Neutropenia

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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]

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

Neutropenia is defined as an abnormally low absolute number of neutrophils - mature granulocytes - in the blood. Neutrophils serve as one of the body's primary defenses against bacterial, fungal, and viral infections. Some patients, such as those with constitutional/benign ethnic neutropenia, suffer relatively few complications, however neutropenia related to cytotoxic chemotherapy, hematopoietic stem cell transplant, or other causes of bone marrow suppression may present as a medical emergency.

neutropenia

neutropenia

neutropenia

neutropenia

Classification

Calculated based on blood count differential, neutropenia is defined as an absolute neutrophil count (ANC) less than 1,500 cells per microliter and is calculated by multiplying the total white blood cell (WBC) count by the percentage of neutrophils (including both mature neutrophils and band forms).

Neutropenia is typically sub-categorized as:

- Mild: ANC 1,000-1500 cells/microliter

- Moderate: ANC 500-1000 cells/microliter

- Severe (Agranulocytosis): ANC <500 cells/microliter

Pathophysiology

Neutropenia develops as a result of one of the three following mechanisms:

1) Impaired granulocyte production

- Hematologic malignancy with bone marrow infiltration

- Myelosuppressive chemotherapy or other medications that are toxic to the bone marrow

- Nutritional deficiencies

2) Margination (process where free flowing blood cells exit circulation)

- Splenic sequestration

- Adherence to the vascular endothelium

3) Peripheral destruction

- Autoimmune hemolysis

- Drug-induced hemolysis

Causes

The most common etiologies are constitutional or benign ethnic neutropenia (BEN) and drug-induced neutropenia.

BEN is more often seen in blacks, Yemenites, West Indians, and Arab Jordanians with up to 4.5% prevalence in these populations (PMID 17404350). In these individuals, a mutation in the Duffy antigen gene - a gene which encodes a red blood cell receptor used by malaria to enter these cells - both confers a protective effect against this parasite and, for unclear reasons, lowers the circulating neutrophil count. While quite common, the neutropenia is typically mild (ANC 1,000-1500 cells/microliter) and does not predispose to increased risk of infection or increased risk of febrile neutropenia in the setting of chemotherapy as these individuals have normal bone marrow neutrophil reserves (PMID 3181399, PMID 4027348, PMID 20194862).

Malignancy is often associated with neutropenia, due to impaired production from myelodysplastic syndromes and hematological malignancies with bone marrow infiltration, hemolysis and impaired production from cytotoxic chemotherapy, and antibody-mediated destruction of neutrophils.

Alternative etiologies include post-infectious neutropenia resulting from bacterial, fungal, or viral infections. While bacterial infections typically cause leukocytosis, Salmonella and Shigella enteritis, brucellosis, tularemia, tuberculosis, and rickettsial diseases such as Rocky Mountain Spotted Fever (RMSF) can present with neutropenia. Parasitic diseases with neutropenia include Leishmaniasis with hemolysis and splenic sequestration and malaria due to hyper-reactive malarial splenomegaly (HMS). Viral etiologies include HIV, EBV, CMV, HHV-6, viral hepatitis, dengue, yellow fever, and common childhood exanthematous viruses including measles, varicella, and rubella where ANC nadirs around the time of the onset of rash.

Immunodeficiencies are frequently associated with neutropenia (38% in Hyper IgM syndrome, 12% in CVID, and 7% in X-linked agammaglobulinemia) as are autoimmune disorders including up to 50% of patients with systemic lupus erythematosus, yet with lower overall prevalence. While rheumatoid arthritis infrequently presents with neutropenia, severe neutropenia can develop in the setting of large granular lymphocyte (LGL) leukemia or Felty syndrome (PMID 6979979).

Finally, nutritional deficiencies resulting in neutropenia are typically attributed to vitamin B12, folate, and copper and are related to inadequate dietary intake, pernicious anemia, bariatric surgery, and malabsorptive syndromes.

Epidemiology and Demographics

Neutropenia is typically identified in at-risk patients undergoing cytotoxic chemotherapy or on other myelosuppressive medications. As noted above, some ethnicities have an unusually high prevalence of incidentally identified mild neutropenia, also termed constitutional or benign ethnic neutropenia (BEN). This is most common in blacks, Yemenites, West Indians, and Arab Jordanians and is suggested to be caused by a mutation in the Duffy antigen on red blood cells that helps to confer resistance to malaria. As the name suggests, these cases are typically mild and do not result in immunosuppression.

Diagnosis

History

History should focus on symptoms suggestive of malignancy or infections, patient or family history of autoimmune or immunodeficiency disorders, risk factors for infections including HIV and hepatitis, and any unusual dietary practices or history of bariatric surgery. Medications should be reviewed with particular attention to chemotherapeutics, antibiotics, antiepileptics, and psychoactive drugs as well as documenting any new medications started within the preceding few months.

Physical Exam

- Vital signs

- Conjunctival and palatal pallor

- Petechiae or purpura

- Mucositis or other oropharyngeal lesions

- Lymphadenopathy

- Focal lung findings

- Abdominal pain or distension

- Splenomegaly

- Joint swelling or deformity

- Neurological abnormalities

Laboratory Evaluation

- Confirm neutropenia on blood smear and identify any concomitant blood cell abnormalities.

- If etiology is unclear and depending on the clinical scenario, consider checking antinuclear antibody (ANA), anti-double-stranded DNA (anti-dsDNA), complement levels (C3 and C4), erythrocytes sedimentation rate (ESR), C-reactive protein (CRP), and urinalysis.

- Check vitamin B12, folate, and copper levels if there is concern for nutritional deficiencies.

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, 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, 16625125, 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 chest radiograph, normal liver and renal function, no evidence of central line infection, MASCC >21, and neutropenia expected to last <7 days) with close monitoring and access to medical care can consider outpatient treatment with: - Ciprofloxacin 500mg PO BID + amoxicillin/clavulanate 500mg PO TID

High risk patients require hospitalization and parenteral antimicrobial therapy. IDSA guidelines recommend initial monotherapy with: - Cefepime 2g IV Q8H

- Meropenem 1g IV Q8H

- Imipenem/cilastatin 500mg IV Q6H

- Piperacillin/tazobactam 4.5g IV Q6H

- Ceftazidime 2g 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 70mg 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 3mg/kg/day

- Voriconazole 6mg/kg IV Q12H x 2 doses, then 4mg/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: continueantimicrobials as directed by culture data for the standard duration of treatment for the specific infection and until myeloid recovery (ANC>500 cells/microliter). Once counts recover, can consider transition to an oral regimen guided by culture data to complete course of treatment. - Defervescence with negative cultures: continue empiric antimicrobials until ANC>500 cells/microliter. If afebrile withno evidence of infection, can consider transition to oral regimen (e.g. Ciprofloxacin + Amoxicillin/Clavulanate) until myeloid recovery.