4.1. Signs and symptoms that necessitate referral to secondary/tertiary care

Most people receive anticancer treatments as outpatients. The symptoms and/or signs that might predict the development of neutropenic sepsis often occur in patients in the community.

There is considerable variation in the symptoms and/or signs that may indicate neutropenic sepsis and their interpretation. This leads to patients being given varied information on the criteria for urgent admission to hospital.

Over-diagnosis can result in inappropriate admission to hospital and may delay anticancer treatments. Under-diagnosis or delay in diagnosis can put patients at risk of serious or fatal complications. A clearer understanding of how effective specific signs and/or symptoms are in predicting neutropenic sepsis may improve the experience of patients by reducing unnecessary visits to hospitals but improve the early treatment of serious infections.

Clinical evidence (see also full evidence review)

Study quality and results

There was no direct evidence about signs and symptoms of cancer patients in the community that might predict neutropenic sepsis. The available evidence came from retrospective studies of patients who had presented at hospital with treatment induced neutropenia and fever. This evidence is summarised in Table 4.1. By including only patients with confirmed neutropenia and fever these studies are not a representative spectrum of patients in the community (according to the QUADAS checklist in the NICE Technical Manual 2009). The sensitivity and specificity of symptoms or signs for neutropenic sepsis in the community might differ from that in secondary care. Studies typically reported composite outcomes encompassing severe bacterial infection, death and critical care. For these reasons the evidence is of very low quality.

Table 4.1

Signs and symptoms as predictors of adverse outcome in patients with fever and neutropenia.

Evidence statements

There was uncertainty about which signs and symptoms predict neutropenic sepsis and its complications in cancer patients in the community due to a lack of published evidence.

Chills and altered mental status were associated with adverse outcome in two secondary care studies, but most patients with neutropenic sepsis did not experience either of these symptoms.

4.2. Emergency assessment in secondary/tertiary care

Patients with suspected neutropenic sepsis often present to secondary/tertiary care (local/district general or specialist hospital) by self referral or from primary care.

As part of clinical assessment in hospital, such patients will have a variable series of tests performed according to local practice. These tests may include a physical examination, full blood count, biochemical profile and other blood, urine or imaging investigations. They are performed to predict the risk of complications and identify the underlying cause of the symptoms and signs and thus guide management.

Some of the tests are invasive to the patient, costly to the health service and may not inform clinical management.

4.2.1. Investigations appropriate for clinical management and risk stratification

The majority of protocols for the management of suspected neutropenic sepsis recommend certain laboratory investigations. The function of these is to guide patient management by assessing organ function and determining the risk of adverse clinical complications. These predictive tests include C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and other inflammatory markers. Lactate is routinely used in the management of patients with septic shock, but is not frequently measured at the outset of neutropenic sepsis.

Although the absolute neutrophil count is generally used in clinical management to assess neutropenic sepsis, other white cell counts, such as monocyte count or lymphocyte count may also be measured in order to assess the risk of adverse clinical outcomes.

Tests which enable early identification of patients at higher risk of an adverse outcome may prompt more aggressive management and intensive monitoring with a potential reduction in mortality rates. Tests which accurately predict patients at low, or no, risk of adverse clinical outcome may allow reduced intensity treatment.

Clinical question: Which tests predict outcome and response to treatment in patients with suspected neutropenic sepsis?

Clinical evidence (see also full evidence review)

Study quality and results

There were relatively few studies of tests to predict mortality in patients admitted for fever and neutropenia. There was very limited evidence about CRP, lactate, full blood count, liver function tests or kidney function tests for the prediction of length of hospital stay. Our searches identified no studies of tests to predict the requirement for critical care; however there was some evidence about tests to predict severe sepsis and documented infection. This evidence is summarised in Table 4.2.

Table 4.2

Diagnostic Accuracy for Investigations appropriate for risk stratification and management.

Tests were typically done on admission for fever and neutropenia, before the initiation of antimicrobial therapy. Some studies repeated tests over the first few days of fever, to compare how serum levels of biomarkers changed over time in patients with and without severe infection.

25 of the 42 studies were prospective. It was unclear in 16/42 studies how patients were selected for inclusion (for example whether it was a consecutive or random sample of eligible patients) this is a potential source of bias. Blinding was explicitly used in 6/42 studies.

