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National Collaborating Centre for Cancer (UK). Neutropenic Sepsis: Prevention and Management of Neutropenic Sepsis in Cancer Patients. London: National Institute for Health and Clinical Excellence (NICE); 2012 Sep. (NICE Clinical Guidelines, No. 151.)
Neutropenic Sepsis: Prevention and Management of Neutropenic Sepsis in Cancer Patients.
Show detailsNeutropenic sepsis is a life threatening complication of anticancer treatment, the term is used to describe a significant inflammatory response to a presumed bacterial infection in a person with or without fever.
The objective of this chapter is to define neutropenic sepsis to identify those patients for whom treatment for bacterial sepsis should be undertaken before any clear diagnosis of infection is established.
2.1. Definition of neutropenia and fever
The risk of a life threatening infection in patients receiving treatment for cancer is related to the degree of immunosuppression, commonly assessed by the absolute neutrophil count (ANC). The risks of mortality and other adverse clinical outcomes increase as the absolute neutrophil count falls. It has been considered necessary to set thresholds to initiate empiric antibiotic treatment to ensure that occult infection is treated promptly and that patients with very low risk of infection are not exposed to unnecessary antibiotics. The neutrophil count and the degree of fever at the time of hospital presentation influence the decision on whether inpatient admission is necessary.
Protocols for neutropenic sepsis usually define neutropenia as an absolute neutrophil count of less than 0.5 × 109 /litre, or less than 1.0 × 109 /litre and “falling”, the interpretation of which requires some knowledge of chemotherapy regimens and expected patterns of myelosuppression. Fever is a common but not the only manifestation of infection (for example patients may present with hypothermia). A clinically significant fever has been defined variously as 37.5°C, 38°C or 38.5°C over different time points.
An evaluation of how the risk of mortality and other adverse clinical outcomes relate to the absolute neutrophil count and the degree of fever should determine the appropriate threshold for initial empiric treatment. This could reduce unnecessary hospitalisation of those without risk of life threatening infection. Also, there would be consistent advice from health care professionals working in different healthcare settings
Clinical question: How do neutrophil count and temperature relate to the risk of complications of sepsis, in cancer patients with suspected neutropenic sepsis?
Clinical evidence (see also full evidence review)
Study quality and results
No evidence comparing definitions of neutropenia or fever in cancer patients with possible neutropenic sepsis was found.
Eleven observational studies were found about temperature and neutrophil count as prognostic factors in patients receiving treatment for fever and neutropenia. Seven studies included paediatric patients and ten included only patients with fever (definitions ranged from a single temperature measurement greater than 38.0°C to 38.0°C for at least four hours) and neutropenia (ANC <0.5 × 109/litre or 1.0 × 109/litre and falling). These studies probably underestimate the usefulness of neutropenia and fever as prognostic factors in neutropenic sepsis because they are limited to a restricted range of ANC and temperature values, excluding patients with low risk of neutropenic sepsis. The evidence is therefore of low quality.
Literature searches identified no evidence about the relationship between mortality or length of stay and definitions of neutropenia and fever.
Evidence statements
A single study in 102 patients (Apostolopoulou, et al., 2010) reported that ANC >0.5 × 109/litre has high negative predictive value for bacteraemia. All other evidence came from studies of patients with both neutropenia and fever and thus had limited value due to the restricted range of possible temperature and ANC values.
Low quality evidence suggests that defining fever as temperature >39.0°C (instead of >38.0°C) increases the positive predictive value (PPV) of neutropenia and fever for bacteraemia, severe infection and adverse events (Ammann, et al., 2003, Ha, et al., 2010, Hakim et al., 2010, Klassen et al., 2000 and Santolaya, et al., 2001). Although the negative predictive value (NPV) of this definition was not estimable, using the >39.0°C definition would probably decrease NPV (relative to >38.0°C).
Low quality evidence suggests that defining neutropenia as ANC <0.1 ×109/litre (instead of <0.5 ×109/litre or 1.0 ×109/litre and falling) increases the PPV of neutropenia and fever for bacteraemia, severe infection and adverse events (Apostolopoulou, et al., 2010, Ha et al., 2010, Hakim, et al., 2010, Klassen, et al., 2000, Santolaya et al., 2001 and Tezcan, et al., 2006). Again the effect of this change on NPV was not estimable but would probably decrease NPV.
There was low quality evidence from one paediatric study (West, et al., 2004), that each additional degree in temperature above 38.0°C was associated with a relative increase of 1.74 (95% C.I. 1.25 to 2.43) in the odds of receiving critical care within 24 hours of presentation.
Cost-effectiveness evidence
A literature review of published cost-effectiveness analyses did not identify any relevant papers. Further health economic analysis was not undertaken as the topic was about the definition of neutropenic sepsis and therefore did not lend itself to economic evaluation as there was no comparative analysis of cost and outcomes.
Recommendation
- Diagnose neutropenic sepsis in patients having anticancer treatment whose neutrophil count is 0.5 × 109 per litre or lower and who have either:
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a temperature higher than 38°C or
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other signs or symptoms consistent with clinically significant sepsis.
