOL role domain (change from baseline) Range of scores: 0 to 100 Follow-up: 4 months	The mean change in CFQOL role in the placebo group was −0.8 in 1 study, −2.4 in the other study	The mean change in CFQOL role in the mannitol groups was 1.22 higher (2.21 lower to 4.66 higher)		358 (Aitken 2012, Bilton 2011)	⊕⊕⊕⊝ moderate²
Quality of life - CFQOL role domain (change from baseline) Range of scores: 0 to 100 Follow-up: 6 months	The mean change in CFQOL role in the placebo group was 1.1 in 1 study, −1.6 in the other study	The mean change in CFQOL role in the mannitol groups was 1.43 lower (4.87 lower to 2 higher)		324 (Aitken 2012, Bilton 2011)	⊕⊝⊝⊝ very low²^,³^,¹²
Quality of life - CFQOL digestion domain (change from baseline) Range of scores: 0 to 100 Follow-up: 4 months	The mean change in CFQOL digestion in the placebo group was 2.1 in 1 study, 0.2 in the other study	The mean change in CFQOL digestion in the mannitol groups was 1.49 lower (4.77 lower to 1.78 higher)		505 (Aitken 2012, Bilton 2011)	⊕⊕⊕⊝ moderate²
Quality of life - CFQOL digestion domain (change from baseline) Range of scores: 0 to 100 Follow-up: 6 months	The mean change in CFQOL digestion in the placebo group was 2.8 in 1 study, 0 in the other study	The mean change in CFQOL digestion in the mannitol groups was 1.07 lower (5.04 lower to 2.9 higher)		465 (Aitken 2012, Bilton 2011)	⊕⊕⊝⊝ low²^,³
Quality of life - CFQOL weight domain (change from baseline) Range of scores: 0 to 100 Follow-up: 4 months	The mean change in CFQOL weight in the placebo group was 4.6 in 1 study, 7.3 in the other study	The mean change in CFQOL weight in the mannitol groups was 4.23 lower (10.28 lower to 1.83 higher)		360 (Aitken 2012, Bilton 2011)	⊕⊕⊝⊝ low²^,³
Quality of life - CFQOL weight domain (change from baseline) Range of scores: 0 to 100 Follow-up: 6 months	The mean change in CFQOL weight in the placebo group was 7.8 in 1 study, 6.5 in the other study	The mean change in CFQOL weight in the mannitol groups was 3.27 lower (9.84 lower to 3.31 higher)		325 (Aitken 2012, Bilton 2011)	⊕⊕⊝⊝ low²^,³
Adverse events: haemoptysis (mild) Follow-up: 2 weeks	0%	0%	Not estimable	36 (Jaques 2008)¹	⊕⊕⊕⊝ moderate²^,^a^,^b
Adverse events: haemoptysis (severe) Follow-up: 2 weeks	53 per 1000	53 per 1000 (8 to 355)	RR 1 (0.15 to 6.74)	(Jaques 2008)¹	⊕⊝⊝⊝ very low²^,⁹
Adverse events: Bronchospasm (mild) Follow-up: 6 months	0 events in each group	0 events in each group	Not estimable	295 (Bilton 2011)	⊕⊕⊕⊝ moderate ²^,^a^,^b
Adverse events: Haemoptysis (mild) Follow-up: 6 months	Study population		RR 1.73 (0.26 to 11.62)	600 (Aitken 2012, Bilton 2011)	⊕⊝⊝⊝ very low²^,⁹
	8 per 1000	14 per 1000 (2 to 97)
	Moderate
	9 per 1000	16 per 1000 (2 to 105)
Adverse events: Bronchospasm (moderate) Follow-up: 6 months	0 per 1000	0 per 1000 (0 to 0)	RR 2.01 (0.03 to 133.11)	295 (Bilton 2011)	⊕⊝⊝⊝ very low²^,⁹
Adverse events: Haemoptysis (moderate) Follow-up: 6 months	Study population		RR 4.66 (0.5 to 43.49)	600 (Aitken 2012, Bilton 2011)	⊕⊝⊝⊝ very low²^,⁹
	4 per 1000	19 per 1000 (2 to 182)
	Moderate
	4 per 1000	19 per 1000 (2 to 174)
Adverse events: Bronchospasm (severe) Follow-up: 6 months	0 per 1000	0 per 1000 (0 to 0)	RR 2.01 (0.03 to 133.11)	295 (Bilton 2011)	⊕⊝⊝⊝ very low²^,⁹
Adverse events: Haemoptysis (severe) Follow-up: 6 months	Study population		RR 1.55 (0.13 to 18.99)	600 (Aitken 2012, Bilton 2011)	⊕⊝⊝⊝ very low²^,⁹
	4 per 1000	6 per 1000 (1 to 79)
	Moderate
	4 per 1000	6 per 1000 (1 to 76)
Adverse events: bronchospasm in children and young people	0 events	0 events	Not estimable (0 events in either group)	105 (Bilton 2011)	⊕⊕⊕⊝ moderate²^,^a^,^b
Adverse events: bronchospasm in adults	Not calculable (events per group not reported)	Not calculable (events per group not reported)	RR 3.35 (0.16 to 71.50)	190 (Bilton 2011)	⊕⊝⊝⊝ very low²^,⁹
Adverse events: haemoptysis in children and young people	Not calculable (events per group not reported)	Not calculable (events per group not reported)	RR 5.48 (0.69 to 43.50)	259 (Aitken 2012, Bilton 2011)	⊕⊝⊝⊝ very low²^,⁹
Adverse events: haemoptysis in adults	Not calculable (events per group not reported)	Not calculable (events per group not reported)	RR 1.83 (0.64 to 5.23)	341 (Aitken 2012, Bilton 2011)	⊕⊝⊝⊝ very low²^,⁹

*: The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
: Abbreviations: CFQOL: cystic fibrosis quality of life questionnaire; CI: confidence interval; FEV₁: forced expiratory volume in 1 second; HR: hazard ratio; MD: mean difference; RR: risk ratio
1: Cross-over design
2: The quality of the evidence was downgraded by 1 as the participants in the trial underwent a tolerance test at screening. Those who failed were not entered in the study, and this limits the generalisability of the results to the general CF population.
3: The quality of the evidence was downgraded by 1 as the 95% CI crossed 1 clinical MID
4: The quality of the evidence was downgraded by 1, as the 95% CI crossed the null effect
5: The quality of the evidence was downgraded by 1 as the 95% CI crossed 1 default MID
6: The quality of the evidence was downgraded by 1 due to moderate heterogeneity (I2=59%)
7: The quality of the evidence was downgraded by 1 due to moderate heterogeneity (I2=37%).
8: The quality of the evidence was downgraded by 2 due to high heterogeneity (I2=89%)
9: The quality of the evidence was downgraded by 2 as the 95% CI crossed 2 default MIDs
10: The quality of the evidence was downgraded by 1 due to high heterogeneity (I2=77%). It was not downgraded further as both studies showed no differences between groups.
11: The quality of the evidence was downgraded by 2 due to high heterogeneity (I2=70%). Studies show conflicting results.
12: The quality of the evidence was downgraded by 1 due to moderate heterogeneity (I2=41%)
a: Imprecision not calculable because risk ratio could not be estimated as there were 0 events in each group
b: Risk ratio not estimable because there were 0 events in each group

Table 80Summary clinical evidence profile: Comparison 1.2.1. Mannitol versus dornase alfa

Comparison 1.2.1. Mannitol versus dornase alfa
Outcomes	Illustrative comparative risks^* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Assumed risk	Corresponding risk	Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Dornase alfa	Mannitol
FEV₁ (% change from baseline) - Range of scores: 0 to 100 Follow-up: 3 months	Not reported	The mean FEV₁ (% change from baseline) in the intervention mannitol was 2.8 higher (4.8 lower to 10.4 higher)		20 (Minasian 2010)¹	⊕⊝⊝⊝ very low²^,³^,⁴

*: The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
: Abbreviations: CI: confidence interval; FEV₁: forced expiratory volume in 1 second; MD: mean difference
1: Cross-over design
2: The quality of the evidence was downgraded by 1 because this is an open trial, and there is high risk of incomplete reporting
3: The quality of the evidence was downgraded by 1 as the participants in the trial underwent a tolerance test at screening. Those who fail were not entered in the study, and this limits the generalisability of the results to the general CF population
4: The quality of the evidence was downgraded by 2 as the 95% CI crossed 2 clinical MIDs

Table 81Summary clinical evidence profile: Comparison 1.2.2. Mannitol plus dornase alfa versus dornase alfa

Comparison 1.2.2. Mannitol plus dornase alfa versus dornase alfa
Outcomes	Illustrative comparative risks^* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Assumed risk	Corresponding risk	Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Dornase alfa alone	Mannitol + Dornase alfa
FEV₁ (% change from baseline) - Range of scores: 0 to 100 Follow-up: 3 months	Not reported	The mean FEV₁ (% change from baseline) in the mannitol + dornase alfa groups was 4.3 lower (14.1 lower to 5.5 higher)		20 (Minasian 2010)¹	⊕⊝⊝⊝ very low²^,³^,⁴

*: The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
: Abbreviations: CI: confidence interval; FEV₁: forced expiratory volume in 1 second; MD: mean difference
1: Cross-over design
2: The quality of the evidence was downgraded by 1 because this is an open trial, and there is high risk of incomplete reporting
3: The quality of the evidence was downgraded by 1 as the participants in the trial underwent a tolerance test at screening. Those who fail were not entered in the study, and this limits the generalisability of the results to the general CF population
4: The quality of the evidence was downgraded by 2 as the 95% CI crossed 2 clinical MIDs

Table 82Summary clinical evidence profile: Comparison 2.1. Dornase alfa versus placebo

Comparison 2.1. Dornase alfa versus placebo
Outcomes	Illustrative comparative risks^* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Assumed risk	Corresponding risk	Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Placebo	Dornase alfa
Lung function: relative mean % change in FEV₁ Range of scores: 0 to 100 Follow-up: 10 days	The relative mean % change in FEV₁ in the placebo group was 0.15	The relative mean % change in FEV₁ the dornase alfa group was 13.17 higher (0.70 to 25.64 higher)		41 (Shah 1996)	⊕⊝⊝⊝ very low¹^,⁷
Lung function: relative mean % change in FEV₁ Range of scores: 0 to 100 Follow-up: 1 months	The relative mean % change in FEV₁ in the placebo group was −1.9 in the first study, −1.6 in the second study, −1.5 in the third study, 4.2 in the fourth study	The relative mean % change in FEV₁ in the dornase alfa groups was 9.52 higher (0.59 to 18.46 higher)		248 (Laube 1996, Ramsey 1993a, Ranasinha 1993, Shah 1995)	⊕⊝⊝⊝ very low ³^,⁴^,⁷
Lung function: relative mean % change in FEV₁ Range of scores: 0 to 100 Follow-up: 3 months	The relative mean % change in FEV₁ in the placebo group was 0.76 in 1 study, 2.1 in the other study	The relative mean % change in FEV₁ in the dornase alfa groups was 6.7 higher (3.72 to 9.67 higher)		319 (Amin 2011, McCoy 1996)⁵	⊕⊝⊝⊝ very low⁵^,⁶^,⁷
Lung function: relative mean % change in FEV₁ Range of scores: 0 to 100 Follow-up: 6 months	The relative mean % change in FEV₁ in the placebo group was 0	The relative % mean change in FEV₁ in the dornase alfa groups was 5.8 higher (4.41 to 7.19 higher)		647 (Fuchs 1994)	⊕⊕⊝⊝ low⁷^,⁸
subgroup analysis based on disease severity: moderate relative mean % change in FEV₁ – Range of scores: 0 to 100 Follow-up: 1 months	The relative mean % change in FEV₁ in the placebo group was −1.8 in the first study, −1.6 in the second study, −1.5 in the third study	The mean % change in FEV₁ in the dornase alfa groups was 14.32 higher (10.81 to 17.83 higher)		183 (Laube 1996, Ramsey 1993a, Ranasinha 1993)	⊕⊕⊕⊝ low⁹
subgroup analysis based on disease severity: severe FEV₁ relative mean % change in FEV₁ – Range of scores: 0 to 100 Follow-up: 1 months	The relative mean % change in FEV₁ in the placebo group was 4.2	The mean % change in FEV₁ in the dornase alfa groups was 2.8 lower (8.76 lower to 3.16 higher)		65 (Shah 1995)	⊕⊝⊝⊝ very low⁷
subgroup analysis based on disease severity: acute pulmonary exacerbation mean % change in FEV₁ Range of scores: 0 to 100 Follow-up: 1 months	The mean % change in FEV₁ in the placebo group was 19	The mean % change in FEV₁ in the dornase alfa groups was 1 higher (13.93 lower to 15.93 higher)		80 (Wilmott 1996)	⊕⊝⊝⊝ very low²^,¹¹
Lung function: absolute mean % change in FEV₁ Range of scores: 0 to 100 Follow-up: 2 years	The absolute mean % change in FEV₁ in the placebo group was −3.2	The mean % change in FEV₁ in the dornase alfa groups was 3.24 higher (1.03 to 5.45 higher)		410 (Quan 2001)	⊕⊕⊕⊝ moderate⁷
Number of people experiencing exacerbations Follow-up: 6 months	274 per 1000	222 per 1000 (167 to 290)	RR 0.81 (0.61 to 1.06)	647 (Fuchs 1994)	⊕⊕⊝⊝ low⁸^,¹²
Number of people experiencing exacerbations Follow-up: 2 years	239 per 1000	170 per 1000 (117 to 244)	RR 0.71 (0.49 to 1.02)	470 (Quan 2001)	⊕⊕⊕⊝ moderate¹²
Number of days of IV antibiotics use Follow-up: 3 months	The mean number of days of IV antibiotics use in the placebo group was 28.31	The mean number of days of IV antibiotics use in the dornase alfa groups was 2.96 lower (7.29 lower to 1.37 higher)		320 (McCoy 1996)	⊕⊝⊝⊝ very low¹³^,¹⁴
Adverse events: haemoptysis Follow-up: 1 months	Study population		RR 1.23 (0.20 to 7.64)	141 (Ranasinha 1993, Shah 1995)	⊕⊝⊝⊝ very low¹⁴^,¹⁵
	43 per 1000	53 per 1000 (9 to 327)
	Moderate
	43 per 1000	53 per 1000 (9 to 328)
Adverse events: haemoptysis Follow-up: 6 months	Study population		RR 0.82 (0.44 to 1.52)	647 (Fuchs 1996)	⊕⊝⊝⊝ very low⁸^,¹⁴
Adverse events: haemoptysis Follow-up: 6 months	65 per 1000	53 per 1000 (28 to 98)	RR 0.82 (0.44 to 1.52)	647 (Fuchs 1996)	⊕⊝⊝⊝ very low⁸^,¹⁴
Adverse events: voice alteration Follow-up: 1 months	Study population		RR 2.79 (0.03 to 278.07)	233 (Ramsey 1993a, Ranasinha 1993, Shah 1995)	⊕⊝⊝⊝ very low¹⁴^,¹⁶^,¹⁷
	25 per 1000	71 per 1000 (1 to 1000)
	Moderate
	0 per 1000	0 per 1000 (0 to 0)
Adverse events: voice alteration Follow-up: 3 months	62 per 1000	177 per 1000 (89 to 352)	RR 2.87 (1.44 to 5.71)	320 (McCoy 1996)	⊕⊕⊕⊝ moderate¹³
Adverse events: voice alteration Follow-up: 6 months	22 per 1000	37 per 1000 (15 to 93)	RR 1.73 (0.69 to 4.34)	647 (Fuchs 1994)	⊕⊝⊝⊝ very low⁸^,¹⁴
Adverse events: voice alteration Follow-up: 2 years	115 per 1000	110 per 1000 (66 to 183)	RR 0.95 (0.57 to 1.59)	470 (Quan 2001)	⊕⊕⊝⊝ low¹⁴
Quality of life: change in CFQ-R (CFQ-R parents) Range of scores: 0 to 100 Follow-up: 3 months	The change in CFQ-R parents in the placebo group was 0.89	The mean change in CFQ-R parents in the dornase alfa groups was 5.45 lower (15.23 lower to 4.33 higher)		17 (Amin 2011)⁵	⊕⊕⊕⊝ moderate⁷
Quality of life: change in CFQ-R - CFQ-R 14+ Range of scores: 0 to 100 Follow-up: 3 months	The change in CFQ-R 14+ in the placebo group was −5.28	The mean change in CFQ-R 14+ in the dornase alfa groups was 5.21 lower (15.5 lower to 5.08 higher)		17 (Amin 2011)⁵	⊕⊕⊕⊝ moderate⁷

*: The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
: Abbreviations: CFQ-R: cystic fibrosis questionnaire revised; CI: confidence interval; FEV₁: forced expiratory volume in 1 second; IV: intravenous; MD: mean difference; RR: risk ratio
1: The quality of the evidence was downgraded by due to unclear sequence generation, allocation concealment, blinding and reporting
2: The quality of the evidence was downgraded by 2 as the CI crossed 2 clinical MIDs
3: The quality of the evidence was downgraded by 2 due to unclear sequence generation, blinding, allocation concealment and reporting in 3 of the trials, and unclear blinding and reporting in the fourth trial
4: The quality of the evidence was downgraded by 1 due to high heterogeneity (I2=88%). See sensitivity analysis.
5: Amin 2011: cross-over trial
6: The quality of the evidence was downgraded by 1 due to unclear sequence generation, blinding, allocation concealment and reporting in the 1 of the trial
7: The quality of the evidence was downgraded by 1 as the 95% CI crossed 1 clinical MID
8: The quality of the evidence was downgraded by 1 due to unclear blinding, allocation, concealment and reporting
9: The quality of the evidence was downgraded by 2 due to unclear sequence generation, blinding, allocation concealment and reporting in 2 of the trials, and unclear blinding and reporting in the third trial
10: The quality of the evidence was downgraded by 2 due to unclear sequence generation, blinding, allocation concealment and reporting
11: The quality of the evidence was downgraded by 2 due to unclear sequence generation, blinding, allocation concealment and reporting
12: The quality of the evidence was downgraded by 1 as the 95% CI crossed 1 default MID
13: The quality of the evidence was downgraded by 2 due to unclear randomisation, blinding, allocation concealment and reporting
14: The quality of the evidence was downgraded by 2 as the 95% CI crossed 2 default MIDs
15: The quality of the evidence was downgraded by 2 due to unclear sequence generation, blinding, allocation concealment and reporting in both trials
16: The quality of the evidence was downgraded by 2 due to unclear blinding, allocation concealment and reporting in 2 of the trials, and unclear blinding and reporting in the third trial
17: The quality of the evidence was downgraded by 1 due to high heterogeneity (I2=85%)

Table 83Summary clinical evidence profile: Comparison 2.2. Dornase alfa versus nebulised sodium chloride

Comparison 2.2. Dornase alfa versus nebulised sodium chloride
Outcomes	Illustrative comparative risks^* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Assumed risk	Corresponding risk	Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Nebulised sodium chloride	Dornase alfa
Lung function: mean % change in FEV₁ Range of scores: 0 to 100 Follow-up: 3 weeks	The mean % change in FEV₁ in the nebulised sodium chloride group was 7.7	The mean % change in FEV₁ in the dornase alfa groups was 1.6 higher (7.96 lower to 11.16 higher)		48 (Ballmann 1998)¹	⊕⊝⊝⊝ very low²^,³
Lung function: mean % change in FEV₁ Range of scores: 0 to 100 Follow-up: 3 months	Not reported	The mean % change in FEV₁ in the dornase alfa groups was 8 higher (2 to 14 higher)		14 (Suri 2001)¹	⊕⊕⊝⊝ low²^,⁴
Number of days inpatient treatment Follow-up: 3 months	Not reported	The mean number of days inpatient treatment in the dornase alfa groups was 0.4 lower (2.32 lower to 1.52 higher)		14 (Suri 2001)¹	⊕⊕⊕⊝ moderate²

*: The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
: Abbreviations: CI: confidence interval; FEV₁: forced expiratory volume in 1 second; MD: mean difference
1: Cross-over study
2: The quality of the evidence was downgraded by 1 due to unclear blinding, allocation, concealment and reporting
3: The quality of the evidence was downgraded by 2 as the 95% CI crossed 2 clinical MIDs
4: The quality of the evidence was downgraded by 1 as the 95% CI crossed 1 clinical MID

Table 84Summary clinical evidence profile: Comparison 3.1. Nebulised sodium chloride (> 3% concentration) versus placebo (0.9% to 0.12%) or low-concentration (≤ 3%)

Comparison 3.1. Nebulised sodium chloride (> 3% concentration) versus placebo (0.9% to 0.12%) or low-concentration (≤ 3%)
Outcomes	Illustrative comparative risks^* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Assumed risk	Corresponding risk	Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Low concentration (≤ 3% sodium chloride)	High concentration (>3% sodium chloride)
Failed to regain pre-exacerbation FEV₁% predicted Range of scores: 0 to 100 Follow-up: at hospital discharge	431 per 1000	254 per 1000 (155 to 418)	RR 0.59 (0.36 to 0.97)	132 (Dentice 2016)	⊕⊕⊕⊝ moderate¹
Lung function: % change in FEV₁ Range of scores: 0 to 100 Follow-up: 2 weeks	The mean % change in FEV₁ in the ≤3% sodium chloride group was 13.81	The mean % change in FEV₁ in the >3% sodium chloride groups was 14.35 lower (27.8 to 0.9 lower)		30 (Gupta 2012)	⊕⊕⊕⊝ moderate¹
Lung function: % change in FEV₁ Range of scores: 0 to 100 Follow-up: 4 weeks	The mean % change in FEV₁ in the ≤3% sodium chloride group was 12.53 in 1 study, −0.3 in the other study	The mean % change in FEV₁ in the >3% sodium chloride groups was 4.92 lower (17.69 lower to 7.86 higher)		93 (Gupta 2012, Mainz 2016)²	⊕⊝⊝ very low³^,⁴^,⁵
Lung function: % change in FEV₁ Range of scores: 0 to 100 Follow-up: 12 weeks	The mean % change in FEV₁ in the ≤3% sodium chloride group was 3.96	The mean % change in FEV₁ in the >3% sodium chloride groups was 4.1 higher (0.08 lower to 8.28 higher)		149 (Elkins 2006)	⊕⊕⊕⊝ moderate¹
Lung function: % change in FEV₁ Range of scores: 0 to 100 Follow-up: 24 weeks	The mean: % change in FEV₁ in the ≤3% sodium chloride group was 4.46	The mean % change in FEV₁ in the >3% sodium chloride groups was 5.37 higher (1.03 to 9.71 higher)		140 (Elkins 2006)	⊕⊕⊕⊝ moderate¹
Lung function: % change in FEV₁ Range of scores: 0 to 100 Follow-up: 36 weeks	The mean % change in FEV₁ in the ≤3% sodium chloride group was 5	The mean % change in FEV₁ in the >3% sodium chloride groups was 3.63 higher (1.56 lower to 8.82 higher)		134 (Elkins 2006)	⊕⊕⊕⊝ moderate¹
Lung function: % change in FEV₁ Range of scores: 0 to 100 Follow-up: 48 weeks	The mean% change in FEV₁ in the ≤3% sodium chloride group was 4.75	The mean % change in FEV₁ in the >3% sodium chloride groups was 2.31 higher (2.72 lower to 7.34 higher)		134 (Elkins 2006)	⊕⊕⊕⊝ moderate¹
Time to first pulmonary exacerbation Follow-up: mean 1 years	Not reported	Not reported	HR 0.92 (0.74 to 1.14)	453 (Dentice 2016, Rosenfeld 2012)	⊕⊕⊕⊝ moderate⁶
Number of days of treatment for a pulmonary exacerbation Follow-up: 48 weeks	The mean number of days of treatment for a pulmonary exacerbation in the ≤3% sodium chloride group was 52	The mean number of days of treatment for a pulmonary exacerbation in the >3% sodium chloride groups was 1.11 higher (0.89 to 1.33 higher)		321 (Rosenfeld 2012)	⊕⊕⊕⊕ high
Change in quality of life following treatment - CFQOL - physical domain Range of scores: 0 to 100 Follow-up: 7 days	The mean change CFQOL physical domain in the ≤3% sodium chloride groups was 9	The mean change in CFQOL - physical domain in the >3% sodium chloride groups was 2.00 higher (3.12 lower to 7.12 higher)		132 (Dentice 2016)	⊕⊕⊕⊝ moderate¹
Change in quality of life following treatment - CFQOL - burden domain Range of scores: 0 to 100 Follow-up: 7 days	The mean change CFQOL burden domain in the ≤3% sodium chloride groups was 9	The mean change in CFQOL - burden domain in the >3% sodium chloride groups was 0.00 higher (4.78 lower to 4.78 higher)		132 (Dentice 2016)	⊕⊕⊕⊕ high
Change in quality of life following treatment - CFQOL - health domain Range of scores: 0 to 100 Follow-up: 7 days	The mean change in CFQOL health domain in the ≤3% sodium chloride groups was 14	The mean change in CFQOL - health domain in the >3% sodium chloride groups was 2.00 lower (8.15 lower to 4.15 higher)		132 (Dentice 2016)	⊕⊕⊕⊝ moderate¹
Change in quality of life following treatment - CFQOL - respiratory domain Range of scores: 0 to 100 Follow-up: 7 days	The mean change in CFQOL - respiratory domain in the ≤3% sodium chloride groups was 12	The mean change in CFQOL - respiratory domain in the >3% sodium chloride groups was 1.00 higher (4.99 lower to 6.99 higher)		132 (Dentice 2016)	⊕⊕⊕⊝ moderate¹
Change in quality of life following treatment - CFQOL - physical domain Range of scores: 0 to 100 Follow-up: 7 days	The mean change in CFQOLphysical domain in the ≤3% sodium chloride groups was 14	The mean change in CFQOL - physical domain in the >3% sodium chloride groups was 2.00 higher (4.15 lower to 8.15 higher)		132 (Dentice 2016)	⊕⊕⊕⊝ moderate¹
Change in quality of life following treatment - CFQOL - burden domain Range of scores: 0 to 100 Follow-up: 7 days	The mean change CFQOL - burden domain in the ≤3% sodium chloride groups was −1	The mean change in CFQOL - burden domain in the >3% sodium chloride groups was 2.00 higher (4.04 lower to 8.04 higher)		132 (Dentice 2016)	⊕⊕⊕⊝ moderate¹
Change in quality of life following treatment - CFQOL - health domain Range of scores: 0 to 100 Follow-up: 7 days	The mean change in CFQOL - health domain in the ≤3% sodium chloride groups was 18	The mean change in CFQOL - health domain in the >3% sodium chloride groups was 2.00 higher (4.99 lower to 8.99 higher)		132 (Dentice 2016)	⊕⊕⊕⊝ moderate¹
Change in quality of life following treatment - CFQOL - respiratory domain Range of scores: 0 to 100 Follow-up: 7 days	The mean change in CFQOL - respiratory domain in the ≤3% sodium chloride groups was 21	The mean change in CFQOL - respiratory domain in the >3% sodium chloride groups was 2.00 lower (8.67 lower to 4.67 higher)		132 (Dentice 2016)	⊕⊕⊕⊝ moderate¹
Quality of life: CFQ-R respiratory: CFQ parent Range of scores: 0 to 100 Follow-up: 4 weeks	Not reported	The mean CFQ-R respiratory, CFQ parent in the >3% sodium chloride group was 5.9 higher (3.1 lower to 14.9 higher)		20 (Amin 2010)⁷	⊕⊕⊕⊝ moderate¹
Quality of life: CFQ-R respiratory 14+ Range of scores: 0 to 100 Follow-up: 4 weeks	Not reported	The mean CFQ-R respiratory, CFQ 14+ in the >3% sodium chloride groups was 5.2 higher (7 lower to 17.4 higher)		20 (Amin 2010)⁷	⊕⊕⊝⊝ low⁵
Change in quality of life: CFQ - CFQ-R parents Range of scores: 0 to 100 Follow-up: 48 weeks	The mean change in CFQ-R parents in the ≤3% sodium chloride group was 0.9	The mean change in CFQ-R parents in the >3% sodium chloride groups was 1.13 lower (7.49 lower to 5.23 higher)		67 (Elkins 2006)	⊕⊕⊝⊝ low⁵
Change in quality of life: CFQ-R 14+ Range of scores: 0 to 100 Follow-up: 48 weeks	The mean change in CFQ-R 14+ in the ≤3% sodium chloride group was 1.09	The mean change in CFQ-R 14+ in the >3% sodium chloride groups was 7.77 higher (1.86 to 13.68 higher)		92 (Elkins 2006)	⊕⊕⊕⊝ moderate¹
Change in quality of life: CFQ-R respiratory domain Range of scores: 0 to 100 Follow-up: 48 weeks	The mean change in CFQ-R respiratory domain in the ≤3% sodium chloride group was −3.2	The mean change in CFQ-R respiratory domain in the >3% sodium chloride groups was 3.3 higher (0 to 6.6 higher)		321 (Rosenfeld 2012)	⊕⊕⊕⊝ moderate¹

