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Evidence review for investigations before starting treatment for late-onset neonatal infection

Neonatal infection: antibiotics for prevention and treatment

Evidence review G

NICE Guideline, No. 195

London: National Institute for Health and Care Excellence (NICE); .
ISBN-13: 978-1-4731-4080-6

Investigations for late-onset neonatal infection

1.1. Review question

What investigations should be performed before starting treatment in babies with symptoms of late-onset neonatal infection?

1.1.1. Introduction

Neonatal infection is a significant cause of mortality and morbidity in newborn babies. It can lead to life-threatening sepsis, which accounts for 10% of all neonatal deaths. For the purpose of this guideline, late-onset neonatal infection is defined as infection which occurs between 72 hours of birth and 28 days of age (corrected for gestational age).

Accurately determining which babies have late-onset neonatal infection is important to help establish who should receive antibiotic treatment. There are a number of tests that can potentially be used to evaluate whether a baby has late-onset neonatal infection. It is therefore important to determine which tests are the most accurate and cost-effective for use in clinical practice. The aim of this review is to evaluate these tests and determine which are the most effective for the diagnosis of late-onset neonatal infection.

1.1.2. Summary of the protocol

Table 1. PICO table.

Table 1

PICO table.

1.1.3. Methods and process

This evidence review was developed using the methods and process described in Developing NICE guidelines: the manual. Methods specific to this review question are described in the review protocol in Appendix A. For full details of methods used in this review, see the methods document.

Declarations of interest were recorded according to NICE’s 2018 conflicts of interest policy.

Diagnostic accuracy studies were considered in addition to systematic reviews. The review protocol specified that, where possible, subgroup analyses would be conducted for gestational age of the baby (preterm vs term), as well as comparing babies already in hospital with those admitted to the hospital from home. No data were found for either of the subgroups. However, some studies had examined the same diagnostic test but used different thresholds as the cut-off to indicate infection. For any tests where a wide range of cut-off values were used (C-reactive protein and procalcitonin), the data were separated in subgroups based on the threshold used. Studies which investigated C-reactive protein were separated into three groups based on threshold values – either <10 mg/l, 10 mg/l or >10 mg/l. Studies which investigated procalcitonin were separated into two groups – those which used a cut-off ≤10 ng/ml and a single study which used a cut-off value of 1000 ng/ml. This approach was presented to the committee who agreed that the subgroups used were appropriate.

Where data was only reported for some of the outcomes, data for the other outcomes (sensitivity, specificity, likelihood ratios) were calculated based on the information provided in the studies. This meant that comparisons could be made between the diagnostic accuracy of each test.

For imprecision, clinical decision thresholds based on the likelihood ratio were set for each measure, above or below which a test would be recommended or considered of no clinical use. As the committee did not have any preference for clinical decision thresholds, the pre-specified threshold values stated in the methods chapter (2 for LR+ and 0.5 for LR-) were used with the line of no effect as the second clinical decision line in both cases.

1.1.4. Diagnostic evidence

1.1.4.1. Included studies

A search was carried out to identify studies for this evidence review. This returned a total of 4,569 results. The protocol resulted in a higher number of potentially included studies, but the committee highlighted how some of the tests for late-onset neonatal infection are not available in current practice in the NHS and others, such as polymerase chain reaction, require a high volume of blood, and are therefore not practical for use with neonates. Consequently, only the tests which are currently available for neonates in the NHS were included in the analysis. The tests which were excluded from the review following discussion with the committee were: Acute phase reactants (other than C-reactive protein and procalcitonin), white blood cell left shift and band granulocytes, neutrophil to lymphocyte ratio, neutrophil CD64 expression, neutrophil and monocyte CD64 indexes, urinary neutrophil gelatinase-associated lipocalin, 16s rRNA polymerase chain reaction, multiplex polymerase chain reaction and resistin. All other tests that matched the protocol were eligible for inclusion. Using this additional exclusion criteria 106 studies were identified as potential includes. Full text articles were ordered and reviewed against the inclusion criteria, of which 32 cross-sectional studies met the inclusion criteria for the review.

The search was re-run in July 2020 to identify any studies which had been published since the date of the original search. This returned a total of 453 results of which 12 were identified as possible included studies. After full text review, 4 met the inclusion criteria. In total there were therefore 36 cross-sectional studies which met the inclusion criteria for this review.

See appendix B for full literature search strategies and appendix C for a study selection flowchart.

1.1.4.2. Excluded studies

See appendix J for excluded studies and reasons for exclusion.

1.1.5. Summary of studies included in the diagnostic evidence

Table 2. Summary of included clinical studies.

Table 2

Summary of included clinical studies.

See appendix D for full evidence tables.

1.1.6. Summary of the diagnostic evidence

No. studiesSample sizeSensitivity (95%CI)Specificity (95% CI)Effect size* (95%CI)Quality
C-reactive protein (≤10 mg/l): Sample at time of blood culture
142083

0.80

(0.68, 0.88)

0.71

(0.63, 0.78)

LR+ 2.77

(2.33, 3.29)

Very low

LR- 0.29

(0.19, 0.41)

Low
C-reactive protein (10 mg/l): Sample at time of blood culture
5928

0.62

(0.50, 0.73)

0.73

(0.59, 0.83)

LR+ 2.33

(1.55, 3.49)

Very low

LR- 0.53

(0.38, 0.69)

Very low
C-reactive protein (>10 mg/l): Sample at time of blood culture
3325

0.77

(0.56, 0.90)

0.69

(0.38, 0.89)

LR+ 2.93

(0.95, 7.75)

Very low

LR- 0.40

(0.12, 1.08)

Very low
C-reactive protein (≤10 mg/l): Sample taken 12–24 hours after blood culture
2257

0.88

(0.59, 0.97)

0.91

(0.38, 0.99)

LR+ not calculableLow

LR- 0.23

(0.03, 0.99)

Very low
C-reactive protein (10 mg/l): Sample taken 24 hours after blood culture
1416

0.84

(0.76, 0.90)

0.70

(0.65, 0.75)

LR+ 2.82

(2.32, 3.39)

Moderate

LR- 0.23

(0.14, 0.34)

Moderate
C-reactive protein (10 mg/l): Sample taken 48 hours after blood culture
1416

0.73

(0.66, 0.80)

0.79

(0.74, 0.84)

LR+ 3.52

(2.72, 4.52)

Moderate

LR- 0.34

(0.26, 0.44)

Moderate
C-reactive protein (from urine sample – 9.4 ng/ml): Sample taken when infection was diagnosed
166

0.52

(0.35, 0.68)

0.80

(0.64, 0.90)

LR+ 2.58

(1.22, 5.44)

Low

LR- 0.62

(0.39, 0.88)

Moderate
Procalcitonin (lower threshold) (≤10 ng/ml)
7535

0.76

(0.67, 0.84)

0.65

(0.57, 0.72)

LR+ 2.21

(1.64, 2.91)

Low

LR- 0.37

(0.24, 0.54)

Very low
Procalcitonin (higher threshold) (1000 ng/ml)
1169

0.77

(0.50, 0.92)

0.62

(0.54, 0.70)

LR+ 2.02

(1.40, 2.91)

Very low

LR- 0.37

(0.14, 1.01)

Very low
Neutrophil count (>5000 / ≤1800 ≥5400 / age-adjusted count)
3329

0.60

(0.48, 0.70)

0.62

(0.51, 0.72)

LR+ 1.61

(1.05, 2.37)

Very low

LR- 0.66

(0.44, 0.95)

Very low
Neutrophils (I:T ratio) (>0.12 / >0.2 / >0.65)
6961

0.70

(0.39, 0.89)

0.55

(0.26, 0.81)

LR+ 1.62

(1.03, 2.81)

Very low

LR- 0.58

(0.28, 0.96)

Very low
White blood cell count (from blood culture) (<5000 cells/mm3 / <5000 >20000 cells/mm3)
3526

0.46

(0.32, 0.60)

0.87

(0.66, 0.96)

LR+ 4.37

(1.10, 12.70)

Very low

LR- 0.64

(0.43, 0.95)

Very low
White blood cell count (from CSF sample) (>19.5 cells/mm3 / >20 cells/mm3)
26462

0.94

(0.31, 1.00)

0.93

(0.52, 0.99)

LR+ Not calculableVery low

LR- 0.21

(0.00, 1.33)

Very low
Platelet count (100 cells/mm3 / 150 cells/mm3)
2150

0.53

(0.34, 0.71)

0.63

(0.19, 0.92)

LR+ 2.13

(0.48, 8.15)

Very low

LR- 0.98

(0.34, 3.00)

Very low
Surface swabs (anal cleft)
131

0.07

(0.02, 0.26)

0.46

(0.22, 0.71)

LR+ 0.13

(0.03, 0.67)

Low

LR- 2.03

(1.08, 3.79)

Low
Surface swabs (axilla)
131

0.45

(0.26, 0.66)

0.46

(0.22, 0.71)

LR+ 0.84

(0.41, 1.68)

Very low

LR- 1.19

(0.58, 2.47)

Very low
Surface swabs (cubital fossa)
131

0.02

(0.00, 0.19)

0.29

(0.11, 0.57)

LR+ 0.03

(0.00, 0.53)

Low

LR- 3.35

(1.38, 8.10)

Low
Surface swabs (ear)
131

0.55

(0.34, 0.74)

0.79

(0.51, 0.93)

LR+ 2.63

(0.82, 8.46)

Very low

LR- 0.57

(0.33, 0.99)

Low
Surface swabs (external genitalia)
131

0.02

(0.00, 0.19)

0.62

(0.35, 0.84)

LR+ 0.06

(0.00, 1.08)

Low

LR- 1.56

(1.00, 2.43)

Very low
Surface swabs (gastric aspirate)
131

0.45

(0.26, 0.66)

0.71

(0.43, 0.89)

LR+ 1.55

(0.57, 4.21)

Very low

LR- 0.77

(0.45, 1.32)

Very low
Surface swabs (inguinal fold)
131

0.02

(0.00, 0.19)

0.38

(0.16, 0.65)

LR+ 0.04

(0.00, 0.61)

Low

LR- 2.60

(1.25, 5.42)

Low
Surface swabs (lumbar area)
131

0.02

(0.00, 0.19)

0.29

(0.11, 0.57)

LR+ 0.03

(0.00, 0.53)

Low

LR- 3.35

(1.38, 8.10)

Low
Surface swabs (nasal swab)
131

0.50

(0.30, 0.70)

0.71

(0.43, 0.89)

LR+ 1.71

(0.64, 4.57)

Very low

LR- 0.71

(0.40, 1.24)

Very low
Surface swabs (neckfold)
131

0.02

(0.00, 0.19)

0.29

(0.11, 0.57)

