Neutropenic sepsis is a medical emergency. Screen for severe infection and pancytopenia immediately.
Neutropenic sepsis (neutrophils <0.5 × 10⁹/L + fever) is a medical emergency. Without neutrophils, infections progress rapidly to septic shock. Mortality is 10-20% even with prompt antibiotics. NICE NG151 mandates immediate admission and IV antibiotics within 1 hour.
Pancytopenia suggests bone marrow failure (aplastic anaemia, MDS, acute leukaemia). Aplastic anaemia has 50% 5-year mortality without treatment. Same-day haematology enables urgent bone marrow biopsy and supportive care (transfusions, G-CSF).
Drug-induced agranulocytosis occurs with clozapine (0.8% incidence), carbimazole (0.3%), and sulfasalazine (0.1%). Onset is typically 1-3 months after starting. Stopping the drug immediately is life-saving; continuing risks fatal sepsis.
Chemotherapy-induced neutropenia peaks at day 7-14 post-treatment. Any fever in this window is neutropenic sepsis until proven otherwise, even if the patient looks well. Blood cultures are positive in only 20-30%, so treat empirically without waiting for results.
Confirm persistent leucopenia and determine if neutropenia is the primary issue. A single low WCC can be a lab error or transient viral infection.
Transient leucopenia is common after viral infections (influenza, EBV, CMV). WCC can drop to 2-3 × 10⁹/L transiently but recovers within 2 weeks. Repeating FBC avoids unnecessary investigations and anxiety.
Absolute neutrophil count is the key number. A patient with WCC 3.5, neutrophils 40% (ANC 1.4) has mild neutropenia with low infection risk. A patient with WCC 3.5, neutrophils 20% (ANC 0.7) has moderate neutropenia requiring investigation.
Benign ethnic neutropenia (BEN) affects 25-50% of Black African and Afro-Caribbean individuals. It is a normal variant, not a disease. ANC is typically 1.0-1.5 × 10⁹/L, stable over time, with no increased infection risk. Avoid unnecessary haematology referrals by recognizing BEN.
Blood film review can detect myelodysplasia (dysplastic neutrophils, hyposegmented nuclei) and early leukaemia (blasts). Automated counters miss morphological abnormalities in 10-15% of cases.
Classify by severity of neutropenia and whether other cell lines are affected. This determines infection risk and urgency of referral.
Infection risk correlates with ANC. Mild neutropenia (ANC 1.0-1.5) has <5% annual infection risk. Moderate neutropenia (ANC 0.5-1.0) has 10-20% risk. Severe neutropenia (ANC <0.5) has 40% risk of serious infection within 3 months without treatment.
Isolated neutropenia is more likely to be benign (BEN, autoimmune) than pancytopenia. If Hb and platelets are normal, the bone marrow is functioning. Pancytopenia suggests marrow failure or infiltration and requires urgent haematology assessment.
Lymphopenia is less clinically important than neutropenia. Lymphocytes <0.5 × 10⁹/L suggests immunodeficiency (HIV, chemotherapy, immunosuppressants). Check HIV serology if risk factors present.
Benign ethnic neutropenia (BEN) is stable over time. ANC remains 1.0-1.5 × 10⁹/L for years without progression. If ANC is falling or <1.0, BEN is unlikely; investigate further.
Examine for active infection, organomegaly, and signs of underlying systemic disease causing neutropenia.
Oral ulcers and gingivitis are hallmarks of severe neutropenia. Without neutrophils, the mouth cannot mount an inflammatory response to oral bacteria. Severe mucositis with ANC <0.5 increases aspiration pneumonia risk.
Splenomegaly in neutropenia suggests Felty syndrome (RA + splenomegaly + neutropenia). Affects 1% of RA patients, typically after 10+ years of disease. Spleen sequesters neutrophils, worsening neutropenia. Splenectomy may be required if recurrent infections.
Malar rash + lymphopenia + neutropenia is classic for SLE. 50% of SLE patients develop leucopenia. ANA is positive in 95%. Anti-dsDNA and anti-Sm antibodies are specific for SLE.
Absent infection signs in neutropenic patient does not exclude serious infection. Neutrophils are required for pus formation, fever, and inflammatory markers. CRP can be normal despite pneumonia or sepsis. Low threshold for imaging and empirical antibiotics.
Investigate based on the pattern of cytopenia, severity of neutropenia, and clinical context. Target investigations to the likely differential.
B12/folate deficiency is a reversible cause of pancytopenia. Megaloblastic anaemia suppresses all cell lines due to ineffective haematopoiesis. B12 <200 ng/L or folate <2 μg/L confirms deficiency. Treatment with B12 IM or folic acid 5 mg OD reverses cytopenia within 1-2 weeks.
Drug-induced neutropenia accounts for 20-30% of cases in primary care. Mechanism is immune-mediated (antibodies against neutrophils). Clozapine causes agranulocytosis in 0.8% of patients (mandates weekly FBC monitoring). Stopping the drug immediately is life-saving; neutrophil count recovers in 7-14 days.
HIV testing is mandatory in unexplained leucopenia/lymphopenia. HIV causes lymphopenia early (CD4 <500) and neutropenia late (CD4 <200). Undiagnosed HIV is the most common missed diagnosis in immunosuppressed patients presenting to primary care.