*: The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
: Abbreviations: CFQ-R: cystic fibrosis questionnaire revised; CI: confidence interval; FEV₁: forced expiratory volume in 1 second; HR: hazard ratio, MD: mean difference; RR: risk ratio
1: The quality of the evidence was downgraded by 1 as the 95% CI crossed 1 clinical MID
2: Mainz 2016: Cross-over study
3: The quality of the study was downgraded by 1 due to unclear risk of bias in relation to random sequence generation, allocation concealment and selective reporting in 1 study
4: The quality of the evidence was downgrade by 2 due to serious inconsistency (I2=77%)
5: The quality of the evidence was downgraded by 2 as the 95% CI crossed 2 clinical MIDs
6: The quality of the evidence was downgraded by 1 as the 95% CI crossed the null effect
7: Amin 2010: cross-over study

Table 85Summary clinical evidence profile: Comparison 4. Acetylcysteine versus placebo

Comparison 4. Acetylcysteine versus placebo
Outcomes	Illustrative comparative risks^* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Assumed risk	Corresponding risk	Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Placebo	Acetylcysteine
Lung function: change in FEV₁ % predicted Range of scores: 0 to 100 Follow-up: 4 weeks	The mean change in FEV₁ in the placebo group was −1.41	The mean change in FEV₁ % predicted in the acetylcysteine groups was 3.51 higher (0.65 lower to 7.67 higher)		21 (Skov 2015)	⊕⊝⊝⊝ very low¹^,²
Lung function: change in FEV₁ % predicted Range of scores: 0 to 100 Follow-up: 12 weeks	The mean change in FEV₁ in the placebo group was −8.6	The mean change in FEV₁ % predicted in the acetylcysteine groups was 5 higher (10.84 lower to 20.84 higher)		21 (Ratjen 1985)	⊕⊕⊝⊝ low³
Lung function: change in FEV₁ % predicted Range of scores: 0 to 100 Follow-up: 24 weeks	Not reported	The mean change in FEV₁ % predicted in the acetylcysteine groups was 4.4 higher (0.83 to 7.97 higher)		70 (Conrad 2015)	⊕⊕⊕⊝ moderate²
Inflammatory markers: change in sputum IL-8 (log10) Follow-up: 24 weeks	Not reported	The mean change in sputum IL-8 (log10) in the acetylcysteine groups was MD 0.19 higher (0.03 lower to 0.42 higher)		70 (Conrad 2015)	⊕⊕⊕⊕ high⁴
Incidence of pulmonary exacerbations Follow-up: 24 weeks	500 per 1000	415 per 1000 (250 to 695)	RR 0.83 (0.5 to 1.39)	70 (Conrad 2015)	⊕⊕⊝⊝ low³
Quality of life: CFQ-R respiratory Follow-up: 24 weeks	Not reported	The mean CFQ-R respiratory in the acetylcysteine groups was 0.34 lower (6.3 lower to 5.62 higher)		70 (Conrad 2015)	⊕⊕⊝⊝ low³

*: The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
: Abbreviations: CFQ-R: cystic fibrosis questionnaire revised; CI: confidence interval; FEV₁: forced expiratory volume in 1 second; IL-8: interleukin 8; MD: mean difference; RR: risk ratio
1: The quality of the evidence was downgraded by 1 as this is an open trial, and there was unclear randomisation and allocation concealment.
2: The quality of the evidence was downgraded by 1 as the 95% CI crossed 1 clinical MID
3: The quality of the evidence was downgraded by 2 as the 95% CI crossed 2 clinical MIDs
4: Imprecision not calculable, as SD for the control group was not available in the study

Table 86Research Recommendation justification

Research question	What is the most clinical and cost effective dose of rhDNase (dornase alfa; recombinant human deoxyribonuclease) for people with cystic fibrosis?
Why this is needed
Importance to ‘patients’ or the population	Taking daily dornase alfa increases the treatment burden on people with cystic fibrosis who already have complex treatment schedules, including multiple nebulised treatments. It is essential that parents, carers and people with cystic fibrosis are reassured that this dosing frequency is necessary to provide clinical benefit. Parents, carers and people with cystic fibrosis frequently report that reducing the treatment frequency burden increases overall adherence and this will improve the treatment effect. There is some evidence that alternate day dornase alfa is as effective as daily administration, if this is confirmed then overall treatment adherence may improve and moreover cost savings would be made. There is also some evidence that early use of dornase alfa is associated with better survival rates; hence, if alternate day dornase alfa was an option this would potentially lower the threshold for its use.
Relevance to NICE guidance	With this evidence, a definitive recommendation could be made regarding dosing frequency – at present there is varied clinical practice between England and Wales.
Relevance to the NHS	Further evidence in this area will eliminate the need to provide an intense treatment schedule ‘just in case’ it improves respiratory symptoms. There will be a financial advantage if administration frequency can be reduced in the future.
National priorities	Research priorities from the James Lind Alliance highlighted reducing treatment burden as a priority which would fit with this, in addition to its economic advantages.
Current evidence base	The current evidence base includes mostly small, underpowered, short-term trials with limited methodological rigour and are unable to draw conclusions regarding the long-term impact of dornase alfa in people with cystic fibrosis. Most of the studies assess the licensed dose in people who are not naïve to treatment. There is insufficient evidence as yet to answer the question whether reduced dosing frequency of dornase alfa as a first-line treatment is cost-effective, in people with cystic fibrosis who have respiratory symptoms.
Equality	None
Feasibility	The proposed research can be carried out within a realistic timescale and at an acceptable cost. There are no ethical or technical issues.
Other comments	If improvements on alternate day dornase alfa are similar to that given daily, it may be cost-effective to titrate the dose further.

Table 87Research Recommendation Statements

Criterion	Explanation
Population	People with a diagnosis of cystic fibrosis with respiratory symptoms
Intervention	Once daily dornase alfa (2.5 mg)
Comparators	Reduced dosing frequency of dornase alfa, including alternate day dornase alfa (2.5 mg)
Outcomes	Hospitalisations, change in frequency Pulmonary exacerbations, change in frequency and severity Lung function (FEV₁, FVC) Quality of Life (using a validated tool, such CFQ-R or CF-QOL) Patient preference Adverse events Resource use Unit costs
Study design	Multicentre RCT
Timeframe	Five years of randomisation and 5 year of follow up, providing recruitment numbers are sufficient to achieve population numbers of sufficient size to answer the research question.

Table 88Summary of included studies

Study	Intervention/Comparison	Population	Outcomes	Comments
Cochrane systematic reviews
Smyth 2014 Cochrane SR	Intervention Prophylactic anti-staphylococcal anti-biotic + antibiotic ‘as required’ Comparison Placebo + antibiotic ‘as required’	People with a confirmed diagnosis of cystic fibrosis, of any age.	Number of positive pathogen cultures (S aureus) identified during study period - measured as number of children from whom S aureus was isolated at least once by year of age (n/N) Lung function measured as FEV₁ Evidence of inflammation in CT scan - Proxy outcome, X-ray scores (Crispin-Norman score at 1.3 years) Pulmonary exacerbation - Proxy outcome, number of children requiring admission Adherence to treatment Adverse events, minor events Number of children in whom P aeruginosa was identified	SR AMSTAR score: 10/11
Primary studies included in the Cochrane SR
Chatfield 1991 (UK) RCT	Intervention Continuous oral Flucloxacillin Comparison Placebo + antibiotic ‘as required’	Infants with a confirmed diagnosis of cystic fibrosis. Age: not reported	Number of positive pathogen cultures (S aureus) identified during study period - measured as number of children from whom S aureus was isolated at least once by year of age (n/N) Evidence of inflammation in CT scan (only for < 5 yrs) - Proxy outcome, X-ray scores (Crispin-Norman score at 1.3 years) Pulmonary exacerbation - Proxy outcome, number of children requiring admission (annualised rates) Number of children in whom P aeruginosa was identified	Included in Smyth 2014
Stutman 2002 (USA) RCT	Intervention Continuous cephalexin Comparison Placebo + antibiotic ‘as required’	Infants and children with a confirmed diagnosis of cystic fibrosis. Age: 4 to 24 months	Number of positive pathogen cultures (S aureus) identified during study period - measured as number of children from whom S aureus was isolated at least once by year of age (n/N) Lung function - measured as FEV₁ at 6 years Pulmonary exacerbation - Proxy outcome, number of children requiring admission (annualised rates) Minor adverse events, including generalised rash, nappy rash, increased stool frequency Number of children in whom P aeruginosa was identified	Included in Smyth 2014
Weaver 1994 (UK) RCT	Intervention continuous oral Flucloxacillin Comparison Placebo + antibiotic ‘as required’	Infants with a confirmed diagnosis of cystic fibrosis, of any age. Age: not reported	Number of positive pathogen cultures (S aureus) identified during study period - measured as number of children from whom S aureus was isolated at least once by year of age (n/N) Pulmonary exacerbation - Proxy outcome, number of children requiring admission (annualised rates) Number of children in whom P aeruginosa was identified	Included in Smyth 2014 Additional data obtained from Beardsmore 1995

: AB: antibiotics; SR: systematic review

Table 89Summary clinical evidence profile: Comparison 1. Continuous oral Flucloxacillin versus antibiotics ‘as required’

Comparison 1. Continuous oral Flucloxacillin versus antibiotics ‘as required’
Outcomes	Illustrative comparative risks^* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Assumed risk	Corresponding risk	Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Control	Continuous oral Flucloxacillin, antibiotic prophylaxis
Number of children from whom S aureus isolated at least once Follow-up: mean 1 year	373 per 1000	201 per 1000 (101 to 395)	RR 0.54 (0.27 to 1.06)	96 (Chatfield 1991)	⊕⊝⊝⊝ very low¹^,²
Number of children from whom S aureus isolated at least once Follow-up: mean 2 years	Study population		RR 0.44 (0.25 to 0.77)	149 (Chatfield 1991, Weaver 1994)	⊕⊕⊝⊝ low³
	425 per 1000	187 per 1000 (106 to 327)
	Moderate
	483 per 1000	213 per 1000 (121 to 372)
Number of children from whom S aureus isolated at least once Follow-up: mean 3 years	431 per 1000	224 per 1000 (125 to 392)	RR 0.52 (0.29 to 0.91)	119 (Chatfield 1991)	⊕⊝⊝⊝ very low¹^,²
Number of children from whom P aeruginosa isolated at least once Follow-up: mean 1 year	59 per 1000	136 per 1000 (36 to 514)	RR 2.32 (0.62 to 8.73)	95 (Chatfield 1991)	⊕⊝⊝⊝ very low¹^,⁴
Number of children from whom P aeruginosa isolated at least once Follow-up: mean 2 years	Study population		RR 0.74 (0.34 to 1.61)	149 (Chatfield 1991, Weaver 1994)	⊕⊝⊝⊝ very low³^,⁴
	175 per 1000	129 per 1000 (60 to 282)
	Moderate
	217 per 1000	161 per 1000 (74 to 349)
Number of children from whom P aeruginosa isolated at least once Follow-up: mean 3 years	212 per 1000	168 per 1000 (78 to 354)	RR 0.79 (0.37 to 1.67)	120 (Chatfield 1991)	⊕⊝⊝⊝ very low¹^,⁴
Number of children requiring admission due to pulmonary exacerbations (annualised rates) Follow-up: mean 3 years	333 per 1000	327 per 1000 (197 to 540)	RR 0.98 (0.59 to 1.62)	124 (Chatfield 1991, Weaver 1994)	⊕⊝⊝⊝ very low³^,⁴

*: The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
: CI: Confidence interval; RR: Risk ratio
1: The quality of the evidence was downgraded by 2 as this study was rated as high risk of bias (Cochrane review Smyth 2014)
2: The quality of the evidence was downgraded by 1 as the 95% CI crosses 1 default MID
3: The quality of the evidence was downgraded by 2 as these studies was rated as high and moderate risk of bias (Cochrane review Smyth 2014)
4: The quality of the evidence was downgraded by 2 as the 95% CI crosses 2 default MIDs

Table 90Summary clinical evidence profile: Comparison 2. Continuous oral Cephalexin versus antibiotics ‘as required’

Comparison 2. Continuous oral Cephalexin versus antibiotics ‘as required’
Outcomes	Illustrative comparative risks^* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Assumed risk	Corresponding risk	Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Antibiotics ‘as required’	Continuous oral Cephalexin, antibiotic prophylaxis
Number of children from whom S aureus isolated at least once Respiratory cultures Follow-up: mean 1 years	468 per 1000	145 per 1000 (79 to 266)	RR 0.31 (0.17 to 0.57)	152 (Stutman 2002)	⊕⊕⊕⊝ moderate¹
Number of children from whom S aureus isolated at least once Respiratory cultures Follow-up: mean 2 years	658 per 1000	217 per 1000 (145 to 336)	RR 0.33 (0.22 to 0.51)	166 (Stutman 2002)	⊕⊕⊕⊝ moderate²
Number of children from whom S aureus isolated at least once Respiratory cultures Follow-up: mean 3 years	688 per 1000	289 per 1000 (199 to 406)	RR 0.42 (0.29 to 0.59)	141 (Stutman 2002)	⊕⊕⊕⊝ moderate³
Number of children from whom S aureus isolated at least once Respiratory cultures Follow-up: mean 4 years	839 per 1000	352 per 1000 (252 to 495)	RR 0.42 (0.3 to 0.59)	127 (Stutman 2002)	⊕⊕⊕⊝ moderate⁴
Number of children from whom S aureus isolated at least once Respiratory cultures Follow-up: mean 5 years	850 per 1000	348 per 1000 (238 to 501)	RR 0.41 (0.28 to 0.59)	98 (Stutman 2002)	⊕⊕⊝⊝ low⁵
Number of children from whom S aureus isolated at least once Respiratory cultures Follow-up: mean 6 years	778 per 1000	280 per 1000 (140 to 552)	RR 0.36 (0.18 to 0.71)	43 (Stutman 2002)	⊕⊕⊝⊝ low⁶
Lung function FEV₁ Follow-up: mean 6 years	The mean lung function in the control group was 115.8	The mean lung function in the intervention groups was 2.3 lower (13.59 lower to 8.99 higher)		119 (Stutman 2002)	⊕⊝⊝⊝ very low⁷^,⁸
Any pulmonary exacerbations % Follow-up: mean 6 years	The mean number of pulmonary exacerbation in the control group was 66.8	The mean number of pulmonary exacerbations in the intervention groups was 4.9 lower (22.24 lower to 12.44 higher)		119 (Stutman 2002)	⊕⊝⊝⊝ very low⁷^,⁹
Number of children requiring admission due to pulmonary exacerbations (annualised rates) not reported Follow-up: mean 6 years	78 per 1000	74 per 1000 (20 to 260)	RR 0.94 (0.26 to 3.32)	119 (Stutman 2002)	⊕⊝⊝⊝ very low⁷^,⁹
Adherence to treatment Parents self-report Follow-up: mean 6 years	The mean adherence to treatment in the control groups was 85 %	The mean adherence to treatment in the intervention groups was 5 higher (0 to 0 higher)		119 (Stutman 2002)	⊕⊕⊕⊝ moderate⁷^,¹⁰
Minor adverse events - generalised rash Parents self-report Follow-up: mean 6 years	The mean number of generalised rash events in the control group was 0.2	The mean – number of generalised rash events in the intervention groups was 0.4 higher (0.07 lower to 0.87 higher)		119 (Stutman 2002)	⊕⊕⊕⊝ moderate⁷
Minor adverse events - nappy rash Parents self-report Follow-up: mean 6 years	The mean number of nappy rash events in the control group was 3.1	The mean – number of nappy rash events in the intervention groups was 0.9 higher (1.06 lower to 2.86 higher)		119 (Stutman 2002)	⊕⊕⊕⊝ moderate⁷
Minor adverse events - increased stool frequency Parents self-report Follow-up: mean 6 years	The mean number of increased stool frequency events in the control group was 4.1	The mean minor increased stool frequency events in the intervention groups was 0.2 higher (2.18 lower to 2.58 higher)		119 (Stutman 2002)	⊕⊕⊕⊝ moderate⁷
Number of children from whom P aeruginosa identified at least once Follow-up: mean 1 years	312 per 1000	358 per 1000 (231 to 564)	RR 1.15 (0.74 to 1.81)	152 (Stutman 2002)	⊕⊝⊝⊝ very low¹^,⁹
Number of children from whom P aeruginosa identified at least once Follow-up: mean 2 years	506 per 1000	435 per 1000 (314 to 603)	RR 0.86 (0.62 to 1.19)	166 (Stutman 2002)	⊕⊕⊝⊝ low²^,¹¹
Number of children from whom P aeruginosa identified at least once Follow-up: mean 3 years	594 per 1000	582 per 1000 (445 to 772)	RR 0.98 (0.75 to 1.3)	141 (Stutman 2002)	⊕⊝⊝⊝ very low³^,⁹
Number of children from whom P aeruginosa identified at least once Follow-up: mean 4 years	Study population		RR 1.1 (0.83 to 1.45)	127 (Stutman 2002)	⊕⊕⊝⊝ low⁴^,¹¹
	589 per 1000	648 per 1000 (489 to 854)
	Moderate
	589 per 1000	648 per 1000 (489 to 854)
Number of children from whom P aeruginosa identified at least once Follow-up: mean 5 years	550 per 1000	709 per 1000 (512 to 979)	RR 1.29 (0.93 to 1.78)	98 (Stutman 2002)	⊕⊝⊝⊝ very low⁵^,¹¹
Number of children from whom P aeruginosa identified at least once Follow-up: mean 6 years	667 per 1000	880 per 1000 (613 to 1000)	RR 1.32 (0.92 to 1.89)	43 (Stutman 2002)	⊕⊝⊝⊝ very low⁶^,¹¹

*: The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
: Abbreviations: CI: confidence interval; FEV₁: forced expiratory volume in 1 second; MD: mean difference; RR: risk ratio
1: This study was assessed by the Cochrane review Smyth 2014 as low risk of bias. However, the quality of the evidence was downgraded by 1 for this outcome, as the losses to follow up are over 20% (n=152; N=209).
2: This study was assessed by the Cochrane review Smyth 2014 as low risk of bias. However, the quality of the evidence was downgraded by 1 for this outcome, as the losses to follow up are over 20% (n=166; N=209).
3: This study was assessed by the Cochrane review Smyth 2014 as low risk of bias. However, the quality of the evidence was downgraded by 1 for this outcome, as the losses to follow up are over 20% (n=141; N=209).
4: This study was assessed by the Cochrane review Smyth 2014 as low risk of bias. However, the quality of the evidence was downgraded by 1 for this outcome, as the losses to follow up are over 20% (n=127; N=209).
5: This study was assessed by the Cochrane review Smyth 2014 as low risk of bias. However, the quality of the evidence was downgraded by 2 for this outcome, as the losses to follow up are over 50% (n=98; N=209).
6: This study was assessed by the Cochrane review Smyth 2014 as low risk of bias. However, the quality of the evidence was downgraded by 2 for this outcome, as the losses to follow up are over 50% (n=43; N=209).
7: This study was assessed by the Cochrane review Smyth 2014 as low risk of bias. However, the quality of the evidence was downgraded by 1 for this outcome, as the losses to follow up are over 20% (n=119; N=209).
8: The quality of the evidence was downgraded by 2, as the 95% CI crossed 2 clinical MIDs
9: The quality of the evidence was downgraded by 2, as the 95% CI crossed 2 default MIDs
10: Imprecision is not calculable with the data reported
11: The quality of the evidence was downgraded by 1, as the 95% CI crossed 1 default MID for dichotomous outcomes

Table 91Summary of included studies for antimicrobials for pulmonary exacerbations with P aeruginosa

