Leukopenia

Leukopenia is a reduction in the total white blood cell count below the lower limit of normal, usually under 4.0 x 10⁹/L in adults. It is most often caused by neutropenia (neutrophils under 1.5 x 10⁹/L) and sometimes lymphopenia (lymphocytes under 1.0 x 10⁹/L), and the risk of infection depends on the cell type affected, the severity, and the duration.

• Neutropenia grades: mild 1.0 to 1.5 x 10⁹/L, moderate 0.5 to 1.0, severe under 0.5 (agranulocytosis).
• Benign (constitutional) ethnic neutropenia: common in people of African, Middle Eastern and some Caribbean ancestry (Duffy null associated neutrophil count), with neutrophil counts of 1.0 to 1.5 x 10⁹/L, normal marrow, and no increased infection risk; it needs no treatment and should not prompt investigation or withholding of drugs such as clozapine (which have specific monitoring ranges).
• Infections: viral (influenza, hepatitis, HIV, EBV, CMV, measles, dengue), bacterial sepsis, typhoid, brucellosis, tuberculosis, malaria, and rickettsial infection.
• Drugs: chemotherapy, methotrexate, azathioprine, antithyroid drugs (carbimazole, propylthiouracil), clozapine, carbamazepine, sulfasalazine, co-trimoxazole, penicillins and cephalosporins, chloramphenicol, dapsone, antiretrovirals (zidovudine), ticlopidine, and phenothiazines.
• Autoimmune and immune: systemic lupus erythematosus, rheumatoid arthritis with Felty syndrome, large granular lymphocyte leukaemia.
• Marrow disorders: aplastic anaemia, myelodysplastic syndrome, leukaemia, lymphoma, myelofibrosis, marrow infiltration, vitamin B12 and folate deficiency, copper deficiency, severe malnutrition, and radiation.
• Others: hypersplenism, congenital neutropenia, cyclic neutropenia, and pseudoneutropenia (marginated cells).

• Often asymptomatic, found on routine blood tests.
• Recurrent or severe infections: fever, sore throat, mouth ulcers, gingivitis, skin abscesses, perianal infection, pneumonia, sinusitis, and sepsis; infections are more severe when the count is under 0.5 x 10⁹/L and prolonged.
• Features of the cause: weight loss, night sweats, lymphadenopathy, splenomegaly, bruising (low platelets), pallor, joint pain, rash, and drug history with timing.
• Examination: mouth, throat, skin, perianal area, lymph nodes, spleen, liver, and joints.
• Febrile neutropenia (a medical emergency): temperature 38.3 degrees Celsius once, or 38.0 for 1 hour, with neutrophils under 1.0 x 10⁹/L (expected to fall under 0.5), with or without localising signs; may present with only malaise, hypotension or confusion.

• Repeat FBC with differential count and blood film in 2 to 4 weeks (earlier if unwell); count again after 3 to 6 months if borderline and the patient is well; look at serial counts and previous baselines.
• Blood film for dysplasia, blasts, atypical lymphocytes, toxic granulation, and parasites.
• Screening tests: renal, liver and thyroid function, vitamin B12, folate, copper, antinuclear antibodies, rheumatoid factor, anti-neutrophil antibodies where available, HIV, hepatitis B and C, EBV and CMV serology, immunoglobulins, and in sick patients blood cultures, chest X-ray and urine culture.
• Abdominal ultrasound for splenomegaly.
• Bone marrow aspirate and trephine, with cytogenetics and flow cytometry, when neutrophils are under 0.5 x 10⁹/L unexplained, other cell lines are low, blasts are on the film, the count is falling, or there is lymphadenopathy or splenomegaly.
• Serial neutrophil counts over 6 weeks (every 2 to 3 days) for cyclic neutropenia; genetic tests for congenital neutropenia.
• Review all medicines and supplements, including herbal products.
• Differentials: pseudoneutropenia, benign ethnic neutropenia, delayed sample processing artefact, laboratory error.

Mild asymptomatic leukopenia (neutrophils 1.0 to 1.5 x 10⁹/L)

• Reassure; confirm a stable count with repeat tests; treat the underlying cause; advise on infection precautions; benign ethnic neutropenia needs no follow up beyond periodic counts; avoid unnecessary marrow tests.