LR+ 0.03

(0.00, 0.53)

Low

LR- 3.35

(1.38, 8.10)

Low
Surface swabs (palms)
131

0.12

(0.04, 0.32)

0.29

(0.11, 0.57)

LR+ 0.17

(0.05, 0.57)

Low

LR- 3.02

(1.23, 7.40)

Low
Surface swabs (pharynx)
131

0.45

(0.26, 0.66)

0.54

(0.29, 0.78)

LR+ 0.99

(0.45, 2.14)

Very low

LR- 1.01

(0.53, 1.94)

Low
Surface swabs (popliteal space)
131

0.02

(0.00, 0.19)

0.29

(0.11, 0.57)

LR+ 0.03

(0.00, 0.53)

Low

LR- 3.35

(1.38, 8.10)

Low
Surface swabs (scalp: occipital)
131

0.07

(0.02, 0.26)

0.38

(0.16, 0.65)

LR+ 0.11

(0.02, 0.57)

Low

LR- 2.48

(1.18, 5.19)

Low
Surface swabs (soles)
131

0.02

(0.00, 0.19)

0.29

(0.11, 0.57)

LR+ 0.03

(0.00, 0.53)

Low

LR- 3.35

(1.38, 8.10)

Low
Surface swabs (umbilicus)
131

0.60

(0.39, 0.77)

0.79

(0.51, 0.93)

LR+ 2.86

(0.90, 9.10)

Very low

LR- 0.51

(0.28, 93)

Low
Tip of the IV long line (longitudinal split method) (Culture of tip yielded ≥15 colony forming units of the same colony type)
1277

0.97

(0.91, 0.99)

0.88

(0.84, 0.92)

LR+ 8.41

(6.06, 11.67)

Moderate

LR- 0.04

(0.01, 0.11)

Moderate
Tip of the IV long line (qualitative method) (Culture of tip yielded ≥15 colony forming units of the same colony type)
185

0.99

(0.89, 1.00)

0.60

(0.45, 0.73)

LR+ 2.48

(1.72, 3.60)

Low
LR- not calculableModerate
Tip of the IV long line (roll plate method) (Culture of tip yielded ≥15 colony forming units of the same colony type)
3387

0.73

(0.50, 0.88)

0.80

(0.53, 0.93)

LR+ 3.96

(1.68, 8.99)

Very low

LR- 0.36

(0.18, 0.60)

Very low
*

LR+: Positive likelihood ratio, LR-: Negative likelihood ratio

See appendix F for full GRADE tables

1.1.7. Economic evidence

1.1.7.1. Included studies

A single search was performed to identify published economic evaluations of relevance to any of the questions in this guideline update (see Appendix B). This search retrieved 4,398 studies. Based on title and abstract screening, all the studies could confidently be excluded for this question.

The search was re-run in July 2020 to identify any studies which had been published since the date of the original search. This returned a total of 577 results. Based on title and abstract screening, all the studies could confidently be excluded for this question. Thus, the review for this question does not include any study from the existing literature.

1.1.7.2. Excluded studies

See appendix J for excluded studies.

1.1.8. Economic model

No economic modelling was undertaken for this review because of a lack of economic evidence and because the committee agreed that other topics were higher priorities for economic evaluation.

1.1.9. The committee’s discussion and interpretation of the evidence

1.1.9.1. The outcomes that matter most

The committee discussed the potential effects of true positive, true negative, false positive and false negative outcomes from tests used to identify late-onset neonatal infection. A test that correctly identifies all babies with infection (true positives) would result in antibiotics being prescribed to all those who need treatment, reducing the serious harms associated with neonatal infection. If a test correctly identifies all those without infection (true negatives) then it will avoid over-prescribing of antibiotics. This is a particular challenge when evaluating neonatal infection as it is difficult to diagnose and can therefore result in all, or most, babies being prescribed antibiotics to avoid any infections being missed and being left untreated.

If a test does not accurately identify babies with infection and those without infection, then there are a number of potential harms. False positive results will result in babies being given antibiotics unnecessarily, exposing them to the risk of side effects. As antibiotics can only be given in hospital, this can lead to separation of the mother and baby, potentially causing anxiety and distress to the family. False positive results will also incur the costs associated with a hospital stay and can contribute to the development of antibiotic resistance. However, a false negative result is the biggest concern for parents and clinicians as there can be serious consequences if neonatal infection is left untreated. The most serious consequence is death of the baby, but delayed treatment can also have long-term health consequences, such as neuro-disability, which can have both emotional and financial impacts on the family as well as downstream treatment costs for the healthcare system. False negatives for babies with meningitis may result in a shorter treatment duration than necessary which can have long-term consequences for the baby, such as issues with neurodevelopment. A false negative may also affect communication with parents, who may be given a different prognosis than would be expected for meningitis. Consequently, the committee prioritised negative likelihood ratios over positive likelihood ratios – the committee believed that it was important that negative test results were accurate, and that neonatal infection was not incorrectly ruled out.

1.1.9.2. The quality of the evidence

Thirty-four studies were included in the review, and the majority of the evidence evaluated either CRP or procalcitonin. The evidence was very low to moderate quality, with most outcome measures rated as either low or very low quality. Most studies were directly applicable to the research question, although 3 were downgraded due to a lack of information about the age of the babies included in the study. Another study evaluating surface swabs was downgraded for differences in the population and clinical practice between the study setting (India) and the UK. Outcomes from this study were low to very low quality, with considerable imprecision. Many of the likelihood ratios suggested that a positive test from a surface swab could indicate either an increase or a decrease in the probability of a baby having an infection. These conflicting results were also seen for negative likelihood ratios. This supported a recommendation from the 2012 version of this guideline for early-onset infection, that skin swab microscopy or culture should not be performed as part of the investigations for infection. The committee therefore decided to apply this recommendation to both early- and late- onset neonatal infection.

One of the key issues raised by the committee was the use of blood cultures as the reference standard in most of the studies. Positive blood cultures are considered the gold standard test for diagnosing neonatal infection, but it is widely acknowledged that this is not a perfect method. Babies can have a negative blood culture despite having neonatal infection. Blood samples are difficult to obtain in neonates and may be contaminated and accurate results depend on proper technique in taking and incubating the sample. This could affect the results of a study, as a baby with neonatal infection but a negative blood culture will appear as a false positive result if a diagnostic test correctly identifies them as having an infection. However, as blood cultures reflect current practice and are still considered the most accurate test for diagnosing late-onset infection, the committee did not think the studies should be downgraded for risk of bias.

The committee noted that a very wide range of cut-off values were used for the diagnostic tests within the analysis, in particular for CRP levels. The most commonly used threshold for CRP in the UK is 10 mg/l, and so the committee thought that these data were the most applicable to decision making. Much of the evidence for CRP was based on the test being performed at the same time as the blood culture when a baby was first identified as being at risk of infection. The committee explained that CRP is often low at the start of an infection and takes approximately one day before there is a detectable response. The result of a single CRP test is therefore not considered a useful marker in practice. Instead, clinicians usually take one sample at the time of the initial blood culture to obtain a baseline reading, and then repeat the test 18–24 hours later to see if there has been a change in CRP concentration. If there is little change in CRP concentration during this period, then clinicians can rule out infection and antibiotic treatment can be stopped. Only three studies performed more than one CRP test, with the results indicating that, at a cut-off value of 10 mg/l, the test was more sensitive 24 hours after the first blood sample. Likelihood ratios indicated that when a CRP test took place at the time of the initial blood culture, a positive result would indicate a moderate increase in the probability of a baby having infection, and a negative result would increase a slight decrease in the probability of infection. When a CRP test took place 24 or 48 hours later, a positive result would still indicate a moderate increase, but a negative result would indicate a moderate decrease in infection risk, thereby giving a clinician more confidence in the result. However, these studies evaluated absolute CRP values in relation to a pre-specified threshold rather than looking for a change in CRP over time. Consequently, the committee could not recommend how much CRP should increase before a clinician can be confident that a baby has late-onset neonatal infection.

Three studies examined the diagnostic accuracy of culturing the tip of the IV long line for identifying IV catheter-related infections. There were some questions over how well the methods of these studies would relate to clinical practice, as it would be unlikely that a clinician would remove an IV line to test the IV tip while the baby was still unwell. There were also concerns over how appropriate the tests were to evaluate infection. Three techniques were evaluated, and the committee highlighted that the Maki roll plate method is the most common in clinical practice. However, this evaluates the presence of extra-luminal rather than intra-luminal bacteria and is therefore likely to miss many of the organisms associated with neonatal infection. In contrast the longitudinal split and qualitative methods would identify intra-luminal bacteria. However, these are not used commonly in UK practice as the methods may introduce contamination into the IV tips, thereby potentially giving false positive results and resulting in babies being given antibiotic treatment unnecessarily. The committee agreed that while these methods may be useful once antibiotic treatment has been started to identify whether the correct antibiotic is being used, they are less useful for diagnosing infection and making decisions on whether antibiotic treatment should be started.

Other tests included in the review (neutrophil count, IT ratio and white blood cell count) had low diagnostic accuracy, with lower sensitivity than CRP and likelihood ratios that suggested that a negative result would only indicate a slight decrease in the probability of infection. The committee therefore decided these would not be an effective method of ruling out neonatal infection and could instead result in many babies receiving unnecessary treatment. The results for platelet counts showed a similar degree of imprecision to surface swabs, with likelihood ratios indicating that neither a positive or negative test result could guarantee whether a baby had an increased or decreased probability of infection. The committee agreed that these results could not be used to inform the recommendations.

1.1.9.3. Benefits and harms

A test that can accurately identify whether a baby has late-onset neonatal infection can help to ensure that only babies with an infection will be given antibiotics. This also reduces the adverse effects associated with unnecessary treatment for both the baby and the baby’s family, as well as reducing the costs associated with treatment. Although blood cultures are currently the gold standard technique, it can take more than 30 hours for blood culture results to be available and as a result, many babies are treated for suspicion of infection rather than confirmed infection until the results of the blood culture are returned. A test that could identify which babies had infection more quickly and accurately than a blood test would therefore help to reduce the number of babies who are treated with antibiotics until culture results are available.

No tests showed sufficient diagnostic accuracy to recommend them as an alternative to blood culture, but a combination of evidence and clinical experience from the committee was used to suggest that CRP is a useful test alongside blood cultures. Although the baseline value is unlikely to change the number of babies receiving treatment, the additional information provided by the results of the second CRP test can identify babies who do not have infection, thereby reducing the number of babies who continue antibiotic treatment unnecessarily. For this reason, the committee were keen to highlight the importance of performing two CRP tests, one when starting treatment to provide a baseline value for the baby, and another 18–24 hours later to identify any rise in CRP levels that are typical of a response to infection. The committee also considered whether the likelihood of a baby having an infection might be taken more seriously if there were positive results from a number of tests rather than just blood cultures and CRP tests. However, there was low quality evidence for the other tests in the review, and the committee decided that they did not show sufficient diagnostic accuracy for this to be considered. Given the poor diagnostic accuracy, the committee decided against making a research recommendation for further evidence on these tests.