Study	Intervention/Comparison	Population	Outcomes	Comments
Cochrane systematic reviews
Hurley 2015 Cochrane SR	Comparison 1. Single IV agents compared (Elborn 1992, Salh 1992) Comparison 2. Single IV (with placebo) vs combination of IV antibiotics (Macystis fibrosisarlane 1985, Master 2001) Comparison 3. Single IV vs combination of IV antibiotics (De Boeck 1989, Conway 1997, Gold 1985, McCarty 1988, Wesley 1988) Comparison 4. Combination of antibiotics vs combination of antibiotics (Blumer 2005, Richard 1997, Schaad 1989)	Participants diagnosed with cystic fibrosis using the Cystic Fibrosis Foundation diagnostic consensus statement, of all ages and all levels of severity. All studies that explicitly aimed to trial an IV antibiotic for the treatment of pulmonary exacerbation were considered.	Lung function (FEV₁) Time to next exacerbation Quality of life (CFQ-R) Mortality (cystic fibrosisrelated and all causes) Adverse events	AMSTAR score: 11/11
Primary studies included in the Cochrane SR
Blumer 2005 (USA) RCT	Intervention 1: IV meropenem 40 mg/kg up to a maximum dose of 2 g and IV tobramcyin (given for a mean of 13.5 days) Intervention 2: IV ceftazidime 50 mg/kg up to a maximum dose of 2 g and IV tobramycin (given for a mean of 14.1 days) Tobramycin dose adjusted to give a peak serum concentration of>= 8 µg/mL and trough concentration of < 2 µg/mL	N=121 participants with a recent (usually < 1 month) culture of P aeruginosa or B cepacia complex recruited at a protocol-de fined exacerbation. Age: ≥ 5 years of age	Lung function (FEV₁)	Included in Cochrane SR Hurley 2015
Conway 1997 (UK) RCT	Intervention 1: IV colistin (2 MU 3× daily). Intervention 2: IV colistin (2 MU 3× daily) and a second anti-pseudomonal antibiotic	N=71 adults with cystic fibrosis and chronic P aeruginosa experiencing a protocol-defined exacerbation. Mean age (SD): 21 (4.2) years.	FEV₁ Mortality Adverse effects	Included in Cochrane SR Hurley 2015
De Boeck 1989 (Belgium RCT	Intervention 1: IV ceftazidime 50 mg/kg 3× daily. Intervention 2: IV piperacillin 75 mg/kg 4× daily and IV tobramycin 10 mg/kg/day in3 doses	N=21 participants with cystic fibrosis and a protocol-defined pulmonary exacerbation, chronically infected with P aeruginosa that was sensitive to piperacillin, tobramycin and ceftazidime Mean age 14.8 years	FEV₁ Time to readmission Mortality	Included in Cochrane SR Hurley 2015
Elborn 1992 (UK) RCT	Intervention 1: IV ceftazidime 2 g 3× daily. Intervention 2: IV aztreonam 2 g 3× daily.	N=24 participants with cystic fibrosis and chronic P aeruginosa infection experiencing exacerbations. Mean (range) age: 20 (14 to 48) years	FEV₁	Included in Cochrane SR Hurley 2015
Gold 1985 (Canada) RCT	Intervention 1: IV ceftazidime 200 mg/kg/day in 4 doses. Intervention 2: IV ticarcillin 300 mg/kg/day in 4 doses and IV tobramycin 10 mg/kg/day in 3 doses	N=30 participants with cystic fibrosis and P aeruginosa infection present at the previous clinic visit, experiencing an acute respiratory exacerbation. Age >12 years. Mean age (SD): 18.9 (1.1) in group 1; 17.8 (0.8) in group 2	FEV₁ Adverse effects	Included in Cochrane SR Hurley 2015
Macystis fibrosisarlane 1985 (Australia) RCT	Intervention 1: IV piperacillin 50 mg/kg 4-hourly. Intervention 2: IV placebo 5% dextrose 4-hourly Intervention 3: IV piperacillin 100 mg/kg 8-hourly. Intervention 4: IV placebo 5% dextrose 8-hourly. All participants received IV tobramycin 2.5 mg/kg 3× daily, oral flucloxacillin 25 mg/kg/day in 4 doses and oral probenecid (suggested to increase antibiotic concentrations) 250 - 500 mg 3× daily Duration: 14 days.	N=19 participants aged over 8 years with cystic fibrosis with P aeruginosa in sputum admitted to hospital for worsening respiratory status. Mean age: 13.7 to 15.6 years	FEV₁ Adverse effects	Included in Cochrane SR Hurley 2015 Pseudomonas was not eradicated from the sputum in any of the patients
Master 2001 (Australia) RCT	Intervention 1: IV ceftazidime 50 mg/kg/dose 3× daily and IV tobramycin 3 mg/kg/dose 3× daily Intervention 2: IV tobramycin 9 mg/kg/day 1× daily. Duration: at least 10 days.	N=51 participants with cystic fibrosis experiencing a protocol-defined exacerbation with P aeruginosa isolated from sputum. Participants with an FVC lower than 40% predicted were excluded. Mean age (SD): 16 (7) years in group 1; 14 (5) years in group 2	FEV₁ Adverse effects	Included in Cochrane SR Hurley 2015
McCarty 1988 (USA) RCT	Intervention 1: IV piperacillin 600 mg/kg/day (regimen not detailed) Intervention 2: IV piperacillin 600 mg/kg/day and tobramycin 8 - 10 mg/kg/day (regimen not detailed Duration: at least 10 days.	N=17 children with cystic fibrosis admitted for treatment of pulmonary exacerbations with P aeruginosa. Age range: 2 to 12 years.	FEV₁ Eradication of pseudomonas Adverse effects	Included in Cochrane SR Hurley 2015
Richard 1997 (Switzerland) RCT	Intervention 1: oral ciprofloxacin 15 mg/kg 2× daily. Intervention 2: IV ceftazidime 50 mg/kg 3× daily and IV tobramycin 3 mg/kg 3× daily Duration: 14 days.	N=108 children with cystic fibrosis and P aeruginosa infection and experiencing a protocol-defined pulmonary exacerbation with P aeruginosa. Mean age: 10.2 years in group 1; 11 years in group 2. Age range: 5 to <17.	Eradication of pseudomonas Adverse effects	Included in Cochrane SR Hurley 2015
Salh 1992 (UK) RCT	Intervention 1; IV aztreonam 8 g/day in 4 doses. Intervention 2: IV ceftazidime 8 g/day in 4 doses. Duration: 2 weeks	N=22 participants with cystic fibrosis and P aeruginosa sensitive to the study drugs who were admitted to hospital due to an infective exacerbation Age range: 16 to 32 years.	FEV₁	Included in Cochrane SR Hurley 2015
Schaad 1987 (Switzerland) RCT	Intervention 1: IV ceftazidime 250 mg/kg/day in 4 doses and IV amikacin 33 mg/kg/day in 3 doses Intervention 2: IV ceftazidime 250 mg/kg/day in 4 doses and IV amikacin 33 mg/kg/day in 3 doses and nebulised amikacin 100 mg 2× daily Duration: 15 days	N=62 participants with cystic fibrosis admitted with an acute pulmonary exacerbation who had P aeruginosa isolated on admission. Those who had been admitted to hospital in the recent 6 months were excluded (n=87 courses of therapy by random assignment) Age range: 3 to 24 years.	Adverse effects	Included in Cochrane SR Hurley 2015
Schaad 1989 (Switzerland) RCT	Intervention 1: IV aztreonam 300 mg/kg/day in 4 doses and IV amikacin 36 mg/kg/day in 3 doses Intervention 2: IV ceftazidime 300 mg/kg/day in 4 doses and IV amikacin 36 mg/kg/day in 3 doses for 2 weeks followed by oral ciprofloxacin 30 mg/kg/day for 4 weeks Duration: 2 weeks IV treatment, with oral treatment extended for a further 4 weeks in1 group	N=42 participants with cystic fibrosis admitted with a protocol-defined pulmonary exacerbation and P aeruginosa isolated at admission. Those who had been admitted to hospital in previous 4 months were excluded (n=56 treatment courses by random assignment) Mean age (SD): 15.4 (6) years (range 2.3 to 25.4 years).	Eradication of Pseudomonas FEV₁ Adverse effects	Included in Cochrane SR Hurley 2015
Wesley 1988 (New Zealand) RCT	Intervention 1: IV ceftazidime 150 mg/kg/day (regimen not detailed) Intervention 2: IV tobramycin 7.5 mg/kg/day and IV ticarcillin 300 mg/kg/day (regimen not detailed) Duration: 14 days	N=13 children with cystic fibrosis and severe chest disease with pseudomonas chest exacerbation. Age range: 9 to 15 years.	Number of admission requiring iv antibiotics or death Adverse effects	Included in Cochrane SR Hurley 2015 Conference abstract

: FEV₁: Forced Expiratory volume. Information provided in the table is adapted from Hurley 2015.

Table 92Summary of included studies for antimicrobials for the treatment of acute infection with P aeruginosa

Study	Intervention/Comparison	Population	Outcomes	Comments
Cochrane systematic reviews
Langton 2014 Cochrane SR	Comparisons of combinations of oral, inhaled or intravenous antibiotics (Proesman 2013, Tacetti 2012)	Children and adults with confirmed cystic fibrosis with a first ever positive microbiological isolate of P aeruginosa from a respiratory tract specimen.	FEV₁ Trial discontinuation due to lack of compliance (proxy outcome for treatment failure) Adverse effects	AMSTAR score: 10/11
Primary studies included in the Cochrane systematic reviews
Proesmans 2013 (Belgium) RCT	Intervention Inhaled TSI (300 mg 2× daily for 28 days), 3 months Control Combination therapy with inhaled colistin (2 MU 2× daily)+ oral ciprofloxacin (10 mg/kg 3× daily), 3 months	N=58 children with cystic fibrosis, all with new isolation of P aeruginosa (sputum or cough swabs) Treatment: n=29 Control: n=29 Age: median age 9 years, interquartile range (4.7–13.1 years)	Adverse effects	Included in Langton 2014 Cochrane SR This study did not report the outcome ‘eradication of pathogen’ but reported ‘number of positive respiratory culture for pseudomonas. There was no difference between groups in positive pseudomonas culture 6 months and 24 months follow-up
Taccetti 2012 (Italy) RCT	Group A 28 days therapy 2 × daily inhalation of 2 MU colistin with 2 × daily doses of ciprofloxacin 15 mg/kg/dose. Group B 28 days therapy TSI (300 mg 2 × daily) with 2 × daily doses of ciprofloxacin 15 mg/kg/dose	N=223 participants with cystic fibrosis with first ever or new P aeruginosa infection. New infection defined as P aeruginosa isolation following bacterial clearance documented by 3 negative cultures within the previous 6 months Group A: n=105 (52 male and 53 female) Group B: n=118 (64 male and 54 female) Age: over 1 year.	FEV₁ Trial discontinuation due to lack of compliance (proxy outcome for treatment failure)	Included in Langton 2014 Cochrane SR This study did not report the outcome ‘eradication of pathogen’ but reported ‘number of positive respiratory culture for pseudomonas’. No difference was found in positive respiratory cultures of pseudomonas at end of treatment between both regimes. An increased incidence of the emerging pathogen S maltophilia was reported following treatment,

Table 93Summary of included studies for the antimicrobial treatment of infection with or exacerbation due to S aureus

Study	Intervention/Comparison	Population	Outcomes	Comments
Cochrane systematic reviews
Lo 2015 Cochrane SR	Intervention Any combination of topical, inhaled, oral or intravenous antibiotics with the primary aim of eradicating MRSA Comparison Placebo Standard treatment No treatment	Children and adults with confirmed diagnosis of cystic fibrosis with a confirmed positive microbiological isolate of MRSA on clinically relevant cystic fibrosis respiratory cultures.	No studies were identified for inclusion in this review	AMSTAR score:10/11

: CYSTIS FIBROSIS: cystic fibrosis; SR: systematic review; MRSA: methicillin-resistant S aureus

Table 94Summary of included studies for the antimicrobial treatment of infection with or exacerbation due B Cepacia Complex (BCC)

Study	Intervention/Comparison	Population	Outcomes	Comments
Cochrane systematic reviews
Horsley 2016 Cochrane SR	Intervention Any antibiotic treatment regimen for treating an exacerbation of CF lung disease Comparison Placebo Different antibiotic regimen	Patients with cystic fibrosis of any age with evidence of pulmonary infection with organisms of the BCC (defined as at least 2 positive sputum or bronchoalveolar lavage specimens within the last 6 months	No studies were identified for inclusion in this review	AMSTAR score:11/1 1
Regan 2016 Cochrane SR	Intervention Any antibiotic or antibiotic adjuvant therapy used alone or in combination to eradicate BCC infection Comparison Placebo No treatment Alternative antimicrobial agent (excluding the participant’s usual therapeutic regimen)	Any person of any age with a confirmed clinical diagnosis of cystic fibrosis who acquires a new infection or a re-infection with BCC. People will all disease severity were included.	No studies were identified for inclusion in this review	AMSTAR score:10/11

: BCC: B Cepacia Complex; CYSTIS FIBROSIS: cystic fibrosis; SR: systematic review

Table 95Summary of included studies for the antimicrobial treatment of infection with or exacerbation due to non-tuberculous mycobacteria (NTM)

Study	Intervention/Comparison	Population	Outcomes	Comments
Cochrane systematic reviews
Waters 2016 Cochrane SR	Intervention Antibiotics to treat NTM pulmonary infection Comparison No antibiotic treatment Different NTM antibiotic regimen	Children and adults with a confirmed clinical diagnosis of cystic fibrosis, who have NMT pulmonary infection. People will all disease severity were included.	No studies were identified for inclusion in this review	AMSTAR score: 10/11 Last search September 2016

Table 96Summary clinical evidence profile: Comparison 1. Single IV agents compared for pulmonary exacerbations with P aeruginosa

Comparison 1. Single IV agents compared for pulmonary exacerbations with P aeruginosa
Outcomes	Illustrative comparative risks^* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Assumed risk	Corresponding risk	Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Single IV agents	Single IV agents
[ceftazidime versus aztreonam] FEV₁ (absolute change) litres Follow-up: 2 weeks	The mean absolute change in FEV₁ litres in the IV aztreonam group ranged between 0.27 and 0.54	The mean absolute change in FEV₁ litres in the IV ceftazidime group was 0.06 lower (0.44 lower to 0.32 higher)		46 (Elborn 1992, Salh 1992)	⊕⊕⊝⊝ low¹^,²

*: The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
: Abbreviations: CI: confidence interval; FEV₁: forced expiratory volume in 1 second; MD: mean difference
1: The quality of the evidence was downgraded by 1 as 4 participants received both drugs in Salh 1992 study,
2: The quality of the evidence was downgraded by 1 due to serious heterogeneity (chi-squared p<0.1, I-squared inconsistency statistic of 50%-74.99%)

Table 97Comparison 2. Single IV antibiotic (with placebo) versus combination IV antibiotic for pulmonary exacerbations with P aeruginosa

Comparison 2. Single IV antibiotic (with placebo) versus combination IV antibiotic for pulmonary exacerbations with P aeruginosa
Outcomes	Illustrative comparative risks^* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Assumed risk	Corresponding risk	Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Combination IV antibiotics	Single IV antibiotic (with placebo)
[tobramycin + placebo versus tobramycin + ceftazidime] FEV₁ % predicted (absolute change) - Follow-up: 10 days	The mean FEV₁% predicted (absolute change) in the tobramycin + ceftazidime group was 12.8	The mean FEV₁ % predicted (absolute change) in the tobramycin + placebo groups was 2.2 lower (6.63 lower to 2.23 higher)		98 (Master 2001)	⊕⊕⊝⊝ low¹^,²
[tobramycin + placebo versus piperacillin + tobramycin] FEV₁% predicted (relative change) - Follow-up: 2 weeks	The mean FEV₁% predicted (relative change) in the piperacillin + tobramycin group was 12.2	The mean FEV₁% predicted (relative change) in the tobramycin + placebo groups was 4.2 lower (26.5 lower to 18.1 higher)		9 (Macystis fibrosisarlane 1985)	⊕⊝⊝⊝ very low³^,⁴
[tobramycin + placebo versus piperacillin + tobramycin] FEV₁% predicted (relative change) - Follow-up: 2 weeks	The mean FEV₁% predicted (relative change) in the piperacillin + tobramycin group was 1.8	The mean FEV₁% predicted (relative change) - in the tobramycin + placebo groups was 7.95 higher (8.78 lower to 24.68 higher)		9 (Macystis fibrosisarlane 1985)	⊕⊝⊝⊝ very low³^,⁴
[tobramycin + placebo versus piperacillin all regimens] Adverse effects - sensitivity reaction - number of participants Follow-up: 2 weeks	300 per 1000	51 per 1000 (3 to 888)	RR 0.17 (0.01 to 2.96)	18 (Macystis fibrosisarlane 1985)	⊕⊕⊝⊝ low³^,⁵
[tobramycin + placebo versus tobramycin + ceftazidime] Adverse effects - Number of hospital admissions due to Tinnitus Follow-up: 2 weeks	39 per 1000	43 per 1000 (6 to 290)	RR 1.09 (0.16 to 7.4)	98 (Master 2001)	⊕⊝⊝⊝ very low¹^,⁶
[tobramycin + placebo versus tobramycin + ceftazidime] Adverse effects - serum - Creatinine Follow-up: 2 weeks	The mean serum creatinine in the tobramycin + ceftazidime groups was 0	The mean serum creatinine in the Tobramycin + placebo groups was 4 lower (9.38 lower to 1.38 higher)		44 (Master 2001)	⊕⊝⊝⊝ very low¹^,⁶
[tobramycin + placebo versus tobramycin + ceftazidime] Adverse effects - serum - NAG Follow-up: 2 weeks	The mean serum NAG in the tobramycin + ceftazidime groups was	The mean serum NAG in the Tobramycin + placebo groups was 2.1 lower (3.46 lower to 0.74 lower)		44 (Master 2001)	⊕⊕⊕⊝ moderate¹

*: The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
: Abbreviations: CI: confidence interval; FEV₁: forced expiratory volume in 1 second; MD: mean difference; NAG: N-acetyl glucosamine; RR: risk ratio
1: The quality of the evidence was downgraded by 1 as each participant contributed to multiple treatment episodes.
2: The quality of the evidence was downgraded by 1 as the 95% CI crossed 1 clinical MID
3: The quality of the evidence was downgraded by 1 due to attrition bias (2 participants withdrew and did not contribute to analysis) and 1 participant received 2 treatment courses.
4: The quality of the evidence was downgraded by 2 as the 95% CI crossed 2 clinical MIDs
5: The quality of the evidence was downgraded by 1 due to very serious imprecision as 95%CI crossed 1 default MIDs
6: The quality of the evidence was downgraded by 2 as the 95% CI crossed 2 default MIDs

Table 98Comparison 3. Single IV antibiotic versus combination IV antibiotic for pulmonary exacerbations with P aeruginosa

Comparison 3. Single IV antibiotic versus combination IV antibiotic for pulmonary exacerbations with P aeruginosa
Outcomes	Illustrative comparative risks^* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Assumed risk	Corresponding risk	Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Combination IV antibiotic	Single IV antibiotic
[piperacillin versus piperacillin + tobramycin] Eradication: number people in whom pseudomonas isolates were eradicated at end of course - Follow-up: 10 days	632 per 1000	265 per 1000 (114 to 600)	RR 0.42 (0.18 to 0.95)	38 (McCarty 1988)	⊕⊕⊝⊝ low¹^,²
[ceftazidime versus IV tobramycin + ticarcillin] FEV₁ (relative change) - % Follow-up: 10 to 14 days	The mean FEV₁ (relative change) in the tobramycin + ticarcillin groups was 33.3	The mean FEV₁ (relative change) in the ceftazidime groups was 19.6 lower (38.26 to 0.94 lower)		30 (Gold 1985)	⊕⊕⊝⊝ low³^,⁴
[colistin versus colistin + “other”] FEV₁ (absolute change) ml Follow-up: 12 days	The mean FEV₁ (absolute change) in the colistin + “other” groups was 300	The mean FEV₁ (absolute change) in the colistin groups was 160 lower (309.72 to 10.28 lower)		71 (Conway 1997)	⊕⊕⊝⊝ low⁵
[ceftazidime versus tobramycin + piperacillin] FEV₁ % predicted (absolute change) Follow-up: 12 days	The mean FEV₁ % predicted (absolute change) in the ceftazidime groups was 1 higher (8.85 lower to 10.85 higher)	The mean FEV₁ % predicted (absolute change) in the ceftazidime groups was 1 higher (8.85 lower to 10.85 higher)		21 (De Boeck 1989)	⊕⊝⊝⊝ very low³^,⁶
[ceftazidime versus tobramycin + piperacillin] Time to readmission - months Follow-up: 24 to 26 months	The mean time to readmission in the tobramycin + piperacillin groups was 9 months	The mean time to readmission in the piperacillin groups was 1 month lower (5.52 lower to 3.52 higher)		19 (De Boeck 1989)	⊕⊝⊝⊝ very low³^,⁷
[ceftazidime versus tobramycin + ticarcillin] Number of admissions, requiring IV antibiotics or death - Follow-up: 3 months	500 per 1000	585 per 1000 (265 to 1000)	RR 1.17 (0.53 to 2.55)	22 (Wesley 1988)	⊕⊝⊝⊝ very low⁷^,⁸
[ceftazidime versus tobramycin + piperacillin] Mortality - Follow-up: 4 months	91 per 1000	100 per 1000 (7 to 1000)	RR 1.1 (0.08 to 15.36)	21 (De Boeck 1989)	⊕⊕⊝⊝ low⁹^,¹⁰
[IV colistin versus IV colistin + “other”] Mortality – Follow-up: 12 weeks	29 per 1000	9 per 1000 (0 to 220)	RR 0.32 (0.01 to 7.7)	71 (Conway 1997)	⊕⊕⊝⊝ low⁵^,¹⁰
[ceftazidime versus IV tobramycin + ticarcillin] Adverse effects: liver transaminase enzyme elevation Follow-up: 10–14 days	87 per 1000	133 per 1000 (29 to 618)	RR 1.53 (0.33 to 7.11)	52 (Gold 1987 and Wesley 1988)^a^,^b	⊕⊝⊝⊝ very low⁷^,¹¹
[colistin versus combination anti-pseudomonal antibiotics] Adverse effects: neurological adverse effects Follow-up: 12 days	1000 per 1000	940 per 1000 (860 to 1000)	RR 0.94 (0.86 to 1.04)	17 (McCarty 1988)	⊕⊕⊝⊝ low⁵
[piperacillin versus piperacillin + tobramycin] Adverse effects: rash Follow-up: 10 days	111 per 1000	41 per 1000 (2 to 888)	(McCarty 1988)	(McCarty 1988)	⊕⊝⊝⊝ very low¹^,⁷
[piperacillin versus piperacillin + tobramycin] Adverse effects -fever Follow-up: 10 days	111 per 1000	124 per 1000 (9 to 1000)	RR 1.12 (0.08 to 15.19)	17 (McCarty 1988)	⊕⊝⊝⊝ very low¹^,⁷
[ceftazidime versus tobramycin + ticarcillin] Adverse effects – proteinuria Follow-up: 10 - 14 days	59 per 1000	59 per 1000 (4 to 866)	RR 1 (0.07 to 14.72)	34 (Gold 1985)^a	⊕⊝⊝⊝ very low³^,⁷
[colistin versus combination anti-pseudomonal antibiotics] Adverse effects - renal toxicity - Change in blood urea (mmol/l) Follow-up: 12 days	The mean renal toxicity - change in blood urea (mmol/l) in the combination anti-pseudomonal AB groups was 0.83	The mean renal toxicity - change in blood urea (mmol/l) in the colistin groups was 0.26 lower (0.93 lower to 0.41 higher)		71 (Conway 1997)	⊕⊝⊝⊝ very low⁵^,¹²
[colistin versus combination anti-pseudomonal antibiotics] Adverse effects: renal toxicity - Change in serum creatinine (mol/l) Follow-up: 12 days	The mean change in serum creatinine (mol/l) in the combination anti-pseudomonal AB groups was −5.85	The mean change in serum creatinine (mol/l) in the colistin groups was 8.85 higher (0.66 lower to 18.36 higher)		71 (Conway 1997)	⊕⊝⊝⊝ very low⁵^,⁷

*: The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
: Abbreviations: CI: confidence interval; FEV₁: forced expiratory volume in 1 second; IV: intravenous; MD: mean difference; mmol/l: millimoles per litre; RR: risk ratio
a: Gold 1985: total of 34 treatment observations in N=30
b: Wesley 1988: total of 23 observations in N=13
1: The quality of the evidence was downgraded by 2 due to no blinding and 3 participants were included twice in analysis
2: Minimal important difference for this outcome (MID) = any difference is clinically significant
3: The quality of the evidence was downgraded by 1 due to no blinding.
4: The quality of the evidence was downgraded by 1 as 95% CI crossed 1 clinical MID
5: The quality of the evidence was downgraded by 2 due to single blinding and 18 participants were enrolled twice.
6: The quality of the evidence was downgraded by 2 due as 95%CI crossed 2 clinical MIDs.
7: The quality of the evidence was downgraded by 2 as 95% CI crossed 2 default MIDs
8: The quality of the evidence was downgraded by 1 as 13 participants received 23 courses of treatment.
9: The quality of the evidence was downgraded by 1 due to multiple enrolment of participants (40 participants contribute to 46 treatment episodes).
10: The quality of the evidence was downgraded by 1, as the 95% CI crossed the null effect (mortality could either decrease or increase)
11: The quality of the evidence was downgraded by 1 due lack of blinding in 1 trial, and because some participants were enrolled twice
12: The quality of the evidence was downgraded by 1 as 95% CI crossed 1 default MID

Table 99Comparison 4. Combination IV antibiotics versus combination IV antibiotics for pulmonary exacerbations with P aeruginosa

Comparison 4. Combination IV antibiotics versus combination IV antibiotics for pulmonary exacerbations with P aeruginosa
Outcomes	Illustrative comparative risks^* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Assumed risk	Corresponding risk	Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Combination IV	Combination IV
[aztreonam + amikacin versus ceftazidime + amikacin] Eradication of pathogen Follow-up: 2 weeks	571 per 1000	606 per 1000 (394 to 943)	RR 1.06 (0.69 to 1.65)	56 a (Schaad 1989)	⊕⊝⊝⊝ very low¹^,²
[aztreonam + amikacin versus ceftazidime + amikacin] FEV₁ % predicted (absolute change) - (combination B) Follow-up: 2 weeks	The mean FEV₁ % predicted (absolute change) in the versus IV ceftazidime + IV amikacin groups was 9	The mean FEV₁ % predicted (absolute change) in the Aztreonam + IV amikacin groups was 4 higher (0.25 lower to 8.25 higher)		49a (Schaad 1989)	⊕⊕⊝⊝ low¹^,³
[meropenem + tobramycin versus ceftazidime + tobramycin] FEV₁ % predicted (absolute change) - Follow-up: 2 to 4 weeks^b	The mean FEV₁ % predicted (absolute change) in the versus IV ceftazidime + IV tobramycin groups was 11.1	The mean FEV₁ % predicted (absolute change) in the IV meropenem + IV tobramycin groups was 2.7 higher (0.76 lower to 6.16 higher)		97 (Blumer 2005)	⊕⊕⊝⊝ low³^,⁴
[meropenem + tobramycin versus ceftazidime + tobramycin] FEV₁ % predicted (relative % change) - Follow-up: 2 to 4 weeks^b	The mean FEV₁ % predicted (relative % change) in the versus IV ceftazidime + IV tobramycin groups was 29.4	The mean FEV₁ % predicted (relative % change) in the IV meropenem + IV tobramycin groups was 9.4 higher (8.44 lower to 27.24 higher)		97 (Blumer 2005)	⊕⊝⊝⊝ very low⁴^,⁵
[aztreonam + amikacin versus ceftazidime + amikacin] Adverse effects - Rash Follow-up: 2 weeks	71 per 1000	14 per 1000 (1 to 285)	RR 0.2 (0.01 to 3.99)	56a (Schaad 1989)	⊕⊝⊝⊝ very low¹^,⁶
[aztreonam + amikacin versus ceftazidime + amikacin] Adverse effects - Liver transaminases - AST + ALT Follow-up: 2 weeks	71 per 1000	143 per 1000 (29 to 718)	RR 2 (0.4 to 10.05)	56a (Schaad 1989)	⊕⊝⊝⊝ very low¹^,⁶
[aztreonam + amikacin versus ceftazidime + amikacin] Adverse effects - Thrombocytopenia Follow-up: 2 weeks	0 per 1000	0 per 1000 (0 to 0)	RR 7 (0.38 to 129.55)	56a (Schaad 1989)	⊕⊝⊝⊝ very low¹^,⁶

*: The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
: Abbreviations: AST: aminotransferase, ALT: alanine aminotransferase; CI: confidence interval; FEV₁: forced expiratory volume in 1 second; IV: intravenous; MD: mean difference; RR: risk ratio
a: total of 56 treatment courses were randomised, N=42 participants
b: 2 to 4 weeks after discontinuation of 2 week course.
1: The quality of the evidence was downgraded by 1 due to attrition bias (clinical outcomes available for only around 50% of participants).
2: The quality of the evidence was downgraded by 2, as the 95% CI crossed the null effect and the CI was very wide
3: The quality of the evidence was downgraded by 1 as 95%CI crossed 1 clinical MID.
4: The quality of the evidence was downgraded by 1 due to attrition bias (some data missing).
5: The quality of the evidence was downgraded by 2 as 95%CI crossed 2 clinical MIDs.
6: The quality of the evidence was downgraded by 2 as 95%CI crossed 2 default MIDs.

