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Management and Preventive Measures for Febrile Neutropenia
Febrile neutropenia (FN) is a serious complication often associated with cancer chemotherapy. Bone marrow suppression is the most common dose-limiting toxicity of traditional cytotoxic chemotherapy agents and has also been observed with targeted and immunological therapies. Consequences of FN can include dose reductions, treatment delays, and substantial impact on morbidity and mortality. Findings from a study across inpatient and outpatient care settings demonstrated a 16.8% risk of developing FN during a course of chemotherapy.1 The Infectious Diseases Society of America defines neutropenia as an absolute neutrophil count (ANC) of 500 cells/mm3 or less than 1,000 cells/mm3 with an anticipated decline to less than 500 cells/mm3 within 48 hours.2–5 Others define ANCs of less than 1,000 cells/mm3 or 500 cells/mm3 as moderate or severe neutropenia, respectively. Neutropenic patients are at increased risk of developing serious infections. FN is described by clinical practice guidelines as neutropenia with a single oral or tympanic temperature greater than or equal to 101°F (38.3°C) or greater than or equal to 100.4°F (38°C) for at least one hour.2–5
Neutropenia can result as a consequence of bone marrow injury either due to the cancer itself, chemotherapy and radiation, other underlying disease processes, or a combination of events. The release of endogenous cytokines by epithelial cells can cause fever during neutropenia.6 Barriers and mucosal linings in the body, including those in the gastrointestinal tract and sinuses, provide host defense against pathogens. Damage to the host barriers by chemotherapy and radiation along with potential organism access through central venous lines can lead to microbial invasion.6–7 Because the patient is neutropenic, typical signs and symptoms of infection, such as warmth and swelling, may not be present. Given the sustained inflammatory response with fever resulting from mucosal barrier injury, it is not always clear whether infection is the true underlying cause.6 The infectious etiology will not be determined in most cases; clinically documented infections occur in up to 30% of episodes, with even less microbiologically documented.3
Many patients with FN may have an established or occult infection. Initially, infections tend to be primarily bacterial, but they could be fungal or viral. Common bacterial pathogens in immunocompromised patients include gram-positive bacteria, such as coagulase-negative staphylococci, Staphylococcus aureus, Enterococcus species, and Streptococcus species.3 The use of indwelling catheters has led to higher frequency of gram-positive bacterial infections.3 More recently, drug-resistant gram-negative organisms including Pseudomonas aeruginosa, Acinetobacter species, Stenotrophomonas maltophilia, Escherichia coli, and Klebsiella species have been identified as etiologic agents.8 Fungi such as Candida species or Aspergillus species are more likely encountered after prolonged neutropenia and administration of broad-spectrum antibiotics.3 Subsequent infections may be caused by antibiotic-resistant bacteria, fungi, or viruses.