The committee considered the recommendations from the 2012 version of this guideline on diagnosing early-onset neonatal infection. It discussed how the bacteria that cause infections differ between early-onset infection and late-onset infection. However, it agreed that the tests used to identify early-onset infection would still be appropriate, even if the organisms responsible for the infection differed. As such, it made similar recommendations to those for the early-onset infection section of the guideline. This included performing a blood culture before the first dose of antibiotics so that a blood sample was available for analysis as quickly as possible, and so that a baseline value was available for the baby before treatment began.

There was no evidence into the effectiveness of urine culture for diagnosing late-onset neonatal infection and the committee did not think this would be a useful test for babies in the neonatal unit. They therefore made a similar recommendation to that for early-onset neonatal infection which recommends against the use of urine culture. However, it was highlighted that urine culture can be an important test in other settings, such as to test for urinary tract infection when a baby is admitted to a paediatric unit with fever. A second recommendation on urine culture was therefore included which supported its use in babies who are being cared for outside of neonatal units. This is consistent with the recommendations from the NICE guideline on urinary tract infection in under 16s.

A test that can accurately diagnose meningitis is also important to ensure that all babies with meningitis receive the correct treatment. Lumbar puncture is the gold standard test for identifying babies with meningitis. Although there was no evidence in this review for the safety of lumbar punctures, the committee discussed how, in it’s clinical experience, the benefits of identifying babies with meningitis outweighs the risks of the procedure, which it considered to be low. The use of lumbar punctures was already recommended in the 2012 version of this guideline for babies with suspected early-onset infection, and the committee therefore included this in the recommendations. Given the importance of diagnosing meningitis, the committee made a strong recommendation in favour of lumbar puncture if there is a strong suspicion of sepsis or meningitis, but stated that this should only take place if it is safe to do so.

1.1.9.4. Cost effectiveness and resource use

The committee agreed that, as its recommendations are consistent with current practice, there would be no major resource impact associated with their adoption. The committee was mindful that, as well as having potentially catastrophic consequences for the neonate, any infection that is missed can generate very substantial costs for the health and care system. Therefore, even if there is an increase in CRP tests and lumbar puncture, this is likely to be offset by savings associated with accurately diagnosed and managed cases. Correct identification of all those without infection (true negatives) will avoid over-prescribing of antibiotics. This reduces the adverse effects and costs associated with unnecessary treatment for both the baby and the baby’s family.

1.1.9.5. Other factors the committee took into account

The committee discussed how basing the recommendations on those used for diagnosing early-onset infection was useful as these were designed to meet the criteria stated in the Public Health England ‘Start Smart – Then Focus’ guidance which outlines procedures for antimicrobial stewardship in secondary care. This should help to ensure that babies who develop neonatal infection get the antibiotic treatment they require without increasing the risk of over-prescribing and the development of antimicrobial resistance.

1.1.10. Recommendations supported by this evidence review

This evidence review supports recommendations 1.7.1–1.7.8.

1.1.11. References – included studies

    1.1.11.1. Effectiveness
    • Aminullah A (2001) The role of plasma C-reactive protein in the evaluation of antibiotic treatment in suspected neonatal sepsis. Medical Journal of Indonesia 1: 16–21
    • Anwar ul Haq, H.M., Anjum, A.A., Bharo, M.A. et al. (2019) Accuracy of C - Reactive protein (CRP) for the diagnosis of neonatal sepsis having blood culture as gold standard. Medical Forum Monthly 30(8): 55–58
    • Anwer, S K and Mustafa, S (2000) Rapid identification of neonatal sepsis. JPMA. The Journal of the Pakistan Medical Association 50(3): 94–8 [PubMed: 10795470]
    • Balasubramanin, P., Bandiya, P., Niranjan, S.H. et al. (2018) Role of CSF-CRP as a Diagnostic Marker in Neonatal Meningitis. Journal of Neonatology 32(4): 112–117
    • Beltempo, Marc, Viel-Theriault, Isabelle, Thibeault, Roseline et al. (2018) C-reactive protein for late-onset sepsis diagnosis in very low birth weight infants. BMC pediatrics 18(1): 16 [PMC free article: PMC5791164] [PubMed: 29382319]
    • Berger, C, Uehlinger, J, Ghelfi, D et al. (1995) Comparison of C-reactive protein and white blood cell count with differential in neonates at risk for septicaemia. European journal of pediatrics 154(2): 138–44 [PubMed: 7720743]
    • Blommendahl, Janne, Janas, Martti, Laine, Seppo et al. (2002) Comparison of procalcitonin with CRP and differential white blood cell count for diagnosis of culture-proven neonatal sepsis. Scandinavian journal of infectious diseases 34(8): 620–2 [PubMed: 12238581]
    • Boo, N Y; Nor Azlina, A A; Rohana, J (2008) Usefulness of a semi-quantitative procalcitonin test kit for early diagnosis of neonatal sepsis. Singapore medical journal 49(3): 204–8 [PubMed: 18363001]
    • Boonkasidecha, Suppawat, Panburana, Jantana, Chansakulporn, Somboon et al. (2013) An optimal cut-off point of serum C-reactive protein in prediction of neonatal sepsis. Journal of the Medical Association of Thailand = Chotmaihet thangphaet 96suppl1: 65–70 [PubMed: 23724458]
    • Huang, H., Tan, J., Gong, X. et al. (2019) Comparing single vs. Combined cerebrospinal fluid parameters for diagnosing full-term neonatal bacterial meningitis. Frontiers in Neurology 10(jan): 12 [PMC free article: PMC6351467] [PubMed: 30728800]
    • Iskandar, A., Arthamin, M.Z., Indriana, K. et al. (2019) Comparison between presepsin and procalcitonin in early diagnosis of neonatal sepsis. Journal of Maternal-Fetal and Neonatal Medicine 32(23): 3903–3908 [PubMed: 29742943]
    • Jacquot, A, Labaune, J-M, Baum, T-P et al. (2009) Rapid quantitative procalcitonin measurement to diagnose nosocomial infections in newborn infants. Archives of disease in childhood. Fetal and neonatal edition 94(5): f345–8 [PubMed: 19439432]
    • Joji, R.; Takpere, A.Y.; Gupta, S. (2018) Evaluation of diagnostic value of C reactive protein in neonatal sepsis. Asian Journal of Microbiology, Biotechnology and Environmental Sciences 20(2): 409–412
    • Khair, K B, Rahman, M A, Sultana, T et al. (2012) Early diagnosis of neonatal septicemia by hematologic scoring system, C-reactive protein and serum haptoglobin. Mymensingh medical journal : MMJ 21(1): 85–92 [PubMed: 22314460]
    • Khan, F. (2019) C-reactive Protein as a Screening Biomarker in Neonatal Sepsis. Journal of the College of Physicians and Surgeons--Pakistan : JCPSP 29(10): 951–953 [PubMed: 31564268]
    • Kumar, R, Musoke, R, Macharia, W M et al. (2010) Validation of c-reactive protein in the early diagnosis of neonatal sepsis in a tertiary care hospital in Kenya. East African medical journal 87(6): 255–61 [PubMed: 23057268]
    • Lopez Sastre, Jose B, Perez Solis, David, Roques Serradilla, Vicente et al. (2006) Procalcitonin is not sufficiently reliable to be the sole marker of neonatal sepsis of nosocomial origin. BMC pediatrics 6: 16 [PMC free article: PMC1526729] [PubMed: 16709255]
    • Marconi, Camila, de Lourdes Rs Cunha, Maria, Lyra, Joao C et al. (2008) Comparison between qualitative and semiquantitative catheter-tip cultures: laboratory diagnosis of catheter-related infection in newborns. Brazilian journal of microbiology : [publication of the Brazilian Society for Microbiology] 39(2): 262–7 [PMC free article: PMC3768388] [PubMed: 24031213]
    • Martin-Rabadan, P, Perez-Garcia, F, Zamora Flores, E et al. (2017) Improved method for the detection of catheter colonization and catheter-related bacteremia in newborns. Diagnostic microbiology and infectious disease 87(4): 311–314 [PubMed: 28129948]
    • Mkony, Martha Franklin, Mizinduko, Mucho Michael, Massawe, Augustine et al. (2014) Management of neonatal sepsis at Muhimbili National Hospital in Dar es Salaam: diagnostic accuracy of C-reactive protein and newborn scale of sepsis and antimicrobial resistance pattern of etiological bacteria. BMC pediatrics 14: 293 [PMC free article: PMC4262228] [PubMed: 25475836]
    • Nakamura, H, Uetani, Y, Nagata, T et al. (1989) Serum C-reactive protein in the early diagnosis of neonatal septicemia and bacterial meningitis. Acta paediatrica Japonica : Overseas edition 31(5): 567–71 [PubMed: 2515735]
    • Omar, J., Isa, S., Ismail, T.S.T. et al. (2019) Procalcitonin as an early laboratory marker of sepsis in neonates: Variation in diagnostic performance and discrimination value. Malaysian Journal of Medical Sciences 26(4): 61–69 [PMC free article: PMC6719890] [PubMed: 31496894]
    • Ozdemir, S.A., Colak, R., Ergon, E.Y. et al. (2020) Diagnostic Value of Urine sTREM-1 and Urine C-reactive Protein for Infants with Late Onset Neonatal Sepsis. Journal of Pediatric Infectious Diseases 15(2): 72–78
    • Palmer, Ayo, Carlin, John B, Freihorst, Joachim et al. (2004) The use of CRP for diagnosing infections in young infants < 3 months of age in developing countries. Annals of tropical paediatrics 24(3): 205–12 [PubMed: 15479569]
    • Philip AG and Hewitt JR (1980) Early diagnosis of neonatal sepsis. Pediatrics 65(5): 1036–1041 [PubMed: 7367117]
    • Ponnusamy, Vennila, Venkatesh, Vidheya, Curley, Anna et al. (2012) Segmental percutaneous central venous line cultures for diagnosis of catheter-related sepsis. Archives of disease in childhood. Fetal and neonatal edition 97(4): f273–8 [PubMed: 22174018]
    • Puri, J, Revathi, G, Faridi, M M et al. (1995) Role of body surface cultures in prediction of sepsis in a neonatal intensive care unit. Annals of tropical paediatrics 15(4): 307–11 [PubMed: 8687208]
    • Ramgopal, Sriram, Walker, Lorne W, Nowalk, Andrew J et al. (2019) Immature neutrophils in young febrile infants. Archives of disease in childhood 104(9): 884–886 [PMC free article: PMC7266081] [PubMed: 31221623]
    • Rosenfeld, Charles R, Shafer, Grant, Scheid, Lisa M et al. (2019) Screening and Serial Neutrophil Counts Do Not Contribute to the Recognition or Diagnosis of Late-Onset Neonatal Sepsis. The Journal of pediatrics 205: 105–111e2 [PubMed: 30318373]
    • Seibert, K, Yu, V Y, Doery, J C et al. (1990) The value of C-reactive protein measurement in the diagnosis of neonatal infection. Journal of paediatrics and child health 26(5): 267–70 [PubMed: 2265018]
    • Sharma A, Kutty CV, Sabharwal U et al. (1993) Evaluation of sepsis screen for diagnosis of neonatal septicemia. Indian journal of pediatrics 60(4): 559–563 [PubMed: 8262592]
    • Smith, P Brian, Garges, Harmony P, Cotton, C Michael et al. (2008) Meningitis in preterm neonates: importance of cerebrospinal fluid parameters. American journal of perinatology 25(7): 421–6 [PMC free article: PMC2715150] [PubMed: 18726835]
    • Sucilathangam, G., Amuthavalli, K., Velvizhi, G. et al. (2012) Early diagnostic markers for neonatal sepsis: Comparing procalcitonin (PCT) and C-reactive protein (CRP). Journal of Clinical and Diagnostic Research 6(4suppl2): 627–631
    • West, B.A., Peterside, O., Ugwu, R.O. et al. (2012) Prospective evaluation of the usefulness of C-reactive protein in the diagnosis of neonatal sepsis in a sub-Saharan African region. Antimicrobial Resistance and Infection Control 1: 22 [PMC free article: PMC3436619] [PubMed: 22958461]