Table 100Comparison 5. Two IV antibiotics + inhaled antibiotic versus 2 IV without inhaled antibiotic for pulmonary exacerbations with P aeruginosa

Comparison 5. Two IV antibiotics + inhaled antibiotic versus 2 IV without inhaled antibiotic for pulmonary exacerbations with P aeruginosa
Outcomes	Illustrative comparative risks^* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Assumed risk	Corresponding risk	Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	2 IV without inhaled antibiotic	2 IV antibiotic + inhaled antibiotic
[IV ceftazidime + IV amikacin + inhaled amikacin versus IV ceftazidime + IV amikacin] Eradication of P aeruginosa Follow-up: 15 days	409 per 1000	749 per 1000 (503 to 1000)	RR 1.83 (1.23 to 2.73)	84 (Schaad 1987)	⊕⊕⊕⊝ moderate¹
[IV ceftazidime + IV amikacin + inhaled amikacin versus IV ceftazidime + IV amikacin] Adverse effects: raised liver transaminases Follow-up: 4 to 6 weeks	250 per 1000	168 per 1000 (58 to 480)	RR 0.67 (0.23 to 1.92)	54 (Schaad 1987)	⊕⊝⊝⊝ very low¹^,²

*: The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
: CI: Confidence interval; RR: Risk ratio;
1: The quality of the evidence was downgraded by 1 as 18 participants were recruited twice and 6 participants enrolled 3 times.
2: The quality of the evidence was downgraded by 2 due to serious imprecision as 95% CI crosses 2 default MIDs.

Table 101Comparison 6. IV ceftazidime + IV tobramycin versus oral ciprofloxacin for pulmonary exacerbations with P aeruginosa

Comparison 6. IV ceftazidime + IV tobramycin versus oral ciprofloxacin for pulmonary exacerbations with P aeruginosa
Outcomes	Illustrative comparative risks^* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Assumed risk	Corresponding risk	Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Oral ciprofloxacin	IV ceftazidime + IV tobramycin
Eradication of P aeruginosa Follow-up: 2 weeks	245 per 1000	624 per 1000 (365 to 1000)	RR 2.55 (1.49 to 4.39)	89 (Richard 1997)	⊕⊕⊕⊝ moderate¹
Adverse effects - Treatment-related events Follow-up: 2 weeks	164 per 1000	188 per 1000 (83 to 427)	RR 1.15 (0.51 to 2.61)	108 (Richard 1997)	⊕⊝⊝⊝ very low¹^,²

*: The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
: Abbreviations: CI: confidence interval; IV: intravenous; RR: risk ratio
1: The quality of the evidence was downgraded by 1 due to no blinding.
2: The quality of the evidence was downgraded by 2 as 95% CI crossed 2 default MIDs.

Table 102Comparison 7. Oral ciprofloxacin + inhaled colistin versus inhaled tobramycin for acute infection with P aeruginosa

Comparison 7. Oral ciprofloxacin + inhaled colistin versus inhaled tobramycin for acute infection with P aeruginosa
Outcomes	Illustrative comparative risks^* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Assumed risk	Corresponding risk	Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Inhaled tobramycin	Oral ciprofloxacin + inhaled colistin
Adverse events - Severe cough Follow-up: 3 months	34 per 1000	11 per 1000 (0 to 271)	RR 0.33 (0.01 to 7.86)	58 (Proesmans 2013)	⊕⊝⊝⊝ very low¹^,²

*: The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
: Abbreviations: CI: confidence interval; RR: risk ratio
1: The quality of the evidence was downgraded by 1 due to no blinding. Blinding was not possible due to route of administration (oral versus inhaled).
2: The quality of the evidence was downgraded by 2 due to very serious imprecision as 95% CI crossed 2 default MIDs.

Table 103Comparison 8. Inhaled colistin + oral ciprofloxacin versus inhaled tobramycin + oral ciprofloxacin for acute infection with P aeruginosa

Comparison 8. Inhaled colistin + oral ciprofloxacin versus inhaled tobramycin + oral ciprofloxacin for acute infection with P aeruginosa
Outcomes	Illustrative comparative risks^* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Assumed risk	Corresponding risk	Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Inhaled tobramycin + oral ciprofloxacin	Inhaled colistin + oral ciprofloxacin
Relative change in % predicted FEV₁ from baseline Follow-up: 54 days	The mean relative change in % predicted FEV₁ from baseline in the control groups was 2.15	The mean relative change in % predicted FEV₁ from baseline in the intervention groups was 2.4 lower (5.885 lower to 1.0855 higher)		128 (Taccetti 2012)	⊕⊝⊝⊝ very low¹^,²
Treatment failure - trial discontinuation due to Lack of compliance Follow-up: 28 days	110 per 1000	105 per 1000 (50 to 224)	RR 0.95 (0.45 to 2.03)	223 (Taccetti 2012)	⊕⊝⊝⊝ very low¹^,³^,⁴
Adverse events - Vomiting Follow-up: 28 days	17 per 1000	9 per 1000 (1 to 104)	RR 0.56 (0.05 to 6.11)	223 (Taccetti 2012)	⊕⊝⊝⊝ very low¹^,⁵
Adverse events - Photosensitivity Follow-up: 28 days	0 per 1000	0 per 1000 (0 to 0)	RR 3.37 (0.14 to 81.79)	223 (Taccetti 2012)	⊕⊝⊝⊝ very low¹^,⁵
Adverse events - Wheeze Follow-up: 28 days	8 per 1000	3 per 1000 (0 to 77)	RR 0.37 (0.02 to 9.09)	223 (Taccetti 2012)	⊕⊝⊝⊝ very low¹^,⁵
Adverse events leading to trial discontinuation - Pulmonary exacerbation during early eradication treatment leading to treatment failure Follow-up: 28 days	42 per 1000	38 per 1000 (11 to 138)	RR 0.9 (0.25 to 3.26)	223 (1 study)	⊕⊝⊝⊝ very low¹^,⁴

*: The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
: Abbreviations: CI: confidence interval; FEV₁: forced expiratory volume in 1 second; IV: intravenous; RR: risk ratio
1: The quality of the evidence was downgraded by 1 due to serious imprecision as there was no blinding (openlabel).
2: The quality of the evidence was downgraded by 2 due to serious imprecision as 95% CI crosses two clinical MIDs.
3: The quality of the evidence was downgraded due to indirect outcome for discontinuation due to adverse events. It is unclear if discontinuation is due to adverse events or other factors.
4: The quality of the evidence was downgraded by 2, as the 95% CI crossed the null effect and the CI was very wide
5: The quality of the evidence was downgraded by 2 due to serious imprecision as 95% CI crosses 2 default MIDs.

Table 104Cost of antimicrobials to resolve acute pulmonary infection with P aeruginosa

Antimicrobial (quantity, basic price)	Unit cost
Ciprofloxacin (oral)
100mg tablets (6, £1.86)	£0.31
250mg tablets (10, £0.74)	£0.07
250mg/5ml oral suspension (100ml, £19.80)	£0.99/5ml
500mg tablets (10, £0.87)	£0.09
750mg tablets (10, £8.00)	£0.80
Chloramphenicol (oral)
250mg capsules (60, £377.00)	£6.28
Aztreonam (inhaled or oral)^a
Cayston 75mg powder and solvent for nebuliser solution vials with Altera Nebuliser Handset (84, £2,181.53)	£25.97
Azactam 1g powder for solution for injection vials (1, £9.40)	£9.40
Azactam 2g powder for solution for injection vials (1, £18.82)	£18.82
Meropenem IV^a
1g powder for solution for injection vials (10, £153.50)	£15.35
500mg powder for solution for injection vials (10, £76.90)	£7.69
Ceftazidime IV^a
500mg powder for solution for injection vials (1, £4.25)	£4.25
1g powder for solution for injection vials (10, £13.90)	£1.39
2g powder for solution for injection vials (10, £27.70)	£2.77
3g powder for solution for injection vials (1, £25.76)	£25.76
Piperacillin-Tazobactam IV^a
Piperacillin 2g / Tazobactam 250mg powder for solution for injection vials (1, £7.91)	£7.91
Piperacillin 4g / Tazobactam 500mg powder for solution for injection vials (1, £12.90)	£12.90
Tazocin 4.5g powder for solution for injection vials (1, £15.17)	£15.17
Fosfomycin IV^a
Fomicyt 2g powder for solution for infusion vials (10, £150.00)	£15.00
Fomicyt 4g powder for solution for infusion vials (10, £300.00)	£30.00
Ticarcillin-Clavulanate IV^a
Timentin 3.2g powder for solution for infusion vials (4, £21.32)	£5.33

(a): Taken from the BNF November 2016

Table 105Summary of included studies for antimicrobials for chronic pulmonary infection with P aeruginosa

Study	Intervention/Comparison	Population	Outcomes	Comments
Technology Appraisal
NICE TA 276 (Tappenden 2013)	Comparison 1: Tobramycin DPI vs Tobramycin nebulised (EAGER trial) Comparison 2: Colistimethate sodium DPI vs tobramycin nebulised (COLO/DPI/02/06) Comparison 3: Colistimethate sodium DPI vs colistimethate sodium nebulised (Davies 2004, COLO/DPI/02/05)	People with cystic fibrosis ≥ 6 years and chronic P aeruginosa pulmonary colonisation.	Lung function, FEV₁% Frequency and severity of respiratory exacerbations proxy for Time to next pulmonary exacerbation Rate and extent of microbiological response (Eradication of the specified organism from sputum/airway cultures) Quality of life Adverse events Not reported: Nutritional status Emergence of resistant organisms/antibiotic resistance	All studies are RCTs, open label EAGER trial: Konstan 2011a Other outcomes included in the TA: Respiratory symptoms
Cochrane systematic reviews
Remmington 2016 Cochrane SR	Comparison 1: Ciprofloxacin (500 mg) vs placebo (Sheldon 1993)	People with cystic fibrosis diagnosed by clinical features and all levels of severity of lung disease.	Comparison 1: Ciprofloxacin vs placebo FEV₁ Eradication of the organism Adverse events	AMSTAR: 11/11
Ryan 2011 Cochrane SR	Comparison 1: Aztreonam lysine vs placebo (McCoy 2008) Comparison 2: Colistin vs placebo (Hodson 2002, Jensen 1987) Comparison 3: Tobramycin vs placebo (Chuchalin 2007, Hodson 2002, Lenoir 2007, Murphy 2004, Ramsay 1993, Ramsay 1999)	People with cystic fibrosis diagnosed by clinical features and all levels of severity of lung disease.	Comparison 1: Aztreonam lysine vs placebo FEV₁%: Included in NMA Exacerbations: Included in NMA QoL Adverse events Not reported: Eradication of the organism Nutritional status Emergence of resistant organisms/antibiotic resistance Comparison 2: Colistin vs placebo FEV₁%: Included in NMA Exacerbations: Included in NMA Not reported: Eradication of the organisms* Nutritional status* QoL Adverse events Emergence of resistant organisms/antibiotic resistance Comparison 3: Tobramycin vs placebo FEV₁%: Included in NMA Exacerbations: Included in NMA Adverse events Not reported: Eradication of the organisms* Nutritional status* QoL Emergence of resistant organisms/antibiotic resistance*	AMSTAR: 11/11 *reported in individual studies
Primary studies included in the TA or in the Cochrane SR
Chuchalin 2007 (Hungary, Poland, Russia) RCT	Intervention Tobramycin (nebulised) 300 mg. 24 weeks: 4 weeks “on treatment”, followed by 4 weeks “off treatment” Comparison Placebo	N=247 people with cystic fibrosis and P aeruginosa ≥6 years Age range: 6 to 45	Lung function (FEV₁) Exacerbations Nutritional status Eradication of the organism Adverse events Mortality Emergence of resistant organisms	Included in Cochrane SR Ryan 2011 Included in NMA and review
COLO/DP I/02/05 (UK) Open label RCT, with cross-over	Intervention Colistin sodium DPI 125 mg, twice daily Comparison Colistin sodium solution 2 MU, twice daily Duration: 8 weeks	N=16 people with cystic fibrosis with chronic P aeruginosa infection ≥8 years Mean (SD) age: 20.3 (12.87) years	Lung function (FEV₁) Adverse events	Included in NICE TA 276 Included in the review
COLO/DPI/02/06 (EU, Russia, Ukraine) Open label RCT	Intervention Colistin sodium DPI 125 mg; twice daily Comparison Tobramycin inhalation solution 300 mg/5 ml; twice daily Duration: 24 weeks	N=380 people with cystic fibrosis and P aeruginosa ≥6 years Mean (SD) age: 21.3 (9.72) vs 20.9 (9.30) years	Lung function (FEV₁) Time to next exacerbation Nutritional status Quality of life Adverse events	Included in NICE TA 276 Included in the review
Hodson 2002 (UK) Open label RCT	Intervention Tobramycin (nebulised) 300 mg daily in 5ml twice daily Comparison Colistin (nebulised) 1MU in 3ml in saline twice daily Duration: 28 days	N=126 randomised (n=115 treated) people with cystic fibrosis Age range: 17 to 50 years	Pulmonary function (FEV₁) Eradication of the organism Adverse effects Emergence of resistant organisms	Included in Cochrane SR Ryan 2011 Included in NMA and review
Jensen 1987 (Denmark) RCT	Intervention Colistin (nebulised) 1 million units, twice daily for 3 months Comparison Placebo (normal saline)	N=40 people with cystic fibrosis and chronic P aeruginosa infection ≥6 years Age range: 7 to 35 years	Lung function (FEV₁) Eradication of the organism Emergence of resistant organisms	Included in Cochrane SR Ryan 2011 Included in NMA and review
Konstan 2011a (EAGER trial) (15 countries, not specified)	Intervention Tobramycin inhalation powder 112 mg, 4-capsules, twice daily Comparison Tobramycin (nebulised) 300mg/5 ml, twice daily	N=121 people with cystic fibrosis ≥ 6 years and positive cultures of P aeruginosa within 6 months of screening Mean age (SD): 26 (11.4) vs 25 (10.2)	Lung function (FEV₁) Exacerbations (hospitalization) Eradication of the organism Adverse events	Included in NICE TA 276 Included in NMA and the review
Lenoir 2007 (France, Italy, Moldova, Ukraine) RCT	Intervention Tobramycin (nebulised) 300 mg twice daily for 4 weeks followed by a 4-week run-out phase Comparison Placebo	N=59 with cystic fibrosis and P aeruginosa infection ≥6 years Age range: 6 to 30 years	Lung function (FEV₁) Eradication of the organism Adverse effects	Included in Cochrane SR Ryan 2011 Included in NMA and review
McCoy 2008 (Australia, Canada, New Zealand and USA) RCT	Intervention Aztreonam lysine 75 mg, for 4 weeks, 2 or 3-times daily Comparison Placebo (5 mg lactose in 1 ml 0.17% sodium chloride)	N=246 people with cystic fibrosis and documented P aeruginosa infection Age range: 7 to 65 years	FEV₁ Time to next exacerbation Adverse events Note: FEV₁ was not included in the review as it was reported narratively only, and could not be meta-analysed	Included in Cochrane SR Ryan 2011 Included in NMA and review
Murphy 2004 (USA) Open label RCT	Intervention Tobramycin (nebulised), 300 mg twice daily. Alternating 4-weekly cycles for 56 weeks Comparison No treatment	N=184 children and young people with cystic fibrosis with ≥2 cultures of P aeruginosa Age range: 6 to 15 years	Exacerbations (hospitalization)	Included in NMA only
Ramsey 1993 (USA) Crossover RCT	Intervention Tobramycin (nebulised) 600 mg, 3-times daily for 28 days, then cross-over for 2 28-days periods Comparison Placebo (0.5 normal saline)	N=71 people with cystic fibrosis and P aeruginosa sputum culture susceptible to tobramycin Mean age (SD): 17.7 years (1.25)	Lung function (FEV₁) Exacerbations	Included in Cochrane SR Ryan 2011 Included in NMA and review
Ramsey 1999 (USA) RCT	Intervention Tobramycin (nebulised) 300mg twice daily for three 28-day on-off cycles Comparison Placebo (0.225 normal saline and 1.25 mg quinine)	N=520 people with cystic fibrosis infected with P aeruginosa Age: 18 years or older	Lung function (FEV₁) Exacerbations (hospitalization) Adverse events Note: FEV₁ was not included in the review as it was reported narratively only, and could not be meta-analysed	Included in Cochrane SR Ryan 2011 Included in NMA and review
Sheldon 1993 (Canada) RCT	Intervention Ciprofloxacin 500 mg, for 10 days every 3 months for 4 courses Comparison Placebo	N=40 adults with cystic fibrosis and chronically infected with P aeruginosa (31 completed the trial) Age ≥ 18 years	Weight Adverse events Mortality Emergence of resistant organisms	Included in Cochrane SR Remington 2013 Included in review and review
Additional primary studies
Assael 2013 (Europe and USA) Open label RCT	Intervention Aztreonam lysine 28-day course × 3 Comparison Tobramycin (inhaled) 28 days course, 3000 mg, 2-times/day	N=273 people with cystic fibrosis ≥6 years and PA-positive sputum culture within the previous 3 months Mean age (SD): 25.5 years (9.0)	Pulmonary function (FEV₁) Exacerbations (requiring IV and/or additional antibiotics for respiratory events) Eradication of the organism Adverse effects	Open label Included in NMA and review
Flume 2016 (USA) RCT	Intervention Aztreonam lysine plus tobramycin (nebulised) Comparison Tobramycin (nebulised) Enrolled subjects received TIS 300 mg twice daily (BID) during a 28-day run-in phase This was followed by randomisation to a 24-week comparative phase. Subjects received 3 cycles of 28-days of double-blind AZLI or placebo (1:1 randomisation) alternating with 28-days of open-label TIS.	N=88 people with cystic fibrosis ≥ 6 years and documented P aeruginosa infection Mean age (SD): 28.4 years (11.4)	Exacerbations (requiring IV and/or additional antibiotics for respiratory events, time to first event and rate of hospitalisations) Adverse effects Adjusted mean CFQ-R scores averaged from weeks 4, 12, and 20 Adjusted mean FEV₁% predicted average from weeks 4, 12 and 20	Included in NMA and review
Galeva 2013 (EDIT trial) (Bulgaria, Estonia, Latvia, Lithuania, Romania, Russia, Egypt, and India) RCT	Intervention Tobramycin inhalation powder 112mg twice daily, as capsules administered via the T-326 dry powder inhaler Comparison Placebo	N=62 people with cystic fibrosis ≥6 years, and a positive sputum or throat culture for P.A within 6 months of screening and positive sputum culture for P.A at the screening visit Mean age (SD), years 12.9 (4.3) vs. 12.9 (4.7)	Pulmonary function (FEV₁) Exacerbations (hospitalization) Adverse effects	Included in NMA and review
Konstan 2011 (EVOLVE trial) (Bulgaria, Lithuania, Serbia, Argentina, Brazil, Chile, Mexico, USA) RCT	Intervention Tobramycin inhalation powder (112 mg), 28 day cycle followed by 2 28-day cycles open-label tobramycin inhalation powder Comparison Placebo, 28-day cycle followed by 2 28-day cycles open-label tobramycin inhalation powder Total duration 24 weeks	N=95 children, young people and adults with cystic fibrosis with a positive sputum or throat culture for P aeruginosa within 6 months of screening and a positive sputum culture for P aeruginosa at the screening visit Age: 6 to 21 years	Pulmonary function (FEV₁) Suppression of the organism Adverse events	Included in NMA and review
Retsch-Bogart 2009 (USA) RCT	Intervention Aztreonam lysine 75mg aztreonam, 52.5mg of lysine monohydrate Comparison Placebo (5mg lactulose)	N=164 people with cystic fibrosis and P aeruginosa documented infection ≥ 6 years Mean age (range): 31.7 (11–74); 27.4 (7–54)	Exacerbations (hospitalization) Eradication of the organism Quality of life Adverse effects	Included in NMA and review
Schuster 2013 (Europe - countries not specified) Open label RCT	Intervention Colistin DPI 1.6625 MU twice daily, 24 weeks Comparison Tobramycin inhalation solution 300 mg/5 ml twice-daily, three 28-day cycles	N=380 people with cystic fibrosis chronically colonised with P aeruginosa infection, ≥ 6 years Mean (SD) age: 21.1 (9.49) years	FEV₁% Adverse events	Open label Included in NMA and review
Trapnell 2012 (USA) RCT	Intervention Fosfomycin/Tobramycin (160/40 mg or 80/20 mg) Comparison Placebo	N=119 people with cystic fibrosis ≥ 18 years and confirmed P aeruginosa infection 80/20 mg: n=38 160/40 mg: n=41 Placebo: n=40 Mean age: 32 years (10.1)	FEV₁ Exacerbations (hospitalisation)	Included in NMA and review
Wainwright 2011 (Australia, USA) RCT	Intervention Aztreonam lysine 28 days + 14 days follow-up 75 mg/day, 3-times Comparison Placebo	N=157 people with cystic fibrosis ≥ 6 years Age range: 6 to 17 years	Exacerbations (hospitalization) Eradication of the organism Adverse effects	Included in NMA and review

: Cystic fibrosis: cystic fibrosis; CFQ-R: Cystic Fibrosis Questionnaire-Revised; DPI: dry powder for inhalation; FEV₁: forced expiratory volume; ITT: intention to treat analysis: RCT: randomized controlled trial

Table 106Summary of included studies for antimicrobials for chronic pulmonary infection with S aureus

Study	Intervention/Comparison	Population	Outcomes	Comments
Cochrane systematic reviews
Ahmed 2016 Cochrane SR	Intervention Any combination of topical, inhaled, oral or IV antimicrobials used with the objective of suppressive therapy for chronic Comparison Placebo or no treatment	Children and adults with confirmed diagnosis of cystic fibrosis and confirmed microbiological evidence of S aureus (MSSA strains only).	No studies were identified for inclusion in this review	AMSTAR score:10/11
Lo 2015 Cochrane SR	Intervention Any combination of topical, inhaled, oral or IV antimicrobials to eradicate MRSA Comparison Placebo, standard treatment or not treatment	Children and adults with cystic fibrosis with a confirmed positive microbiological isolate of methicillin-resistant S aureus (MRSA).	No studies were identified for inclusion in this review	This review includes people with different disease severity.

