Neutropenia

Etiology and Risk Factors

Neutropenia can be congenital or acquired and results from decreased production, accelerated use or destruction, or a shift of neutrophils from the blood into tissues or the spleen (Norris, 2020).

Causes include (Davoren & Hsu, 2019; Norris, 2020; Pereiras & Arnall, 2026):

• Cancer chemotherapy and radiation
• Idiosyncratic drug reactions, such as clozapine
• Immune-mediated drug reactions in which drugs act as haptens, such as penicillins and propylthiouracil
• Viral infections, the most common infection-related cause
• Overwhelming bacterial sepsis
• Autoimmune disease, including systemic lupus erythematosus and Felty syndrome
• Leukemia, marrow infiltration by tumor, myelodysplastic syndromes, and aplastic anemia
• B12, folate, or copper deficiency
• Hypersplenism
• Congenital neutropenias, including severe congenital neutropenia and cyclic neutropenia

Epidemiology and Clinical Context

Neutropenia is a commonly encountered problem and can arise from many conditions (Davoren & Hsu, 2019). Drug-induced neutropenia is most often associated with cancer chemotherapy, and febrile neutropenia is a key factor limiting the dose of many cytotoxic regimens. Older adults, patients with a high disease burden, poor nutritional or hydration status, or prior cytopenias are at higher risk of drug-induced neutropenia (Norris, 2020).

Copper deficiency is an easily missed cause of combined anemia and neutropenia, particularly after bariatric surgery or with excessive zinc exposure, and may be mistaken for myelodysplastic syndrome (Pereiras & Arnall, 2026). Congenital forms are rare. Cyclic neutropenia is often recognized in early childhood because of recurrent fevers and oral ulcers (Davoren & Hsu, 2019; Norris, 2020).

Pathophysiology

Neutrophils are the first line of defense against bacteria and fungi that live on the skin and in the gastrointestinal tract. They kill ingested organisms with enzymes such as myeloperoxidase and with oxygen free radicals generated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Davoren & Hsu, 2019).

A neutrophil takes nearly 2 weeks to mature from a marrow progenitor but survives less than a day in the blood, and its main work occurs after it leaves the vessel for infected tissue. The circulating count remains stable because the marrow holds a storage pool 5 to 10 times larger than the circulating pool. When that reserve is exhausted or production stops, the blood count can fall within days (Davoren & Hsu, 2019).

Infection risk depends on both the depth and the duration of neutropenia. Bacterial infections from enteric organisms predominate early, especially after chemotherapy, which also damages the gastrointestinal mucosa and opens a route into the bloodstream. Fungal infection becomes more likely when neutropenia lasts more than several days (Chan & Nguyen, 2026; Davoren & Hsu, 2019).

Cyclic neutropenia shows how neutrophil production is regulated. Heterozygous mutations in ELANE, the gene for neutrophil elastase, cause neutrophil counts to fall to near zero for 3 to 5 days about every 3 weeks. The mutant enzyme appears to exaggerate normal negative feedback on myeloblast differentiation and accelerate apoptosis of early progenitors, so the storage pool is inadequate at each trough. Monocyte counts rise as neutrophils fall because the shared progenitor shifts toward the monocyte line (Davoren & Hsu, 2019).

Clinical Manifestations

Common manifestations include (Davoren & Hsu, 2019; Norris, 2020):

• Fever, which may be the only early sign of serious infection
• Malaise and chills
• Stomatitis and oral ulcers
• Gingivitis
• Pharyngitis
• Skin infections, including furunculosis and cellulitis
• Diarrhea
• Cervical lymphadenopathy in cyclic neutropenia

The inflammatory response depends on the cells that are missing. With severe neutropenia, pus, erythema, and localizing signs may be minimal, so serious infection can look deceptively mild (Norris, 2020). Untreated infection can become rapidly fatal, particularly when the ANC is below about 250/μL (Davoren & Hsu, 2019; Norris, 2020).