Appendices

Appendix B. Literature search strategies

Clinical search literature search strategy

The search was conducted on 30th October 2019. The following databases were searched: Medline, Medline In Process, Medline E-pub Ahead of print, Embase, (all via the Ovid platform), Cochrane Database of Systematic Reviews, (via the Wiley platform), and the DARE database (via the CRD platform).

Population and investigations terms

The search terms used to identify the population and investigations are reproduced below for all databases. The population and investigations terms were combined as ‘And’ to identify papers that discussed both.

Medline, Medline in Process & Medline E-pub Ahead of Print

  1. exp Infant, Newborn/
  2. Term Birth/
  3. Infant Care/
  4. Perinatal Care/
  5. Intensive Care Units, Neonatal/
  6. Intensive Care, Neonatal/
  7. Infant Health/
  8. (newborn* or new born* or neonat* or neo-nat* or perinat* or peri-nat*).tw.
  9. ((premature* or pre-mature* or preterm* or pre-term*) adj4 (child* or infant* or baby* or babies* or offspring)).tw.
  10. or/1–9
  11. exp Bacterial Infections/
  12. ((bacter* or strep* or staph* or GNB) adj4 (infect* or diseas* or contaminat* or mening* or pneumon* or nosocomial*)).tw.
  13. exp Sepsis/
  14. (sepsis or septic?emia* or py?emia* or pyho?emia*).tw.
  15. (septic* adj4 shock*).tw.
  16. (bacter?emia* or bacill?emia*).tw.
  17. (blood* adj4 (infect* or contamin* or invas* or invad*)).tw.
  18. or/11–17
  19. exp Streptococcus/
  20. exp Staphylococcus/
  21. (streptococc* or staphylococc*).tw.
  22. (GBS or MRSA or NRCS-A or MSSA).tw.
  23. (met?icillin-resistant adj3 aureus).tw.
  24. exp Escherichia coli/
  25. ((Escheric* or E) adj2 coli).tw.
  26. exp Listeria/
  27. listeria*.tw.
  28. exp Klebsiella/
  29. klebsiella*.tw.
  30. exp Pseudomonas/
  31. (pseudomonas or chryseomonas or flavimonas).tw.
  32. Enterobacteriaceae/
  33. (enterobact* or sodalis or paracolobactrum or ewingella or leclercia).tw.
  34. ((enteric or coliform) adj2 bac*).tw.
  35. exp Neisseria/
  36. neisseria*.tw.
  37. exp Haemophilus influenzae/
  38. ((h?emophil* or H or bacter* or bacill* or mycobacter* or coccobac*) adj2 (influenz* or pfeiffer* or meningitidis)).tw.
  39. exp Serratia/
  40. serratia*.tw.
  41. exp Cronobacter/
  42. (cronobact* or sakazaki* or malonatic*).tw.
  43. exp Acinetobacter/
  44. (acinetobact* or herellea* or mima or baumanni* or genomosp* or calcoacetic*).tw.
  45. exp Fusobacterium/
  46. (fusobact* or sphaerophor* or necrophorum or nucleatum).tw.
  47. exp Enterococcus/
  48. enterococc*.tw.
  49. or/19–48
  50. 18 or 49
  51. 10 and 50
  52. ((newborn* or new born* or neonat* or neo-nat* or perinat* or peri-nat*) adj4 infect*).tw.
  53. ((premature* or pre-mature* or preterm* or pre-term*) adj4 (child* or infant* or baby* or babies* or offspring) adj4 infect*).tw.
  54. 52 or 53
  55. 51 or 54
  56. ((inflam* or excit*) adj4 (marker* or flag* or indicat*)).tw.
  57. C-Reactive Protein/
  58. (C adj2 react* adj4 protein*).tw.
  59. (Creact* adj4 protein*).tw.
  60. CRP.tw.
  61. Acute-Phase Reaction/
  62. Acute-Phase Proteins/
  63. (acute* adj2 phas* adj4 (react* or respons* or state* or protein*)).tw.
  64. APR.tw.
  65. Serum Amyloid A Protein/
  66. (serum* adj4 amyloid* adj4 A).tw.
  67. SAA.tw.
  68. Orosomucoid/
  69. (orosomucoid* or seromucoid*).tw.
  70. (serum* adj4 (fibronectin* or sialomuin*)).tw.
  71. alpha-2-Antiplasmin/
  72. ((acid* or alpha*) adj4 (antiplasmin* or anti-plasmin* or glycoprotein*)).tw.
  73. (alpha* adj4 plasmin* adj4 inhibitor*).tw.
  74. AGP.tw.
  75. Hepcidins/
  76. hepcidin*.tw.
  77. Blood Sedimentation/
  78. ((blood* or erythrocyte*) adj4 sediment*).tw.
  79. Haptoglobins/
  80. haptoglobin*.tw.
  81. (h?emoglobin* adj4 bind* adj4 protein*).tw.
  82. Procalcitonin/
  83. Calcitonin/
  84. (procalcitonin* or calcitonin*).tw.
  85. PCT.tw.
  86. exp Interleukins/
  87. Interleukin 1 Receptor Antagonist Protein/
  88. (interleukin* or IL-6 or IL6 or IL-1 or IL1).tw.
  89. Cytokines/
  90. exp Receptors, Cytokine/
  91. cytokine*.tw.
  92. exp Leukocyte Count/
  93. ((leukocyte* or leucocyte* or lymphocyte* or WBC*) adj4 (count* or number* or polymorphonuclear* or total* or calculat* or amount* or estimat* or quant* or sum*)).tw.
  94. (white* adj2 (blood* or cell*) adj4 (count* or number* or polymorphonuclear* or total* or calculat* or amount* or estimat* or quant* or sum*)).tw.
  95. exp Colony-Stimulating Factors/
  96. ((colony* or colonies*) adj4 stimulat* adj4 (factor* or activit* or determin* or influenc* or agen*)).tw.
  97. Granulocytes/
  98. Neutrophils/
  99. (granulocyte* or neutrophil* or neutrocyt*).tw.
  100. ((LE or band or granuloid*) adj4 cell*).tw.
  101. (G-CSF or GM-CSF or “CSF-2” or TC-GM-CSF or CSF-GM or rhGM-CSF).tw.
  102. Platelet Count/
  103. ((platelet* or thrombocyt*) adj4 (count* or number* or total* or calculat* or amount* or estimat* or quant* or sum*)).tw.
  104. Cerebrospinal Fluid/an, di, dg [Analysis, Diagnosis, Diagnostic Imaging]
  105. ((cerebrospinal* or cerebr*-spinal* or cephalorhachidian* or cranial* or spinal* or brain*-ventricl* or neurolymph* or neuro-lymph*) adj4 (fluid* or liquid* or solut*) adj4 (exam* or test* or analys* or inspect* or explor* or scan* or investigat*)).tw.
  106. (CSF* adj4 (exam* or test* or analys* or inspect* or explor* or scan* or investigat*)).tw.
  107. Spinal Puncture/
  108. ((spinal* or spine* or lumbar*) adj4 (puncture* or tap*)).tw.
  109. Latex Fixation Tests/
  110. (latex* adj4 (test* or kit* or method* or fixat* or agglutinat* or antigen* or assay* or serotyp* or react*)).tw.
  111. (streptex* or pastorex* or wellcogen*).tw.
  112. (LPA or LAT or LFT).tw.
  113. Reagent Strips/
  114. ((urin* or reagent* or immunochromographic* or immuno-chromographic* or Nephur* or test*) adj4 (strip* or dipstick* or dip-stick* or tap* or paper*)).tw.
  115. StripAssay*.tw.
  116. exp Polymerase Chain Reaction/
  117. (polymerase* adj4 chain* adj4 react*).tw.
  118. PCR.tw.
  119. Urinalysis/
  120. Urine/mi [Microbiology]
  121. urinalys*.tw.
  122. (urin* adj4 (cultur* or mcroscop* or test* or analys* or exam* or investigat*)).tw.
  123. UA.tw.
  124. exp Catheters/
  125. Catheterization/
  126. exp Urinary Catheterization/
  127. (catheter* or cannula*).tw.
  128. ((suprapubic* or supra-pubic* or bladder* or detrusor*) adj4 (aspirat* or punctur*)).tw.
  129. (SPA or SBA).tw.
  130. (iQ200* or (iChem* adj4 workstation*)).tw.
  131. Flow Cytometry/
  132. (flow* adj4 (cytometr* or microfluoromet* or cytofluorometr* or lateral*)).tw.
  133. (LFB or LFA).tw.
  134. Sysmex*.tw.
  135. (Xpert adj4 (MTB or RIF)).tw.
  136. ((rapid* or quick* or accelerat* or fast* or speed* or swift*) adj4 (test* or kit* or method* or detect* or discover* or identif* or recogni* or assay* or agglutinat* or immunoassay* or immunochromatographic*)).tw.
  137. (RDT or RADT or DIMA).tw.
  138. exp Fluorescent Antibody Technique/
  139. ((fluorescen* or immunofluorescen* or immuno-fluorescen*) adj4 (techni* or antibod* or anti-bod* or trac* or cell* or hybridi?ation* or test* or method* or identif* or detect*)).tw.
  140. FISH.tw.
  141. Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization/
  142. (matrix* adj10 spectrom*).tw.
  143. (MALDI* or MALD-MS* or TOF-MS* or LDI-MS*).tw.
  144. FilmArray*.tw.
  145. “Staining and Labeling”/
  146. (gram* adj4 (stain* or label*)).tw.
  147. Limulus Test/
  148. (limulus* adj4 (lysate* or test* or assay* or exam* or analys* or investigat* or method* or detect* or endotoxin* or toxin* or coagul* or serum*)).tw.
  149. LAL.tw.
  150. swab*.tw.
  151. ((surface* or exterior* or outer* or superficial*) adj4 (culture* or wipe* or mop or smear*)).tw.
  152. ((skin* or dermis* or epidermis* or nose* or nasal* or paranasal* or ear or ears or umbilic* or rectal* or rectum* or axilla* or underarm* or under-arm* or armpit* or arm-pit* or groin* or genital* or eye* or ocular* or oculus* or throat* or pharyn* or laryn* or neck*) adj4 (culture* or wipe* or mop or smear*)).tw.
  153. Infusions, Intravenous/
  154. ((IV or I-V or intravenous*) adj4 (line* or infusion* or sampl* or fragment* or specimen* or indicat* or segment* or drip* or admin* or dos* or inject* or deliver* or transfus* or tip*)).tw.
  155. exp Radiography, Thoracic/
  156. X-Rays/
  157. ((chest* or thorax* or thorac* or bronch* or lung*) adj4 (x-ray* or xray* or radio* or roentgen* or imag*)).tw.
  158. or/56–157
  159. 55 and 158
  160. Animals/ not Humans/
  161. 159 not 160
  162. limit 161 to english language