Evidence statements

Mortality

Lactate, albumin and creatinine levels had reasonable specificity (93%, 88% and 89% respectively) but low sensitivity (53% or less) to predict short term mortality in patients with fever and neutropenia, with only data from a single study for each of these tests. Santolaya, et al., (2007) and Wilbur, et al., (2000) reported blood urea nitrogen (at thresholds of 180 and 260 mg/L respectively) had good specificity (86% to 94%) but moderate to low sensitivity (43% to 69%) to predict short term mortality.

Santolaya, et al., (2007) only reported the sensitivity and specificity of laboratory tests whose results differed significantly between patients who died and survived. In their study ANC, AMC, CRP and BUN differed significantly between the two groups, whereas there was no significant difference between the groups in terms of platelets, creatinine, glycemia or lactate dehydrogenase (LDH).

Length of hospital stay

Pastura, et al., (2004) carried out a prospective study to derive a predictive model for length of hospital stay in children with haematological malignancy, neutropenia and presumed infection. Granulocyte count < 0.1 × 10⁹/L was considered as a predictive factor in this study, but was excluded from the final multivariate model due to lack of statistical significance. Pastura, et al., final predictive model included ill appearance, age ≥6 years, presence of CVC and disease status as relapse.

Critical care and severe sepsis

Ammann, et al., (2010) reported a prospective study of predictive factors for serious medical complications in children with fever and chemotherapy induced neutropenia. Serious medical complications were defined as death, complication requiring intensive care treatment or complication judged as potentially life threatening by the treating doctor. Ammann, et al., (2010) constructed a multivariate risk score for serious complications, by selecting factors (from a list of 31 candidates) significantly associated with serious complications on univariate analysis. Their final model included four predictive factors: chemotherapy more intensive than that used as maintenance therapy for Acute Lymphoblastic Leukaemia, haemoglobin level ≥90 g/L at presentation, leukocyte count <0.3 g/L at presentation and platelet count <50 g/L at presentation.

Five studies (Ahn, et al., 2010; Erten, et al., 2004; Hamalainen, et al., 2008, 2010 and Santolaya, 2008) compared the mean levels of serum CRP at admission in patients who did and did not develop severe sepsis. Although mean serum CRP level was higher in patients who went on to develop severe sepsis (mean difference 45 mg/L higher, 95% C.I. 32 to 58 mg/L higher) there was considerable overlap between the two groups. Hamalainen, et al., (2008, 2010) recorded CRP levels in the days following admission for fever and neutropenia. They observed a widening difference between the serum CRP levels of patients with severe sepsis and others over the first days of fever – from 53 mg/L on admission to 135 mg/L after four days.

Documented infection

Meta-analysis according to cut-off threshold was done for CRP (Table 4.2). In theory sensitivity should decrease and specificity should increase as the CRP threshold is raised, but this was not the case perhaps due to heterogeneity. AMC and ANC were poor predictors of documented infection.

Some studies (Arber, et al., 2000, El-Maghraby, et al., 2007, Engel, et al., 1998 Hitoglou-Hatzi 2005, Katz, et al., 1993, Massaro, et al., 2007, Martinez-Albarran, et al., 2009, Santolaya, et al., 1994, Tezcan, et al., 2006 and Yonemori, et al., 2001) compared the mean levels of serum CRP at admission for fever and neutropenia in those patients who went on to have a documented infection and patients with fever of unknown or viral origin. Mean CRP level was invariably higher in the patients who went on to have a documented infection: mean difference 35 mg/L higher (95% C.I. 26 to 44 mg/L higher). The greatest differences were seen in studies involving children, however there was significant heterogeneity in the results from paediatric studies.

There was a large range of serum CRP levels recorded in those with documented infections and in those with fever of unknown origin with considerable overlap in the distribution of CRP levels in the two groups. Thus it is unlikely that a single CRP threshold could achieve acceptable sensitivity and specificity for the prediction of documented infection.

Cost-effectiveness evidence

A literature review of published cost-effectiveness analyses did not identify any relevant papers. The topic focused on the identification of patients at high risk of an adverse outcome. However management of these patients was beyond the scope of the guideline, as they would be managed by intensive/critical care units. Therefore further health economic analysis was not undertaken

Recommendation

• Include in the initial clinical assessment of patients with suspected neutropenic sepsis:

  -

  history and examination

  -

  full blood count, kidney and liver function tests (including albumin), C-reactive protein, lactate and blood culture (see also recommendations in section 4.2.2).

