Supplemental Online Case Discussion: Febrile Neutropenia

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1 Supplemental Online Case Discussion: Febrile Neutropenia Alison C. Young, Fiona J. Collinson St James s Institute of Oncology, St James s University Hospital, Leeds, West Yorkshire, United Kingdom Case History A 57-year-old woman with a history of rigors at home was admitted acutely 8 days after her third cycle of adjuvant epirubicin and cyclophosphamide chemotherapy for breast cancer. In the 48 hours before admission she developed a cough productive of yellow phlegm and felt increasingly short of breath, particularly on exertion. Past medical history included mild chronic obstructive pulmonary disease (COPD) for which she uses a salbutamol inhaler when required. On admission, vital signs were recorded as temperature 38.8 C, pulse 122 beats per minute, blood pressure 90/60 mmhg, and oxygen saturations 89% on room air. A full blood count revealed hemoglobin count 9.2g/dL; white blood cell, /L; neutrophils, /L; and platelets, /L. Renal function and liver function were all within normal limits and a C-reactive protein was measured at 220 mg/l. Urine dipstick was negative. Management This woman was febrile on day 8 following systemic chemotherapy, which is commonly around the nadir for the neutrophil count after chemotherapy and it should therefore be assumed she was suffering from febrile neutropenia until proven otherwise. The patient s Multinational Association of Supportive Care in Cancer (MASCC) index score was 17 (Table 1), which put her at a high risk of medical complications [1]; therefore, she would need admission for further management of this acute episode. A full history and examination of the patient should be undertaken and further investigations carried out as clinically indicated. It is essential to pay particular regard to any potential focus of infection. Peripheral blood cultures should be taken immediately and empiric intravenous antibiotics should be started, as per local guidelines, without waiting for confirmation of the neutrophil count. Recommended initial antibiotic therapy in a patient such as this would be beta-lactam monotherapy with piperacillin and tazobactam; Figure 1 shows an example of antibiotic guidelines for the management of febrile neutropenia. In England, there is a national target of 1 hour that has been set from the point at which a likely diagnosis of febrile neutropenia is made, based on clinical assessment, to administration of antibiotic therapy [2] (Fig. 2). In a patient such as this with febrile neutropenia, management according to the Sepsis Six, a care bundle that has been shown to be associated with significant mortality reductions when applied within the first hour, should be considered if severe sepsis is suspected (Fig. 1) [3]. In this woman, a sputum culture and chest x-ray would be indicated, because the clinical presentation is suggestive of a likely exacerbation of her known COPD, and as such, it may be appropriate to consider the addition of an antibiotic specifically aimed at covering likely respiratory organisms, such as clarithromycin, depending on local guidelines. Early senior review of the patient is essential, and there should be a low threshold for assessment by the outreach/intensive care team if there is no response to treatment, in particular as this woman is being treated with curative intent. The patient should be regularly reviewed, at least daily. Empiric antibiotic treatment should be altered in light of any positive culture results. If the patient remains clinically unwell despite appropriate management, then consideration of antibiotic modification should be made in line with microbiological advice and local guidelines. Persistent fever, in an otherwise clinically stable or improving patient, is not an indication for changing antibiotics. If, however, the patient responds very well to initial management, with resolving signs and symptoms of infection, and the risk of developing medical complications is reassessed at 48 hours as low by repeat MASCC scoring, then intravenous antibiotics can be switched to oral antibiotics at this time. Once the febrile neutropenia has responded adequately to treatment, demonstrated by resolution of fever, subjective clinical improvement, or normalization of observations, antibiotic treatment can be stopped irrespective of the neutrophil count. Duration of antibiotics should be guided by the clinical situation; in cases in which an organism is isolated, duration of antibiotics should be based on rational treatment durations for the specific documented infection, and in cases in which no organism is isolated, antibiotics should be terminated once the neutrophil count is above /L or all signs and symptoms of infection have resolved irrespective of neutrophil recovery. Blood cultures in patients such as this often yield negative results, and in more than 70% of cases, the infective organism is never identified [4]. Once the febrile neutropenic episode has been treated and the patient has recovered, the balance of risks and benefits of continuing chemotherapy treatment need to be considered. In this patient, who is receiving adjuvant chemotherapy, the benefits to continuing treatment are likely to outweigh the potential risks, but consideration of the addition of growth colony-stimulating factor (GCSF) to reduce the risk of further episodes of febrile neutropenia and to maintain chemotherapy dose intensity should be made.