Embase

  1. newborn/
  2. term birth/
  3. infant care/
  4. perinatal care/
  5. neonatal intensive care unit/
  6. newborn intensive care/
  7. child health/
  8. (newborn* or new born* or neonat* or neo-nat* or perinat* or peri-nat*).tw.
  9. ((premature* or pre-mature* or preterm* or pre-term*) adj4 (child* or infant* or baby* or babies* or offspring)).tw.
  10. or/1–9
  11. exp bacterial infection/
  12. ((bacter* or strep* or staph* or GNB) adj4 (infect* or diseas* or contaminat* or mening* or pneumon* or nosocomial*)).tw.
  13. exp sepsis/
  14. (sepsis or septic?emia* or py?emia* or pyho?emia*).tw.
  15. (septic* adj4 shock*).tw.
  16. (bacter?emia* or bacill?emia*).tw.
  17. (blood* adj4 (infect* or contamin* or invas* or invad*)).tw.
  18. or/11–17
  19. exp Streptococcus/
  20. exp Staphylococcus/
  21. (streptococc* or staphylococc*).tw.
  22. (GBS or MRSA or NRCS-A or MSSA).tw.
  23. (met?icillin-resistant adj3 aureus).tw.
  24. exp Escherichia coli/
  25. ((Escheric* or E) adj2 coli).tw.
  26. exp Listeria/
  27. listeria*.tw.
  28. exp Klebsiella/
  29. klebsiella*.tw.
  30. exp Pseudomonas/
  31. (pseudomonas or chryseomonas or flavimonas).tw.
  32. Enterobacteriaceae/
  33. (enterobact* or sodalis or paracolobactrum or ewingella or leclercia).tw.
  34. ((enteric or coliform) adj2 bac*).tw.
  35. exp Neisseria/
  36. neisseria*.tw.
  37. exp Haemophilus influenzae/
  38. ((h?emophil* or H or bacter* or bacill* or mycobacter* or coccobac*) adj2 (influenz* or pfeiffer* or meningitidis)).tw.
  39. exp Serratia/
  40. serratia*.tw.
  41. exp cronobacter/
  42. (cronobact* or sakazaki* or malonatic*).tw.
  43. exp Acinetobacter/
  44. (acinetobact* or herellea* or mima or baumanni* or genomosp* or calcoacetic*).tw.
  45. exp Fusobacterium/
  46. (fusobact* or sphaerophor* or necrophorum or nucleatum).tw.
  47. exp Enterococcus/
  48. enterococc*.tw.
  49. or/19–48
  50. 18 or 49
  51. 10 and 50
  52. ((newborn* or new born* or neonat* or neo-nat* or perinat* or peri-nat*) adj4 infect*).tw.
  53. ((premature* or pre-mature* or preterm* or pre-term*) adj4 (child* or infant* or baby* or babies* or offspring) adj4 infect*).tw.
  54. 52 or 53
  55. 51 or 54
  56. ((inflam* or excit*) adj4 (marker* or flag* or indicat*)).tw.
  57. C reactive protein/
  58. (C adj2 react* adj4 protein*).tw.
  59. (Creact* adj4 protein*).tw.
  60. CRP.tw.
  61. acute phase response/
  62. acute phase protein/
  63. (acute* adj2 phas* adj4 (react* or respons* or state* or protein*)).tw.
  64. APR.tw.
  65. serum amyloid A/
  66. (serum* adj4 amyloid* adj4 A).tw.
  67. SAA.tw.
  68. orosomucoid/
  69. (orosomucoid* or seromucoid*).tw.
  70. (serum* adj4 (fibronectin* or sialomuin*)).tw.
  71. alpha 2 antiplasmin/
  72. ((acid* or alpha*) adj4 (antiplasmin* or anti-plasmin* or glycoprotein*)).tw. (
  73. (alpha* adj4 plasmin* adj4 inhibitor*).tw.
  74. AGP.tw. (
  75. hepcidin/
  76. hepcidin*.tw.
  77. erythrocyte sedimentation rate/
  78. ((blood* or erythrocyte*) adj4 sediment*).tw.
  79. haptoglobin/
  80. haptoglobin*.tw.
  81. (h?emoglobin* adj4 bind* adj4 protein*).tw.
  82. procalcitonin/
  83. calcitonin/
  84. (procalcitonin* or calcitonin*).tw.
  85. PCT.tw.
  86. interleukin 1/ or interleukin 1 derivative/ or interleukin derivative/
  87. interleukin 1 receptor blocking agent/
  88. interleukin 6/
  89. (interleukin* or IL-6 or IL6 or IL-1 or IL1).tw.
  90. cytokine/
  91. exp cytokine receptor/ (
  92. cytokine*.tw.
  93. exp leukocyte count/
  94. ((leukocyte* or leucocyte* or lymphocyte* or WBC*) adj4 (count* or number* or polymorphonuclear* or total* or calculat* or amount* or estimat* or quant* or sum*)).tw.
  95. (white* adj2 (blood* or cell*) adj4 (count* or number* or polymorphonuclear* or total* or calculat* or amount* or estimat* or quant* or sum*)).tw.
  96. colony stimulating factor/
  97. ((colony* or colonies*) adj4 stimulat* adj4 (factor* or activit* or determin* or influenc* or agen*)).tw.
  98. granulocyte/
  99. neutrophil/
  100. (granulocyte* or neutrophil* or neutrocyt*).tw.
  101. ((LE or band or granuloid*) adj4 cell*).tw.
  102. (G-CSF or GM-CSF or “CSF-2” or TC-GM-CSF or CSF-GM or rhGM-CSF).tw.
  103. platelet count/
  104. ((platelet* or thrombocyt*) adj4 (count* or number* or total* or calculat* or amount* or estimat* or quant* or sum*)).tw.
  105. cerebrospinal fluid analysis/ or cerebrospinal fluid examination/
  106. ((cerebrospinal* or cerebr*-spinal* or cephalorhachidian* or cranial* or spinal* or brain*-ventricl* or neurolymph* or neuro-lymph*) adj4 (fluid* or liquid* or solut*) adj4 (exam* or test* or analys* or inspect* or explor* or scan* or investigat*)).tw.
  107. (CSF* adj4 (exam* or test* or analys* or inspect* or explor* or scan* or investigat*)).tw. (
  108. lumbar puncture/
  109. ((spinal* or spine* or lumbar*) adj4 (puncture* or tap*)).tw.
  110. latex agglutination test/
  111. (latex* adj4 (test* or kit* or method* or fixat* or agglutinat* or antigen* or assay* or serotyp* or react*)).tw.
  112. (streptex* or pastorex* or wellcogen*).tw.
  113. (LPA or LAT or LFT).tw.
  114. test strip/
  115. ((urin* or reagent* or immunochromographic* or immuno-chromographic* or Nephur* or test*) adj4 (strip* or dipstick* or dip-stick* or tap* or paper*)).tw.
  116. StripAssay*.tw.
  117. exp polymerase chain reaction/
  118. (polymerase* adj4 chain* adj4 react*).tw.
  119. PCR.tw.
  120. exp urinalysis/
  121. urinalys*.tw.
  122. (urin* adj4 (cultur* or mcroscop* or test* or analys* or exam* or investigat*)).tw.
  123. UA.tw.
  124. exp catheter/
  125. catheterization/
  126. exp bladder catheterization/
  127. (catheter* or cannula*).tw.
  128. ((suprapubic* or supra-pubic* or bladder* or detrusor*) adj4 (aspirat* or punctur*)).tw.
  129. (SPA or SBA).tw.
  130. (iQ200* or (iChem* adj4 workstation*)).tw.
  131. flow cytometry/
  132. (flow* adj4 (cytometr* or microfluoromet* or cytofluorometr* or lateral*)).tw.
  133. (LFB or LFA).tw.
  134. Sysmex*.tw.
  135. (Xpert adj4 (MTB or RIF)).tw.
  136. ((rapid* or quick* or accelerat* or fast* or speed* or swift*) adj4 (test* or kit* or method* or detect* or discover* or identif* or recogni* or assay* or agglutinat* or immunoassay* or immunochromatographic*)).tw.
  137. (RDT or RADT or DIMA).tw.
  138. exp fluorescent antibody technique/
  139. ((fluorescen* or immunofluorescen* or immuno-fluorescen*) adj4 (techni* or antibod* or anti-bod* or trac* or cell* or hybridi?ation* or test* or method* or identif* or detect*)).tw.
  140. FISH.tw.
  141. exp matrix-assisted laser desorption-ionization mass spectrometry/
  142. (matrix* adj10 spectrom*).tw.
  143. (MALDI* or MALD-MS* or TOF-MS* or LDI-MS*).tw.
  144. FilmArray*.tw.
  145. gram staining/
  146. (gram* adj4 (stain* or label*)).tw.
  147. limulus lysate test/
  148. (limulus* adj4 (lysate* or test* or assay* or exam* or analys* or investigat* or method* or detect* or endotoxin* or toxin* or coagul* or serum*)).tw.
  149. LAL.tw.
  150. swab*.tw.
  151. ((surface* or exterior* or outer* or superficial*) adj4 (culture* or wipe* or mop or smear*)).tw.
  152. ((skin* or dermis* or epidermis* or nose* or nasal* or paranasal* or ear or ears or umbilic* or rectal* or rectum* or axilla* or underarm* or under-arm* or armpit* or arm-pit* or groin* or genital* or eye* or ocular* or oculus* or throat* or pharyn* or laryn* or neck*) adj4 (culture* or wipe* or mop or smear*)).tw.
  153. intravenous drug administration/
  154. ((IV or I-V or intravenous*) adj4 (line* or infusion* or sampl* or fragment* or specimen* or indicat* or segment* or drip* or admin* or dos* or inject* or deliver* or transfus* or tip*)).tw.
  155. exp thorax radiography/
  156. X ray/
  157. ((chest* or thorax* or thorac* or bronch* or lung*) adj4 (x-ray* or xray* or radio* or roentgen* or imag*)).tw.
  158. or/56–157
  159. 55 and 158
  160. nonhuman/ not human/
  161. 159 not 160
  162. limit 161 to english language
  163. limit 162 to (conference abstract or conference paper or “conference review”)
  164. 162 not 163

CDSR

#1.