The consequences of febrile neutropenia are varied; many patients may receive antibiotics and have no further incident, but others may have life-threatening infections.3 At minimum, the resulting chemotherapy dose reductions and delays may impact the curative potential of treatment. In the metastatic setting, data from a retrospective health care claims study of more than 15,000 adults undergoing treatment demonstrated febrile neutropenia occurrence in up to 20%.9 Most were hospitalized, with a median length of stay of 7–7.5 days and mean costs of up to $19,456.9 Therefore, providers attempt to stratify patients at presentation into those at higher risk for infections.3
PATIENT EVALUATION AND RISK ASSESSMENT
Because there is uncertainty about underlying infectious causes and potential clinical severity, several national consensus expert groups provide guidance for the initial risk assessment of patients presenting with FN (
The Multinational Association for Supportive Care in Cancer (MASCC) risk index score was developed to identify patients with FN at low risk of serious medical complications or death.10 The MASCC score uses identifiable characteristics at the onset of FN to predict low risk of complications and the potential for successful outpatient management (
The Clinical Index of Stable Febrile Neutropenia (CISNE) is an emerging prognostic score for predicting serious complications in outpatients with solid tumors and stable FN episodes (
A neutropenic patient presenting with a fever is an oncological emergency and must be treated immediately. Cultures should be drawn, one from each lumen of a central line and one peripheral culture or two peripheral cultures if a central line is not present.3 If clinically indicated, cultures or x-rays may be obtained from other suspected sites of infection. The MASCC score can be used to determine whether a patient is high or low risk. A low-risk patient may potentially be given oral antibiotics for treatment, but inpatient admission and IV antibiotics are indicated for high-risk patients. However, clinical discretion is advised based on the severity of a neutropenic patient’s infection. A short inpatient admission to receive IV antibiotics may be indicated initially even when the patient is deemed low risk. In all cases, treatment should be continued until the ANC is 500 cells/mm3 or greater and the patient is afebrile for at least 48 hours. Otherwise, the choice of antimicrobial therapy and duration should meet standard treatment length for any documented infection (i.e., pneumonia, urinary tract infection) or previous history of resistant organisms.3,5
Low-risk patients can be selected carefully for outpatient antibiotics, but they must be monitored very closely for clinical deterioration and must be located within a reasonable distance to a hospital in case one is needed. First-line options include fluoroquinolone (FQ) monotherapy, such as moxifloxacin or ciprofloxacin in combination with amoxicillin/clavulanic acid or clindamycin in place of amoxicillin/clavulanic acid in penicillin-allergic patients.3,5 If a patient remains febrile for 48 hours, antibiotic coverage should be broadened, and the patient will need to be admitted to the hospital.3
High-risk patients are admitted and will need to receive an antipseudomonal beta-lactam agent, such as cefepime, piperacillin-tazobactam, meropenem, or imipenem-cilastatin.3,5 Institutional susceptibility patterns should be considered when selecting therapy. Pseudomonas is a main target during initial empiric therapy. Empiric coverage specifically directed at gram-positive organisms is not routinely recommended unless there is an underlying clinical indication.3,5 Vancomycin is recommended as empiric treatment for specific indications, including skin/soft tissue infections, pneumonia, catheter-related infections, or hemo-dynamically unstable patients.3 If vancomycin was initiated and no bacterial indication has been documented within three days, it should be discontinued.3,5 Coagulase-negative staphylococci are the most commonly identified cause of bacteremia in neutropenic patients and typically do not cause rapid deterioration, so more serious gram-negative pathogens are targeted.3 In patients who do not respond to the initial therapy, antimicrobial coverage should be broadened to include resistant gram-negative/positive pathogens, anaerobic bacteria, and fungi (
Empiric antifungal treatment should also be considered if a patient has a persistent fever for four days after initiation of therapy.3,5 If the patient presented to the hospital without antifungal prophylaxis, then Candida is likely and can be treated with fluconazole. However, patients who required fungal prophylaxis and then experienced FN are at risk for fluconazole-resistant fungi (C. krusei or C. glabrata) or an invasive mold infection (Aspergillus). If a resistant Candida strain is suspected, then an echinocandin, such as caspofungin, is recommended.3,5 A halo sign on chest computed tomography or a positive galactomannan test may help determine an Aspergillus infection, but a negative galactomannan test is not diagnostic due to low sensitivity. If Aspergillus is suspected, voriconazole would be an appropriate choice for empiric therapy, with escalation to amphotericin B if needed.5
In addition to antibiotics, a myeloid growth factor (MGF) regimen may be part of a treatment plan for select patients; several agents, including a biosimilar, are on the market (