Linking Evidence to Recommendations
The aim of this topic was to see how the neutrophil count and temperature relate to the risk of complications of sepsis in patients with cancer and suspected neutropenic sepsis.
The GDG considered that outcomes of serious infection, mortality, critical care, clinically documented infection and complications to be the most clinically relevant to the question. Avoiding death or the complications of severe infections, which include the need for admission to a critical care facility, are the main reason for treatment of people with reduced immune function and potential infection. Length of stay was also considered an important outcome but no evidence was found about the relationship between length of stay and the definition of neutropenia or fever.
The GDG noted that there was no evidence available comparing the definitions of neutropenia or fever in cancer patients with possible neutropenic sepsis. They also noted that the evidence probably underestimated the usefulness of neutrophil count and temperature as predictive factors for neutropenic sepsis because the studies are limited to a restricted range of absolute neutrophil count and temperature values. The overall quality of the evidence was low.
The GDG acknowledged that having a very narrow definition of neutropenic sepsis could result in some patients with sepsis being missed and going on to develop life-threatening infection (a poor negative predictive value, NPV). Conversely a broad definition could result in over treatment or unnecessary investigation of patients without such infections (a poor positive predictive value PPV). The GDG recognised that neutropenic sepsis may also present in patients who are unwell together with other constellations of symptoms in the absence of fever (see also section 4.1). In recommending a definition of neutropenic sepsis, the GDG sought an appropriate balance between under and over diagnosis and treatment.
It was the opinion of the GDG that although some patients receiving anticancer treatment who present unwell and are subsequently found to have a neutrophil count above 0.5 × 109/litre will not be categorised as having neutropenic sepsis but will require management of their sepsis.
The GDG noted that no relevant, published economic evaluations had been identified and no additional economic analysis had been undertaken in this area. The opinion of the GDG was that this recommendation would results in a change in practice and that the potential costs of dealing with a patient whose neutropenic sepsis had been missed would be higher than those of a patient without neutropenic sepsis who was over-treated. The GDG agreed that it was higher priority to prevent patients with neutropenic sepsis from developing life- threatening infection and therefore chose to recommend a relatively broad definition, accepting that this could result in some patients without neutropenic sepsis receiving over treatment.
The GDG concluded that neutropenic sepsis should be diagnosed in patients receiving anticancer treatment with a neutrophil count is 0.5 × 109 per litre or lower and a temperature higher than 38°C or with other symptoms and signs consistent with significant sepsis
References
- Ammann RA, Hirt A, Luthy AR, Aebi C. Identification of children presenting with fever in chemotherapy-induced neutropenia at low risk for severe bacterial infection. Med.Pediatr.Oncol. 2003;41:436–443. [PubMed: 14515382]
- Apostolopoulou E, Raftopoulos V, Terzis K, Elefsiniotis I. Infection Probability Score, APACHE II and KARNOFSKY scoring systems as predictors of bloodstream infection onset in hematology-oncology patients. BMC.Infect.Dis. 2010;10(135) [PMC free article: PMC2890000] [PubMed: 20504343]
- Ha YE, Song JH, Kang WK, Peck KR, Chung DR, Kang CI, et al. Clinical factors predicting bacteremia in low-risk febrile neutropenia after anti-cancer chemotherapy. Support.Care Cancer. 2010 [PubMed: 20931237]
- Hakim H, Flynn PM, Srivastava DK, Knapp KM, Li C, Okuma J, et al. Risk prediction in pediatric cancer patients with fever and neutropenia. Pediatr.Infect.Dis.J. 2010;29:53–59. [PubMed: 19996816]
- Klaassen RJ, Goodman TR, Pham B, Doyle JJ. “Low-risk” prediction rule for pediatric oncology patients presenting with fever and neutropenia. J.Clin.Oncol. 2000;18:1012–1019. [PubMed: 10694551]
- Santolaya ME, Alvarez AM, Becker A, Cofre J, Enriquez N, O'Ryan M, et al. Prospective, multicenter evaluation of risk factors associated with invasive bacterial infection in children with cancer, neutropenia, and fever. J.Clin.Oncol. 2001;19:3415–3421. [PubMed: 11454890]
- Tezcan G, Kupesiz A, Ozturk F, Ogunc D, Gultekin M, Yesilipek A, et al. Episodes of fever and neutropenia in children with cancer in a tertiary care medical center in Turkey. Pediatr.Hematol.Oncol. 2006;23:217–229. [PubMed: 16517538]
- West DC, Marcin JP, Mawis R, He J, Nagle A, Dimand R. Children with cancer, fever, and treatment-induced neutropenia: risk factors associated with illness requiring the administration of critical care therapies. Pediatr.Emerg.Care. 2004;20:79–84. [PubMed: 14758303]
- Diagnosis of neutropenic sepsis - Neutropenic Sepsis: Prevention and Management ...Diagnosis of neutropenic sepsis - Neutropenic Sepsis: Prevention and Management of Neutropenic Sepsis in Cancer Patients
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