2 2 Febrile Neutropenia Table 1. MASCC scoring system Burden of febrile neutropenia with no/mild symptoms 5 Systolic blood pressure >90 mmhg 5 No chronic obstructive airway disease 4 Solid tumor or hematological malignancy with no previous fungal infection 4 No dehydration requiring parenteral fluids 3 Burden of febrile neutropenia with moderate symptoms 3 Outpatient status 3 Age <60 years 2 High risk MASCC score 21. Low risk MASCC score >21. Abbreviation: MASCC, Multinational Association of Supportive Care in Cancer. Figure 1. Antibiotic guidelines for the management of febrile neutropenia (Leeds Cancer Centre, United Kingdom). Abbreviations: BP, blood pressure; CVC, central venous catheter; CXR, chest x-ray; temp, temperature; G3/4, grade 3 or 4; LRTI, lower respiratory tract infection; MEWS, Modified Early Warning Score; MRSA, methicillin-resistant Staphylococcus aureus; Pip/Taz, piperacillin and tazobactam. The Oncologist

3 Young, Collinson 3 Figure 2. The Sepsis Six. The Sepsis Six 1. High flow oxygen 2. Blood cultures and consider source 3. Intravenous antibiotics 4. Intravenous fluid resuscitation 5. Check hemoglobin and serial lactates 6. Hourly urine output measurement Discussion Sepsis Definition and Outcomes Fever is a well-recognized complication in neutropenic patients receiving systemic anticancer treatment. Febrile neutropenia is a common oncological emergency and can be defined as a temperature of >38 C with a neutrophil count of < /L in a patient undergoing systemic anticancer treatment, usually chemotherapy [5]. Febrile neutropenia is a significant cause of cancer-related mortality, with increasing deaths attributable over the past 10 years, particularly in those older than 65 years. It is important to note that many of these deaths occur in patients with atypical presentations (e.g., no fever, diarrhea, confusion), and so it is extremely important to empirically treat these patients even in the absence of classic signs of sepsis such as fever. The commonest sites of infection include the respiratory tract, the gastrointestinal tract, and the skin. The National Confidential Enquiry into Patient Outcome and Death (NCEPOD) report on patient deaths within 30 days of systemic anticancer treatment also showed significant variation nationally in England in the care patients received, and reported that the management of febrile neutropenia was unsatisfactory [6]. The number of relevant published guidelines available reflects the importance of appropriate management of febrile neutropenia internationally, including NICE [5], ASCO [7], and ESMO [8]. Risk factors for developing febrile neutropenia in patients receiving systemic anticancer treatment include older age, poorer performance status, advanced stage of disease, and presence of comorbidities, and specific risk is also related to the underlying primary cancer site and specific chemotherapeutic drugs received (and whether colony-stimulating factors were administered) [9]. Mortality from febrile neutropenia has declined with improvement in management but remains significant. Overall mortality rates are approximately 5% in patients with solid tumors but may be as high as 11% in some hematological malignancies, such as acute leukemia. Prognosis is worse in those patients with proven bacteremia, with mortality rates of 18% in gram-negative and 5% in gram-positive bacteremia [8]. Initial Antibiotic Management Standard management of febrile neutropenia includes prompt administration of broad-spectrum antibiotics, tailored as microbiological culture results become available. Early empiric antibiotic use in this patient group is well recognized to be associated with improved outcomes, compared with awaiting positive microbiological culture results [10]. This is due to the potential for infection to progress rapidly and become lifethreatening in patients who are immunocompromised. Over time, there has been an increase in the number of bloodstream gram-positive organisms causing infections, predominantly associated with the introduction of indwelling plastic catheters in the 1980s, with coagulase-negative staphylococci being the most commonly isolated pathogen in this setting. In a significant proportion of patients, however, microbiological cultures are negative and the site and nature of the infection is not identified. Earlier research into febrile neutropenia compared different regimens of empiric broad-spectrum antibiotics and optimized the initial drug regimen recommended. The evidence supports the use of a broad-spectrum antibiotic, which includes antipseudomonal activity. The exact choice of antibiotics will depend on local policy, which relates to local antibiotic susceptibility patterns, the likelihood of potential for infection with multi-drug resistant organisms, the potential site of infection (e.g., presence of indwelling intravenous catheter), the presence of any organ dysfunction, and drug allergies. Routine