Table 107Summary of included studies for antimicrobials for chronic pulmonary infection with A fumigatus

Study	Intervention/Comparison	Population	Outcomes	Comments
Cochrane systematic reviews
Elphick 2014 Cochrane SR	Intervention Antifungal treatments, including major treatments such as oral azoles and nebulised amphotericin Comparison No treatment, placebo or different dosages	Children and adults with cystic fibrosis and allergic bronchopulmonary aspergillosis.	No studies were identified for inclusion in this review
Additional primary studies
Aaron 2012 (Canada) RCT	Intervention Itraconazole capsules daily dose of 5 mg/kg once daily; if the dose exceeded 200 mg/day it was given twice daily Comparison Placebo	N=35 People with cystic fibrosis ≥ 6 years of age and chronically colonised with A Fumigatus (defined as at least 2 positive sputum cultures within the last 12 months)	Lung function, measured as FEV₁% predicted at 24 and 48 weeks Time to next pulmonary exacerbation proxy outcomes: number of patients that experienced pulmonary exacerbations requiring oral or IV AB number of patients that experienced pulmonary exacerbations requiring hospitalization Quality of life, measured with the tool CFQ-R at 24 weeks Adverse events, reported during the 24-week study duration Not reported: Eradication of the specified organism from sputum/airway cultures Nutritional status Emergence of resistant organisms/antibiotic resistance	(+) low risk of bias for sequence generation, blinding and selective reporting (+) first prospective RCT (+) ITT analysis (?) unclear risk of bias for allocation concealment (-) pilot study small sample size, authors failed to recruit more patients to extend the study (-) Failure to achieve therapeutic levels of Itraconazole in many patients

Table 108Odds ratios (95% CrI) from conventional (white area) and network metaanalysis (grey area) for the number of people experiencing at least one exacerbation with short-term (4–10 weeks) treatment

	Placebo	Aztreonam lysine	Tobramycin (nebulised)	Tobramycin + Fosfomycin (nebulised)
Placebo		0.3 (0.08, 0.92)	3 (0.55, 24.66)	0.9 (0.25, 3.81)
Aztreonam lysine	0.3 (0.08, 0.92)
Tobramycin (nebulised)	3 (0.55, 24.66)	10.43 (1.31, 122.2)
Tobramycin + Fosfomycin (nebulised)	0.9 (0.25, 3.81)	3.11 (0.55, 21.38)	0.3 (0.03, 2.78)

: Results in the top right diagonal of the table are the mean differences and 95% CrI from the conventional meta-analyses of direct evidence between the column-defined treatments compared to the row-defined treatment. Mean differences greater than 0 favour the column-defined treatment.
: Results in the bottom left are the mean differences and 95% CrI from the NMA model of direct and indirect evidence between the row-defined treatments compared to the column-defined treatments. Mean differences greater than 0 favour the row-defined treatment.
: Numbers in bold denote results for which the 95% CrI does not include the null effect of 0

Table 109Median treatment ranking (with their 95% CrI) of all interventions in the network and the probability of being the best treatment for reducing the number of people experiencing at least one exacerbation with short-term (410 weeks) treatment

	Median (95% CrI) treatment rank	Probability of being the best treatment (%)
Placebo	3 (2–4)	0.70%
Aztreonam lysine	1 (1–2)	88.30%
Tobramycin (nebulised)	4 (2–4)	1.00%
Tobramycin + Fosfomycin (nebulised)	2 (1–4)	10.00%

Table 110Quality assessment of the evidence for the NMA – number of patients with at least one exacerbation in the short-term

NMA	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Quality
Short-term (4–10 weeks) number of patients with at least one exacerbation (3 studies)	Serious¹	No serious inconsistency	No serious indirectness	Serious²	None	Low

1: For all three studies the risk of bias was unclear
2: No intervention has rank credible intervals ≤33% of total distribution of comparators

Table 111Odds ratios (95% CrI) from conventional (white area) and network metaanalysis (grey area) for the number of people experiencing at least one exacerbation with long-term (>10 weeks) treatment

	Placebo	Aztreonam lysine	Tobramycin (nebulised)	No treatment	Tobramycin (powder)	Combination^a
Placebo			0.88 (0.65, 1.20)
Aztreonam lysine	0.40 (0.22, 0.71)		2.20 (1.36, 3.61)
Tobramycin (nebulised)	0.88 (0.65, 1.20)	2.20 (1.36, 3.61)		2.84 (1.28, 6.71)	1.14 (0.75, 1.75)	0.77 (0.33, 1.78)
No treatment	2.51 (1.07, 6.22)	6.27 (2.46, 16.81)	2.84 (1.28, 6.71)
Tobramycin (powder)	1.01 (0.60, 1.70)	2.52 (1.33, 4.84)	1.14 (0.75, 1.75)	0.40 (0.16, 1.00)
Combination^a	0.67 (0.27, 1.65)	1.68 0.63, 4.48)	0.77 (0.33, 1.78)	0.27 (0.08, 0.86)	0.67 (0.26, 1.72)

: Results in the top right diagonal of the table are the mean differences and 95% CrI from the conventional meta-analyses of direct evidence between the column-defined treatments compared to the row-defined treatment. Mean differences greater than 0 favour the column-defined treatment.
: Results in the bottom left are the mean differences and 95% CrI from the NMA model of direct and indirect evidence between the row-defined treatments compared to the column-defined treatments. Mean differences greater than 0 favour the row-defined treatment.
: Numbers in bold denote results for which the 95% CrI does not include the null effect of 0
(a): 28 days aztreonam lysine (nebulised) alternating with 28 days tobramycin (nebulised)

Table 112Median treatment ranking (with their 95% CrI) of all interventions in the network and the probability of being the best treatment for reducing the number of people experiencing at least one exacerbation with long-term (>10 weeks) treatment

	Median (95% CrI) treatment rank	Probability of being the best treatment (%)
Placebo	4 (2, 5)	0.03%
Aztreonam lysine	1 (1, 2)	85.01%
Tobramycin (nebulised)	3 (2, 5)	0.01%
No treatment	6 (5, 6)	0.00%
Tobramycin (powder)	4 (2, 5)	0.12%
Combination a	2 (1, 5)	14.83%

: 28 days aztreonam lysine (nebulised) alternating with 28 days tobramycin (nebulised)

Table 113Quality assessment of the evidence for the NMA – number of patients with at least one exacerbation in the long-term

NMA	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Quality
Long-term (>10 weeks) number of patients with at least one exacerbation (6 studies)	Serious¹	No serious inconsistency	No serious indirectness	No serious imprecision	None	Moderate

1: For two studies the risk of bias was high and for four studies the risk of bias was unclear

Table 114Summary clinical evidence profile: Comparison 1. Aztreonam lysine versus placebo

Comparison 1.: Aztreonam versus placebo
Outcomes	Illustrative comparative risks^* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Assumed risk	Corresponding risk	Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Placebo	Aztreonam lysine
Lung function: relative change in FEV₁% predicted Scale from: 0 to 100 Follow-up: 28 days	The mean relative change in FEV₁% predicted at 28 days follow up in the placebo group was −2.5	The mean relative change in FEV₁% predicted at 28 days follow up in the aztreonam lysine groups was 2.79 higher (0.48 to 5.1 higher)		157 (Wainwright 2011)	⊕⊕⊕⊝ moderate¹
Number of patients with 1 or more exacerbations	NMA outcome
Suppression of the organism: adjusted mean change sputum density log10 CFU/g Follow-up: 28 days	Not reported	The mean adjusted mean change sputum density in the aztreonam lysine groups was 1.40 lower (1.94 lower to 0.85 higher)		321 (Retsch-Bogart 2009, Wainwright 2011)	⊕⊕⊕⊕ high
Nutritional status % weight change (kg) Follow-up: 28 days	The mean % weight change (kg) in the placebo groups ranged between 1 and 1.1	The mean % weight change (kg) in the aztreonam lysine groups was 1 higher (0.33 to 1.67 higher)		164 (Retsch-Bogart 2009)	⊕⊕⊕⊕ high
Quality of life: change in CFQR body image Follow-up: 28 days	The mean change in CFQ-R body image in the placebo groups ranged between 1 and 1.1	The mean change in CFQ-R body image in the aztreonam lysine groups was 2.44 higher (0.35 lower to 5.23 higher)		320 (Retsch-Bogart 2009, Wainwright 2011)	⊕⊕⊕⊝ moderate¹
Quality of life: change in CFQR digestion Follow-up: 28 days	The mean change in CFQ-R digestion in the placebo groups ranged between 1.9 and 5.5	The mean change in CFQ-R digestion in the aztreonam lysine groups was 0.45 lower (3.53 lower to 2.63 higher)		321 (Retsch-Bogart 2009, Wainwright 2011)	⊕⊕⊕⊕ high
Quality of life: change in CFQR eating Scale from: 0 to 100 Follow-up: 28 days	The mean change in CFQ-R eating in the placebo groups ranged between −4.7 and −1.2	The mean change in CFQ-R eating in the aztreonam lysine groups was 4.99 higher (1.47 lower to 11.46 higher)		321 (Retsch-Bogart 2009, Wainwright 2011)	⊕⊝⊝⊝ very low¹^,²
Quality of life: change in CFQR emotional functioning Scale from: 0 to 100 Follow-up: 28 days	The mean change in CFQ-R emotional functioning in the placebo groups ranged between −1.3 and 3.7	The mean change in CFQ-R emotional functioning in the aztreonam lysine groups was 2.36 higher (3.13 lower to 7.84 higher)		320 (Retsch-Bogart 2009, Wainwright 2011)	⊕⊝⊝⊝ very low¹^,²
Quality of life: change in CFQR health perceptions Follow-up: 28 days	The mean change in CFQ-R health perceptions in the placebo groups ranged between −4.8 and −1.8	The mean change in CFQ-R health perceptions in the aztreonam lysine groups was 6.82 higher (0.75 to 12.89 higher)		272 (Retsch-Bogart 2009, Wainwright 2011)	⊕⊝⊝⊝ very low¹^,²
Quality of life: change in CFQR physical functioning Follow-up: 28 days	The mean change in CFQ-Rhealth perceptions in the placebo groups ranged between −6.9 and −0.69	The mean change in CFQ-Rhealth perceptions in the aztreonam lysine groups was 5.60 higher (0.96 lower to 12.15 higher)		320 (Retsch-Bogart 2009, Wainwright 2011)	⊕⊝⊝⊝ very low¹^,²
Quality of life: change in CFQ-Rrespiratory symptoms Follow-up: 28 days	The mean change in CFQ-Rrespiratory symptoms in the placebo groups ranged between −2.6 and 2.9	The mean change in CFQ-Rrespiratory symptoms in the aztreonam lysine groups was 4.81 higher (4.6 lower to 14.21 higher)		321 (Retsch-Bogart 2009, Wainwright 2011)	⊕⊝⊝⊝ very low¹^,²
Quality of life: change in CFQ-Rrole/school Follow-up: 28 days	The mean change in CFQ-Rrole/school in the placebo groups ranged between −4.2 and 0.29	The mean change in CFQ-Rrole/school in the aztreonam lysine groups was 2.97 higher (3.2 lower to 9.13 higher)		272 (Retsch-Bogart 2009, Wainwright 2011)	⊕⊝⊝⊝ very low¹^,²
Quality of life: change in CFQ-Rsocial functioning Follow-up: 28 days	The mean change in CFQ-Rsocial functioning in the placebo groups ranged between −3.6 and −2.6	The mean change in CFQ-Rsocial functioning in the aztreonam lysine groups was 3.54 higher (0.78 to 6.31 higher)		319 (Retsch-Bogart 2009, Wainwright 2011)	⊕⊕⊕⊝ moderate¹
Quality of life: change in CFQ-Rtreatment burden Follow-up: 28 days	The mean change in CFQ-Rtreatment burden in the placebo groups ranged between −3.1 and 5.1	The mean change in CFQ-Rtreatment burden in the aztreonam lysine groups was 0.36 lower (7.42 lower to 6.69 higher)		321 (Retsch-Bogart 2009, Wainwright 2011)	⊕⊝⊝⊝ very low²^,³
Quality of life: change in CFQ-Rvitality Follow-up: 28 days	The mean change in CFQ-Rvitality in the placebo groups ranged between −4.4 and −2.2	The mean change in CFQ-Rvitality in the aztreonam groups was 5.46 higher (0.16 to 10.76 higher)		272 (Retsch-Bogart 2009, Wainwright 2011)	⊕⊕⊝⊝ low¹^,²
Quality of life: change in CFQ-Rweight Follow-up: 28 days	The change in CFQ-Rweight in the placebo groups ranged between 1.4 and 2.6	The change in CFQ-Rweight in the aztreonam lysine groups was 2.58 higher (2.83 lower to 7.98 higher)		272 (Retsch-Bogart 2009, Wainwright 2011)	⊕⊕⊕⊝ moderate¹
Minor adverse events: chest discomfort Follow-up: 28 days	48 per 1000	62 per 1000 (18 to 224)	RR 1.31 (0.37 to 4.71)	164 (Retsch-Bogart 2009)	⊕⊕⊝⊝ low⁴
Minor adverse events: cough Follow-up: 28 days	Study population		RR 1.10 (0.87 to 1.38)	532 (Retsch-Bogart 2009, McCoy 2009 2009, Wainwright 2011)	⊕⊕⊝⊝ low⁴
	340 per 1000	374 per 1000 (296 to 470)
	Moderate
	342 per 1000	376 per 1000 (298 to 472)
Minor adverse events: headache Follow-up: 28 days	Study population		RR 0.94 (0.34 to 2.61)	321 (Retsch-Bogart 2009, Wainwright 2011)	⊕⊝⊝⊝ very low⁴^,⁶
	121 per 1000	114 per 1000 (41 to 316)
	Moderate
	121 per 1000	114 per 1000 (41 to 316)
Major adverse events: dyspnoea Follow-up: 28 days	95 per 1000	63 per 1000 (21 to 183)	RR 0.66 (0.22 to 1.92)	164 (Retsch-Bogart 2009)	⊕⊕⊝⊝ low⁴
Major adverse events: haemoptysis Follow-up: 28 days	Study population		RR 0.86 (0.44 to 1.7)	375 (Retsch-Bogart 2009, Mccoy 2009)	⊕⊕⊝⊝ low⁴
	94 per 1000	81 per 1000 (41 to 159)
	Moderate
	94 per 1000	81 per 1000 (41 to 160)
Mortality Follow-up: 28 days	No events	No events	-	211 (Mccoy 2009)	⊕⊕⊕⊕ High
Emergence of resistant organisms: persistent isolation of S aureus Follow-up: 42 days	62 per 1000	27 per 1000 (6 to 135)	RR 0.44 (0.09 to 2.19)	155 (Retsch-Bogart 2009)	⊕⊕⊕⊝ moderate⁵
Emergence of resistant organisms: persistent isolation of B cepacia Follow-up: 42 days	No events	No events	-	155 (Retsch-Bogart 2009)	⊕⊕⊕⊕ High
Emergence of resistant organisms: persistent isolation of S. maltophilia Follow-up: 42 days	0 per 1000	0 per 1000 (0 to 0)	RR 5.47 (0.27 to 112.04)	155 (Retsch-Bogart 2009)	⊕⊕⊝⊝ low⁴
Emergence of resistant organisms: persistent isolation of A. xilosidans Follow-up: 42 days	25 per 1000	14 per 1000 (1 to 146)	RR 0.55 (0.05 to 5.91)	155 (Retsch-Bogart 2009)	⊕⊕⊝⊝ low⁴

*: The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
: Abbreviations: cystic fibrosisQ-R: cystic fibrosis questionnaire revised; CI: confidence interval; FEV₁: forced expiratory volume in 1 second; MD: mean difference; RR: risk ratio
1: The quality of the evidence was downgraded by 1 as the 95% CI crossed 1 clinical MID
2: The quality of the evidence was downgraded by 1 or by 2 due to the moderate of high heterogeneity in the different CFQ-Rdomains (eating I2=79%; emotional functioning I2=80%; health perceptions I2=62%; respiratory symptoms I2=85%; role/school I2=73%; treatment burden I2=79%; vitality I2=40%)
3: The quality of the evidence was downgraded by 2 as the 95% CI crossed 2 clinical MIDs
4: The quality of the evidence was downgraded by 2 as the 95% CI crossed 2 default MIDs
5: The quality of the evidence was downgraded by 1 as the 95% CI crossed 1 default MID
6: The quality of the evidence was downgraded by 2 due to high heterogeneity (I2=62%)

Table 115Summary clinical evidence profile: Comparison 2. Ciprofloxacin versus placebo

Comparison 2.: Ciprofloxacin versus placebo
Outcomes	Illustrative comparative risks^* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Assumed risk	Corresponding risk	Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Placebo	Ciprofloxacin
Lung function	Not reported
Number of people with one or more exacerbations	NMA outcome
Nutritional status: weight kg Follow-up: 6 to 12 months	The mean weight in the placebo group was 51.3	The mean change in weight in the ciprofloxacin groups was 4.4 higher (3.7 lower to 12.5 higher)		31 (Sheldon 1993)	⊕⊝⊝⊝ very low¹^,²
Minor adverse events gastrointestinal Follow-up: 12 months	0 per 1000	0 per 1000 (0 to 0)	RR 5 (0.26 to 98)	40 (Sheldon 1993)	⊕⊝⊝⊝ very low³^,⁴
Mortality Follow-up: 12 months	50 per 1000	50 per 1000 (4 to 745)	RR 1 (0.07 to 14.9)	40 (Sheldon 1993)	⊕⊕⊝⊝ low⁵
Emergence of resistant organisms - isolation of resistant strains of P aeruginosa Follow-up: 12 months	312 per 1000	666 per 1000 (297 to 1000)	RR 2.13 (0.95 to 4.8)	(Sheldon 1993)	⊕⊝⊝⊝ very low¹^,²
Emergence of resistant organisms - isolation of resistant strains of S aureus Follow-up: 12 months	375 per 1000	266 per 1000 (94 to 761)	RR 0.71 (0.25 to 2.03)	31 (Sheldon 1993)	⊕⊝⊝⊝ very low¹^,⁴

*: The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
: Abbreviations: CI: confidence interval; FEV₁: forced expiratory volume in 1 second; MD: mean difference; RR: risk ratio
1: The quality of the evidence was downgraded by 2 due to unclear blinding and reporting and high loss to follow-up
2: The quality of the evidence was downgraded by 1 as the 95% CI crossed 1 default MID
3: The quality of the evidence was downgraded by 1 due to unclear blinding and reporting
4: The quality of the evidence was downgraded by 2 as the 95% CI crossed 2 default MIDs
5: The quality of the evidence was downgraded by 2 as the 95% CI crossed the line of null effect, and the CI is very wide (trial underpowered to detect a difference)

Table 116Summary clinical evidence profile: Comparison 3.1. Colistin versus placebo

Comparison 3.1.: Colistin versus placebo
Outcomes	Illustrative comparative risks^* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Assumed risk	Corresponding risk	Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Placebo	Colistin
Lung function: change in FEV₁ % predicted Follow-up: 3 months	The mean change in FEV₁ % predicted in the placebo groups was −17	The mean change in FEV₁ % predicted in the colistin groups was 6.00 higher (1.07 lower to 13.07 higher)		40 (Jensen 1987)	⊕⊕⊝⊝ low¹^,²
Number of patients with 1 or more exacerbations	NMA outcome
Suppression of the organism: eradication of P aeruginosa from the sputum Follow-up: 3 months	PA was not eradicated from the sputum of any patient during the 3-month trial		-	40 (Jensen 1987)	⊕⊕⊕⊝ moderate¹^,³
Emergence of resistant organisms: superinfection with other colistinresistant organisms Follow-up: 3 months	No super infection with other colistin-resistant microorganisms, including Ps. Cepacia, Serratia Macencens, Proteus mirabilis, Grampositive organisms or funghi during the 3-month trial		-	40 (Jensen 1987)	⊕⊕⊕⊝ moderate¹^,³
Emergence of resistant organisms: resistance to colistin Follow-up: 3 months	Resistance to colistin did no develop in any strain during the 3-month trial		-	40 (Jensen 1987)	⊕⊕⊕⊝ moderate¹^,³
Emergence of resistant organisms: resistance to other commonly used antipseudomonas treatment Follow-up: 3 months	No change in resistance pattern to other commonly used antipseudomonas during the 3-month trial		-	40 (Jensen 1987)	⊕⊕⊕⊝ moderate¹^,³

*: The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
: CI: Confidence interval;
1: The quality of the evidence was downgrade by 1 due to unclear randomisation, allocation and blinding methods. Poor reporting.
2: The quality of the evidence was downgraded by 1 due to serious imprecision, as the 95% CI crossed 1 clinical MID
3: Not calculable, as data reported narratively only.

Table 117Summary clinical evidence profile: Comparison 3.2. Colistin inhalation powder versus colistin inhalation solution

Comparison 3.2. Colistin inhalation powder versus colistin inhalation solution
Outcomes	Illustrative comparative risks^* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Assumed risk	Corresponding risk	Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Colistin inhalation solution (COLI neb)	Colistin inhalation powder (COLI DPI)
Lung function: % mean change in FEV₁ % predicted Scale from: 0 to 100 Follow-up: 4 weeks	Not reported	The % mean change in FEV₁ % predicted in the COLI DPI groups was 3.01 lower (18.71 lower to 12.69 higher)		31 (COLO/DPI/02/05)	⊕⊝⊝⊝ very low¹^,²
Number of patients with 1 or more exacerbations	NMA outcome
Minor adverse events: vomiting Follow-up: 8 weeks	0 per 1000	0 per 1000 (0 to 0)	RR 4.71 (0.24 to 90.69)	31 (COLO/DPI/02/05)	⊕⊝⊝⊝ very low¹^,³
Minor adverse events: productive cough Follow-up: 8 weeks	67 per 1000	125 per 1000 (13 to 1000)	RR 1.88 (0.19 to 18.6)	31 (COLO/DPI/02/05)	⊕⊝⊝⊝ very low¹^,³
Minor adverse events: chest discomfort Follow-up: 8 weeks	133 per 1000	251 per 1000 (53 to 1000)	RR 1.88 (0.4 to 8.78)	31 (COLO/DPI/02/05)	⊕⊝⊝⊝ very low¹^,³
Serious adverse events - AE: dyspnoea Follow-up: 8 weeks	267 per 1000	187 per 1000 (51 to 701)	RR 0.7 (0.19 to 2.63)	31 (COLO/DPI/02/05)	⊕⊝⊝⊝ very low¹^,³

*: The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
: CI: Confidence interval; RR: Risk ratio;
1: The quality of the evidence was downgraded by 1 as this is an open trial, and the randomisation is unclear
2: The quality of the evidence was downgraded by 2 as the 95% CI crossed 2 clinical MIDs
3: The quality of the evidence was downgraded by 2 as the 95% CI crossed 2 default MIDs

Table 118Summary clinical evidence profile: Comparison 3.3. Colistin versus Tobramycin