Linking Evidence to Recommendations

The aim of this topic was to identify which tests can predict the risk of adverse clinical complications in patients with suspected neutropenic sepsis, thereby guiding clinical management

The GDG considered the outcomes of mortality, documented infection and length of stay to be the most important outcomes to the question. However the evidence on both mortality and length of stay was limited. No evidence was found for the outcome of critical care; however studies reported on the ability of tests to predict severe sepsis (a composite outcome including septic shock (and its related complications), prolonged fever or death). The GDG agreed to use severe sepsis as a proxy for critical care.

The overall quality of the evidence was low and the number of studies reporting the effectiveness of each test was small. The GDG agreed, based on clinical experience that examining the patient and performing a full blood count, kidney and liver function tests and blood culture provided useful information in identifying patients at high risk of complications. The GDG also noted that the evidence indicated that raised levels of lactate, and to a lesser extent CRP, were suggestive of a patient being at increased risk of severe sepsis.

The GDG noted that no relevant, published economic evaluations had been identified and no additional economic analysis had been undertaken in this area. However it was the opinion of the GDG that recommending patient examination, full blood count, liver and kidney function tests, CRP, and blood culture was unlikely to represent an additional cost because these tests were already in common use in this group of patients. The GDG also agreed that whilst lactate testing was not in common use, the benefit provided in terms of early identification of patients at high risk of complications outweighed the minimal costs associated with undertaking this test.

The GDG therefore decided to recommend examining the patient and performing a full blood count, liver and kidney function tests, CRP, lactate and blood culture to assess patients with suspected neutropenic sepsis. The GDG agreed to specifically recommend albumin as part of the liver function tests because albumin is not reported by some laboratories in the ‘liver function test’ panel and the evidence had shown it was effective.

4.2.2. Further assessment

Certain additional investigations may be undertaken to determine the underlying cause of the sepsis to guide management of specific infections. These tests include peripheral blood culture, chest x-ray and urinalysis.

There is considerable variation in which investigations are performed both between hospital and clinicians. These investigations can be invasive for the patient and expensive to the hospital. Therefore it is useful to identify which investigations are most effective in determining the underlying cause of the sepsis.

Clinical question: Should additional peripheral blood culture (in patients with a central line), CRP (c-reactive protein), urinalysis, chest x-ray, lactate and blood gases be used in the emergency empiric assessment of a person with suspected neutropenic sepsis?

Clinical evidence (see also full evidence review)

Study quality and results

The overall quality of the 38 included observational studies was low, because most did not include a representative spectrum of patients. 32/38 of the studies included only patients with confirmed neutropenia and fever, a subset of the relevant population of patients presenting with fever where neutropenia is suspected but not yet confirmed. The accuracy of tests in the emergency department setting could be different from that reported in the included studies.

Only 2/38 studies were carried out in emergency departments: Ha, et al., 2010 (but including only low risk patients – MASCC ≥21) and Moon, et al., (2009).

Evidence statements

The evidence is summarised in Table 4.3.

Table 4.3

Chest X-ray and additional peripheral blood cultures in the emergency assessment of patients with suspected neutropenic sepsis.

Chest X-ray

Diagnosis of sepsis

Chest X-ray had a high sensitivity for bacterial pneumonia in two studies (Oude Nihuis, et al., 2003 and Renoult, et al., 2004), all cases of bacterial pneumonia were evident on the chest X-ray. A systematic review of the clinical features of radiographic pneumonia in children with fever and neutropenia (Phillips, et al,, 2011), identified 4 studies with 278 patients. The prevalence of pneumonia was 5% and Philips, et al., (2011) estimated that symptoms of respiratory distress had a negative predictive value of 98% (95% C.I. 96% to 99%). The probability of pneumonia in a child without respiratory symptoms was 1.9%.

In five studies, chest X-ray had widely varying sensitivity and specificity for severe sepsis or its complications (Badiei, et al., 2011, Chayakulkeeree, et al., 2003, Klastersky, et al., 2000, Moon, et al., 2009, and Wilbur, et al., 2000). Moon, et al., (2009) considered the use of chest X-ray in the emergency department to predict complicated fever in patients presenting with fever and neutropenia. In this study chest X-ray had a high positive likelihood ratio of 20.26 for complicated fever – a positive chest X-ray increased the odds of complicated fever by a factor of 20.

Clinical value of test

Two studies considered the influence of chest X-ray on clinical management (Oude Nihuis, et al., 2003 and Renoult, et al., 2004). Both concluded that the results of chest X-ray did not influence the choice of antibiotic treatment.

Time to diagnosis or initiation of treatment

None of the included studies reported this outcome.

