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Revision as of 16:14, 26 September 2016
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Neutropenia On the Web |
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American Roentgen Ray Society Images of Neutropenia |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Aric Hall, M.D. Beth Israel Deaconess Medical Center, Boston, MA[2] Associate Editor(s)-in-Chief: Faizan Sheraz, M.D. [3]; Daniel A. Gerber, M.D. [4]
Synonyms and keywords: Agranulocytosis, agranulosis, benign familial neutropenia, chronic benign neutropenia, cyclic neutropenia, CN, cyclic hematopoiesis, granulocytopenia, granulopenia, human cyclic neutropenia, neutropaenia, neutrophilic leukopenia, neutrophilic leukocytopenia, neutrophilic leucopenia, neutrophilic leucocytopenia
Neutropenia is defined absolute neutrophil count < 1.5 x 109/L.
Agranulocytosis is defined as severe neutropenia < 0.5 x 109/L.
Although agranulocytosis and granulocytopenia should include reduced numbers of all granulocytes (either neutrophils, eosinophils, or basophils), the majority of cases of granulocytopenia are actually neutropenia since neutrophils constitute the majority of leukocytes; the term granulocytopenia almost always refers to deficient neutrophils. To read about eosinophilic leukopenia and basophilic leukopenia, click here.
Overview
Classification
Pathophysiology
Causes
Epidemiology and Demographics
Diagnosis
Treatment
Asymptomatic, mild to moderate neutropenia can often be monitored closely on an outpatient basis with serial CBCs and evaluation for medications, infections, or alternative sources of neutropenia as described in detail above. Offending medications are often held and the patient is monitored for response to discontinuation while evaluating for alternative, more concerning etiologies. With mild neutropenia, medications can often be reintroduced after neutrophil counts recover as the neutropenia is typically dose-dependent.
Patients who are febrile, acutely ill, or with severe neutropenia often warrant urgent hospitalization for close monitoring and treatment. Offending medications must be discontinued as drug-induced agranulocytosis presents up to a 10% mortality and is very likely to recur if the offending agent is restarted.
Febrile Neutropenia
Diagnosis
In patients with severe neutropenia, the neutrophil-mediated inflammatory process in the setting of infection is often blunted. Fever can be the sole presenting symptom. The risk of infection increases with the degree and duration of neutropenia with prolonged neutropenia defined as >7 days.
Per 2002 IDSA and 2013 ASCO guidelines (PMID 21258094, PMID 23319691), febrile neutropenia requires both of the following criteria:
1) Fever: single oral temperature >38.3 C/101 F or sustained temperature >38 C/100.4 F for 1 hour.
2) Severe neutropenia: ANC< 500 cells/microliter.
Pathogenesis
1) Damage to the immune system and/or mucosal barriers by an underlying malignancy.
2) Damage to the immune system and/or mucosal barriers by chemotherapy.
The majority of cases of neutropenic fever are attributed to chemotherapy-induced mucositis, which permits endogenous bacterial and fungi to seed the bloodstream. Defects in neutrophilic phagocytosis, as well as antibody production, immune complex clearance, and T-cell mediated cytotoxic killing by hematologic malignancies or immunosuppressive chemotherapies predispose to infection by encapsulated and intracellular organisms.
Common pathogens include
Gram-positive bacteria
- Staphylococci (including MRSA; S.epidermidis accounts for 50% of all Gram-positive febrile neutropenia)
- Streptococci
- Enterococci (including VRE)
- Listeria
Gram-negative bacteria
- Enterobacteriaceae (E.coli, Klebsiella, Enterobacter, including ESBL-producers)
- Pseudomonas
- Citrobacter
- Acinetobacter
- Neisseria
- Haemophilus
- Salmonella
Fungi (rare in low-risk patients)
- Candida
- Aspergillus
- Cryptococcus
- Reactivation of endemic fungi (Histoplasma, Blastomyces, Coccidioides)
Anaerobes are less commonly identified, yet can cause intra-abdominal, pelvic, or periodontal infections.
Diagnostic Evaluation
- Targeted history
- Detailed physical exam focusing on: mental status, skin, eyes, mucus membranes and oropharynx, lungs, abdomen, and perineum (digital rectal exam should be avoided in neutropenic patients)
- CBC with differential
- Serum electrolytes, creatinine, liver function tests
- Urinalysis with culture
- Blood cultures including separate cultures from each indwelling catheter
- Cultures from any suspected sites of infection including serum or BAL galactomannan if at increased risk for aspergillosis
- Consider chest radiographs or CT scan of the chest and/or abdomen to detect infiltrates and bowel wall thickening in the appropriate clinical context
Despite prompt and thorough evaluation, a source of infection is identified in less than 1/3 of patients. Bacteremia, present in up to 25%, often serves as the only source of positive culture data (PMID 21258094). As such, rapid risk stratification and appropriate empiric treatment is necessary.