initial treatment is usually with a single agent, except in complicated cases or those requiring improved gram-positive cover; NICE guidance, for example, recommends β-lactam monotherapy with piperacillin and tazobactam (Tazocin) antibiotic and advises against the use of aminoglycosides as initial therapy in this setting [5]. Indications for adding other antibiotics include the use of vancomycin for patients with indwelling catheters and suspicion of either exit-site infection or signs/symptoms associated with catheter use, the use of aminoglycosides such as gentomicin for high-risk patients (such as in adult leukemia or suspected Pseudomonas aeruginosa infection), and metronidazole when anaerobic coverage is required. The pattern of causative organisms in febrile neutropenia has changed over the years due to the introduction of indwelling vascular access devices in the 1980s, from largely gramnegative organisms to gram-positive skin organisms including Staphylococcus epidermidis, Staphylococcus aureus, and Streptococcus [4]. Rising antibiotic resistance is an important factor when choosing appropriate antibiotic treatment, and local patterns of resistance must always be considered in the treatment of febrile neutropenia. Risk Stratification Febrile neutropenia is now recognized to be a heterogeneous entity, and there are validated methods to stratify patients according to their risk of developing serious medical complications [1, 11], the most widely used being the MASCC score [1] (Table 1). This allows clinicians to assess the risk of complications developing. In low-risk patients (score 21), the risk of serious medical complications is estimated to be 6% and the mortality risk is estimated to be 1% [1]. The frequent homogeneous treatment of all patients with febrile neutropenia means that up to 50% of patients are potentially overtreated and admitted acutely for a significant number of days for intravenous antibiotics. There is good evidence supporting the use of oral antibiotics in this setting [12 14], although caveats in trial design and recruitment have prevented widespread international uptake to date.

4 4 Febrile Neutropenia New Developments As discussed earlier, the NCEPOD report highlighted deficiencies in the management of febrile neutropenia, and the standard of care delivered across the U.K. varied significantly [6]. In particular, it was reported that 1 in 5 hospitals did not have a policy for the emergency admission of patients with systemic anti-cancer treatment (SACT) toxicity, that 42% of patients were admitted to general medicine following an SACT complication rather than to oncology or hematology specialists, that 6% of hospitals had no policy for the management of febrile neutropenia, and that audit of cases of febrile neutropenia was only being carried out in 45% of hospitals for patients with solid tumors and in 51% of hospitals for patients with hematological malignancies. The report also highlighted that some patients delayed seeking medical advice for 24 hours or longer. This report, along with the National Chemotherapy Advisory Group report, [3] has resulted in the development of acute oncology services nationally, as well as the development of specific guidelines for the management of such patients by NICE [5]. Recommendation for the development of specific policies for the management of febrile neutropenia across all National Health Service trusts has been made, and patient education and information about febrile neutropenia, including how and when to contact 24-hour specialist oncology services, was recognized as key to its successful management. This is not a problem unique to the U.K., as highlighted by the development of a clinical guideline for the use of antimicrobial agents in neutropenic patients with cancer by the Infectious Diseases Society of America [4]. Early outpatient management has the potential to reduce exposure to hospital-acquired infections, decrease resource utilization with associated cost savings, and improve patient and family satisfaction. Early outpatient management will, however, only be appropriate for a cohort of low-risk patients, including those who do not have any comorbidities requiring inpatient care, can comply with reviews/medical contact required, live within a certain distance of the hospital, have an appropriate caregiver available, and have access to a telephone and transport to hospital if required, for example, due to deteriorating condition. Patients taking oral antibiotics must also be able to tolerate treatment, for example, not have nausea or vomiting or issues with swallowing or absorption. Strategies will have to be put in place for remote monitoring if low-risk patients are to be managed in the outpatient setting to ensure those who clinically deteriorate are identified quickly and that their care is escalated appropriately. There is also now evidence that primary antibiotic prophylaxis, commonly