Comparison 3.3. Colistin versus Tobramycin
Outcomes	Illustrative comparative risks^* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Assumed risk	Corresponding risk	Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Tobramycin	Colistin
[COLI nebulised versus TOBI nebulised] Lung function: mean % change in FEV₁ % predicted Scale from: 0 to 100 Follow-up: 1 to 3 months	The mean % change in FEV₁ % predicted in the tobramycin groups was 6.7	The mean % change in FEV₁ % predicted in the intervention groups was 6.33 lower (12.7 lower to 0.04 higher)		109 (Hodson 2002)	⊕⊝⊝⊝ very low¹^,²
[COLI DPI versus TOBI nebulised] Lung function: mean % change in FEV₁ % predicted Scale from: 0 to 100 Follow-up: 4 weeks	Not reported	The mean % change in FEV₁ % predicted in the intervention groups was 1.67 lower (5.43 lower to 2.09 higher)		374 (COLO/DPI/02/06)	⊕⊕⊝⊝ low²^,³
[COLI DPI versus TOBI nebulised] Lung function: mean % change in FEV₁ % predicted Scale from: 0 to 100 Follow-up: 12 weeks	Not reported	The mean % change in FEV₁ % predicted in the intervention groups was 2.63 lower (6.67 lower to 1.41 higher)		374 (COLO/DPI/02/06)	⊕⊕⊝⊝ low²^,³
[COLI versus TOBI] Lung function: mean % change in FEV₁ % predicted Scale from: 0 to 100 Follow-up: 24 weeks	Not reported	The mean % change in FEV₁ % predicted in the intervention groups was 0.99 higher (0.95 to 1.03 higher)		658 (COLO/DPI/02/06, Schuster 2013)	⊕⊕⊝⊝ low⁴
Number of patients with 1 or more exacerbations	NMA outcome
[COLI DPI versus TOBI nebulised] Time to next pulmonary exacerbation: time to first additional anti P aeruginosa treatment (days)	The mean time to first additional anti P aeruginosa treatment in the tobramycin groups was 51.79 days	The mean time to first additional anti P aeruginosa treatment in the colistin groups was 3.49 higher (5.14 lower to 12.12 higher)		374 (COLO/DPI/02/06)	⊕⊝⊝⊝ very low³^,⁵
[COLI DPI versus TOBI nebulised] Suppression of the organism: change in sputum PA density Log10 CFU/ml Follow-up: 4 weeks	The mean change in sputum pa density log10 CFU/ML in the tobramycin groups was −0.79	The mean change in sputum pa density log10 CFU/ML in the colistin groups was 0.32 higher (0.32 lower to 0.96 higher)		79 (COLO/DPI/02/06)	⊕⊕⊝⊝ low¹
[COLI DPI versus TOBI nebulised] Nutritional status: BMI change kg Follow-up: 24 weeks	The mean BMI change in the colistin groups was 0.17	The mean BMI change in the colistin groups was 0.09 lower (0.26 lower to 0.88 higher)		374 (COLO/DPI/02/06)	⊕⊕⊝⊝ low³^,⁶
[COLI DPI versus TOBI nebulised] Quality of life: change in CFQ-R physical Scale from: 0 to 100. Follow-up: 24 weeks	The mean change in quality of life CFQ-R physical in the tobramycin groups was −1.56	The mean change in quality of life: CFQ-R physical in the colistin groups was 1.82 higher	P=0.353	374 (COLO/DPI/02/06)	⊕⊕⊕⊝ moderate³^,⁷
[COLI DPI versus TOBI nebulised] Quality of life: change in CFQ-R vitality Scale from: 0 to 100. Follow-up: 24 weeks	The mean change in quality of life: CFQ-R vitality in the tobramycin groups was −1.40	The mean change in quality of life: CFQ-R vitality in the colistin groups was 2.27 higher	P=0.293	374 (COLO/DPI/02/06)	⊕⊕⊕⊝ moderate³^,⁷
[COLI DPI versus TOBI nebulised] Quality of life: change in CFQ-R emotion Scale from: 0 to 100. Follow-up: 24 weeks	The mean change in quality of life: CFQ-R emotion in the tobramycin groups was 0.47	The mean change in quality of life: CFQ-R emotion in the colistin groups was 1.75 higher	P=0.244	374 (COLO/DPI/02/06)	⊕⊕⊕⊝ moderate³^,⁷
[COLI DPI versus TOBI nebulised] Quality of life: change in CFQ-R eating Scale from: 0 to 100. Follow-up: 24 weeks	The mean change in quality of life: CFQ-R eating in the tobramycin groups was 0.66	The mean change in quality of life: CFQ-R eating in the colistin groups was 0.19 lower	P=0.925	372 (COLO/DPI/02/06)	⊕⊕⊕⊝ moderate³^,⁷
[COLI DPI versus TOBI nebulised] Quality of life: change in CFQ-R treatment burden Scale from: 0 to 100. Follow-up: 24 weeks	The mean change in quality of life: CFQ-R treatment burden in the control tobramycin was 2.75	The mean change in quality of life: CFQ-R treatment burden in the colistin groups was 2.87 higher	P=0.091	374 (COLO/DPI/02/06)	⊕⊕⊕⊝ moderate³^,⁷
[COLI DPI versus TOBI nebulised] Quality of life: change in CFQ-R health perception Scale from: 0 to 100. Follow-up: 24 weeks	The mean change in quality of life: CFQ-R health perception in the tobramycin groups was −2.71	The mean change in quality of life: CFQ-R health perception in the intervention groups was 2.96 higher	P=0.159	374 (COLO/DPI/02/06)	⊕⊕⊕⊝ moderate³^,⁷
[COLI DPI versus TOBI nebulised] Quality of life: change in CFQ-R social Scale from: 0 to 100. Follow-up: 24 weeks	The mean change in quality of life: CFQ-R social in the tobramycin groups was 2.18	The mean change in quality of life: CFQ-R social in the colistin groups was 0.92 higher	P=0.153	374 (COLO/DPI/02/06)	⊕⊕⊕⊝ moderate³^,⁷
[COLI DPI versus TOBI nebulised] Quality of life: change in CFQ-R body image Scale from: 0 to 100. Follow-up: 24 weeks	The mean change in change in quality of life: CFQ-R body image in the tobramycin groups was 5.98	The mean change in quality of life: CFQ-R body image in the colistin groups was 1.85 higher	P=0.385	374 (COLO/DPI/02/06)	⊕⊕⊕⊝ moderate³^,⁷
[COLI DPI versus TOBI nebulised] Quality of life: change in CFQ-R role Scale from: 0 to 100. Follow-up: 24 weeks	The mean change in quality of life: CFQ-R role in the tobramycin groups was 1.87	The mean change in quality of life: CFQ-R role in the colistin groups was 1.22 lower	P=0.607	374 (COLO/DPI/02/06)	⊕⊕⊕⊝ moderate³^,⁷
[COLI DPI versus TOBI nebulised] Quality of life: change in CFQ-R weight Scale from: 0 to 100. Follow-up: 24 weeks	The mean change in quality of life: CFQ-R weight in the tobramycin groups was −1.93	The mean change in quality of life: CFQ-R weight in the colistin groups was 2.81 higher	P=0.461	374 (COLO/DPI/02/06)	⊕⊕⊕⊝ moderate³^,⁷
[COLI DPI versus TOBI nebulised] Quality of life: change in CFQ-R respiratory Scale from: 0 to 100. Follow-up: 24 weeks	The mean change in quality of life: CFQ-R respiratory in the tobramycin groups was 3.51	The mean change in quality of life: CFQ-R respiratory in the colistin groups was 0.53 lower	P=0.756	374 (COLO/DPI/02/06)	⊕⊕⊕⊝ moderate³^,⁷
[COLI DPI versus TOBI nebulised] Quality of life: change in CFQ-R digestion Scale from: 0 to 100. Follow-up: 24 weeks	The mean change in quality of life: CFQ-R digestion in the tobramycin groups was 2.89	The mean change in quality of life: CFQ-R digestion in the colistin groups was 3.22 higher	P=0.077	374 (COLO/DPI/02/06)	⊕⊕⊕⊝ moderate³^,⁷
[COLI nebulised versus TOBI nebulised] Minor adverse events: sputum Follow-up: 4 weeks	113 per 1000	129 per 1000 (48 to 349)	RR 1.14 (0.42 to 3.08)	115 (Hodson 2002)	⊕⊝⊝⊝ very low¹^,⁸
[COLI nebulised versus TOBI nebulised] Minor adverse events: pharyngitis Follow-up: 4 weeks	132 per 1000	49 per 1000 (13 to 178)	RR 0.37 (0.1 to 1.35)	115 (Hodson 2002)	⊕⊝⊝⊝ very low¹^,⁸
[COLI nebulised versus TOBI nebulised] Minor adverse events: cough Follow-up: 4 weeks	94 per 1000	177 per 1000 (66 to 478)	RR 1.88 (0.7 to 5.07)	115 (Hodson 2002)	⊕⊝⊝⊝ very low¹^,⁸
[COLI DPI versus TOBI nebulised] Minor adverse events: productive cough Follow-up: 24 weeks	228 per 1000	203 per 1000 (139 to 299)	RR 0.89 (0.61 to 1.31)	380 (COLO/DPI/02/06)	⊕⊝⊝⊝ very low³^,⁸
[COLI DPI versus TOBI nebulised] Minor adverse events: chest discomfort Follow-up: 24 weeks	176 per 1000	139 per 1000 (86 to 222)	RR 0.79 (0.49 to 1.26)	380 (COLO/DPI/02/06)	⊕⊝⊝⊝ very low³^,⁸
[COLI DPI versus TOBI nebulised] Minor adverse events: vomiting Follow-up: 24 weeks	41 per 1000	32 per 1000 (11 to 91)	RR 0.77 (0.27 to 2.19)	380 (COLO/DPI/02/06)	⊕⊝⊝⊝ very low³^,⁸
[COLI nebulised versus TOBI nebulised] Serious adverse events: patients with >1 serious AE Follow-up: 4 weeks	151 per 1000	113 per 1000 (44 to 291)	RR 0.75 (0.29 to 1.93)	115 (Hodson 2002)	⊕⊝⊝⊝ very low¹^,⁸
[COLI DPI versus TOBI nebulised] Serious adverse events: patients withdrawn Follow-up: 24 weeks	26 per 1000	118 per 1000 (46 to 304)	RR 4.54 (1.76 to 11.74)	380 (COLO/DPI/02/06)	⊕⊕⊕⊝ moderate³
[COLI DPI versus TOBI nebulised] Serious adverse events: haemoptysis Follow-up: 24 weeks	67 per 1000	107 per 1000 (55 to 209)	RR 1.59 (0.81 to 3.1)	380 (COLO/DPI/02/06)	⊕⊝⊝⊝ very low¹^,⁶
[COLI nebulised versus TOBI nebulised] Serious adverse events: dyspnoea - Follow-up: 4 weeks	94 per 1000	113 per 1000 (38 to 335)	RR 1.2 (0.4 to 3.55)	115 (Hodson 2002)	⊕⊝⊝⊝ very low¹^,⁸
Serious adverse events: dyspnoea Follow-up: 24 weeks	269 per 1000	261 per 1000 (189 to 366)	RR 0.97 (0.7 to 1.36)	380 (COLO/DPI/02/06)	⊕⊝⊝⊝ very low³^,⁸
[COLI nebulised versus TOBI nebulised] Emergence of resistant organisms: emergence of highly tobramycinresistant P aeruginosa Follow-up: 24 weeks	0 events	0 events	-	115 (Hodson 2002)	⊕⊕⊝⊝ low¹

*: The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
: Abbreviations: CFQ-R: cystic fibrosis questionnaire revised; CI: confidence interval; COLI: colistin; DPI: dry powder for inhalation; FEV₁: forced expiratory volume in 1 second; MD: mean difference; RR: risk ratio; TOBI: tobramycin
1: The quality of the evidence was downgraded by 2 because this is an open trial, and risk of bias for randomisation and allocation concealment was unclear
2: The quality of the evidence was downgraded by 1 as the 95% CI crossed 1 clinical MID
3: The quality of the evidence was downgraded by 1 because this is an open trial, and risk of bias for randomisation was unclear
4: The quality of the evidence was downgraded by 2 because both studies were open trials, and risk of bias for randomisation and allocation concealment was unclear
5: The quality of the evidence was downgraded by 2, as the 95% CI is very large and crosses the line of no effect
6: The quality of the evidence was downgraded by 1 as the 95%CI crossed 1 default MID
7: Not calculable, p-value > 0.05
8: The quality of the evidence was downgraded by 2 as the 95%CI crossed 2 default MIDs

Table 119Summary clinical evidence profile: Comparison 4.1. Tobramycin versus placebo

Comparison 4.1. Tobramycin versus placebo
Outcomes	Illustrative comparative risks^* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Assumed risk	Corresponding risk	Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Placebo	Tobramycin
Lung function: mean % change in FEV₁ % predicted Scale from: 0 to 100 Follow-up: 1 to 3 months	Not reported	The mean lung function: mean % change in FEV₁ % predicted in the tobramycin groups was 9.36 higher (5.01 to 13.7 higher)		516 (Galeva 2013, Konstan 2011/EVOLVE trial, Lenoir 2007, Ramsey 1993)	⊕⊕⊝⊝ low¹^,²
Number of patients with 1 or more exacerbations	NMA outcome
Suppression of the organism: eradication of the organism (negative culture) Follow-up: 4 weeks	Study population		RR 2.46 (1.20 to 5.04)	357 (Chuchalin 2007, Galeva 2013, Lenoir 2007)	⊕⊕⊕⊕ high
	121 per 1000	299 per 1000 (146 to 612)
	Moderate
	143 per 1000	352 per 1000 (172 to 721)
Suppression of the organism: eradication of the organism (negative culture) Follow-up: 6 weeks	100 per 1000	103 per 1000 (23 to 471)	RR 1.03 (0.23 to 4.71)	59 (Lenoir 2007)	⊕⊕⊕⊝ moderate³
Suppression of the organism: eradication of the organism (negative culture) Follow-up: 8 weeks	120 per 1000	145 per 1000 (72 to 289)	RR 1.2 (0.6 to 2.4)	242 (Chuchalin 2007)	⊕⊕⊕⊝ moderate³
Suppression of the organism: eradication of the organism (negative culture) Follow-up: 20 weeks	165 per 1000	334 per 1000 (194 to 574)	RR 2.03 (1.18 to 3.49)	235 (Chuchalin 2007)	⊕⊕⊕⊕ high
Suppression of the organism: eradication of the organism (negative culture) Follow-up: 24 weeks	202 per 1000	239 per 1000 (144 to 397)	RR 1.18 (0.71 to 1.96)	243 (Chuchalin 2007)	⊕⊕⊕⊝ moderate³
Suppression of the organism: change in P aeruginosa sputum density log10 CFU/g Follow-up: 4 weeks	The mean change in P aeruginosa sputum density log10 CFU/g in the placebo groups was 0	The mean change in P aeruginosa sputum density log10 CFU/g in the tobramycin groups was 1.2 lower (2.03 to 0.37 lower)		55 (Galeva 2013)	⊕⊕⊕⊝ moderate⁴
Suppression of the organism: change in non-mucoid P aeruginosa sputum density log10 CFU/g Follow-up: 4 weeks	The mean change in non-mucoid P aeruginosa sputum density log10 CFU/g in the placebo groups was −0.15	The mean change in non-mucoid P aeruginosa sputum density log10 CFU/g in the tobramycin groups was 1.76 lower (2.52 to 1 lower)		95 (Konstan 2011/EVOLVE trial)	⊕⊕⊝⊝ low⁵
Suppression of the organism: change in mucoid P aeruginosa sputum density log10 CFU/g Follow-up: 4 weeks	The mean suppression of the organism: change in mucoid P aeruginosa sputum density log10 CFU/g in the placebo groups was −0.43	The mean suppression of the organism: change in mucoid P aeruginosa sputum density log10 CFU/g in the tobramycin groups was 2.18 lower (2.97 to 1.39 lower)		95 (Konstan 2011/EVOLVE trial)	⊕⊕⊝⊝ low⁵
Nutritional status: body weight change kg Follow-up: 12 weeks	The mean nutritional status: body weight change in the control groups was 0.16	The mean body weight change in the tobramycin groups was 0.23 higher (0.23 lower to 0.69 higher)		59 (Lenoir 2007)	⊕⊕⊕⊕ high
Nutritional status: body weight change kg Follow-up: 24 weeks	The mean body weight change in the tobramycin groups was 1.05	The mean body weight change in the tobramycin groups was 0.75 higher (0.22 to 1.28 higher)		245 (Chuchalin 2007)	⊕⊕⊕⊝ moderate⁴
Minor adverse events: minor adverse (any) Follow-up: 4 weeks	Study population		RR 0.66 (0.49 to 0.89)	150 (Galeva 2013, Konstan 2011/EVOLVE trial)	⊕⊝⊝⊝ very low⁴^,⁶
	640 per 1000	422 per 1000 (314 to 570)
	Moderate
	423 per 1000	279 per 1000 (207 to 376)
Minor adverse events: minor adverse events (any) Follow-up: 24 weeks	153 per 1000	156 per 1000 (84 to 288)	RR 1.02 (0.55 to 1.88)	246 (Chuchalin 2007)	⊕⊕⊝⊝ low⁷
Minor adverse events: auditory impairment Follow-up: 4 weeks	77 per 1000	103 per 1000 (18 to 572)	RR 1.34 (0.24 to 7.43)	55 (Galeva 2013)	⊕⊕⊝⊝ low⁷
Minor adverse events: auditory impairment Follow-up: 24 weeks	0 events	0 events	-	300 (Ramsey 1999)	⊕⊕⊕⊕ high
Minor adverse events: auditory impairment Follow-up: 42 weeks	0 events	0 events	-	71 (Ramsey 1993)	⊕⊕⊕⊕ high
Minor adverse events: cough Follow-up: 4 weeks	173 per 1000	289 per 1000 (14 to 1000)	RR 1.67 (0.08 to 36.11)	150 (Galeva 2013, Konstan 2011/EVOLVE trial)	⊕⊝⊝⊝ very low⁶^,⁷^,⁸
Minor adverse events: tinnitus Follow-up: 24 weeks	0 events	-	RR 17.26 (1 to 297.54)	520 (Ramsey 1999)	⊕⊕⊕⊝ moderate⁴
Headaches Follow-up: 4 weeks	20 per 1000	7 per 1000 (1 to 67)	RR 0.36 (0.04 to 3.29)	95 (Konstan 2011/EVOLVE trial)	⊕⊝⊝⊝ very low⁵^,⁷
Major adverse events: any Follow-up: 4 weeks	Study population		RR 0.52 (0.16 to 1.64)	150 (Galeva 2013, Konstan 2011/EVOLVE trial)	⊕⊝⊝⊝ very low⁶^,⁷
	107 per 1000	55 per 1000 (17 to 175)
	Moderate
	39 per 1000	20 per 1000 (6 to 64)
Major adverse events: any Follow-up: 24 weeks	259 per 1000	106 per 1000 (60 to 189)	RR 0.41 (0.23 to 0.73)	246 (Chuchalin 2007)	⊕⊕⊕⊕ high
Major adverse events: haemoptysis Follow-up: 4 weeks	20 per 1000	22 per 1000 (1 to 338)	RR 1.07 (0.07 to 16.54)	95 (Konstan 2011/EVOLVE trial)	⊕⊝⊝⊝ very low⁵^,⁷
Major adverse events: haemoptysis Follow-up: 24 weeks	309 per 1000	269 per 1000 (204 to 349)	RR 0.87 (0.66 to 1.13)	520 (Ramsey 1999)	⊕⊕⊕⊝ moderate⁴
Major adverse events: pneumothorax Follow-up: 24 weeks	15 per 1000	4 per 1000 (0 to 35)	RR 0.25 (0.03 to 2.26)	520 (Ramsey 1999)	⊕⊕⊝⊝ low⁷
Mortality Follow-up: 4 weeks	20 per 1000	7 per 1000 (0 to 173)	RR 0.35 (0.01 to 8.49)	95 (1 study)	⊕⊕⊝⊝ low⁹
Mortality Follow-up: 3 to 12 months	17 per 1000	3 per 1000 (1 to 19)	RR 0.17 (0.03 to 1.09)	767 (Chuchalin 2007, Ramsey 1999)	⊕⊕⊕⊝ moderate³
Emergence of resistant organisms: frequency of Tobramycinresistant P aeruginosa Follow-up: 24 weeks	105 per 1000	204 per 1000 (90 to 463)	RR 1.95 (0.86 to 4.42)	672 (Chuchalin 2007, Ramsey 1999)	⊕⊝⊝⊝ very low⁴^,¹⁰
Emergence of resistant organisms: frequency of new isolates of drug resistant B cepacia Follow-up: 24 weeks	0 events	0 events	-	258 (Ramsey 1999)	⊕⊕⊕⊕ high
Emergence of resistant organisms: frequency of new isolates of drug resistant S maltophilia Follow-up: 24 weeks	4 per 1000	12 per 1000 (1 to 111)	RR 3.05 (0.32 to 29.1)	520 (Ramsey 1999)	⊕⊕⊝⊝ low⁷
Emergence of resistant organisms: frequency of new isolates of drug resistant A. xylosidans Follow-up: 24 weeks	4 per 1000	4 per 1000 (0 to 62)	RR 1.02 (0.06 to 16.15)	520 (Ramsey 1999)	⊕⊕⊝⊝ low⁷
Emergence of resistant organisms: frequency of new isolates of drug resistant aspergillus Follow-up: 24 weeks	104 per 1000	21 per 1000 (7 to 59)	RR 0.2 (0.07 to 0.57)	389 (Ramsey 1999)	⊕⊕⊕⊕ high

*: The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
: Abbreviations: CFU/G: colony forming units per gram; CI: confidence interval; FEV₁: forced expiratory volume in 1 second; kg: kilogrammes; MD: mean difference; RR: risk ratio
1: The quality of the evidence was downgraded by 1, as 1 of the trials had unclear risk of bias for the domains randomisation, allocation concealment, and blinding and another trial had unclear risk of bias for the domains randomisation, allocation concealment and high risk of bias for blinding
2: The quality of the evidence was downgraded by 1 due to moderate inconsistency (I2=51%). Sub-group analysis was not conducted, as all of the trials showed a beneficial effect of tobramycin
3: The quality of the evidence was downgraded by 1 as the 95% CI crossed the null effect
4: The quality of the evidence was downgraded by 1 as the 95% CI crossed 1 default MID
5: The quality of the evidence was downgraded by 2 due to unclear risk of bias for the domains randomisation, allocation concealment and high risk of bias for blinding
6: The quality of the evidence was downgraded by 2, as the largest trial had unclear risk of bias for the domains randomisation, allocation concealment and high risk of bias for blinding
7: The quality of the evidence was downgraded by 2 as the 95% CI crossed 2 default MIDs
8: The quality of the evidence was downgraded by 2 due to very serious inconsistency (I2=77%).
9: The quality of the evidence was downgraded by 2 as the 95% CI is very wide and it crossed the null effect. The study is underpowered to detect differences
10: The quality of the evidence was downgraded by 2 due to very serious inconsistency (I2=79%)

Table 120Summary clinical evidence profile: Comparison 4.2. Tobramycin inhalation powder versus tobramycin inhalation solution

Comparison 4.2. Tobramycin inhalation powder versus tobramycin inhalation solution
Outcomes	Illustrative comparative risks^* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Assumed risk	Corresponding risk	Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Tobramycin inhalation solution (TOBI neb)	Tobramycin inhalation powder (TOBI DPI)
Lung function: % mean change in FEV₁ % predicted Scale from: 0 to 100 Follow-up: 4 weeks	Not reported	The mean % mean change in FEV₁ % predicted in the TOBI DPI groups was 0.8 lower (3.9 lower to 2.3 higher)		517 (Konstan 2011a/EA GER trial)	⊕⊕⊝⊝ low¹^,²
Lung function: % mean change in FEV₁ % predicted Scale from: 0 to 100 Follow-up: 20 weeks	Not reported	The mean % mean change in FEV₁ % predicted in the TOBI DPI groups was 1.10 higher (2.33 lower to 4.53 higher)		517 (Konstan 2011a/EAGER trial)	⊕⊕⊝⊝ low¹^,²
Lung function: % mean change in FEV₁ % predicted Scale from: 0 to 100 Follow-up: 24 weeks	Not reported	The mean % mean change in FEV₁ % predicted in the TOBI DPI groups was 2.20 higher (1.11 lower to 5.51 higher)		517 (Konstan 2011a/EAGER trial)	⊕⊕⊝⊝ low¹^,²
Number of patients with 1 or more exacerbations	NMA outcome
Suppression of the organism: mean change in P aeruginosa sputum density log10 CFU Follow-up: 4 weeks	The mean change in P aeruginosa sputum density log10 CFU in the TOBI neb groups was −1.32	The mean change in P aeruginosa sputum density log10 CFU in the TOBI DPI groups was 0.44 lower (0.79 to 0.09 lower)		517 (Konstan 2011a/EAGER trial)	⊕⊕⊕⊝ moderate¹
Suppression of the organism: mean change in P aeruginosa sputum density log10 CFU Follow-up: 20 weeks	The mean change in P aeruginosa sputum density log10 CFU in the TOBI neb groups was −0.77	The mean change in P aeruginosa sputum density log10 CFU in the TOBI DPI groups was 0.84 lower (1.17 to 0.51 lower)		517 (Konstan 2011a/EAGER trial)	⊕⊕⊝⊝ low¹^,³
Adverse events - any mild or moderate AE Follow-up: 24 weeks	684 per 1000	732 per 1000 (657 to 821)	RR 1.07 (0.96 to 1.2)	517 (Konstan 2011a/EAGER trial)	⊕⊕⊕⊝ moderate¹
Adverse events - any serious AE Follow-up: 24 weeks	292 per 1000	271 per 1000 (207 to 362)	RR 0.93 (0.71 to 1.24)	517 (Konstan 2011a/EAGER trial)	⊕⊕⊝⊝ low¹^,³
mild AE: productive cough Follow-up: 24 weeks	196 per 1000	182 per 1000 (126 to 261)	RR 0.93 (0.64 to 1.33)	517 (Konstan 2011a/EAGER trial)	⊕⊝⊝⊝ very low¹^,⁴
mild AE: headache	120 per 1000	114 per 1000 (71 to 184)	RR 0.95 (0.59 to 1.54)	517 (Konstan 2011a/EAGER trial)	⊕⊝⊝⊝ very low¹^,⁴
mild AE: vomiting Follow-up: 24 weeks	57 per 1000	61 per 1000 (30 to 125)	RR 1.07 (0.53 to 2.17)	517 (Konstan 2011a/EAGER trial)	⊕⊝⊝⊝ very low¹^,⁴
serious AE: dyspnoea Follow-up: 24 weeks	124 per 1000	156 per 1000 (100 to 243)	RR 1.25 (0.8 to 1.95)	517 (Konstan 2011a/EAGER trial)	⊕⊝⊝⊝ very low¹^,⁴
serious AE: haemoptysis Follow-up: 24 weeks	124 per 1000	129 per 1000 (82 to 207)	RR 1.04 (0.66 to 1.66)	517 (Konstan 2011a/EAGER trial)	⊕⊝⊝⊝ very low¹^,⁴

*: The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
: Abbreviations: CFU: colony forming units; CI: confidence interval; FEV₁: forced expiratory volume in 1 second; MD: mean difference; RR: risk ratio
1: The quality of the evidence was downgraded by 1 as this is an open trial, and randomisation is unclear
2: The quality of the evidence was downgraded by 1 as the 95% CI crossed 1 clinical MID
3: The quality of the evidence was downgraded by 1 as the 95% CI crossed 1 default MID
4: The quality of the evidence was downgraded by 2 as the 95% CI crossed 2 default MID

Table 121Summary clinical evidence profile: Comparison 4.3. Tobramycin versus Aztreonam lysine