MeSH descriptor: [Infant, Newborn] explode all trees

#2.

MeSH descriptor: [Term Birth] this term only

#3.

MeSH descriptor: [Infant Care] this term only

#4.

MeSH descriptor: [Perinatal Care] this term only

#5.

MeSH descriptor: [Intensive Care Units, Neonatal] this term only

#6.

MeSH descriptor: [Intensive Care, Neonatal] this term only

#7.

MeSH descriptor: [Infant Health] this term only

#8.

((newborn* or new born* or neonat* or neo-nat* or perinat* or peri-nat*)):ti,ab,kw

#9.

((premature* or pre-mature* or preterm* or pre-term*) near/4 (child* or infant* or baby* or babies* or offspring)):ti,ab,kw

#10.

{or #1–#9}

#11.

MeSH descriptor: [Bacterial Infections] explode all trees

#12.

((bacter* or strep* or staph* or GNB) near/4 (infect* or diseas* or contaminat* or mening* or pneumon* or nosocomial*)):ti,ab,kw

#13.

MeSH descriptor: [Sepsis] explode all trees

#14.

(sepsis or septic?emia* or py?emia* or pyho?emia*):ti,ab,kw

#15.

(septic* near/4 shock*):ti,ab,kw

#16.

(bacter?emia* or bacill?emia*):ti,ab,kw

#17.

((blood*) near/4 (infect* or contamin* or invas* or invad*)):ti,ab,kw

#18.

{or #11–#17}

#19.

MeSH descriptor: [Streptococcus] explode all trees

#20.

MeSH descriptor: [Staphylococcus] explode all trees

#21.

(streptococc* or staphylococc*):ti,ab,kw

#22.

(GBS or MRSA or NRCS-A or MSSA):ti,ab,kw

#23.

(met?icillin-resistant near/3 aureus):ti,ab,kw

#24.

MeSH descriptor: [Escherichia coli] explode all trees

#25.

((Escheric* or E) near/2 (coli)):ti,ab,kw

#26.

MeSH descriptor: [Listeria] explode all trees

#27.

(listeria*):ti,ab,kw

#28.

MeSH descriptor: [Klebsiella] explode all trees

#29.

(klebsiella*):ti,ab,kw

#30.

MeSH descriptor: [Pseudomonas] explode all trees

#31.

(pseudomonas or chryseomonas or flavimonas):ti,ab,kw

#32.

MeSH descriptor: [Enterobacteriaceae] explode all trees

#33.

(enterobact* or sodalis or paracolobactrum or ewingella or leclercia):ti,ab,kw

#34.

((enteric or coliform) near/2 (bac*)):ti,ab,kw

#35.

MeSH descriptor: [Neisseria] explode all trees

#36.

(neisseria*):ti,ab,kw

#37.

MeSH descriptor: [Haemophilus influenzae] explode all trees

#38.

((h?emophil* or H or bacter* or bacill* or mycobacter* or coccobac*) near/2 (influenz* or pfeiffer* or meningitidis)):ti,ab,kw

#39.

MeSH descriptor: [Serratia] explode all trees

#40.

(serratia*):ti,ab,kw

#41.

MeSH descriptor: [Cronobacter] explode all trees

#42.

(cronobact* or sakazaki* or malonatic*):ti,ab,kw

#43.

MeSH descriptor: [Acinetobacter] explode all trees

#44.

(acinetobact* or herellea* or mima or baumanni* or genomosp* or calcoacetic*):ti,ab,kw

#45.

MeSH descriptor: [Fusobacterium] explode all trees

#46.

(fusobact* or sphaerophor* or necrophorum or nucleatum):ti,ab,kw

#47.

MeSH descriptor: [Enterococcus] explode all trees

#48.

(enterococc*):ti,ab,kw

#49.

{or #19–#48}

#50.

#18 or #49

#51.

#10 and #50

#52.

((newborn* or new born* or neonat* or neo-nat* or perinat* or peri-nat*) near/4 (infect*)):ti,ab,kw

#53.

((premature* or pre-mature* or “preterm*” or “pre-term*”) near/4 (child* or infant* or baby* or babies* or offspring) near/4 (infect*)):ti,ab,kw

#54.

#52 or #53

#55.

#51 or #54

#56.

((inflam* or excit*) near/4 (marker* or flag* or indicat*)):ti,ab,kw

#57.

MeSH descriptor: [C-Reactive Protein] this term only

#58.

((“C”) near/2 (react*) near/4 (protein*)):ti,ab,kw

#59.

((Creact*) near/4 (protein*)):ti,ab,kw

#60.

(CRP):ti,ab,kw

#61.

MeSH descriptor: [Acute-Phase Reaction] this term only

#62.

MeSH descriptor: [Acute-Phase Proteins] this term only

#63.

((acute*) near/2 (phas*) near/4 (react* or respons* or state* or protein*)):ti,ab,kw

#64.

(APR):ti,ab,kw

#65.

MeSH descriptor: [Serum Amyloid A Protein] this term only

#66.

((serum* near/4 amyloid* near/4 “A”)):ti,ab,kw

#67.

(SAA):ti,ab,kw

#68.

MeSH descriptor: [Orosomucoid] this term only

#69.

(orosomucoid* or seromucoid*):ti,ab,kw

#70.

((serum*) near/4 (fibronectin* or sialomuin*)):ti,ab,kw

#71.

MeSH descriptor: [alpha-2-Antiplasmin] this term only

#72.

((acid* or alpha*) near/4 (antiplasmin* or anti-plasmin* or glycoprotein*)):ti,ab,kw

#73.

((alpha* near/4 plasmin* near/4 inhibitor*)):ti,ab,kw

#74.

(AGP):ti,ab,kw

#75.

MeSH descriptor: [Hepcidins] this term only

#76.

(hepcidin*):ti,ab,kw

#77.

MeSH descriptor: [Blood Sedimentation] this term only

#78.

((blood* or erythrocyte*) near/4 (sediment*)):ti,ab,kw

#79.

MeSH descriptor: [Haptoglobins] this term only

#80.

(haptoglobin*):ti,ab,kw

#81.

((h?emoglobin* near/4 bind* near/4 protein*)):ti,ab,kw

#82.

MeSH descriptor: [Procalcitonin] this term only

#83.

MeSH descriptor: [Calcitonin] this term only

#84.

(procalcitonin* or calcitonin*):ti,ab,kw

#85.

(PCT):ti,ab,kw

#86.

MeSH descriptor: [Interleukins] explode all trees

#87.

MeSH descriptor: [Interleukin 1 Receptor Antagonist Protein] this term only

#88.

(interleukin* or IL-6 or IL6 or IL-1 or IL1):ti,ab,kw

#89.

MeSH descriptor: [Cytokines] this term only

#90.

MeSH descriptor: [Receptors, Cytokine] explode all trees

#91.

(cytokine*):ti,ab,kw

#92.

MeSH descriptor: [Leukocyte Count] explode all trees

#93.

((leukocyte* or leucocyte* or lymphocyte* or WBC*) near/4 (count* or number* or polymorphonuclear* or total* or calculat* or amount* or estimat* or quant* or sum*)):ti,ab,kw

#94.

((white*) near/2 (blood* or cell*) near/4 (count* or number* or polymorphonuclear* or total* or calculat* or amount* or estimat* or quant* or sum*)):ti,ab,kw

#95.

MeSH descriptor: [Colony-Stimulating Factors] explode all trees

#96.

((colony* or colonies*) near/4 (stimulat*) near/4 (factor* or activit* or determin* or influenc* or agen*)):ti,ab,kw

#97.

MeSH descriptor: [Granulocytes] this term only

#98.

MeSH descriptor: [Neutrophils] this term only

#99.

(granulocyte* or neutrophil* or neutrocyt*):ti,ab,kw

#100.

((LE or band or granuloid*) near/4 (cell*)):ti,ab,kw

#101.

(G-CSF or GM-CSF or “CSF-2” or TC-GM-CSF or CSF-GM or rhGM-CSF):ti,ab,kw

#102.

MeSH descriptor: [Platelet Count] this term only

#103.

((platelet* or thrombocyt*) near/4 (count* or number* or total* or calculat* or amount* or estimat* or quant* or sum*)):ti,ab,kw

#104.

MeSH descriptor: [Cerebrospinal Fluid] this term only

#105.

((cerebrospinal* or “cerebr*-spinal*” or cephalorhachidian* or cranial* or spinal* or “brain*-ventricl*” or neurolymph* or “neuro-lymph*”) near/4 (fluid* or liquid* or solut*) near/4 (exam* or test* or analys* or inspect* or explor* or scan* or investigat*)):ti,ab,kw

#106.

((CSF*) near/4 (exam* or test* or analys* or inspect* or explor* or scan* or investigat*)):ti,ab,kw

#107.

MeSH descriptor: [Spinal Puncture] this term only

#108.

((spinal* or spine* or lumbar*) near/4 (puncture* or tap*)):ti,ab,kw

#109.

MeSH descriptor: [Latex Fixation Tests] this term only

#110.

((latex*) near/4 (test* or kit* or method* or fixat* or agglutinat* or antigen* or assay* or serotyp* or react*)):ti,ab,kw

#111.