Drug induced neutropenia

• Stop the offending drug promptly (agranulocytosis due to carbimazole, clozapine, sulfasalazine, and others) with the prescriber and do not rechallenge; recovery in 1 to 3 weeks; give filgrastim for severe or prolonged cases.
• Counsel patients on antithyroid drugs, clozapine and sulfasalazine to report sore throat or fever immediately and have an urgent FBC.

Neutropenia with infection risk (neutrophils under 1.0 x 10⁹/L)

• Hygiene: hand washing, oral care with soft toothbrush and chlorhexidine 0.2 percent rinse, avoid rectal temperature, thermometers, enemas and suppositories, avoid contact with sick people, and food safety (avoid raw foods).
• Vaccination (inactivated influenza, pneumococcal); avoid live vaccines in severe immunosuppression.
• Prophylactic antibiotics or antifungals only under haematology or oncology direction for prolonged severe neutropenia (for example levofloxacin 500 mg daily, fluconazole 200 mg daily).

Febrile neutropenia (emergency)

• Immediate assessment, blood cultures from every lumen and peripheral vein, urine and sputum cultures, chest X-ray, lactate, and renal and liver function; start empirical broad spectrum intravenous antibiotics within 1 hour: piperacillin tazobactam 4.5 g every 6 hours (or 4.5 g every 8 hours in less severe cases) with dose adjustment for renal impairment; add gentamicin 5 mg/kg daily or amikacin 15 mg/kg daily if septic shock or resistant organisms are suspected, and vancomycin 15 to 20 mg/kg every 8 to 12 hours for line infection, skin or soft tissue infection, pneumonia, or haemodynamic instability.
• Penicillin allergy (severe): meropenem 1 g every 8 hours with a glycopeptide or aminoglycoside, or ciprofloxacin 400 mg every 12 hours plus vancomycin, according to local microbiology.
• Escalate to meropenem 1 g every 8 hours if the patient is unwell or has had resistant organisms; start antifungal therapy (caspofungin 70 mg then 50 mg daily, or liposomal amphotericin B 3 mg/kg daily) if fever persists beyond 4 to 7 days.
• Fluids, oxygen and sepsis resuscitation; admit to a monitored area.
• Low risk patients (expected short neutropenia, stable, no comorbidity, reliable carer) may be treated with oral amoxicillin clavulanate 625 mg three times daily plus ciprofloxacin 750 mg twice daily after specialist assessment.
• Granulocyte colony stimulating factor: filgrastim 5 micrograms/kg subcutaneously daily until neutrophils recover (over 1.0 x 10⁹/L on two days) for severe sepsis, congenital or drug induced agranulocytosis, and chemotherapy induced neutropenia in high risk patients; not for benign ethnic neutropenia.

Treat the cause

• Infections: treat the organism (antiviral, antimicrobial; antiretroviral therapy for HIV, antituberculous therapy, antimalarial therapy).
• Nutritional: hydroxocobalamin 1 mg intramuscularly, folic acid 5 mg daily, copper replacement for deficiency.
• Autoimmune neutropenia, Felty syndrome, large granular lymphocytosis: immunosuppression by a specialist (methotrexate 7.5 to 15 mg weekly, prednisolone, rituximab).
• Haematological malignancy, myelodysplasia, aplastic anaemia, severe congenital neutropenia: urgent haematology referral; marrow transplant when indicated.

Lymphopenia

• Find the cause (HIV, steroids, chemotherapy, critical illness, malnutrition, autoimmune disease, lymphoma); CD4 count and viral load if HIV-positive; Pneumocystis prophylaxis with co-trimoxazole 480 mg daily (or 960 mg three times weekly) when CD4 is under 200 cells/microlitre.

Follow up

• Repeat counts within 1 to 4 weeks depending on severity and cause, then at 3 to 6 months if stable; urgent referral to haematology for neutrophils under 0.5 x 10⁹/L, a falling count, other cytopenias, blasts, or lymphoproliferative signs; advise patients to seek help the same day for fever of 38 degrees Celsius or higher, rigors, or sore throat.