Peripheral blood culture (in patients with a central line)

Diagnosis of sepsis

Scheienmann, et al., (2010) found that peripheral blood cultures were positive in some cases where central cultures were not. In their series of 228 episodes of bacteraemia the peripheral blood culture was the only positive culture in 28 cases. Thus doing both peripheral blood cultures and central cultures could improve sensitivity for the detection of bacteraemia.

Blot, et al., (1998) reported that in patients where both central venous and peripheral blood cultures were positive the differential time to positivity (DPT) could help indicate catheter related sepsis. Earlier positivity of the central venous culture of two or more hours, when compared to the peripheral culture, increased the odds of catheter-related sepsis by three times.

Clinical value of test

There was no direct evidence about the influence of peripheral blood cultures on clinical management decisions. However, Scheienmann, et al., (2010) surveyed Canadian healthcare professionals about their attitudes to obtaining peripheral blood cultures. The main reason given by the healthcare professionals for not obtaining peripheral blood cultures was that they do not provide any additional information and that phlebotomy is associated with a risk of complications

Time to diagnosis or initiation of treatment

None of the included studies reported this outcome.

CRP, lactate and blood gases

Evidence for these tests was reviewed in section 4.2.1.

Urinalysis

Diagnostic accuracy

Moon, et al., (2009) reported a positive test for urine nitrates had sensitivity of 5% and specificity of 90% for complications of neutropenic sepsis. Thus a positive test was unlikely both in those with and without complications. Other studies mentioned using urinalysis in their initial assessment of patients with suspected neutropenic sepsis (for example Katz, et al., 1992) but did not report its results.

Clinical value of test, time to diagnosis or initiation of treatment

The influence of urinalysis on treatment decisions, time to diagnosis or initiation of treatment was not reported.

Cost-effectiveness evidence

A literature review of published cost-effectiveness analyses did not identify any relevant papers. This was considered an important topic because doing an initial assessment could avoid over-treatment and guide the subsequent treatment strategy; but it may also cause a delay in treatment and thus increase the risk to the patient. However due to the lack of a clear definition of ‘treatment’ it was not possible to measure the cost of treatment, nor was it possible to define a standard treatment for all patients as this would depend on each patients individual health status. Therefore, further health economic analysis was not undertaken.

Recommendations

• After completing the initial clinical assessment (see recommendations in section 4.2.1), try to identify the underlying cause of the sepsis by carrying out:

  -

  additional peripheral blood culture in patients with a central venous access device if clinically feasible

  -

  urinalysis in all children aged under 5 years.

• Do not perform a chest X-ray unless clinically indicated.

Linking Evidence to Recommendations

The aim of this topic was to identify the value of additional investigations in identifying the underlying cause of the sepsis

The GDG considered that the outcomes of time to diagnosis or initiation of treatment together with the diagnostic accuracy and clinical value of each test to be the most relevant to the question. No evidence was reported for time to diagnosis or initiation of treatment. Evidence was reported for the diagnostic accuracy and clinical value of each test.

The GDG acknowledged that the available data was indirect because the population in the evidence was mostly patients with proven neutropenic sepsis, rather than suspected neutropenic sepsis. Therefore the values of the tests were likely to be exaggerated compared to their value in the larger population of patients with suspected neutropenic sepsis. In order to extrapolate this data to the population of interest the GDG decided to assume that the clinical utility of different tests would be less than reported in the evidence.

The overall quality of the evidence addressing CRP and peripheral blood culture was of low quality, and of low quality or non-existent in relation to the other tests.

The GDG recognised that a chest x-ray may be relevant in certain clinical situations but concluded that the evidence did not show that routine use in the initial assessment resulted in a change to the immediate management of a patient and therefore recommended that it is not performed unless clinically indicated.

The GDG unanimously agreed that despite the low quality of the evidence a blood culture should be performed due to the potential effect the results may have on a patient's subsequent management. The GDG recognised that undertaking venepuncture for peripheral blood cultures may be an unpleasant experience, particularly in children, and may delay commencing antimicrobial treatment. They also noted that the quality of evidence for the additional value of peripheral blood cultures was low. Consequently the GDG decided to recommend that in patients with central venous access devices an additional peripheral venous culture should be taken if clinically feasible.

The GDG noted that in their clinical experience, children under the age of 5 are not always able to verbalise their symptoms and agreed that performing urinalysis would pick up any urinary tract infections, which would require specific treatment.

The GDG noted that the tests of lactate and CRP are already recommended as part of the initial clinical assessment of a patient (Section 4.2.1).