(streptex* or pastorex* or wellcogen*):ti,ab,kw

#112.

(LPA or LAT or LFT):ti,ab,kw

#113.

MeSH descriptor: [Reagent Strips] this term only

#114.

((urin* or reagent* or immunochromographic* or immuno-chromographic* or Nephur* or test*) near/4 (strip* or dipstick* or dip-stick* or tap* or paper*)):ti,ab,kw

#115.

(StripAssay*):ti,ab,kw

#116.

MeSH descriptor: [Polymerase Chain Reaction] explode all trees

#117.

((polymerase*) near/4 (chain*) near/4 (react*)):ti,ab,kw

#118.

(PCR):ti,ab,kw

#119.

MeSH descriptor: [Urinalysis] this term only

#120.

MeSH descriptor: [Urine] this term only and with qualifier(s): [microbiology - MI]

#121.

(urinalys*):ti,ab,kw

#122.

((urin*) near/4 (cultur* or mcroscop* or test* or analys* or exam* or investigat*)):ti,ab,kw

#123.

(UA):ti,ab,kw

#124.

MeSH descriptor: [Catheters] explode all trees

#125.

MeSH descriptor: [Catheterization] this term only

#126.

MeSH descriptor: [Urinary Catheterization] explode all trees

#127.

(catheter* or cannula*):ti,ab,kw

#128.

((suprapubic* or supra-pubic* or bladder* or detrusor*) near/4 (aspirat* or punctur*)):ti,ab,kw

#129.

(SPA or SBA):ti,ab,kw

#130.

((iQ200*) or (iChem* near/4 workstation*)):ti,ab,kw

#131.

MeSH descriptor: [Flow Cytometry] this term only

#132.

((flow*) near/4 (cytometr* or microfluoromet* or cytofluorometr* or lateral*)):ti,ab,kw

#133.

(LFB or LFA):ti,ab,kw

#134.

(Sysmex*):ti,ab,kw

#135.

((Xpert) near/4 (MTB or RIF)):ti,ab,kw

#136.

((rapid* or quick* or accelerat* or fast* or speed* or swift*) near/4 (test* or kit* or method* or detect* or discover* or identif* or recogni* or assay* or agglutinat* or immunoassay* or immunochromatographic*)):ti,ab,kw

#137.

(RDT or RADT or DIMA):ti,ab,kw

#138.

MeSH descriptor: [Fluorescent Antibody Technique] this term only

#139.

((fluorescen* or immunofluorescen* or immuno-fluorescen*) near/4 (techni* or antibod* or anti-bod* or trac* or cell* or hybridi?ation* or test* or method* or identif* or detect*)):ti,ab,kw

#140.

(FISH):ti,ab,kw

#141.

MeSH descriptor: [Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization] this term only

#142.

((matrix* near/10 spectrom*)):ti,ab,kw

#143.

(MALDI* or MALD-MS* or TOF-MS* or LDI-MS*):ti,ab,kw

#144.

(FilmArray*):ti,ab,kw

#145.

MeSH descriptor: [Staining and Labeling] this term only

#146.

((gram*) near/4 (stain* or label*)):ti,ab,kw

#147.

MeSH descriptor: [Limulus Test] this term only

#148.

((limulus*) near/4 (lysate* or test* or assay* or exam* or analys* or investigat* or method* or detect* or endotoxin* or toxin* or coagul* or serum*)):ti,ab,kw

#149.

(LAL):ti,ab,kw

#150.

(swab*):ti,ab,kw

#151.

((surface* or exterior* or outer* or superficial*) near/4 (culture* or wipe* or mop or smear*)):ti,ab,kw

#152.

((skin* or dermis* or epidermis* or nose* or nasal* or paranasal* or ear or ears or umbilic* or rectal* or rectum* or axilla* or underarm* or under-arm* or armpit* or arm-pit* or groin* or genital* or eye* or ocular* or oculus* or throat* or pharyn* or laryn* or neck*) near/4 (culture* or wipe* or mop or smear*)):ti,ab,kw

#153.

MeSH descriptor: [Infusions, Intravenous] this term only

#154.

((IV or I-V or intravenous*) near/4 (line* or infusion* or sampl* or fragment* or specimen* or indicat* or segment* or drip* or admin* or dos* or inject* or deliver* or transfus* or tip*)):ti,ab,kw

#155.

MeSH descriptor: [Radiography, Thoracic] explode all trees

#156.

MeSH descriptor: [X-Rays] this term only

#157.

((chest* or thorax* or thorac* or bronch* or lung*) near/4 (x-ray* or xray* or radio* or roentgen* or imag*)):ti,ab,kw

#158.

{or #56–#157}

#159.