Risk Stratification
Low risk: typically patients with solid tumors on chemotherapy plus the following:
- Anticipated neutropenia (ANC<500 cells/microliter) <7 days
- No significant hepatic or renal dysfunction
- No significant comorbidities**
- MASCC Risk Score >21 (PPV 91%, specificity 68%, sensitivity 71%)
High risk
- Anticipated neutropenia (ANC<500 cells/microliter) >7 days
- Significant hepatic or renal dysfunction
- Significant comorbidities**
- Disease progression
- MASCC Risk Score <21 (PPV 91%, specificity 68%, sensitivity 71%)
**Significant comorbidities:
- Hemodynamic instability
- Mucositis
- GI symptoms
- Acute neurological changes
- Intravascular catheters
- Pulmonary infiltrates or underlying chronic lung disease
Treatment
Resuscitate all patients screening positive for sepsis syndromes per goal-directed therapy. Initiate empiric antibiotics as early as possible after cultures are drawn and within 60 minutes of presentation as there is significantly higher mortality when antibiotic administration is delayed (PMID 4994878, PMID 16625125, PMID 24752269). Initial antibiotic selection should provide broad coverage of the most common, most virulent, and most likely pathogens and should be bactericidal so as not to rely on assistance from the host's impaired immune system. Remove central venous catheters when possible if there is suspicion for infection or with positive blood cultures.
Low risk patients: ANC>100 cells/microliter, normal liver and renal function, normal chest x-ray, no evidence of central line infection, MASCC >21, and duration of neutropenia expected <7 days in a patient with close monitoring and access to medical care.
- Ciprofloxacin 500mg PO BID + amoxicillin/clavulanate 500mg PO TID
High risk patients: hospitalize and initiate empiric parenteral antimicrobial therapy. IDSA guidelines recommend initial monotherapy with:
- Cefepime 2 g IV Q8H
- Meropenem 1 g IV Q8H
- Imipenem/cilastatin 500 mg IV Q6H
- Piperacillin/tazobactam 4.5 g IV Q6H
- Ceftazidime 2 g IV Q8H (recent data shows increasing resistance to ceftazidime and inferior Gram-positive coverage to alternative regimens)
Indications for resistant Gram-positive coverage:
Vancomycin or linezolid is NOT recommended as part of initial treatment unless one of the following is present and, if started, should be discontinued after 2-3 days if there is no evidence of Gram-positive infection:
- Hemodynamic instability
- Suspected catheter-associated infection
- Mucositis or cellulitis
- Pneumonia
- History of MRSA infection or colonization
- Gram-positive bacteremia prior to final culture results
- Recent fluoroquinolone prophylaxis
Alternative regimens:
- Pneumonia: Broaden coverage to include Vancomycin or Linezolid and a macrolide or fluoroquinolone. Consider PJP.
- Diarrhea: Evaluate for C.difficile, treat if positive.
- Sinusitis: Urgent ENT evaluation. Broaden coverage to include invasive fungi.
- Oral ulceration: Consider broadening coverage to include Acyclovir for HSV and/or Fluconazole for Candida.
- BMT: Evaluate for CMV. Consider broadening coverage to include Ganciclovir.
- Hemodynamic instability: Broaden coverage to include resistant Gram-positive, Gram-negative, and anaerobic bacteria and fungi, typically with Vancomycin or Linezolid, a Carbapenem, and Amphotericin, Voriconazole, or Caspofungin.
Persistent Fever
Continue empiric therapy until either culture data is available to direct management or after 3-5 days if the patient fails to improve as the median time to defercescence in adequately treated patients is 5 days with hematologic malignancies and 2-3 days with solid tumors. If the patient is still febrile or develops recurrent fevers after this time period:
- Re-evaluate sources of infection.
- Re-evaluate indications for resistant Gram-positive coverage and consider adding vancomycin or linezolid.
- Re-evaluate indications for resistant Gram-negative organisms and anaerobes and consider broadening to carbepenem antibiotics.
- Consider fungal coverage in high risk patients if fevers persist after 4-7 days of appropriate antibiotic coverage and duration of neutropenia is expected to last >7 days.
- Caspofungin 70 mg IV x 1 dose, then 50mg IV daily. Caspofungin provides excellent coverage for Candida and is well tolerated, however nodular pulmonary infiltrates warrant coverage of Aspergillus with Voriconazole or Amphotericin B as echinocandins do not provide adequate coverage of Aspergillus or endemic fungi.
- Liposomal Amphotericin B 3 mg/kg/day
- Voriconazole 6 mg/kg IV Q12H x 2 doses, then 4 mg/kg IV Q12H
In cases of severe or refractory febrile neutropenia, consider granulocyte colony stimulating factor (G-CSF) to facilitate neutrophil count recovery, however routine use is NOT recommended as it does not reduce duration of fever or mortality despite shortening duration of neutropenia (PMID 21095116).
Duration of Antimicrobials
Documented infection: Continue antimicrobials as directed by culture data. Continue treatment for the standard duration for that particular infection and until myeloid recovery (ANC>500 cells/microliter). If counts recover prior to completing the treatment course, consider transition to an oral regimen guided by culture data.
Negative Cultures: Continue empiric antimicrobial regimen until myeloid recovery (ANC>500 cells/microliter). If afebrile with no evidence of ongoing infection, consider transition to oral regimen (e.g. Ciprofloxacin + Amoxicillin/Clavulanate) and continue until myeloid recovery.