Preventive measures for infection are taken in cancer patients; hand washing is the single most important nonpharmacological step. Other options may include antimicrobials directed toward bacterial, viral, and fungal pathogen prophylaxis or stimulation of neutrophil production via MGF. The decision to initiate prophylactic antimicrobials is based on the individual’s risk of infection, which is elevated if a patient is expected to have profound neutropenia (defined as an ANC of 100 cells/mm3 or less for more than seven days) or anticipated neutropenia for more than 10 days.3,5 To determine the likelihood of profound neutropenia, it is important to consider the type of malignancy and which medications are used. Hematologic malignancies inherently will cause prolonged neutropenia due to both the effects of the malignancy on the bone marrow in addition to myelosuppresive chemotherapy. Patients receiving a bone marrow transplant (BMT) require more specialized antimicrobial prophylaxis, and solid tumor malignancies may cause neutropenia if they spread to the bone marrow or if the patient receives intensive myelosuppresive chemotherapy. Once prophylaxis is initiated, it will be maintained until the patient is no longer neutropenic and started again if indicated.5
Antibacterial prophylaxis has caused substantial reductions in infection-related mortality in neutropenic patients and is recommended for high-risk patients as noted above.5,18 Results from a meta-analysis of 52 trials of neutropenic patients with primarily hematologic malignancies demonstrated the efficacy of FQs in prevention of bacterial infections without breeding resistant organisms.18 Levofloxacin is the recommended FQ based on national guidelines.5 Levofloxacin at high doses (500–750 mg) has a broader scope of coverage, in comparison to ciprofloxacin or moxifloxacin, by covering pseudomonas, other gram-negative rods, and some gram-positive pathogens (including streptococci).5,19 In patients unable to take an FQ, trimethoprim/sulfamethoxazole (TMP/SMX) or a third-generation cephalosporin may be used.5
Viral prophylaxis with acyclovir is indicated in patients who are herpes simplex virus seropositive and likely to be neutropenic due to a risk of viral reactivation.5 In addition, patients who required treatment for a viral illness during prior therapy will require viral prophylaxis.5 Patients undergoing hematopoietic stem cell transplantation (HSCT) will have different needs for viral prophylaxis due to an increased risk for varicella zoster activation with the prolonged immunosuppression associated with treatment. For example, in the HSCT setting, acyclovir dosing is 800 mg by mouth twice a day (rather than 400 mg) and is continued until one year post-transplant or until immunosuppression is complete.20
Fungal prophylaxis is also indicated for patients at high risk for profound neutropenia, but differs in agents based on coverage for Candida or Aspergillus. Fluconazole is effective at decreasing fungal-related infections due to Candida, although other triazoles or echinocandins are alternatives.3,5 Patients with acute myeloid leukemia or myelodysplastic syndrome who are receiving chemotherapy are at an increased risk of invasive Aspergillus infections, and posaconazole has prevented more fungal infections and increased overall survival in this population.21 In other populations, such as HSCT patients, Aspergillus prophylaxis is not recommended unless patients have had a prior occurrence.3
MGFs prevent the risk of FN by boosting the patient’s immune system, increasing production of neutrophils to combat the myelosuppresive effects of chemotherapy. Common chemotherapy regimens are believed to cause profound neutropenia, and the addition of an MGF may be recommended with these regimens. As a general recommendation, if FN risk is 20% or greater with a chemotherapy regimen, an MGF should be used.17 Examples of chemotherapy regimens with greater than 20% risk include dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin), dose-dense AC with T (doxorubicin, cyclophosphamide, followed by paclitaxel), hyperCVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone), VIP (etoposide, ifosfamide, cisplatin), and dose-dense MVAC (methotrexate, vinblastine, doxoruvicin, cisplatin).17 FN risk between 10% and 20% is deemed intermediate risk, and MGF use is determined by provider preference based on individual patient risk factors, such as age, coexisting conditions, and prior chemotherapy.17 Chemotherapy regimens for acute leukemia are highly myelosuppresive; however, use of MGF in these populations is limited to specific protocols and circumstances. There is concern about promoting the growth of malignant cells being produced within the bone marrow. In addition, the timing of MGF administration may confound results of bone marrow biopsy interpretation.22
Allogeneic HSCT patients have a more complex regimen of antimicrobial prophylaxis due the removal of the host immune system and prolonged immunosuppression correlated with graft-versus-host disease. Viral prophylaxis is maintained for longer periods and at higher doses. Unlike other malignancies, allogeneic BMT patients have a high risk of cytomegalovirus (CMV) infections during the early post-engraftment phase and will require treatment if CMV-seropositive with valganciclovir.5 There is an increased risk of encapsulated organism infection in BMT patients after day 30, and up to one year post-transplant. TMP/SMX is used as a first-line therapy for encapsulated organism prevention, with dapsone and pentamidine as alternative therapies.23 Fungal prevention with fluconazole will be continued until immunosuppression treatments are completed. Ultimately, patients receiving HSCT will be on more prophylactic medications and have a longer duration of therapy compared with patients receiving conventional chemotherapy.