#55 and #158

DARE

  1. MeSH DESCRIPTOR Infant, Newborn EXPLODE ALL TREES
  2. MeSH DESCRIPTOR Term Birth
  3. MeSH DESCRIPTOR Infant Care
  4. MeSH DESCRIPTOR Perinatal Care
  5. MeSH DESCRIPTOR Intensive Care Units, Neonatal
  6. MeSH DESCRIPTOR Intensive Care, Neonatal
  7. MeSH DESCRIPTOR Infant Health
  8. (newborn* or new born* or neonat* or neo-nat* or perinat* or peri-nat*)
  9. ((premature* or pre-mature* or preterm* or pre-term*) NEAR4 (child* or infant* or baby* or babies* or offspring))
  10. (#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9)
  11. MeSH DESCRIPTOR Bacterial Infections EXPLODE ALL TREES
  12. ((bacter* or strep* or staph* or GNB) NEAR4 (infect* or diseas* or contaminat* or mening* or pneumon* or nosocomial*))
  13. MeSH DESCRIPTOR Sepsis EXPLODE ALL TREES
  14. (sepsis or septic?emia* or py?emia* or pyho?emia*)
  15. (septic* NEAR4 shock*)
  16. (bacter?emia* or bacill?emia*)
  17. ((blood*) NEAR4 (infect* or contamin* or invas* or invad*))
  18. (#11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17)
  19. MeSH DESCRIPTOR Streptococcus EXPLODE ALL TREES
  20. MeSH DESCRIPTOR Staphylococcus EXPLODE ALL TREES
  21. (streptococc* or staphylococc*)
  22. (GBS or MRSA or NRCS-A or MSSA)
  23. (met?icillin-resistant NEAR3 aureus)
  24. MeSH DESCRIPTOR Escherichia coli EXPLODE ALL TREES
  25. ((Escheric* or E) NEAR2 (coli))
  26. MeSH DESCRIPTOR Listeria EXPLODE ALL TREES
  27. (listeria*)
  28. MeSH DESCRIPTOR Klebsiella EXPLODE ALL TREES
  29. (klebsiella*)
  30. MeSH DESCRIPTOR Pseudomonas EXPLODE ALL TREES
  31. (pseudomonas or chryseomonas or flavimonas)
  32. MeSH DESCRIPTOR Enterobacteriaceae EXPLODE ALL TREES
  33. (enterobact* or sodalis or paracolobactrum or ewingella or leclercia)
  34. ((enteric or coliform) NEAR2 (bac*))
  35. MeSH DESCRIPTOR Neisseria EXPLODE ALL TREES
  36. (neisseria*)
  37. MeSH DESCRIPTOR Haemophilus influenzae EXPLODE ALL TREES
  38. ((h?emophil* or H or bacter* or bacill* or mycobacter* or coccobac*) NEAR2 (influenz* or pfeiffer* or meningitidis))
  39. MeSH DESCRIPTOR Serratia EXPLODE ALL TREES
  40. (serratia*)
  41. MeSH DESCRIPTOR Cronobacter EXPLODE ALL TREES
  42. (cronobact* or sakazaki* or malonatic*)
  43. MeSH DESCRIPTOR Acinetobacter EXPLODE ALL TREES
  44. (acinetobact* or herellea* or mima or baumanni* or genomosp* or calcoacetic*)
  45. MeSH DESCRIPTOR Fusobacterium EXPLODE ALL TREES
  46. (fusobact* or sphaerophor* or necrophorum or nucleatum)
  47. MeSH DESCRIPTOR Enterococcus EXPLODE ALL TREES
  48. (enterococc*)
  49. (#19 OR #20 OR #21 OR #22 OR #23 OR #24 OR #25 OR #26 OR #27 OR #28 OR #29 OR #30 OR #31 OR #32 OR #33 OR #34 OR #35 OR #36 OR #37 OR #38 OR #39 OR #40 OR #41 OR #42 OR #43 OR #44 OR #45 OR #46 OR #47 OR #48)
  50. (#18 OR #49)
  51. (#10 AND #50)
  52. ((newborn* or new born* or neonat* or neo-nat* or perinat* or peri-nat*) NEAR4 (infect*))
  53. ((prematur*e or pre-mature* or preterm* or pre-term*) NEAR4 (child* or infant* or baby* or babies* or offspring) NEAR4 (infect*))
  54. (#52 OR #53)
  55. (#51 OR #54)
  56. ((inflam* or excit*) NEAR4 (marker* or flag* or indicat*))
  57. MeSH DESCRIPTOR C-Reactive Protein
  58. ((C) NEAR2 (react*) NEAR4 (protein*))
  59. (Creact* NEAR4 protein*)
  60. (CRP)
  61. MeSH DESCRIPTOR Acute-Phase Reaction
  62. MeSH DESCRIPTOR Acute-Phase Proteins
  63. ((acute*) NEAR2 (phas*) NEAR4 (react* or respons* or state* or protein*))
  64. (APR)
  65. MeSH DESCRIPTOR Serum Amyloid A Protein
  66. ((serum*) NEAR4 (amyloid*) NEAR4 (A))
  67. (SAA)
  68. MeSH DESCRIPTOR Orosomucoid
  69. (orosomucoid* or seromucoid*)
  70. ((serum*) NEAR4 (fibronectin* or sialomuin*))
  71. MeSH DESCRIPTOR alpha-2-Antiplasmin
  72. ((acid* or alpha*) NEAR4 (antiplasmin* or anti-plasmin* or glycoprotein*))
  73. ((alpha*) NEAR4 (plasmin*) NEAR4 (inhibitor*))
  74. (AGP)
  75. MeSH DESCRIPTOR Hepcidins
  76. (hepcidin*)
  77. MeSH DESCRIPTOR Blood Sedimentation
  78. ((blood* or erythrocyte*) NEAR4 (sediment*))
  79. MeSH DESCRIPTOR Haptoglobins
  80. (haptoglobin*)
  81. ((h?emoglobin*) NEAR4 (bind*) NEAR4 (protein*))
  82. MeSH DESCRIPTOR Calcitonin
  83. (procalcitonin* or calcitonin*)
  84. (PCT)
  85. MeSH DESCRIPTOR Interleukins EXPLODE ALL TREES
  86. MeSH DESCRIPTOR Interleukin 1 Receptor Antagonist Protein
  87. (interleukin* or IL-6 or IL6 or IL-1 or IL1)
  88. MeSH DESCRIPTOR Cytokines
  89. MeSH DESCRIPTOR Receptors, Cytokine EXPLODE ALL TREES
  90. (cytokine*)
  91. MeSH DESCRIPTOR Leukocyte Count EXPLODE ALL TREES
  92. ((leukocyte* or leucocyte* or lymphocyte* or WBC*) NEAR4 (count* or number* or polymorphonuclear* or total* or calculat* or amount* or estimat* or quant* or sum*))
  93. ((white*) NEAR2 (blood* or cell*) NEAR4 (count* or number* or polymorphonuclear* or total* or calculat* or amount* or estimat* or quant* or sum*))
  94. MeSH DESCRIPTOR Colony-Stimulating Factors EXPLODE ALL TREES
  95. ((colony* or colonies*) NEAR4 (stimulat*) NEAR4 (factor* or activit* or determin* or influenc* or agen*))
  96. MeSH DESCRIPTOR Granulocytes
  97. MeSH DESCRIPTOR Neutrophils
  98. (granulocyte* or neutrophil* or neutrocyt*)
  99. ((LE or band or granuloid*) NEAR4 (cell*))
  100. (G-CSF or GM-CSF or “CSF-2” or TC-GM-CSF or CSF-GM or rhGM-CSF)
  101. MeSH DESCRIPTOR Platelet Count
  102. ((platelet* or thrombocyt*) NEAR4 (count* or number* or total* or calculat* or amount* or estimat* or quant* or sum*))
  103. MeSH DESCRIPTOR Cerebrospinal Fluid
  104. ((cerebrospinal* or cerebr*-spinal* or cephalorhachidian* or cranial* or spinal* or brain*-ventricl* or neurolymph* or neuro-lymph*) NEAR4 (fluid* or liquid* or solut*) NEAR4 (exam* or test* or analys* or inspect* or explor* or scan* or investigat*))
  105. ((CSF*) NEAR4 (exam* or test* or analys* or inspect* or explor* or scan* or investigat*))
  106. MeSH DESCRIPTOR Spinal Puncture
  107. ((spinal* or spine* or lumbar*) NEAR4 (puncture* or tap*))
  108. MeSH DESCRIPTOR Latex Fixation Tests
  109. ((latex*) NEAR4 (test* or kit* or method* or fixat* or agglutinat* or antigen* or assay* or serotyp* or react*))
  110. (streptex* or pastorex* or wellcogen*)
  111. (LPA or LAT or LFT)
  112. MeSH DESCRIPTOR Reagent Strips
  113. ((urin* or reagent* or immunochromographic* or immuno-chromographic* or Nephur* or test*) NEAR4 (strip* or dipstick* or dip-stick* or tap* or paper*))
  114. (StripAssay*)
  115. MeSH DESCRIPTOR Polymerase Chain Reaction EXPLODE ALL TREES
  116. (PCR)
  117. ((polymerase*) NEAR4 (chain*) NEAR4 (react*))
  118. MeSH DESCRIPTOR Urinalysis
  119. MeSH DESCRIPTOR Urine WITH QUALIFIER MI
  120. (urinalys*)
  121. ((urin*) NEAR4 (cultur* or mcroscop* or test* or analys* or exam* or investigat*))
  122. (UA)
  123. MeSH DESCRIPTOR Catheters EXPLODE ALL TREES
  124. MeSH DESCRIPTOR Catheterization
  125. MeSH DESCRIPTOR Urinary Catheterization EXPLODE ALL TREES
  126. (catheter* or cannula*)
  127. ((suprapubic* or supra-pubic* or bladder* or detrusor*) NEAR4 (aspirat* or punctur*))
  128. (SPA or SBA)
  129. ((iQ200*) or (iChem* NEAR4 workstation*))
  130. MeSH DESCRIPTOR Flow Cytometry
  131. ((flow*) NEAR4 (cytometr* or microfluoromet* or cytofluorometr* or lateral*))
  132. (LFB or LFA)
  133. (Sysmex*)
  134. ((Xpert) NEAR4 (MTB or RIF))
  135. ((rapid* or quick* or accelerat* or fast* or speed* or swift*) NEAR4 (test* or kit* or method* or detect* or discover* or identif* or recogni* or assay* or agglutinat* or immunoassay* or immunochromatographic*))
  136. (RDT or RADT or DIMA)
  137. MeSH DESCRIPTOR Fluorescent Antibody Technique EXPLODE ALL TREES
  138. ((fluorescen* or immunofluorescen* or immuno-fluorescen*) NEAR4 (techni* or antibod* or anti-bod* or trac* or cell* or hybridi?ation* or test* or method* or identif* or detect*))
  139. (FISH)
  140. MeSH DESCRIPTOR Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
  141. ((matrix* NEAR10 spectrom*))
  142. (MALDI* or MALD-MS* or TOF-MS* or LDI-MS*)
  143. (FilmArray*)
  144. MeSH DESCRIPTOR Staining and Labeling
  145. ((gram*) NEAR4 (stain* or label*))
  146. MeSH DESCRIPTOR Limulus Test
  147. ((limulus*) NEAR4 (lysate* or test* or assay* or exam* or analys* or investigat* or method* or detect* or endotoxin* or toxin* or coagul* or serum*))
  148. (LAL)
  149. (swab*)
  150. ((surface* or exterior* or outer* or superficial*) NEAR4 (culture* or wipe* or mop or smear*))
  151. ( (skin* or dermis* or epidermis* or nose* or nasal* or paranasal* or ear or ears or umbilic* or rectal* or rectum* or axilla* or underarm* or under-arm* or armpit* or arm-pit* or groin* or genital* or eye* or ocular* or oculus* or throat* or pharyn* or laryn* or neck*) NEAR4 (culture* or wipe* or mop or smear*))
  152. MeSH DESCRIPTOR Infusions, Intravenous
  153. ((IV or I-V or intravenous*) NEAR4 (line* or infusion* or sampl* or fragment* or specimen* or indicat* or segment* or drip* or admin* or dos* or inject* or deliver* or transfus* or tip*))
  154. MeSH DESCRIPTOR Radiography, Thoracic EXPLODE ALL TREES
  155. MeSH DESCRIPTOR X-Rays
  156. ((chest* or thorax* or thorac* or bronch* or lung*) NEAR4 (x-ray* or xray* or radio* or roentgen* or imag*))
  157. #56 OR #57 OR #58 OR #59 OR #60 OR #61 OR #62 OR #63 OR #64 OR #65 OR #66 OR #67 OR #68 OR #69 OR #70 OR #71 OR #72 OR #73 OR #74 OR #75 OR #76 OR #77 OR #78 OR #79 OR #80 OR #81 OR #82 OR #83 OR #84 OR #85 OR #86 OR #87 OR #88 OR #89 OR #90 OR #91 OR #92 OR #93 OR #94 OR #95 OR #96 OR #97 OR #98 OR #99 OR #100 OR #101 OR #102 OR #103 OR #104 OR #105 OR #106 OR #107 OR #108 OR #109 OR #110 OR #111 OR #112 OR #113 OR #114 OR #115 OR #116 OR #117 OR #118 OR #119 OR #120 OR #121 OR #122 OR #123 OR #124 OR #125 OR #126 OR #127 OR #128 OR #129 OR #130 OR #131 OR #132 OR #133 OR #134 OR #135 OR #136 OR #137 OR #138 OR #139 OR #140 OR #141 OR #142 OR #143 OR #144 OR #145 OR #146 OR #147 OR #148 OR #149 OR #150 OR #151 OR #152 OR #153 OR #154 OR #155 OR #156
  158. #55 AND #157
  159. * IN DARE
  160. #158 AND #159

Systematic Review Search Filter

The following systematic review filter was combined as ‘And’ with the population and investigations terms for the Medline databases and Embase. CDSR and DARE are systematic review databases so did not require the addition of a filter.

The Medline version of the filter is reproduced below. Embase has a validated translation of this that was used in the search.

  1. MEDLINE or pubmed).tw.
  2. systematic review.tw.
  3. systematic review.pt.
  4. meta-analysis.pt.
  5. intervention$.ti.
  6. or/1–5

Virus terms

The following terms were combined as ‘Not’ with the other sections of the search strategy to remove any papers focused on viral illness.

The Medline virus terms are listed below. These were translated across all databases used in the search:

  1. exp Virus Diseases/
  2. exp Viruses/
  3. (virus* or viral* or retrovir* or arbovir* or lentivir* or deltaretrovir* or adenovir*).tw.
  4. HIV*.tw.
  5. (cytomegalovir* or CMV*).tw.
  6. herpes*.tw.
  7. (papillomavir* or HPV*).tw.
  8. ((hepatitis* or hepatitid*) adj2 (A or B or C or D or E)).tw.
  9. (parechovir* or echovir*).tw.
  10. (yellow* adj2 fever*).tw.
  11. rhinovir*.tw.
  12. (coronavir* or deltacoronavir*).tw.
  13. rotavir*.tw.
  14. (enterovir* or coxsackie*).tw.
  15. exp Malaria/
  16. (malaria* or paludism*).tw.
  17. exp Syphilis/
  18. (syphili* or neurosyphili* or neuro-syphili*).tw.
  19. or/1–18

Health Economics literature search strategy

Download PDF (338K)

Appendix C. Diagnostic evidence study selection

Download PDF (124K)

Appendix D. Diagnostic evidence

Download PDF (1.3M)

Appendix F. GRADE tables

Download PDF (332K)

Appendix G. Economic evidence study selection

Download PDF (122K)

Appendix H. Economic evidence tables

No economic evidence is available as none of the studies in the economic search results was found to be relevant.

Appendix I. Health economic model

This question was not prioritised for original economic analysis.

Appendix J. Excluded studies

Clinical studies (PDF, 330K)

Final

Evidence reviews underpinning recommendations 1.7.1–1.7.8 in the NICE guideline

These evidence reviews were developed by NICE Guideline Updates Team

Disclaimer: The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or service users. The recommendations in this guideline are not mandatory and the guideline does not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or their carer or guardian.

Local commissioners and/or providers have a responsibility to enable the guideline to be applied when individual health professionals and their patients or service users wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with compliance with those duties.

NICE guidelines cover health and care in England. Decisions on how they apply in other UK countries are made by ministers in the Welsh Government, Scottish Government, and Northern Ireland Executive. All NICE guidance is subject to regular review and may be updated or withdrawn.

Copyright © NICE 2021.
Bookshelf ID: NBK571219PMID: 34133107

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