Autoimmune neutropenia (SLE, RA, Felty syndrome) is suggested by positive ANA (SLE), RF (RA), or anti-neutrophil antibodies. SLE causes neutropenia in 50% of patients. Immunosuppression with prednisolone or azathioprine improves neutrophil count but increases infection risk paradoxically.
Refer based on severity of neutropenia, presence of pancytopenia, and infection risk. Severe neutropenia requires same-day haematology.
ANC <0.5 × 10⁹/L is the threshold for same-day referral even without fever. Infection risk is 40% within 3 months. Haematology can arrange G-CSF injections (filgrastim 300 mcg SC daily) to boost neutrophil production within 48-72 hours.
Pancytopenia requires urgent bone marrow biopsy to differentiate aplastic anaemia (empty marrow), MDS (dysplastic marrow), and acute leukaemia (blast infiltration). Aplastic anaemia has 50% 5-year mortality without treatment (immunosuppression or bone marrow transplant).
Benign ethnic neutropenia (BEN) does NOT require haematology referral if ANC is stable 1.0-1.5 × 10⁹/L over 3-6 months. Reassure patient this is a normal variant. Annual FBC monitoring in primary care is sufficient.
Drug-induced agranulocytosis requires immediate drug cessation and same-day haematology. G-CSF shortens duration of neutropenia from 10-14 days to 5-7 days, reducing infection risk. Clozapine must never be restarted after agranulocytosis (30% recurrence rate).
Treatment targets the underlying cause. Primary care can manage benign causes and infection prophylaxis; severe neutropenia requires specialist input for G-CSF or immunosuppression.
Infection prophylaxis in neutropenia (ANC <1.0 × 10⁹/L persistent):
Stopping the causative drug is curative in drug-induced neutropenia. Neutrophil count typically recovers within 7-14 days once the drug is cleared. Clozapine-induced agranulocytosis has 30% recurrence if restarted; it is absolutely contraindicated after one episode.
G-CSF (filgrastim) stimulates neutrophil production in bone marrow. It shortens duration of severe neutropenia from 10-14 days to 5-7 days, reducing infection risk by 50%. Used in chemotherapy-induced neutropenia (prophylactic or therapeutic) and aplastic anaemia bridging to definitive treatment.
Co-trimoxazole prophylaxis prevents Pneumocystis jirovecii pneumonia (PJP), which has 30-40% mortality in neutropenic patients. PJP occurs at CD4 <200 in HIV or ANC <0.5 × 10⁹/L for >7 days in other causes. Co-trimoxazole 960 mg three times weekly reduces PJP risk by 90%.
Empirical antibiotics in neutropenic fever save lives. Delaying antibiotics to await culture results increases mortality from 10% to 40%. Tazocin (piperacillin/tazobactam) covers Pseudomonas, E. coli, and Staph aureus — the commonest organisms in neutropenic sepsis.
Lifestyle interventions reduce infection risk in patients with chronic neutropenia. Education on recognizing early infection signs is critical.
Hand hygiene reduces infection transmission by 30-50%. Neutropenic patients cannot fight off normal skin flora (Staph aureus, Strep pyogenes). Alcohol gel kills 99.9% of bacteria within 30 seconds.
Food hygiene prevents gastrointestinal infections (Salmonella, Campylobacter, Listeria). Neutropenic patients have 10× higher risk of bacteraemia from GI infections. Avoiding raw foods reduces risk by 70%.
Live vaccines (MMR, yellow fever, BCG) contain attenuated virus/bacteria. In neutropenic/immunosuppressed patients, live vaccines can cause disseminated infection. Inactivated vaccines (flu, pneumococcal) are safe and recommended.
Early recognition of infection is life-saving. Neutropenic patients cannot mount typical signs (pus, high WCC, high CRP). Fever may be the only sign of serious infection. Educating patients to seek help immediately for fever >38°C reduces mortality from 40% to 10%.
Monitor neutrophil trajectory, watch for infection, and re-refer if ANC falling or recurrent infections. Chronic neutropenia requires long-term surveillance.
ANC trajectory is more important than absolute value. A falling ANC (1.5 → 1.0 → 0.7 over 3 months) suggests evolving bone marrow failure or worsening autoimmune disease, even if each value is "mild." Rising ANC indicates recovery or response to treatment.
Benign ethnic neutropenia (BEN) is stable over years. ANC remains 1.0-1.5 × 10⁹/L without treatment. If ANC is falling or <1.0, BEN is unlikely; investigate for other causes (autoimmune, bone marrow failure). Annual monitoring in primary care avoids unnecessary specialist input.
Neutropenic fever is a medical emergency regardless of how well the patient looks. Sepsis mortality in ANC <0.5 is 20-40% if antibiotics delayed >6 hours. NICE NG151 mandates IV antibiotics within 1 hour of presentation to hospital.
Recurrent infections (>2 per year) in neutropenic patient warrant haematology review. May indicate inadequate neutrophil function despite acceptable count, or progression of underlying disease. G-CSF prophylaxis or immunoglobulin replacement may be needed.