The GDG acknowledged that as a result of recommending a reduced number of tests as part of the initial assessment, there is a potential risk of missing the underlying cause of the infection. However the GDG felt that this risk was minimal and that reducing the number of tests would reduce the investigative burden on patients and simplify the investigative pathway.

The GDG noted that no relevant, published economic evaluations had been identified and no additional economic analysis had been undertaken in this area. The GDG considered based in their clinical experience that there may be potential cost savings as a result of the reduced investigations.

Therefore the GDG decided to recommend that the additional investigations of peripheral blood culture and urinalysis in children should be performed, as part of the initial assessment of a patient with suspected neutropenic sepsis. They have also recommended not performing a chest x-ray unless clinically indicated.

4.3. Assessing the patient's risk of septic complications

Many patients treated for neutropenic sepsis are found not to have either clinical or microbiologically proven infection. These patients are at low risk of serious adverse outcomes and may be suitable for either outpatient management from the outset or for early discharge after a period of inpatient observation and investigation (a “step-down” approach).

The ideal stratification system would accurately identify a group of low risk patients with no risk of mortality from sepsis, would be simple to use by healthcare professionals without specific oncology or haematology experience, and use clinical features and laboratory tests which are widely available and inexpensive. There are a number of stratification or “early warning” scoring systems used in both general paediatric and adult practice which may be useful in supporting a step-down approach.

There is no single system in widespread use in either adult or paediatric practice and there are considerable variations in whether a system is used and which one. A simple, reliable and safe system has the potential to significantly reduce hospitalisation without increasing adverse clinical outcomes

Clinical evidence (see also full evidence review)

Study quality and results

Eight prospective or retrospective observational studies were identified that validated the Multinational Association of Supportive Care in Cancer (MASCC) risk index (Baskaran, et al., 2008; De Souza Viana, et al., 2008; Innes, et al., 2008; Ahn, et al., 2010; Uys, et al., 2007; Klastersky, et al., 2006; Hui, et al., 2010 and Cherif, et al., 2006). These papers provided data on the sensitivity and specificity of this risk score in determining which adult patients presenting with neutropenia and fever, were at low risk of developing ‘serious medical complications’. There was no specific evidence on ‘early warning signs’ in neutropenic sepsis.

Phillips, et al., (2010) presented a systematic review of the discriminatory performance of risk prediction rules in febrile neutropenic episodes in children and young people. Only six of the twenty included studies were prospective, but the studies were at low risk of verification procedure bias and unclear risk of interpretation bias (according to the QUADAS criteria). Three other papers about paediatric clinical decision rules were identified (Dommett, et al., 2009; Ammann, et al., 2010 and Macher, et al., 2010).

The evidence for risk scores evaluated in at least three studies is summarised in Table 4.4. For both paediatric and adult studies there was inconsistency in results, with unexplained heterogeneity so the overall quality of evidence was low.

Table 4.4

Studies of clinical decision rules to identify patients at low risk of adverse outcome in patients with fever and neutropenia.

Evidence statements

Six studies evaluated the Klaassen rule which uses a single feature: an absolute monocyte count of greater than 100/mm³ to predict paediatric patients with significant infection. Sensitivity ranged from 37% to 100% and specificity from 23% to 58%.

Evidence from three studies suggests the Amman rule (Ammann, et al., 2003) to predict paediatric patients at low risk of significant bacterial infection has high sensitivity (95% to 100%) but low specificity (9% to 22%). This means that most patients at low risk of adverse outcome would be labelled as high risk.

The Alexander rule to predict adverse clinical consequences in paediatric patients with fever and neutropenia was evaluated by three studies (Alexander, et al., 2002; Ammann, et al., 2010 and Dommet, et al., 2009). Results were heterogeneous with sensitivity ranging from 59% to 94% and specificity 9% to 65%.

Four studies evaluated the PINDA rule for identification of paediatric patients at low risk of significant bacterial infection. Two South American studies from the rule's authors (Santoloya, et al., 2002 and 2003) showed high sensitivity and specificity, however these findings were not replicated by two European validation studies (Ammann, et al., 2010 and Macher, et al., 2009).

Other paediatric clinical decision rules have been proposed (Phillips, et al., 2010) but are validated by less than three studies.

Eight studies reported the sensitivity and specificity of the MASCC risk score to identify adult patients with neutropenia and fever at low risk of serious medical complications. There was considerable heterogeneity in study results which precluded statistical meta-analysis, but no obvious explanatory factor was identified. The sensitivity of MASCC score < 21 (for the prediction of serious medical complications) ranged between 40% and 80% whilst the specificity ranged between 59% and 95%.

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