Diagnostic Evaluation

Immediate Assessment

In a patient with fever and known or suspected neutropenia, obtain vital signs, an ANC, and cultures promptly. Empiric therapy begins immediately after cultures and should not be delayed for culture results (Chan & Nguyen, 2026).

History

Assess:

• Chemotherapy regimen and timing of the last dose
• Prescription and over-the-counter medications
• Recent viral illness
• Autoimmune disease
• Nutritional risk, bariatric surgery, and zinc exposure
• Pattern of recurrent infections, fevers, or mouth ulcers
• Central venous catheter or other device
• Bleeding, bruising, or fatigue suggesting other cytopenias

Laboratory Testing

• CBC with differential: Establishes the ANC (Norris, 2020).
• ANC calculation: Total white blood cell count multiplied by the combined percentage of segmented neutrophils and bands (Chan & Nguyen, 2026).
• Peripheral smear: Distinguishes isolated neutropenia from involvement of other cell lines and identifies blasts or dysplastic changes (Davoren & Hsu, 2019).
• Nutritional studies: B12, folate, and copper when macrocytosis, other cytopenias, or risk factors are present (Pereiras & Arnall, 2026).
• Cultures: Blood cultures and site-directed cultures when fever is present (Chan & Nguyen, 2026).

Febrile Neutropenia Criteria

Febrile neutropenia is defined as (Chan & Nguyen, 2026):

• A single oral temperature of at least 38.3°C (101°F), or a temperature of at least 38.0°C (100.4°F) sustained for 1 hour, and
• An ANC below 500/μL, or below 1000/μL with a predicted decline to below 500/μL within 48 hours

The Multinational Association for Supportive Care in Cancer (MASCC) risk index identifies low-risk patients who may be candidates for outpatient management (Chan & Nguyen, 2026).

Additional Testing

Cyclic neutropenia is documented by serial counts over several weeks. A marrow examined at the nadir shows increased early myeloid precursors that can resemble leukemia, while a marrow examined about 10 days later can appear normal (Davoren & Hsu, 2019).

Expected Findings

Findings that support clinically significant neutropenia include (Chan & Nguyen, 2026; Davoren & Hsu, 2019; Norris, 2020):

• Reduced ANC, with infection risk rising sharply below 500/μL
• Fever or infection with muted local inflammatory findings
• Recurrent oral or skin infection; cyclic neutropenia may show predictable nadirs with reciprocal monocytosis

Differential Diagnosis

Drug-Induced Neutropenia

Chemotherapy suppresses marrow production, while idiosyncratic and immune-mediated reactions occur only in susceptible patients and usually reverse after the drug is stopped (Norris, 2020).

Infection-Related Neutropenia

Viral infections are the most common infectious cause. Overwhelming bacterial sepsis can consume neutrophils faster than the marrow replaces them (Davoren & Hsu, 2019; Norris, 2020). See Sepsis and Septic Shock.

Marrow Failure or Infiltration

Aplastic anemia, leukemia, metastatic tumor, and myelodysplastic syndromes usually affect more than one cell line. Because neutrophils have the shortest life span, neutropenia may appear before anemia becomes severe (Norris, 2020).

Autoimmune Neutropenia

Primary autoimmune neutropenia is a rare, usually benign disorder of young children. Secondary forms occur with systemic lupus erythematosus and Felty syndrome, the combination of rheumatoid arthritis, splenomegaly, and neutropenia (Norris, 2020).

Nutritional Deficiency

Megaloblastic anemia from B12 or folate deficiency and copper deficiency can cause neutropenia along with anemia (Davoren & Hsu, 2019; Pereiras & Arnall, 2026).

Findings That Reduce Diagnostic Probability

Few findings exclude a cause of neutropenia by themselves. The following findings should redirect the evaluation:

• Recovery of the ANC after a viral illness, or after a suspected drug is stopped, supports a transient infectious or drug-related cause rather than a persistent disorder (Norris, 2020).
• Pancytopenia, blasts, or dysplastic cells argue against an isolated drug or viral cause and point toward marrow disease (Davoren & Hsu, 2019; Norris, 2020).
• Macrocytosis with hypersegmented neutrophils suggests B12 or folate deficiency (Davoren & Hsu, 2019).
• A regular pattern of fevers and mouth ulcers about every 3 weeks suggests cyclic neutropenia rather than recurrent unrelated infections (Davoren & Hsu, 2019).

Treatment and Management

Addressing the Cause

Offending drugs are stopped when possible, and idiosyncratic drug reactions typically reverse after discontinuation. Hospitalized patients with severe neutropenia are commonly placed on neutropenic precautions (Norris, 2020). Nutritional deficiencies are replaced, and marrow disorders are treated according to the underlying diagnosis (Davoren & Hsu, 2019; Pereiras & Arnall, 2026).

Febrile Neutropenia

Management includes (Chan & Nguyen, 2026):

• Begin empiric broad-spectrum antibiotics immediately after cultures are obtained.
• Hospitalize patients who do not meet low-risk criteria for parenteral therapy, typically an antipseudomonal β-lactam such as cefepime or meropenem.
• Consider oral outpatient therapy for low-risk patients identified by MASCC scoring.
• Continue empiric therapy until the ANC recovers above 500/μL in patients with negative cultures.
• Add coverage for resistant gram-positive organisms or fungi according to specific criteria and clinical course (Chan & Nguyen, 2026).

Prevention

Prevention strategies include (Chan & Nguyen, 2026):

• Primary prophylaxis with a granulocyte colony-stimulating factor, such as filgrastim or pegfilgrastim, is recommended beginning with the first cycle when a chemotherapy regimen carries a febrile neutropenia risk of 20% or more.
• Colony-stimulating factors shorten the duration of severe neutropenia and reduce the risk of febrile neutropenia.
• Prophylactic fluoroquinolones, preferably levofloxacin, are reserved for patients expected to have an ANC below 1000/μL for more than 7 days (Chan & Nguyen, 2026).

Cyclic Neutropenia

Filgrastim raises the mean neutrophil count at every point in the cycle and shortens the cycle from about 21 to 14 days. Gingivitis is the most noticeably improved problem (Davoren & Hsu, 2019).

Complications and Red Flags

Urgent escalation is required for:

• Fever in a patient receiving chemotherapy
• ANC below 500/μL with any sign of infection
• Hypotension, tachycardia, altered mentation, or other signs of sepsis
• Mucositis or perianal pain in a neutropenic patient
• Infection at a central venous catheter site
• Persistent fever despite empiric antibiotics
• New pancytopenia or blasts on the smear

Clinical Reasoning Priorities

Urgency depends on the depth and duration of neutropenia and the patient’s clinical status. Additional cytopenias, macrocytosis, or abnormal smear findings redirect the evaluation toward marrow or nutritional disease rather than isolated neutropenia (Chan & Nguyen, 2026; Davoren & Hsu, 2019; Norris, 2020).

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References

Chan, A., & Nguyen, L. (2026). Supportive care in oncology. In M. A. Chisholm-Burns, P. M. Malone, J. M. Kolesar, K. C. Lee, P. B. Bookstaver, & K. R. Matthias (Eds.), Pharmacotherapy principles & practice (7th ed.). McGraw Hill.

Davoren, J. B., & Hsu, G. (2019). Blood disorders. In G. D. Hammer & S. J. McPhee (Eds.), Pathophysiology of disease: An introduction to clinical medicine (8th ed.). McGraw-Hill Education.

Norris, T. L. (2020). Porth’s essentials of pathophysiology (5th ed.). Wolters Kluwer.

Pereiras, M. A., & Arnall, J. R. (2026). Anemia. In M. A. Chisholm-Burns, P. M. Malone, J. M. Kolesar, K. C. Lee, P. B. Bookstaver, & K. R. Matthias (Eds.), Pharmacotherapy principles & practice (7th ed.). McGraw Hill.