Comparison 4.3. Tobramycin versus Aztreonam
Outcomes	Illustrative comparative risks^* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Assumed risk	Corresponding risk	Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Aztreonam lysine	Tobramycin
[TOBI nebulised versus AZLI inhaled] Lung function: % change in FEV₁ % predicted Scale from: 0 to 100 Follow-up: 3 months	The mean % change in FEV₁ % predicted in the aztreonam lysine groups was 2.05	The mean % change in FEV₁ % predicted in the tobramycin groups was 2.71 lower (2.88 to 2.54 lower)		268 (Assael 2013)	⊕⊕⊕⊝ moderate¹
Number of patients with 1 or more exacerbations	NMA outcome
[TOBI nebulised versus AZLI inhaled] Suppression of the organism: adj mean change sputum density log¹⁰ PA CFU/g- Follow-up: 20 weeks	The adjusted mean change sputum density log¹⁰ pa CFU/g in the aztreonam lysine groups was −0.55	The adjusted mean change sputum density log¹⁰ pa CFU/g in the tobramycin groups was 0.23 higher (0.3 lower to 0.76 higher)		194 (Assael 2013)	⊕⊕⊝⊝ low¹^,²
[TOBI nebulised versus AZLI inhaled] Nutritional status: % adj mean weight change – Follow-up: 20 weeks	The adjusted mean weight change in the aztreonam lysine groups was 0.58	The adjusted mean weight change in the tobramycin groups was 0.52 lower (1.68 lower to 0.64 higher)		268 (Assael 2013)	⊕⊕⊝⊝ low¹^,²
[TOBI nebulised versus AZLI inhaled] Quality of life: CFQR respiratory, adj mean change – Follow-up: 20 weeks	The adjusted mean change in CFQ-R respiratory in the aztreonam lysine groups was 6.3	The adjusted mean change in CFQ-R respiratory in the tobramycin groups was 4.1 lower (8.59 lower to 0.39 higher)		268 (Assael 2013)	⊕⊕⊝⊝ low¹^,³
[TOBI nebulised versus AZLI inhaled] Minor adverse events: chest discomfort – Follow-up: 3 months	103 per 1000	99 per 1000 (48 to 202)	RR 0.96 (0.47 to 1.96)	268 (Assael 2013)	⊕⊝⊝⊝ very low¹^,⁴
[TOBI nebulised versus AZLI inhaled] Minor adverse events: cough – Follow-up: 3 months	706 per 1000	791 per 1000 (685 to 904)	RR 1.12 (0.97 to 1.28)	268 (Assael 2013)	⊕⊕⊝⊝ low¹^,²
[TOBI nebulised versus AZLI inhaled] Minor adverse events: headache - Follow-up: 3 months	213 per 1000	205 per 1000 (128 to 326)	RR 0.96 (0.6 to 1.53)	268 (Assael 2013)	⊕⊝⊝⊝ very low¹^,⁴
[TOBI nebulised versus AZLI inhaled] Minor adverse events: vomiting- Follow-up: 3 months	103 per 1000	106 per 1000 (53 to 214)	RR 1.03 (0.51 to 2.08)	268 (Assael 2013)	⊕⊝⊝⊝ very low¹^,⁴
[TOBI nebulised versus AZLI inhaled] Major adverse events: dyspnoea - Follow-up: 3 months	228 per 1000	160 per 1000 (96 to 262)	RR 0.7 (0.42 to 1.15)	268 (Assael 2013)	⊕⊕⊝⊝ low¹^,²
[TOBI nebulised versus AZLI inhaled] Major adverse events: haemoptysis Follow-up: 3 months	228 per 1000	160 per 1000 (96 to 262)	RR 0.7 (0.42 to 1.15)	268 (Assael 2013)	⊕⊕⊝⊝ low¹^,²

*: The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
: Abbreviations: AZLI: aztreonam lysine; CFQ-R: cystic fibrosis questionnaire revised; CFU/g: colony forming units per gram; CI: confidence interval; FEV₁: forced expiratory volume in 1 second; MD: mean difference; RR: risk ratio; TOBI: tobramycin
1: The quality of the evidence was downgraded by 1 because this is an open trial
2: The quality of the evidence was downgraded by 1 as the 95% CI crossed 1 default MID
3: aThe quality of the evidence was downgraded by 1 as the 95% CI crossed 1 clinical MID
4: The quality of the evidence was downgraded by 2 as the 95% CI crossed 2 default MIDs

Table 122Summary clinical evidence profile: Comparison 5. Combination of fosfomycin + tobramycin versus placebo

Comparison 5. Combination of fosfomycin + tobramycin versus placebo
Outcomes	Illustrative comparative risks^* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Assumed risk	Corresponding risk	Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Placebo	Combination of fosfomycin + tobramycin (FTI)
Lung function: relative change in FEV₁% predicted Scale from: 0 to 100 Follow-up: 4 weeks [FTI 80/20 mg]	Not reported	The relative change in FEV₁% predicted in the fosfomycin + tobramycin groups was 7.5 higher (3.6 to 11.4 higher)		70 (Trapnell 2012)	⊕⊕⊕⊝ moderate¹
Lung function: relative change in FEV₁% predicted Scale from: 0 to 100 Follow-up: 4 weeks [FTI160/40 mg]	Not reported	The mean relative change in FEV₁% predicted in the fosfomycin + tobramycin groups was 6.2 higher (2.42 to 9.98 higher)		73 (Trapnell 2012)	⊕⊕⊝⊝ low¹^,²
Suppression of the organism: change in sputum P aeruginosa density, log10 CFU/g Follow-up: 4 weeks [FTI 80/20 mg]	Not reported	The mean change in sputum P aeruginosa density, log10 CFU/g in the fosfomycin + tobramycin groups was 1.04 lower (1.82 to 0.26 lower)		70 (Trapnell 2012)	⊕⊕⊝⊝ low¹^,³
Suppression of the organism: change in sputum P aeruginosa density, log10 CFU/g mg Follow-up: 4 weeks [FTI160/40 mg]	Not reported	The mean change in sputum P aeruginosa density, log10 CFU/g in the fosfomycin + tobramycin groups was 0.28 lower (1.06 lower to 0.5 higher)		73 (Trapnell 2012)	⊕⊕⊝⊝ low¹^,³

*: The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
: Abbreviations: CFU: colony forming units; CI: confidence interval; FEV₁: forced expiratory volume in 1 second; FTI: Fosfomycin/tobramycin inhaled; MD: mean difference; mg: milligrams; RR: risk ratio
1: The quality of the evidence was downgraded by 1 due to unclear risk of bias for allocation concealment and data reporting
2: The quality of the evidence was downgraded by as the 95 % CI crossed 1 clinical MID
3: The quality of the evidence was downgraded by as the 95% CI crossed 1 default MID

Table 123Summary clinical evidence profile: Comparison 6. Continuous alternating therapy versus intermittent treatment: aztreonam lysine + tobramycin or placebo + tobramycin

Comparison 6. Continuous alternating therapy versus intermittent treatment: aztreonam + tobramycin or placebo + tobramycin
Outcomes	Illustrative comparative risks^* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Assumed risk	Corresponding risk	Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Intermittent treatment: aztreonam lysine + tobramycin or placebo + tobramycin	Continuous alternating therapy
Lung function: % change in FE1% predicted Scale from: 0 to 100 Follow-up: 20 weeks¹	The mean % change in FEV₁% predicted in the intermittent treatment groups was 0.04	The mean % change in FEV₁% predicted in the continuous alternating therapy groups was 1.33 higher (1.05 to 1.61 higher)		88 (Flume 2016)	⊕⊕⊕⊝ moderate²
Time to next pulmonary exacerbation	-	-	HR 0.89 (0.49 to 1.6)	88 (Flume 2016)	⊕⊕⊝⊝ low²^,³
Quality of life: change in CFQ-R Scale from: 0 to 100 Follow-up: 20 weeks¹	The mean change in CFQ-R in the intermittent treatment groups was −2.06	The mean change in CFQ-R in the continuous alternating therapy groups was 3.06 higher (2.35 to 3.77 higher)		88 (Flume 2016)	⊕⊕⊝⊝ low²^,⁴
Minor adverse events: cough Follow-up: 3 months	435 per 1000	761 per 1000 (526 to 1000)	RR 1.75 (1.21 to 2.54)	88 (Flume 2016)	⊕⊕⊝⊝ low²^,⁵
Serious adverse events: dyspnoea Follow-up: 3 months	522 per 1000	308 per 1000 (183 to 527)	RR 0.59 (0.35 to 1.01)	88 (Flume 2016)	⊕⊕⊝⊝ low²^,⁵
Serious adverse events (not treatment related) Follow-up: 3 months	522 per 1000	501 per 1000 (334 to 751)	RR 0.96 (0.64 to 1.44)	88 (Flume 2016)	⊕⊝⊝⊝ very low²^,⁶

*: The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
: Abbreviations: CFQ-R: cystic fibrosis questionnaire reviewed; CI: confidence interval; FEV₁: forced expiratory volume in 1 second; MD: mean difference; mg: milligrams; RR: risk ratio
1: Values at 4, 12 and 20 weeks were averaged
2: The quality of the evidence was downgraded by 1 due to unclear allocation concealment, blinding, and data collection/reporting
3: The quality of the evidence was downgraded by 1 as the 95% CI crossed the null effect line
4: The quality of the evidence was downgraded by 1 as the 95% CI crossed 1 clinical MID
5: The quality of the evidence was downgraded by 1 as the 95%CI crossed 1 default MID
6: The quality of the evidence was downgraded by 2 as the 95%CI crossed 2 default MIDs

Table 124Summary clinical evidence profile: Comparison 7. Itraconazole versus placebo

Comparison 7. Itraconazole versus placebo
Outcomes	Illustrative comparative risks^* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Assumed risk	Corresponding risk	Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Placebo	Itraconazole
Lung function: percentage change in FEV₁ predicted from baseline Scale from: 0 to 100 Follow-up: mean 24 weeks	The mean lung function in the placebo group was: 0.32	The mean lung function change in the itraconazole group was 4.94 lower (15.33 lower to 5.45 higher)	-	35 (Aaron 2012)	⊕⊝⊝⊝ very low¹^,²^,³
Lung function: percentage change in FEV₁ predicted from baseline Scale from: 0 to 100 Follow-up: mean 48 weeks	Not reported	The mean lung function change in the itraconazole group was 3.71 lower (−13.26 lower to 20.68 higher)	Not estimable	35 (Aaron 2012)	⊕⊝⊝⊝ very low¹^,²^,³
Time to next pulmonary exacerbation Follow-up: mean 24 weeks	The median time to next exacerbation in the placebo group was: 134 days	The median time to next exacerbation in the itraconazole group was: 77 days	adjHR 1.34 (0.57 to 3.14)	35 (Aaron 2012)	⊕⊝⊝⊝ very low¹^,²^,⁴
proxy: number of patients with an exacerbation requiring AB Follow-up: mean 24 weeks	389 per 1000	665 per 1000 (342 to 1000)	RR 1.71 (0.88 to 3.33)	36 (Aaron 2012)	⊕⊝⊝⊝ very low¹^,²^,⁵
proxy: number of patients with an exacerbation requiring AB Follow-up: mean 48 weeks	611 per 1000	831 per 1000 (544 to 1000)	RR 1.36 (0.89 to 2.08)	36 (Aaron 2012)	⊕⊝⊝⊝ very low¹^,²^,⁶
proxy: number of patients with an exacerbation admitted to hospital Follow-up: mean 24 weeks	176 per 1000	166 per 1000 (39 to 715)	RR 0.94 (0.22 to 4.05)	35 (Aaron 2012)	⊕⊝⊝⊝ very low¹^,²^,⁶
proxy: number of patients with an exacerbation admitted to hospital Follow-up: mean 48 weeks	176 per 1000	222 per 1000 (58 to 851)	RR 1.26 (0.33 to 4.82)	35 (Aaron 2012)	⊕⊝⊝⊝ very low¹^,²^,⁴
Quality of life - all domains CFQ-R Scale from: 0 to 100 Follow-up: mean 24 weeks	Not reported	Not reported	Not estimable, but no significant differences found	35 (Aaron 2012)	⊕⊝⊝⊝ very low¹^,²^,⁷
Quality of life – change in respiratory domain CFQ-R Scale from: 0 to 100 Follow-up: mean 24 weeks	The mean change in CFQ-R score for the respiratory domain in the placebo group was: 4.77	The mean change in CFQR score for the respiratory domain in the itraconazole group was: 3.76	Not estimable, but no significant differences (p=0.87)	35 (Aaron 2012)	⊕⊝⊝⊝ very low¹^,²^,⁷
Minor adverse events - increased dyspnoea Follow-up: mean 24 weeks	125 per 1000	111 per 1000 (18 to 700)	RR 0.89 (0.14 to 5.6)	34 (Aaron 2012)	⊕⊝⊝⊝ very low¹^,²^,⁶
Minor adverse events - rash Follow-up: mean 24 weeks	62 per 1000	111 per 1000 (11 to 1000)	RR 1.78 (0.18 to 17.8)	34 (Aaron 2012)	⊕⊝⊝⊝ very low¹^,²^,⁶
Minor adverse events - hyperglycaemia Follow-up: mean 24 weeks	0 per 1000	0 per 1000 (0 to 0)	RR 2.68 (0.12 to 61.58)	34 (Aaron 2012)	⊕⊝⊝⊝ very low¹^,²^,⁶
Minor adverse events - flu-like illness Follow-up: mean 24 weeks	0 per 1000	0 per 1000 (0 to 0)	RR 6.26 (0.35 to 112.7)	34 (Aaron 2012)	⊕⊝⊝⊝ very low¹^,²^,⁶
Minor adverse events - diarrhoea Follow-up: mean 24 weeks	62 per 1000	19 per 1000 (1 to 428)	RR 0.3 (0.01 to 6.84)	34 (Aaron 2012)	⊕⊝⊝⊝ very low¹^,²^,⁶
Minor adverse events (lower scores are better) - conjunctivitis Follow-up: mean 24 weeks	62 per 1000	19 per 1000 (1 to 428)	RR 0.3 (0.01 to 6.84)	34 (Aaron 2012)	⊕⊝⊝⊝ very low¹^,²^,⁶
Major adverse events - haemoptysis Follow-up: mean 24 weeks	62 per 1000	111 per 1000 (11 to 1000)	RR 1.78 (0.18 to 17.8)	34 (Aaron 2012)	⊕⊝⊝⊝ very low¹^,²^,⁶
Major adverse events - spontaneous pneumothorax Follow-up: mean 24 weeks	0 per 1000	0 per 1000 (0 to 0)	RR 2.84 (0.12 to 65.34)	35 (Aaron 2012)	⊕⊝⊝⊝ very low¹^,²^,⁶

*: The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
: Abbreviations: CFQ-R: cystic fibrosis questionnaire reviewed; CI: confidence interval; FEV₁: forced expiratory volume in 1 second; MD: mean difference; RR: risk ratio
1: The quality of the evidence was downgraded by 1 due to unclear allocation, data reporting and sample size
2: The quality of the evidence was downgraded by 1 due to indirectness, as the therapeutic dosages were not achieved in 2/3 of the participants
3: The quality of the evidence was downgraded by 2 as the 95% CI crossed 2 clinical MIDs.
4: The quality of the evidence was downgraded by 2 as the 95% CI crossed the null effect and it is very wide. The study in underpowered to detect differences between groups.
5: The quality of the evidence was downgraded by 1 as the 95% CI crossed 1 default MID.
6: The quality of the evidence was downgraded by 2 as the 95% CI crossed 2 default MIDs
7: Not calculable, as no data was provided in the study.

Table 125Results from the economic model

Treatment	Total costs	Total QALYs	Inc. costs	Inc. QALYs	ICER
Comparison 1
List price
Placebo	£92,040	11.25	-	-	-
Nebulised colistimethate sodium	£105,872	11.52	£13,833	0.33	£52,168
Nebulised tobramycin	£244,919	11.57	£139,047	0.05	£2,824,240
Tobramycin dry powder	£274,658	11.43	£29,739	−0.14	Dominated
PAS price
Placebo	No change	No change	-	-	-
Nebulised colistimethate sodium	No change	No change	No change	No change	No change
Nebulised tobramycin	Reduced	No change	Reduced	No change	Reduced (>£30,000)
Tobramycin dry powder	Reduced	No change	Reduced	No change	No change
Comparison 2
List price
Nebulised colistimethate sodium	£107,149	11.35	-	-	-
Nebulised tobramycin	£244,890	11.58	£137,741	0.23	£602,472
PAS price
Nebulised colistimethate sodium	No change	No change	-	-	-
Nebulised tobramycin	Reduced	No change	Reduced	No change	Reduced (>£30,000)
Comparison 3
List price
Colistimethate sodium dry powder	£276,593	11.37	-	-	-
Nebulised tobramycin	£245,561	11.41	−£31,032	0.04	Dominant
PAS price
Colistimethate sodium dry powder	Reduced	No change	-	-	-
Nebulised tobramycin	Reduced	No change	Increased	No change	Increased (>£20,000)
Comparison 4
List price
Nebulised tobramycin	£245,830	11.35	-	-	-
Nebulised aztreonam lysine	£265,151	11.91	£19,321	0.56	£34,348
Combination^a	£340,265	11.53	£75,114	−0.38	Dominated
PAS price
Nebulised tobramycin	Reduced	No change	-	-	-
Nebulised aztreonam lysine	Reduced	No change	Reduced	No change	Reduced (<£30,000)
Combination^a	Reduced	No change	Reduced	No change	No change

(a): 28 days aztreonam lysine (nebulised) alternating with 28 days tobramycin (nebulised)

Table 126Summary of included studies (NMA and non-NMA outcomes)

Study	Intervention/Comparison	Population	Outcomes	Comments
Cochrane systematic reviews
Balfour-Lynn 2016 Cochrane SR	Intervention: Any inhaled corticosteroid, using any inhalation device, for a period of ≥2 weeks Comparison: Placebo or standard treatment	People of any age, with confirmed diagnosis of cystic fibrosis, regardless of clinical severity.	FEV₁ % predicted time to next exacerbation change in height (cm) Change in height	AMSTAR score: 11/11 Studies included from this review: Balfour-Lynn 1997, Balfour-Lynn 2006, De Boeck 2007
Cheng 2015 Cochrane SR	Intervention: Oral corticosteroids Comparison: Placebo or existing conventional therapy	People with defined cystic fibrosis, of any age, at all stages of lung disease.	Mortality, at 6 months Adverse effects, Absolute change in weight (kg)	AMSTAR score: 10/11 Studies included from this review: Auerbach 1985, Eigen 1995, Greally 1994.
Lands 2016 Cochrane SR	Intervention: Oral NSAIDS for a minimum period of 2 months Comparison: Placebo or existing therapy	People with defined cystic fibrosis, of any age, and any stage of lung disease.	Adverse effects Annual rate of change in % ideal body weight overall and by age	AMSTAR score: 10/11 Studies included from this review: Konstan 1995, Lands 2007, Sordelli 1994.
Southern 2012 Cochrane SR	Intervention: Short or long term use of a macrolide antibiotic Comparison: Placebo, other antibiotic class, other macrolide	People with confirmed diagnosis of cystic fibrosis	Time to next exacerbation Change in weight Exacerbation* Adverse effects Quality of life using CFQ-R	AMSTAR score: 11/11 Studies included from this review: Clement 2006, Equi 2002, Saiman 2003, Saiman 2010, Wolter 2002.
Primary studies included in the Cochrane SR
Auerbach 1985 (USA) RCT	Intervention: Prednisone 2 mg/kg to a maximum of 60 mg Comparison: Placebo	N=45 children with cystic fibrosis Age range: 1 to 12 years Participants with mild to moderate pulmonary disease	Mortality, at 6 months	Included in Cochrane SR Cheng 201 Included in pairwise comparisons only.
Balfour-Lynn 1997 (UK) Cross-over RCT	Intervention: Fluticasone (dry powder) 200 micrograms twice per day Comparison: Placebo	N=23 Mean age 10.3 years (range 7 to 17 years)	Short-term FEV₁ % predicted (6 weeks)	Included in Cochrane SR Balfour-Lynn 2016 Included in NMA only
Balfour-Lynn 2006 (UK) Cross-over RCT	Intervention: Fluticasone propionate via volumatic spacer given at equivalent dose taken (55% had 400 g/d fluticasone and 45% took lower dose); before trial entry Comparison: Placebo via volumatic spacer. If previously given budesonide beclometasone, switched to fluticasone to 2:1 ratio.	N=171 people with cystic fibrosis Age (mean, range): 14 (6 to 53) years in fluticasone group; 15.8 years in placebo	Time to next exacerbation Change in height (cm)	Included in Cochrane SR Balfour-Lynn 2016 Included in pairwise comparisons only.
De Boeck 2007 (Belgium) RCT	Intervention: Fluticasone 500 mcg dry powder inhaler twice daily Comparison: Lactose placebo dispensed in identical canister	N=29 children with cystic fibrosis Mean age (SD): 8.2 (0.6) years intervention group; 9.0 (0.5) in the control group	Change in height	Included in Cochrane SR Balfour-Lynn 2016 Included in NMA and pairwise comparisons.
Clement 2006 (France) RCT	Intervention: Azithromycin 250 mg tablets 3 times a week (>40 kg, 500 mg) Comparison: Placebo	N=82 children and young people with cystic fibrosis Age (mean, SD): 11 (3.3) years	Time to next exacerbation Change in BMI, z score at 12 months follow-up	Included in Cochrane SR Southern 2012 Included in NMA and pairwise comparisons.
Eigen 1995 (USA) RCT	Intervention: Prednisone 2 mg/kg or 1 mg/kg on alternate days to a maximum of 60 mg. Comparison: Placebo	N=285 children and young people with cystic fibrosis Age range: 6 to 14 years	Adverse effects, up to 3 and 4 years follow-up	Included in Cochrane SR Cheng 2015 Included in NMA and pairwise comparisons.
Equi 2002 (UK) RCT	Intervention: Azithromycin 250 mg tablets (>40 kg, 500 mg) per day Comparison: Placebo	N=41 Aged: 8 to 18 years	Short-term FEV₁ % predicted (26 weeks) Short-term exacerbations per patient (26 weeks)	Included in Cochrane SR Southern 2012 Included in NMA only
Greally 1994 (Ireland) RCT	Intervention: Soluble prednisolone 2 mg/kg daily for 14 days then 1 mg/kg/day on alternate days for 10 weeks (maximum dose 40 mg) Comparison: Placebo	N=24 children and young people with cystic fibrosis Age range: 5.5 to 19.5 years	Absolute change in weight (kg)	Included in Cochrane SR Cheng 2015 Included in pairwise comparisons only.
Konstan 1995 (USA) RCT	Intervention: Ibuprofen 20 – 30 mg/kg to a maximum of 1600 mg, determined by pharmacokinetic study Comparison: Placebo	N=85 people with cystic fibrosis Age range: 5 to 39	Adverse effects up to 4 years follow-up Annual rate of change in % ideal body weight overall and by age	Included in Cochrane SR Lands 2016 Included in NMA and pairwise comparisons.
Lands 2007 (Canada) RCT	After pharmacokinetic study: Intervention: Ibuprofen 200 mg tablets at a dose of 20 to 30 mg/kg to a maximum of 1600 mg Comparison: Placebo	N=142 children and young people with cystic fibrosis Age: 6 to 18 years	Adverse effects, up to 2 years follow-up	Included in Cochrane SR Lands 2016 Included in NMA and pairwise comparisons.
Saiman 2003 (USA) RCT	Intervention: Azithromycin 250 mg tablets 3 days a week (>40 kg, 500 mg) Comparison: Placebo	N=185 people with cystic fibrosis Age: > 6 years	Time to next exacerbation Adverse effects at 6 months follow-up Change in weight at 6 months follow-up, and quality of life using CFQ-R	Included in Cochrane SR Southern 2012 Included in NMA and pairwise comparisons.
Saiman 2010 (USA) RCT	Intervention: Azithromycin 250 mg tablets 3 times a week (>36 kg, 500 mg) Comparison: Placebo	N=263 children and young people with cystic fibrosis Age range: 6 to 18 years	Time to next exacerbation* Change in weight at 6 months follow-up	Included in Cochrane SR Southern 2012 Included in NMA and pairwise comparisons.
Sordelli 1994 (Argentina) RCT	Intervention: Piroxicam (16–25kg: 10mg/d; 26–45kg: 15mg/d; >46kg: 20mg/d) Comparison: Placebo	N = 41 children, young people and adults with cystic fibrosis Age range: 5 to 37 years	Long-term exacerbations per patient (12–19 months)	Included in Cochrane SR Lands 2016 Included in NMA only
Wolter 2002 (Australia) RCT	Intervention: Azithromycin 250mg daily Comparison: Placebo	N = 60 young people and adults with cystic fibrosis Mean age (SD): 27.9 (6.5) years	Short-term FEV₁ % predicted (12 weeks) Short-term exacerbations per patient (12 weeks)	Included in Cochrane SR Southern 2012 Included in NMA only
Additional primary studies
Lai 2000 Retrospective cohort study (10 years follow up of a Double-blind multicentre RCT - Eigen 1995)	Group 1: placebo Group 2: 1 mg Prednisone/kg Group 3: 2 mg Prednisone/kg	N = 224 Age range: 6 to 14 years	Height and weight at 18 years of age	Included in pairwise comparisons only.
Robinson 2012 (USA and Australia) Cross-over RCT	Clarithromycin 500mg per day or placebo	N=63 children, young people and adults with cystic fibrosis Mean age (SD): 16 (10.5) years	Short-term FEV₁ % predicted (22 weeks) Short-term exacerbations per patient (22 weeks)	Included in NMA only

: CFQ-R: cystic fibrosis respiratory questionnaire; NSAIDS: non-steroidal anti-inflammatory drugs

Table 127Mean differences (95% CrI) from conventional (white area) and network meta-analysis (grey area) for FEV₁ % predicted with short-term treatment

	Placebo	Macrolide antibiotics	Inhaled corticosteroids
Placebo		2.16 (0.52, 3.79)	-2.00 (-7.65, 3.67)
Macrolide antibiotics	2.16 (0.52, 3.79)
Inhaled corticosteroids	-2.00 (-7.65, 3.67)	-4.16 (-10.04, 1.75)

: Results in the top right diagonal of the table are the mean differences and 95% CrI from the conventional metaanalyses of direct evidence between the column-defined treatments compared to the row-defined treatment. Mean differences greater than 0 favour the column-defined treatment.
: Results in the bottom left are the mean differences and 95% CrI from the NMA model of direct and indirect evidence between the row-defined treatments compared to the column-defined treatments. Mean differences greater than 0 favour the row-defined treatment.
: Numbers in bold denote results for which the 95% CrI does not include the null effect of 0

