Neutropenia

Neutropenia is a reduction in the absolute neutrophil count below 1.5 x 10^9/L in adults (lower thresholds apply in infancy). Infection risk rises as the count falls and with duration: mild is 1.0 to 1.5, moderate 0.5 to 1.0, and severe under 0.5 x 10^9/L (agranulocytosis).

• Benign ethnic (Duffy null associated) neutropenia: common in people of African, Middle Eastern and some Caribbean ancestry, with stable counts of 1.0 to 1.5 x 10^9/L (occasionally as low as 0.8), a normal marrow, no increased infection risk, and no treatment needed.
• Acquired causes: viral infection (hepatitis, HIV, EBV, CMV, influenza, dengue), bacterial sepsis, tuberculosis, typhoid, brucellosis, malaria, drugs (chemotherapy, carbimazole, propylthiouracil, clozapine, sulfasalazine, methotrexate, azathioprine, carbamazepine, co-trimoxazole, penicillins, cephalosporins, chloramphenicol, dapsone, zidovudine, ticlopidine), autoimmune neutropenia, systemic lupus erythematosus, Felty syndrome, large granular lymphocyte leukaemia, vitamin B12, folate and copper deficiency, hypersplenism, aplastic anaemia, myelodysplastic syndrome, leukaemia, marrow infiltration, and radiotherapy.
• Congenital: severe congenital neutropenia (ELANE mutations), cyclic neutropenia (21 day cycles), Shwachman-Diamond syndrome, and others.
• Febrile neutropenia is a medical emergency.

• Often asymptomatic.
• Infection: fever, mouth ulcers, gingivitis, sore throat, skin abscesses, perianal infection, pneumonia, and septicaemia; signs of inflammation may be minimal, with pus often absent.
• Cyclic neutropenia: episodes of fever, mouth ulcers and pharyngitis every 3 weeks lasting 3 to 6 days.
• Examination: mouth, teeth, throat, skin, perianal region (without digital rectal examination), lymph nodes, spleen, joints, and central venous catheter sites.
• Ask about drugs started in the previous 3 months, family history of neutropenia, recurrent infections from childhood, and ancestry.
• Febrile neutropenia: temperature of 38.3 degrees Celsius once, or 38.0 sustained for 1 hour, with neutrophils under 1.0 x 10^9/L expected to fall under 0.5; may present with only malaise, hypotension, or confusion.

• Repeat FBC with differential after 1 to 2 weeks (immediately if unwell) and film review for dysplasia, blasts, atypical lymphocytes, and toxic changes.
• Tests: urea, electrolytes, liver and thyroid function, vitamin B12, folate, copper, antinuclear antibodies, rheumatoid factor, immunoglobulins, HIV, hepatitis B and C, EBV and CMV serology, and in the unwell blood cultures, urine culture, and chest X-ray.
• Serial counts two or three times weekly for 6 weeks to detect cyclic neutropenia.
• Anti-neutrophil antibodies where available; genetic testing for congenital neutropenia.
• Bone marrow aspirate and trephine with cytogenetics when neutrophils are persistently under 0.5 x 10^9/L, other cell lines are affected, blasts are present, or the cause is unclear.
• Review all drugs and supplements; Duffy null status or family history for benign ethnic neutropenia.
• Differentials: pseudoneutropenia (delayed processing, margination), benign ethnic neutropenia, transient viral suppression, aplastic anaemia, leukaemia.

Mild or benign neutropenia (neutrophils 1.0 to 1.5 x 10^9/L, well)

• Reassure and document baseline; no restriction on activities; no prophylactic antibiotics; routine vaccination; recheck FBC at 3 to 6 months; avoid unnecessary marrow tests. Do not withhold essential drugs (including clozapine, which has its own monitoring ranges for those with benign ethnic neutropenia) solely because of this finding.

Drug induced neutropenia

• Stop the suspected drug immediately in consultation with the prescriber; do not rechallenge; the count recovers within 1 to 3 weeks; use filgrastim 5 micrograms/kg subcutaneously daily until the count is over 1.0 x 10^9/L for 2 days if severe, septic, or prolonged.
• Counsel patients on antithyroid drugs, clozapine, sulfasalazine and methotrexate to report fever or sore throat at once and obtain an FBC within hours.

Neutropenia (under 1.0 x 10^9/L) without fever

• Infection precautions: hand hygiene, soft toothbrush, chlorhexidine 0.2 percent mouthwash 10 mL twice daily, avoiding rectal temperatures, suppositories and enemas, food safety (avoid raw meat, unpasteurised dairy), avoiding sick contacts and gardening without gloves.
• Inactivated vaccines (influenza yearly, pneumococcal); avoid live vaccines in severe immunosuppression.
• Prophylaxis only under haematology: levofloxacin 500 mg daily and fluconazole 200 mg daily in prolonged severe neutropenia after chemotherapy; co-trimoxazole 960 mg three times weekly for Pneumocystis in selected patients.

Febrile neutropenia (emergency, start within 1 hour)

• Blood cultures from each lumen and a peripheral vein, urine culture, chest X-ray, lactate, renal and liver function, and examination for sources.
• Piperacillin tazobactam 4.5 g intravenously every 6 hours (renal dose adjustment); add gentamicin 5 mg/kg daily or amikacin 15 mg/kg daily for septic shock, and vancomycin 15 to 20 mg/kg every 8 to 12 hours for catheter infection, skin and soft tissue infection, pneumonia, or instability.
• Meropenem 1 g intravenously every 8 hours when unwell, after previous resistant organisms, or after failure of the first regimen; consider 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.
• Resuscitation with fluids (20 mL/kg crystalloid for hypotension), oxygen, and admission to a monitored bed.
• Low risk patients (expected short neutropenia, stable, no comorbidity, reliable carer, near hospital): oral amoxicillin clavulanate 625 mg three times daily plus ciprofloxacin 750 mg twice daily after specialist assessment.
• Filgrastim 5 micrograms/kg subcutaneously daily until neutrophil recovery for severe sepsis, congenital neutropenia, or chemotherapy related neutropenia in high risk patients; not for benign ethnic neutropenia.

Treat the underlying cause

• Infection: specific antimicrobial; HIV: antiretroviral therapy; deficiency: hydroxocobalamin 1 mg intramuscularly, folic acid 5 mg daily, copper; autoimmune neutropenia, Felty syndrome, and large granular lymphocytosis: immunosuppression (methotrexate 7.5 to 15 mg weekly, prednisolone, rituximab) by a specialist.
• Aplastic anaemia, leukaemia, myelodysplasia, congenital neutropenia: urgent haematology referral.

Follow up

• Repeat FBC within 1 to 4 weeks according to severity, then at 3 to 6 months if stable; refer to haematology if neutrophils are under 0.5 x 10^9/L, falling, accompanied by other cytopenias, or unexplained for over 3 months. Advise the same day review for temperature of 38 degrees Celsius or higher.