Febrile neutropenia is a life-threatening complication often associated with cytotoxic chemotherapy and malignancies that has a significant impact on morbidity and mortality. Utilizing the MASCC and CISNE risk criteria enables health care providers to categorize a patient’s risk for serious medical complications from infections. A patient is either high or low risk, which dictates initial therapy using an oral FQ for outpatient treatment or an IV antipseudomonal beta-lactam agent. Following guideline recommendations and studies published on FN management, empiric treatment may be broadened or narrowed as clinically indicated. Ultimately, it is important to know whether a patient is expected to be at high risk for developing FN or has a history of FN, as prophylactic measures can be taken. Understanding FN and the process of treating or preventing FN in the immunosuppressed population is an important step toward improving patient outcomes.
Risk Assessment for Patients with Febrile Neutropenia
|Low Risk (no high-risk factors and most of the following):||High Risk (any factor listed below):|
aHypotension, pneumonia, new-onset abdominal pain, or neurological changes (as specified by the Infectious Diseases Society of America).
bLeukemia not in complete remission or patients without leukemia with evidence of disease progression after more than two courses of chemotherapy.
CrCl = creatinine clearance; ECOG = Eastern Cooperative Oncology Group; HSCT = hematopoietic stem cell transplantation; MASCC = Multinational Association for Supportive Care in Cancer; ULN = upper limit of normal.
The Multinational Association For Supportive Care in Cancer Risk Index
|Burden of illness|
|• No or mild symptoms||5|
|• Moderate symptoms||3|
|No chronic obstructive pulmonary disease||4|
|Solid tumor or hematologic malignancy with no previous fungal infection||4|
|Adult age < 60 years||2|
The Clinical Index of Stable Febrile Neutropenia Score
|Performance status ≥ 2 (Eastern Cooperative Oncology Group)||2|
|Chronic obstructive pulmonary disease||1|
|Chronic cardiovascular disease||1|
|Grade ≥ 2 mucositis (National Cancer Institute)||1|
|Monocytes < 200 per mcL||1|
Treatment Options for Resistant Pathogens
||Vancomycin, linezolid, daptomycin|
|Extended spectrum beta-lactamases||Carbapenems (meropenem)|
FDA-Approved Myeloid Growth Factors
|Product||How Supplied and Administered|
|Filgrastim (Neupogen, Amgen)||Vial and prefilled syringe; IV infusion or SC injection|
|Filgrastim-sndz (Zarxio, Sandoz)
||Prefilled syringe; SC injection|
|Tbo-filgrastim (Granix, Cephalon)||Prefilled syringe; SC injection|
|Pegfilgrastim (Neulasta, Amgen)||Prefilled syringe and on-body injector; SC injection|
|Sargramostim (Leukine, Partner Therapeutics)||Vial; IV infusion or SC injection|
*Biosimilar to Neupogen.
FDA = Food and Drug Administration; IV = intravenous; SC = subcutaneous.
- Weycker D, Barron R, Kartashov A, et al. Incidence, treatment, and consequences of chemotherapy-induced febrile neutropenia in the inpatient and outpatient settings. J Oncol Pharm Practice 2014;20:190–198.
- 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;31:794–810.