with a quinolone or cotrimoxazole, reduces the incidence of febrile neutropenia [15], but this clearly needs to be balanced against the risks of antibiotic resistance and potential adverse effects of antibiotic use. In the U.K., for example, NICE recommends the use of prophylactic antibiotics only for patients being treated for acute leukemia, stem cell transplants, or solid tumors where significant and prolonged neutropenia is predicted [5]. The use of prophylactic GCSF to try to moderate the severity and duration of neutropenia has been shown to reduce both the rate of febrile neutropenia and the length of hospital stay [16]; however, its use is only recommended internationally in selected patients with a significant risk of febrile neutropenia [17]. Conclusion Febrile neutropenia requires prompt diagnosis and management with empiric broad-spectrum antibiotic treatment. It is important that all hospitals have specific policies in place for the management of febrile neutropenia so that all patients receive the highest standard of care in a timely fashion. Moving forward, risk stratification tools such as MASCC will be key to avoiding the overtreatment of low-risk patients, ensuring early switch to oral antibiotics where appropriate to facilitate early discharge in carefully selected patients, and also ensure the early appropriate inpatient management of high-risk patients. All patients receiving systemic anticancer treatment should receive written information and education on the signs and symptoms of febrile neutropenia and the importance of seeking medical advice immediately when unwell. Significant numbers of patients developing febrile neutropenia will present to hospitals without specialist cancer centers and, as such, the emerging role of acute oncology teams are likely to play increasingly important roles in optimizing the management of febrile neutropenia both nationally and internationally. References 1. Klastersky J, Paesmans M, Rubenstein EB et al. The Multinational Association for Supportive Care in Cancer risk index: A multinational scoring system for identifying low-risk febrile neutropenic cancer patients. J Clin Oncol 2000;18: National Chemotherapy Advisory Group. Chemotherapy services in England: Ensuring quality and safety. London: Department of Health, 2009: Daniels R, Nutbeam T, McNamara G et al. The sepsis six and the severe sepsis resuscitation bundle: A prospective observational cohort study. Emerg Med J 2011;28: Freifeld AG, Bow EJ, Sepkowitz KA et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis 2011;52:e56 e NICE Guidance. Neutropenic sepsis: Prevention and management in people with cancer. NICE guideline CG151, published Sep Available at 6. Mort D, Lansdown M, Smith N et al. For better, for worse? A review of the care of patients who died within 30 days of receiving systemic anticancer therapy. London: National Confidential Enquiry into Patient Outcome and Death (NCE- POD), 2008: Flowers CR, Seidenfeld J, Bow EJ et al. Antimicrobial prophylaxis and outpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 2013;31: de Naurois J, Novitzky-Basso I, Gill MJ et al. Management of febrile neutropenia: ESMO Clinical Practice Guidelines. Ann Oncol 2010;21(suppl 5):v252 v Lyman GH, Abella E, Pettengell R. Risk factors for febrile neutropenia among patients with cancer receiving chemotherapy: A systematic review. Crit Rev Oncol Hematol 2014;90: Pizzo PA. Management of fever in patients with cancer and treatment-induced neutropenia. N Engl J Med 1993;328: Talcott JA, Finberg R, Mayer RJ et al. The medical course of cancer patients with fever and neutropenia: Clinical identification of a lowrisk subgroup at presentation. Arch Intern Med 1988;148: Kern WV, Cometta A, De Bock R et al. Oral versus intravenous empirical antimicrobial therapy for fever in patients with granulocytopenia who are receiving cancer chemotherapy. International Antimicrobial Therapy Cooperative Group of the European Organization for Research and Treatment of Cancer. N Eng J Med 1999;341: The Oncologist

5 Young, Collinson Freifeld A, Marchigiani D, Walsh T et al. A double-blind comparison of empirical oral and intravenous antibiotic therapy for low-risk febrile patients with neutropenia during cancer chemotherapy. N Eng J Med 1999;341: Vidal L, Ben Dor I, Paul M et al. Oral versus intravenous antibiotic treatment for febrile neutropenia in cancer patients. Cochrane Database Syst Rev 2013;10:CD Gafter-Gvili A, Fraser A, Paul M et al. Antibiotic prophylaxis for bacterial infections in afebrile neutropenic patients following chemotherapy. Cochrane Database Syst Rev 2012;1:CD Cooper KL, Madan J, Whyte S et al. Granulocyte colony-stimulating factors for febrile neutropenia prophylaxis following chemotherapy: Systematic review and meta-analysis. BMC Cancer 2011;11: Aapro MS, Bohlius J, Cameron DA et al update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours. Eur J Cancer 2011;47: