Leukopenia

Leukopenia is a reduction in the white blood cell (WBC) count to < 4000/mm³. The condition is further classified by the WBC type that is predominantly reduced (i.e., neutrophils, lymphocytes, eosinophils, monocytes, or basophils). The most common forms of leukopenia are neutropenia and lymphopenia, which have various causative factors that include infection, hematologic abnormalities, malignancy, medications, and autoimmune or inflammatory disorders. Agranulocytosis is the absence of granulocytes or severe neutropenia and is most commonly medication-induced. Diagnosis involves obtaining a CBC with differential and a peripheral blood smear. Further studies (e.g., infectious workup, malignancy evaluation) should be obtained based on the suspected cause. Management depends on the underlying cause of leukopenia.

See “Overview of WBC parameters” for further details on reference ranges.

• Leukopenia: a reduction in WBCs (< 4000/mm³); can be further classified by the WBC type that is predominantly reduced, e.g., neutropenia, lymphopenia ^[1][2]
• Pseudoleukopenia: a false reduction in WBCs due to in vitro leukocyte aggregation ^[3]

Leukopenia can be a reduction in multiple WBC types or an isolated WBC type.

Neutropenia ^[4][5]

• Medications
  • Antimicrobials (e.g., amoxicillin, amphotericin, chloroquine)
  • Antiepileptics (e.g., valproic acid, carbamazepine)
  • Anti-inflammatory agents (e.g., ibuprofen)
  • Cardiovascular drugs (e.g., propranolol, ACE inhibitors, digoxin)
  • Chemotherapeutic agents
  • Antipsychotics (e.g., clozapine)
  • Antithyroid drugs (e.g., methimazole, propylthiouracil)
• Infection
  • Sepsis
  • Bacterial infections (e.g., typhoid fever, brucellosis, rickettsiosis) ^[6]
  • Viral infections (e.g., CMV, EBV, HIV, viral hepatitis) ^[6][7]
  • Fungal infections ^[7]
  • Postinfection
• Autoimmune conditions
  • Rheumatoid arthritis (especially Felty syndrome)
  • Systemic lupus erythematosus (SLE)
• Hematologic or neoplastic disorders
  • Leukemia (e.g., acute myeloid leukemia, large granular lymphocyte leukemia)
  • Myelodysplastic syndrome
  • Myeloma
  • Aplastic anemia ^[8]
• Nutritional
  • Vitamin B₁₂ deficiency
  • Folate deficiency
  • Copper deficiency
  • Malnutrition
• Congenital conditions
  • Constitutional neutropenia
  • Cyclic neutropenia
  • Severe congenital neutropenia ^[9]
• Other
  • Alcohol use disorder
  • Substance use (e.g., cocaine) ^[4][10]
  • Radiation ^[11]
  • Chronic idiopathic neutropenia
  • Hemodialysis ^[12]

Lymphopenia ^[12]

• Infection
  • Viral infections (e.g., HIV, COVID-19, hepatitis, measles) ^[13]
  • Bacterial infections (e.g., tuberculosis, pneumonia)
  • Parasitic infections (e.g., malaria) ^[14]
  • Fungal infections (e.g., histoplasmosis)
  • Sepsis
• Medications ^[15]
  • Chemotherapeutic agents
  • Glucocorticoids
  • Opioids
  • Carbamazepine
• Autoimmune conditions ^[16]
  • SLE
  • Rheumatoid arthritis
  • Vasculitides
  • Sjogren syndrome
  • Crohn disease
• Malignancy ^[17]
  • Non-Hodgkin lymphoma
  • Hodgkin lymphoma ^[18]
  • Solid tumors (e.g., pancreatic cancer, breast cancer, sarcoma)
• Congenital
  • Severe combined immunodeficiency
  • Wiskott-Aldrich syndrome
  • Ataxia telangiectasia
  • DiGeorge syndrome ^[19]
• Other
  • Radiation
  • Malnutrition ^[20]
  • Alcohol use disorder
  • Severe burns ^[20]
  • Amyloidosis ^[20]
  • Postoperative state ^[21]
  • Renal failure
  • Major surgery

Monocytopenia ^[12]

• Medications
  • Glucocorticoids
  • Chemotherapeutic agents
• Infection
  • Sepsis
  • Viral infections (e.g., HIV, EBV) ^[22]
• Hematologic or neoplastic disorders
  • Aplastic anemia
  • Myelodysplastic syndrome ^[23]
  • Acute myeloid leukemia ^[24]
  • Hairy cell leukemia
• Other: hemodialysis

Eosinopenia ^[12]

Low eosinophil levels occur concomitantly with other cytopenias that are caused by bone marrow hypoplasia. ^[12]

• Infection (e.g., typhoid and paratyphoid fever, sepsis) ^[25][26]
• Glucocorticoids
• Autoimmune disorders (e.g., SLE, Cushing syndrome) ^[27]
• Acute inflammation
• Stress

Basopenia ^[28]

Basopenia is difficult to assess due to already low normal counts. Some causes are noted below.

• Medications (e.g, prolonged high-dose glucocorticoids)
• Hypersensitivity reactions (e.g., urticaria)
• Severe stress (e.g., peptic ulcer bleeding, myocardial infarction)
• Cushing syndrome
• Hyperthyroidism
• SLE ^[29]

Focused history ^[4][5]

• Constitutional symptoms (e.g., malaise, weight loss, night sweats)
• Infectious evaluation
  • Infectious symptoms (e.g., subjective fever, rigors, localizing symptoms)
  • History of recurrent or recent infections
• Autoimmune or inflammatory symptoms (e.g., arthralgias, rash, joint pain)
• Detailed medication list
• Dietary history
• History of substance use

Focused physical examination ^[4][5]

• Signs of malignancy or hematologic condition, e.g.:
  • Lymphadenopathy
  • Splenomegaly
  • Hepatomegaly
• Signs of active or recent infection (e.g., fever, healing ulcers, rash)
• Signs of autoimmune condition (e.g., joint abnormalities, rash)

See “Diagnostics for neutropenic fever” for patients with fever and ANC < 500/mm³.

Initial studies ^[4][5][30]

Obtain the following to confirm the presence and type of leukopenia.

• CBC with differential
  • Determine the predominant WBC type that is reduced.
  • Assess for reduction in other cell lines (e.g., pancytopenia).
  • Review prior CBC results to determine the chronicity.
  • Repeat CBC in a few days to weeks in patients with minimal symptoms to establish diagnosis and trend. ^[4][30]
• Peripheral blood smear
  • Assessment for abnormal morphology
  • Assessment for falsely low WBC (e.g., pseudoleukopenia) ^[5]
• BMP: renal function
• LFTs: liver function

Further studies

Further studies are based on clinical suspicion and may include evaluation for:

• Infection
  • Viral studies (e.g., HIV test, hepatitis serology, COVID-19 test)
  • Bacterial studies (e.g., blood cultures, TB testing, studies for tick-borne diseases)
  • Imaging (e.g., CXR for suspected pneumonia)
• Malignancy ^[4]
  • Bone marrow aspiration and biopsy
  • Flow cytometry
• Immunodeficiency
  • Serum immunoglobulins ^[30]
  • See also “Congenital immunodeficiency disorders.”
• Inflammatory conditions ^[4]
  • Inflammatory markers (e.g., ESR, CRP)
  • Serologies (e.g., ANA, rheumatoid factor)
• Nutritional deficiencies ^[5]
  • Vitamin B₁₂ level
  • Folate level
  • Copper level

There is an overlap in the conditions that cause neutropenia and lymphopenia; selected causes are listed for each.

Common causes of neutropenia

Patients with severe neutropenia are at risk of developing secondary infection and may therefore present with clinical features of sepsis.

Common causes of lymphopenia

• Provide immediate inpatient care for acutely ill patients.
  • Stabilize patients and provide sepsis management in cases of severe infection.
  • Initiate antibiotics if indicated.
  • Provide management of neutropenic fever (e.g., neutropenia precautions, empiric antibiotic therapy for neutropenic fever).
• Treatment depends on the underlying cause of leukopenia.
• G-CSF (off-label) may be considered in select cases. ^[5]
• Consult hematology and/or oncology for primary hematologic or malignant conditions.
• Reassure patients with stable, chronic (lasting longer than 6 months), asymptomatic lymphopenia with otherwise normal laboratory, imaging, and clinical findings. ^[30]

New-onset neutropenia in an acutely ill patient is a medical emergency. ^[4]

Definition

Agranulocytosis is the absence of granulocytes or severe neutropenia (usually defined as ANC < 500/mm³). ^[5][7]

Etiology

• Medications (most common) ^[4][7]
  • Chemotherapeutic agents
  • Antibiotics (e.g., trimethoprim/sulfamethoxazole, dapsone, chloramphenicol)
  • Cardiovascular drugs (e.g., ticlopidine, procainamide, flecainide)
  • Antipsychotic drugs (e.g., clozapine)
  • Antithyroid drugs (e.g., propylthiouracil, methimazole)
  • Anticonvulsant drugs (e.g., carbamazepine, valproate, phenytoin) ^[40][41]
  • Anti-inflammatory drugs (e.g., sulfasalazine, NSAIDs)
  • Antifungal agents (e.g., flucytosine)
  • Other: colchicine, ganciclovir ^[41]
• Bone marrow disorders and malignancies: : e.g., aplastic anemia, myelodysplastic syndromes, leukemia ^[6]
• Nutritional deficiency: e.g., protein-calorie malnutrition ^[42]
• Congenital: e.g., severe congenital neutropenia ^[42]
• Autoimmune conditions: e.g., SLE ^[6][42]
• Viral infection: e.g., EBV ^[42]

“Causes Pretty Major Collapse To Defense Cells”: Some drugs that can cause agranulocytosis include Clozapine, Propylthiouracil, Methimazole, Carbamazepine, Ticlopidine, Dapsone, and Chloramphenicol.

Pathophysiology ^[41][43][44]

• Medication-induced
  • Immune-mediated (type II hypersensitivity reaction): Drugs or drug-protein complexes stimulate the development of antibodies against granulocytes.
  • Drug toxicity: direct damage to myeloid precursors (i.e., myelosuppression)
• Autoimmune conditions: peripheral granulocyte destruction

Clinical features ^[7][45]

In medication-induced agranulocytosis, symptoms usually begin within the first three months of treatment with the causative drug. ^[7]

• May be asymptomatic
• Triad of oral ulcerations with stomatitis, sore throat, and fever (agranulocytic angina) ^[46]
• Myalgias, arthralgia, malaise
• Symptoms of infection
• Symptoms of underlying etiology (e.g., bleeding in hematologic disorders)

Diagnostics

See “Diagnostics for leukopenia.”

Monitor WBC count and differential after starting drugs that can cause agranulocytosis.

Treatment ^[4][5][7]

• Stop causative agent if medication-induced.
• In febrile patients, initiate management of neutropenic fever (e.g., antibiotics for infection).
• Consider G-CSF (off-label), e.g., filgrastim, in select cases. ^[5]
• Consult hematology for assistance in management.

• Definition: a condition characterized by a decreased ANC (< 1500/mm³) in the absence of secondary causes and without an increased risk of infection ^[6]
• Epidemiology
  • Most commonly occurs in individuals of African, Middle Eastern, and West Indian descent ^[47]
  • Incidence: approx. 4% in the US ^[48]
• Etiology: associated with a single nucleotide polymorphism in the DARC gene on chromosome 1 ^[49][50]
• Pathophysiology: not fully understood ^[47]
• Clinical features: asymptomatic
• Diagnosis
  • Constitutional neutropenia is a diagnosis of exclusion.
  • Secondary causes of neutropenia (e.g., recurrent infections, cytopenia, splenomegaly, lymphadenopathy) should be ruled out.
  • See “Diagnostics for leukopenia.”
• Management: does not require treatment or additional monitoring
• Special patient subgroups: Patients with constitutional neutropenia should have lower ANC thresholds (e.g., > 500/mm³) for holding and discontinuing treatment with certain chemotherapeutic agents (e.g., doxorubicin) and clozapine than the general population. ^[51][52]

In contrast to other causes of neutropenia (e.g., neutropenic fever, systemic lupus erythematosus, sepsis), the risk of infection is not increased in constitutional neutropenia.