Table 128Median treatment ranking (with their 95% CrI) of all interventions in the network and the probability of being the best treatment for improving/limiting the decline of FEV₁ % predicted in the short-term

	Median (95% CrI) treatment rank	Probability of being the best treatment (%)
Placebo	2 (2–3)	0.37%
Macrolide antibiotics	1 (1–2)	91.21%
Inhaled corticosteroid	3 (1–3)	8.41%

Table 129Quality assessment of the evidence for the NMA for FEV₁ % predicted in the short-term

NMA	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Quality
Short term (1–10 months) FEV % predicted (6 studies)	No serious risk of bias	No serious inconsistency	No serious indirectness	Serious¹	None	Moderate

1: No intervention has rank credible intervals ≤33% of total distribution of comparators

Table 130Mean differences (95% CrI) from conventional (white area) and network meta-analysis (grey area) for FEV₁ % predicted with long-term treatment

	Placebo	NSAIDs	Macrolide antibiotics	Inhaled corticosteroids	Oral corticosteroids
Placebo		2.26 (1.40, 3.11)	-2.8 (-10.02, 4.44)	7.17 (-3.64, 17.95)	4.07 (0.7, 7.49)
NSAIDs	2.26 (1.41, 3.11)
Macrolide antibiotics	-2.81 (-10.05, 4.45)	-5.07 (-12.34, 2.24)
Inhaled corticosteroids	7.17 (-3.64, 17.95)	4.9 (-5.94, 15.73)	9.96 (-2.98, 22.95)
Oral corticosteroids	4.07 (0.7, 7.49)	1.81 (-1.67, 5.33)	6.88 (-1.11, 14.92)	-3.09 (-14.39, 8.24)

: Results in the top right diagonal of the table are the mean differences and 95% CrI from the conventional meta-analyses of direct evidence between the column-defined treatments compared to the row-defined treatment. Mean differences greater than 0 favour the column-defined treatment.
: Results in the bottom left are the mean differences and 95% CrI from the NMA model of direct and indirect evidence between the row-defined treatments compared to the column-defined treatments. Mean differences greater than 0 favour the row-defined treatment.
: Numbers in bold denote results for which the 95% CrI does not include the null effect of 0

Table 131Median treatment ranking (with their 95% CrI) of all interventions in the network and the probability of being the best treatment for improving/limiting the decline of FEV₁ % predicted in the long-term

	Median (95% CrI) treatment rank	Probability of being the best treatment (%)
Placebo	4 (3–5)	8.12%
NSAIDs	3 (1–4)	65.20%
Macrolide antibiotics	5 (2–5)	5.99%
Inhaled corticosteroids	1 (1–5)	7.82%
Oral corticosteroids	2 (1–3)	12.88%

Table 132Quality assessment of the evidence for the NMA for FEV₁ % predicted in the long-term

NMA	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Quality
Long term (>10 months) FEV % predicted (3 studies)	Serious¹	No serious inconsistency	No serious indirectness	Serious²	None	Low

1: Two included studies were at low risk of bias and for the other three studies the risk of bias was unclear.
2: No intervention has rank credible intervals ≤33% of total distribution of comparators

Table 133Quality assessment of the evidence for the NMA for rate of exacerbations in the short-term

Fluticasone compared to placebo for cystic fibrosis
Outcomes	Illustrative comparative risks^* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Assumed rate	Corresponding rate	Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Placebo	Macrolide antibiotics
Rate of exacerbations after short-term (10 month) treatment	The mean rate of exacerbations per patient in the control groups was 0.56	The mean rate of exacerbations in the intervention groups was 0.42 (0.21 to 0.85)	Rate ratio 0.75 (0.37 to 1.51)	226 (Equi 2002, Robnson 2012, Wolter 2002)	⊕⊝⊕⊝ very low¹^,²

*: The basis for the assumed rate (e.g. the median control group rate across studies) is provided in footnotes. The corresponding rate (and its 95% confidence interval) is based on the assumed rate in the comparison group and the relative effect of the intervention (and its 95% CI).
: CI: Confidence interval;
1: Evidence was downgraded by 2 due to very serious inconsistency between studies
2: Evidence was downgraded by 2 due to very serious imprecision as 95%CI crossed two default MIDs

Table 134Rate ratios (95% CrI) from conventional (white area) and network metaanalysis (grey area) for the rate of exacerbations with long-term treatment

	Placebo	Macrolide antibiotics	Inhaled corticosteroids	Oral corticosteroids
Placebo		0.44 (0.03, 3.29)	1.34 (0.22, 9.37)	0.91 (0.08, 10.1)
Macrolide antibiotics	0.44 (0.03, 3.29)
Inhaled corticosteroids	1.34 (0.22, 9.37)	3.14 (0.2, 72.84)
Oral corticosteroids	0.91 (0.08, 10.1)	2.13 (0.09, 66.33)	0.67 (0.03, 13.54)

: Results in the top right diagonal of the table are the rate ratios and 95% CrI from the conventional meta-analyses of direct evidence between the column-defined treatments compared to the row-defined treatment. Rate ratios greater than 1 favour the column-defined treatment.
: Results in the bottom left are the rate ratios and 95% CrI from the NMA model of direct and indirect evidence between the row-defined treatments compared to the column-defined treatments. Rate ratios greater than 1 favour the row-defined treatment.
: Numbers in bold denote results for which the 95% CrI does not include the null effect of 1

Table 135Median treatment ranking (with their 95% CrI) of all interventions in the network and the probability of being the best treatment for reducing the rate of exacerbations in the long-term

	Median (95% CrI) treatment rank	Probability of being the best treatment (%)
Placebo	3 (1–4)	6.37%
Macrolide antibiotics	1 (1–4)	56.82%
Inhaled corticosteroids	3 (1–4)	11.30%
Oral corticosteroids	2 (1–4)	25.51%

Table 136Quality assessment of the evidence for the NMA for rate of exacerbations in the long-term

NMA	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Quality
Long term (>10 months) rate of exacerbations (4 studies)	Serious¹	No serious inconsistency	No serious indirectness	Serious²	None	Low

1: One included study was at low risk of bias, one study was at high risk of bias, and for the other two the risk of bias was unclear
2: No intervention has rank credible intervals ≤33% of total distribution of comparators

Table 137Summary clinical evidence profile: Comparison 1. Fluticasone versus placebo

Comparison 1. Fluticasone versus placebo
Outcomes	Illustrative comparative risks^* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Assumed risk	Corresponding risk	Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Placebo	Fluticasone
Time to first exacerbation Follow-up: 6 months	460 per 10001	483 per 1000 (342 to 645)¹	HR 1.07 (0.68 to 1.6838)²	171 (Balfour-Lynn 2006)	⊕⊕⊝⊝ low¹
Growth (change in height) SDS (standard deviation) score Follow-up: 12 months	The mean growth (change in height) in the placebo groups was −0.01 SDS	The mean growth (change in height) in the fluticasone groups was 0.37 SDS lower (0.77 lower to 0.03 higher)		30 (De Boeck 2007)	⊕⊕⊕⊝ moderate³
Growth (change in height) in paediatric participants cm Follow-up: 8 months	The mean growth (change in height) in paediatric participants in the placebo groups was 3.5 cm	The mean growth (change in height) in paediatric participants in the fluticasone groups was 0.6 cm higher (0.46 lower to 1.66 higher)		80 (Balfour-Lynn 2006)	⊕⊕⊕⊝ moderate³

*: The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
: Abbreviations: CI: confidence interval; HR: hazard ratio; MD: mean difference; SDS: standard deviation score
1: The quality of the evidence was downgraded by 2 as 95%CI crossed the null effect line, and it is very wide.
2: Calculated by the NGA technical team from percentage of participants in group with at least 1 exacerbation.
3: The quality of the evidence was downgraded by 1 because 95%CI crossed 1 default MID.

Table 138Summary clinical evidence profile: Comparison 2. Prednisone/Prednisolone versus placebo

Comparison 2. Prednisone/Prednisolone versus placebo
Outcomes	Illustrative comparative risks^* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Assumed risk	Corresponding risk	Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Placebo	Prednisone/Prednisolone
[2 mg prednisone] Absolute change in weight (kg) Follow-up: 12 weeks	The mean absolute change in weight in the placebo groups was 0.01 kg	The mean absolute change in weight in the prednisone groups was 0.34 kg higher (2.32 lower to 3 higher)		25 (Greally 1994)	⊕⊝⊝⊝ very low¹^,²
[1 mg prednisone] Weight (Kg) Boys at 18 Years of Age	The mean absolute weight in the placebo groups was 63.7 kg	The mean weight in the prednisone groups was 4.6 kg lower (9.69 lower to 0.49 higher)		55 (Lai 2000)	⊕⊕⊝⊝ low³
[2 mg prednisone] Weight (Kg) Boys at 18 Years of Age	The mean absolute weight in the placebo groups was 63.7 kg	The mean weight in the prednisone groups was 6.7 kg lower (11.59 to 1.81 lower)		52 (Lai 2000)	⊕⊕⊕⊝ moderate⁴
[1 mg prednisone] Weight (Kg) Girls at 18 Years of Age	The mean absolute weight in the placebo groups was 51.9 kg	The mean weight in the prednisone groups was 0 kg higher (7.62 lower to 3.02 higher)		43 (Lai 2000)	⊕⊝⊝⊝ very low²
[2 mg prednisone] Weight (Kg) Girls at 18 Years of Age	The mean absolute weight in the placebo groups was 51.9 kg	The mean weight in the prednisone groups was 1.7 kg higher (3.37 lower to 6.77 higher)		46 (Lai 2000)	⊕⊝⊝⊝ very low²
[1 mg prednisone] Height (cm) Boys at 18 Years of Age -	The mean absolute height in the placebo groups was 174.6 cm	The mean height in the prednisone groups was 3.9 cm lower (7.77 to 0.03 lower)		55 (Lai 2000)	⊕⊝⊝⊝ very low³
[2 mg prednisone] Height (cm) Boys at 18 Years of Age	The mean absolute height in the placebo groups was 174.6 cm	The mean height in the prednisone groups was 4.1 cm lower (7.82 to 0.38 lower)		52 (Lai 2000)	⊕⊝⊝⊝ very low³
[1 mg prednisone] Height at 18 Years of Age - Girls cm	The mean absolute height in the placebo groups was 160.3 cm	The mean height in the prednisone groups was 1 cm lower (4.54 lower to 2.54 higher)		43 (Lai 2000)	⊕⊝⊝⊝ very low²
[2 mg prednisone] Height (cm) Girls at 18 Years of Age	The mean absolute height in the placebo groups was 160.3 cm	The mean height in the prednisone groups was 0.5 cm lower (4.43 lower to 3.43 higher)		46 (Lai 2000)	⊕⊝⊝⊝ very low²
[1 mg prednisone] Adverse effects - Cataracts Follow-up: 4 years	74 per 1000	32 per 1000 (8 to 119)	RR 0.43 (0.11 to 1.61)	190 (Eigen 1995)	⊕⊝⊝⊝ very low¹^,²
[2mg prednisone] Adverse effects - Cataracts Follow-up: 3 years	74 per 1000	116 per 1000 (47 to 286)	RR 1.57 (0.64 to 3.88)	190 (Eigen 1995)	⊕⊝⊝⊝ very low¹^,²
[1 mg prednisone] Adverse effects - Diabetes mellitus Follow-up: 4 years	11 per 1000	32 per 1000 (3 to 298)	RR 3 (0.32 to 28.33)	190 (Eigen 1995)	⊕⊝⊝⊝ very low¹^,²
[2 mg prednisone] Adverse effects - Diabetes mellitus Follow-up: 3 years	11 per 1000	63 per 1000 (8 to 515)	RR 6.00 (0.74 to 48.89)	190 (Eigen 1995)	⊕⊝⊝⊝ very low¹^,²
[1 mg prednisone] Adverse effects – Glycosuria Follow-up: 4 years	42 per 1000	63 per 1000 (19 to 217)	RR 1.5 (0.44 to 5.15)	190 (Eigen 1995)	⊕⊝⊝⊝ very low¹^,²
[2 mg prednisone] Adverse events – Glycosuria Follow-up: 3 years	42 per 1000	105 per 1000 (34 to 324)	RR 2.5 (0.81 to 7.69)	190 (Eigen 1995)	⊕⊕⊝⊝ low¹^,³
[1 mg prednisone] Adverse effects - Hyperglycaemia Follow-up: 4 years	21 per 1000	32 per 1000 (5 to 185)	RR 1.5 (0.26 to 8.78)	190 (Eigen 1995)	⊕⊝⊝⊝ very low¹^,²
[2 mg prednisone] Adverse effects - Hyperglycaemia Follow-up: 3 years	21 per 1000	105 per 1000 (24 to 468)	RR 5 (1.13 to 22.21)	190 (Eigen 1995)	⊕⊕⊝⊝ low¹^,³
Mortality Follow-up: 4 years	42 per 1000	16 per 1000 (1 to 368)	RR 0.38 (0.02 to 8.83)	45 (Auberch 1985)	⊕⊕⊕⊝ low⁵^,⁶

*: The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
: Abbreviations: CI: confidence interval; kg: kilogrammes; MD: mean difference; mg: milligrams; RR: risk ratio
1: The quality of the evidence was downgraded by 1, as allocation concealment and blinding were unclear.
2: The quality of the evidence Evidence downgraded by 2 due to serious imprecision as 95% CI crossed 2 default MIDs.
3: The quality of the evidence Evidence downgraded by 1 due to serious imprecision as 95% CI crossed 1 default MID.
4: The quality of the evidence was upgraded by 1 as there is evidence of dose-response within study
5: Allocation concealment and blinding were unclear, but the quality of the evidence was not downgraded for this outcome
6: The quality of the evidence was downgraded by 2 as 95%CI crossed the null effect line, and it is very wide.

Table 139Summary clinical evidence profile: Comparison 3. Azithromycin versus placebo

Comparison 3. Azithromycin versus placebo
Outcomes	Illustrative comparative risks^* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Assumed risk	Corresponding risk	Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Placebo	Azithromycin
Time to next exacerbation: time free of exacerbation Follow-up: mean 6 months	Study population		HR 0.59 (0.44 to 0.79)	445 (Saiman 2003, Saiman 2010)	⊕⊕⊕⊕ high
	348 per 1000	223 per 1000 (172 to 287)¹
	Moderate
	348 per 1000	223 per 1000 (172 to 287)¹
Time to next exacerbation Follow-up: 12 months	Study population		HR 0.37 (0.217 to 0.6299)	82 (Clement 2006)	⊕⊕⊕⊕ high
	48 per 1000¹	18 per 1000 (11 to 30)¹
	Moderate
	36 per 1000¹	13 per 1000 (8 to 23)¹
Mild adverse effects of antibiotic treatment - Hearing impairment Follow-up: 6 months	10 per 1000	12 per 1000 (1 to 181)	RR 1.13 (0.07 to 17.74)	185 (Saiman 2003)	⊕⊕⊝⊝ low²
Mild adverse effects of antibiotic treatment – Tinnitus Follow-up: 6 months	10 per 1000	12 per 1000 (1 to 181)	RR 1.13 (0.07 to 17.74)	185 (Saiman 2003)	⊕⊕⊝⊝ low²
Change in BMI z score Follow-up: 12 months	The mean change in BMI z score in the placebo groups was −0.12	The mean change in BMI z score in the azithromycin groups was 0.15 higher (0.03 lower to 0.33 higher)		82 (Clement 2006)	⊕⊕⊕⊝ moderate³
Change in weight (kg) Follow-up: 6 months	Not reported	The mean change in weight in the azithromycin groups was 0.62 higher (0.26 to 0.98 higher)		440 (Saiman 2003, Saiman 2010)	⊕⊕⊕⊝ moderate³
Quality of life: change in CFQ-R total score Scale from: 0 to 100 Follow-up: 6 months	The mean change in total quality of life score (CFQ-R) in the placebo groups was 0.1	The mean change in total quality of life score (CFQ-R) in the azithromycin groups was 1.6 higher (0.61 lower to 3.81 higher)		177 (Saiman 2003)	⊕⊕⊕⊕ high
Quality of life: change in CFQ-R physical domain Scale from: 0 to 100 Follow-up: 6 months	The mean change in physical domain of CFQ-R score in the placebo groups was −1.9	The mean change in physical domain of CFQ-R score in the azithromycin groups was 2.7 higher (0.09 to 5.31 higher)		177 (Saiman 2003)	⊕⊕⊕⊕ high
Quality of life: change in CFQ-R psychosocial domain Scale from: 0 to 100 Follow-up: 6 months	The mean change in psychosocial domain of CFQ-R score in the placebo groups was 1.2	The mean change in psychosocial domain of CFQR score in the azithromycin groups was 0.4 higher (3 lower to 3.8 higher)		177 (Saiman 2003)	⊕⊕⊕⊕ high
Quality of life: Change in CFQ-R body image domain Scale from: 0 to 100 Follow-up: 6 months	The mean change in body image domain of CFQ-R score in the placebo groups was −0.1	The mean change in body image domain of CFQ-R score in the azithromycin groups was 3.2 higher (0.24 lower to 6.64 higher)		177 (Saiman 2003)	⊕⊕⊕⊕ high

*: The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
: Abbreviations: BMI: body mass index; CFQ-R: cystic fibrosis questionnaire revised; CI: confidence interval; MD: mean difference; RR: risk ratio
1: Calculated by the NGA technical team from probability of remaining free from exacerbation.
2: The quality of the evidence Evidence downgraded by 2 due to serious imprecision as 95% CI crossed two2 default MIDs.
3: The quality of the evidence Evidence downgraded by 1 due to serious imprecision as 95% CI crossed one1 default MID.

Table 140Summary clinical evidence profile: Comparison 4. Ibuprofen versus placebo

Comparison 4. Ibuprofen versus placebo
Outcomes	Illustrative comparative risks^* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Assumed risk	Corresponding risk	Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Placebo	Ibuprofen
Adverse effects: increase in abdominal pain Follow-up: 2 years	56 per 1000	14 per 1000 (2 to 124)	RR 0.26 (0.03 to 2.24)	142 (Lands 2007)	⊕⊕⊝⊝ low¹
Adverse effects: Increase in abdominal pain Follow-up: 4 years	163 per 1000	122 per 1000 (42 to 353)	RR 0.75 (0.26 to 2.17)	84 (Konstan 1995)	⊕⊝⊝⊝ very low¹^,²
Adverse effects: Gastrointestinal bleeding Follow-up: 2 years	0 per 1000	0 per 1000 (0 to 0)²	RR 3.08 (0.13 to 74.46)	142 (Lands 2007)	⊕⊕⊝⊝ low¹
Annual rate of change in % ideal body weight Follow-up: 4 years	The mean annual rate of change in % ideal body weight in the placebo groups was −0.94	The mean annual rate of change in % ideal body weight in the ibuprofen groups was 0.99 higher (0.17 to 1.81 higher)		84 (Konstan 1995)	⊕⊕⊝⊝ low³^,⁴
[Under 13 years at randomisation] Annual rate of change in % ideal body weight (by age) – Follow-up: 4 years	The mean annual rate of change in % ideal body weight (by age) - under 13 years at randomisation in the placebo groups was −1.5	The mean annual rate of change in % ideal body weight (by age) in the ibuprofen groups was 1.45 higher (0.33 to 2.57 higher)		49 (Konstan 1995)	⊕⊕⊝⊝ low³^,⁴
[13 years or older at randomisation] Annual rate of change in % ideal body weight (by age) Follow-up: 4 years	The mean annual rate of change in % ideal body weight (by age) - 13 years or older at randomisation in the placebo groups was −0.15	The mean annual rate of change in % ideal body weight (by age) in the ibuprofen groups was 0.34 higher (0.61 lower to 1.29 higher)		35 (Konstan 1995)	⊕⊝⊝⊝ very low¹^,³

*: The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
: Abbreviations: CI: confidence interval; MD: mean difference; RR: risk ratio
1: The quality of the evidence downgraded by 2 due to serious imprecision as 95% CI crossed 2 default MIDs.
2: Absolute effect not calculable as there are 0 events in control (placebo) arm.
3: The quality of the evidence was downgraded by 1 due to reporting bias.
4: The quality of the evidence downgraded by 1 due to serious imprecision as 95% CI crossed 1 default MID.

Table 141Base case results from the economic model

Treatment	Total costs	Total QALYs	ICER
Macrolide (azithromycin)	£158,404	14.2	-
Oral corticosteroid (prednisolone)	£289,619	12.5	Dominated
NSAID (ibuprofen)	£291,035	12.3	Dominated
No treatment	£302,045	12.4	Dominated
Inhaled corticosteroid (fluticasone)	£411,046	11.1	Dominated

Bookshelf ID: NBK535669

Contents

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9Pulmonary monitoring, assessment and management

9.1. Pulmonary monitoring

9.1.1. Introduction

9.1.2. Description of clinical evidence

9.1.2.1. Review 1. Monitoring for pulmonary disease onset in people with cystic fibrosis without clinical signs or symptoms of lung disease

9.1.2.2. Review 2. Monitoring for evolving pulmonary disease in people with cystic fibrosis with established lung disease

9.1.2.3. Review 3. Monitoring for evolving pulmonary disease in people with cystic fibrosis following an acute pulmonary exacerbation

9.1.3. Summary of included studies

9.1.3.1. Review 1. Monitoring for pulmonary disease onset in people with cystic fibrosis without clinical signs or symptoms of lung disease

9.1.3.2. Review 2. Monitoring for evolving pulmonary disease in people with cystic fibrosis with established lung disease

9.1.3.3. Review 3. Monitoring for evolving pulmonary disease in people with cystic fibrosis following an acute pulmonary exacerbation

9.1.4. Clinical evidence profiles

9.1.4.1. Review 1. Monitoring for pulmonary disease onset in people with cystic fibrosis without clinical signs or symptoms of lung disease

9.1.4.2. Review 2. Monitoring for evolving pulmonary disease in people with cystic fibrosis with established lung disease

9.1.4.3. Review 3. Monitoring for evolving pulmonary disease in people with cystic fibrosis following an acute pulmonary exacerbation

9.1.5. Economic evidence

9.1.6. Evidence statements

9.1.6.1. Review 1. Monitoring for pulmonary disease onset in people with cystic fibrosis without clinical signs or symptoms of lung disease

9.1.6.1.1. Monitoring technique 1. Non-invasive microbiological investigation

9.1.6.1.2. Monitoring technique 2. Invasive microbiological investigation

9.1.6.1.3. Monitoring technique 3. Lung physiological function tests

Lung function

Clearance of the organism from the cultures

Pulmonary exacerbations

Nutritional parameters

Quality of life

9.1.6.1.4. Monitoring technique 4. Imaging tests

Lung function

Clearance of the organism from the cultures

Pulmonary exacerbations

Nutritional parameters

Quality of life

9.1.6.1.5. Comparison 1. Lung function tests versus imaging tests

Lung function

Clearance of the organism from the cultures

Pulmonary exacerbations (proxy outcome for time to chronic infection)

Nutritional parameters

Quality of life

9.1.6.2. Review 2. Monitoring for evolving pulmonary disease in people with cystic fibrosis with established lung disease

9.1.6.3. Review 3. Monitoring for evolving pulmonary disease in people with cystic fibrosis following an acute pulmonary exacerbation

9.1.6.3.1. Monitoring strategy 1. Invasive microbiological investigations and/or imaging techniques in addition to non-invasive microbiological investigations and/or lung function test VERSUS non-invasive microbiological investigations

Comparison 1. Monitoring using bronchoalveolar lavage (BAL) versus standard monitoring

Lung function

Clearance of the organism from the cultures

Time to chronic infection

Nutritional parameters

Quality of life

9.1.6.3.2. Monitoring strategy 2. Invasive microbiological investigations and/or imaging techniques in addition to non-invasive microbiological investigations and/or lung function test VERSUS lung function test

9.1.6.3.3. Monitoring strategy 3. Invasive microbiological investigations and/or imaging techniques in addition to non-invasive microbiological investigations and/or lung function test VERSUS non-invasive microbiological investigations and lung function test

9.1.6.4. Economic evidence statements

9.1.7. Evidence to recommendations

9.1.7.1. Relative value placed on the outcomes considered

9.1.7.2. Consideration of clinical benefits and harms

Asymptomatic people

Symptomatic people

Acute exacerbations

9.1.7.3. Consideration of economic benefits and harm

9.1.7.4. Quality of evidence

9.1.7.5. Other considerations

9.1.7.6. Key conclusions

9.1.8. Recommendations

9.1.9. Research recommendations

9.2. Airway clearance techniques

9.2.1. Introduction

9.2.2. Description of clinical evidence

9.2.3. Summary of included studies

9.2.4. Clinical evidence profile

9.2.5. Economic evidence

9.2.6. Evidence statements

9.2.6.1. Comparison 1. Manual physiotherapy versus no airway clearance techniques

9.2.6.2. Comparison 2. Manual physiotherapy techniques versus oscillating devices

Sputum volume

Patient preference

Pulmonary exacerbations

Pulmonary function tests: FEV1 and FVC

Oxygen saturation

Quality of life

Hospitalisations

9.2.6.3. Comparison 3. Manual physiotherapy versus High Frequency Chest Wall Oscillation

Sputum volume

Pulmonary function tests: FEV₁ and FVC

Pulmonary function tests: FEV₁ and FVC

Pulmonary function tests: FEV₁ and FVC

Pulmonary function tests: FEV₁ and FVC

Pulmonary function tests: FEV₁ and FVC

Pulmonary function tests: FEV₁ and FVC