- Freifeld AG, Bow AJ, 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–e93.
- Klastersky J, deNaurois J, Rolston K, et al. Management of febrile neutropaenia: ESMO clinical practice guidelines. Ann Oncol 2016;27;(suppl 5):v111–v118.
- National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology. Prevention and treatment of cancer-related infections. v. 2.2017 Available at: www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed September 28, 2017
- van der Velden WJ, Herbers AH, Netea MG, Blijlevens NM. Mucosal barrier injury, fever and infection in neutropenic patients with cancer: introducing the paradigm febrile mucositis. Br J Haematol 2014;167;(4):441–452.
- Wenneras C, Hagberg L, Andersson R, et al. Distinct inflammatory mediator patterns characterize infectious and sterile systemic inflammation in febrile neutropenic hematology patients. PLoS One 2014;9;(3):e92319
- Alp S, Akova M. Management of febrile neutropenia in the era of bacterial resistance. Ther Adv Infect Dis 2013;1:37–43.
- Weycker D, Li X, Edelsberg J, et al. Risk and consequences of chemotherapy-induced febrile neutropenia in patients with metastatic solid tumors. J Oncol Pract 2015;11;(1):47–54.
- 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 patients. J Clin Oncol 2000;18;(16):3038–3051.
- Klastersky J, Paesmans M. The multinational association for supportive care in cancer (MASCC) risk index score: 10 years of use for identifying low-risk febrile neutropenic cancer patients. Support Care Cancer 2013;21:1487–1495.
- Carmona-Bayonas A, Gomez J, Gonzalez-Billalabeitia E, et al. Prognostic evaluation of febrile neutropenia in apparently stable adult cancer patients. Br J Cancer 2011;105:612–617.
- Carmona-Bayonas A, Jimenez-Fonseca P, Virizuela Echaburu J, et al. Prediction of serious complications in patients with seemingly stable febrile neutropenia: validation of the clinical index of stable febrile neutropenia in a prospective cohort of patients from the FINITE study. J Clin Oncol 2015;33;(5):465–471.
- Coyne C, Le V, Brennan JJ, et al. Application of the MASCC and CISNE risk-stratification scores to identify low-risk febrile neutropenic patients in the emergency department. Ann Emerg Med 2017;69;(6):755–764.
- Facts and Comparisons eAnswers Indianapolis, Indiana: Wolters Kluwer Clinical Drug Information [subscription required]. Available at: www.wolterskluwercdi.com/facts-comparisons-online. Accessed September 28, 2017
- Clark OA, Lyman GH, Castro AA, et al. Colony-stimulating factors for chemotherapy-induced febrile neutropenia: a meta-analysis of randomized controlled trials. J Clin Oncol 2005;23:4198–4214.
- National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology. Myeloid growth factors. v. 1.2017 Available at: www.nccn.org/professionals/physician_gls/pdf/myeloid_growth.pdf. Accessed September 28, 2017
- Gafter-Gvili A, Paul M, Fraser A, et al. Effect of quinolone prophylaxis in afebrile neutropenic patients on microbial resistance: systematic review and meta-analysis. J Antimicrob Chemother 2007;59:5–22.
- Bucaneve G, Micozzi A, Menichetti F, et al. Levofloxacin to prevent bacterial infection in patients with cancer and neutropenia. N Engl J Med 2013;368:1131–1139.
- Tomblyn M, Chiller T, Einsele H, et al. Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective. Biol Blood Marrow Transplant 2009;15:1143–1238.
- Cornely OA, Maertens J, Winston DJ, et al. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med 2007;356:348–359.
- National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology. Acute lymphoblastic leukemia. v.2.2017 Available at: www.nccn.org/professionals/physician_gls/pdf/all.pdf. Accessed September 28, 2017
- Bennett CL, Djulbegovic B, Norris LB. Colony-stimulating factors for febrile neutropenia during cancer therapy. N Engl J Med 2013;368:1131–1139.