01OverviewDefinition, clinical context and the essential points that orientate the chapter.
Neutrophils provide rapid phagocytic defence at damaged mucosa and sites of bacterial and fungal invasion. Infection risk rises as the count falls, the duration lengthens and mucosal, line or immune barriers are damaged. Profound deficiency can remove pus, focal inflammation and a large CRP response, so sore throat, oral ulcer, perianal discomfort or fever may be the only clue. Steroids can mask fever, while recent G-CSF can change the count rapidly; always interpret the current number within treatment timing.
Causes divide into reduced production, immune destruction, redistribution and sequestration. Chemotherapy and marrow failure reduce production; idiosyncratic drug agranulocytosis may be immune or toxic; autoimmune neutropenia increases destruction; sepsis consumes and redistributes cells; splenomegaly sequesters them. A time course and prior counts are high-value. Acute isolated neutropenia after a new medicine differs from months of stable mild neutropenia, and pancytopenia demands a wider marrow investigation.
Management addresses danger and mechanism. Any febrile severe neutropenia follows the acute sepsis pathway. Stop a plausible culprit and report serious reactions through MHRA systems when appropriate, but coordinate clozapine decisions with its monitoring service and mental-health team. Treat vitamin or infection causes, manage autoimmune disease selectively and refer persistent unexplained cases. G-CSF can shorten profound drug-related or chemotherapy neutropenia in selected patients; evidence and dosing differ, so haematology or oncology sets the plan.
Key points
- Neutropenia is a reduced absolute neutrophil count, commonly graded as mild 1.0–1.5, moderate 0.5–1.0 and severe below 0.5 × 10^9/L, with context and duration determining risk.
- Agranulocytosis usually denotes profound neutropenia, often drug induced, with a high risk of rapidly progressive bacterial or fungal infection.
- Repeat an unexpected result and inspect the film, but treat fever or physiological instability immediately rather than waiting to prove persistence.
- Medicine reconciliation must include recent courses and stopped drugs: antithyroid medicines, clozapine, metamizole exposure abroad, sulfasalazine, antiepileptics, antimicrobials and cytotoxic or immune therapies.
- Viral infection can transiently lower neutrophils, while HIV, hepatitis, EBV or CMV may produce a prolonged pattern guided by exposure and symptoms.
- B12, folate and copper deficiency can suppress several lines; isolated neutropenia with normal indices makes a global nutritional cause less likely but not impossible.
- Duffy-null-associated neutrophil counts are a healthy inherited reference variant common in some ancestries and should not be labelled disease after appropriate assessment.
- Lymphadenopathy, splenomegaly, blasts, dysplasia, other cytopenias or progressive constitutional symptoms raise marrow malignancy, autoimmune disease or hypersplenism.
- Bone-marrow examination is used for unexplained persistent, severe or multilineage cytopenia, not automatically for every stable mild count.
- Granulocyte colony-stimulating factor is used for defined chemotherapy, congenital or severe drug-related settings under specialist guidance and does not replace antibiotics in sepsis.
02AetiologyUnderlying causes, associations and risk factors, with why each one matters.
Drug-related marrow injury
Dose-related cytotoxic suppression or unpredictable immune and toxic reactions can sharply reduce granulopoiesis, sometimes after a medicine has already been stopped.
Marrow or nutritional failure
Aplastic anaemia, myelodysplasia, leukaemia, infiltration, B12, folate and copper deficiency impair production, often affecting additional blood-cell lines.
Immune and infective causes
Autoimmune neutropenia, systemic lupus, HIV and acute viral infections can increase destruction or suppress production, with duration and accompanying features guiding tests.
Constitutional count variation
Duffy-null genotype can produce a stable lower neutrophil count without increased infection, requiring recognition to prevent unnecessary restriction or invasive investigation.
03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.
- 1Reduced granulopoiesis
Stem-cell or myeloid precursor injury limits marrow release, so the count remains low until surviving progenitors recover or growth-factor support takes effect.
- 2Peripheral immune clearance
Drug-dependent or autoimmune antibodies and splenic macrophages can remove circulating neutrophils faster than marrow replacement, sometimes preserving other lineages.
- 3Barrier-dependent infection
Loss of neutrophils combines with oral, intestinal, skin or line disruption, allowing endogenous organisms to invade without a robust local inflammatory response.
04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.
Fever, rigors or malaise may occur without pus, erythema or focal consolidation because neutrophil recruitment is absent.
Sore throat, fever and oral ulcers after carbimazole, clozapine or another implicated medicine demands an urgent count and medicine hold.
Anaemia, thrombocytopenia, macrocytosis, dysplasia or blasts alongside neutropenia raises global marrow failure or clonal disease.
Hypotension, confusion, raised lactate or hypoxia with neutropenia needs immediate antibiotics and organ support regardless of temperature.
Longstanding isolated mild neutropenia without infections or other abnormalities may reflect Duffy-null or another benign constitutional state.
05InvestigationsWhat to request, why it matters and how to interpret it.
Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.
- 01
Repeat full count and manual filmFirst step - Why
- Confirm severity and detect other lineage or morphological clues.
- Interpretation and limitations
- Compare historical counts; blasts, dysplasia, macrocytosis or pancytopenia accelerate haematology referral while a stable isolated pattern changes probability.
- 02
Complete medicine timeline - Why
- Identify cytotoxic, immune or idiosyncratic exposure.
- Interpretation and limitations
- Include recent antibiotics, antithyroid treatment, clozapine, anticonvulsants, supplements and medicines stopped weeks earlier; follow drug-specific monitoring rules.
- 03
Cultures and infection assessment - Why
- Find the source during fever or physiological change.
- Interpretation and limitations
- Take blood cultures from peripheral and line sites when feasible, but do not postpone empirical therapy for results or imaging.
- 04
B12, folate, copper and zinc - Why
- Detect reversible nutrient-related production failure.
- Interpretation and limitations
- Copper deficiency may follow bariatric surgery or excess zinc and often coexists with anaemia or neurological findings.
- 05
Viral and autoimmune tests - Why
- Investigate a clinically supported persistent cause.
- Interpretation and limitations
- Select HIV, hepatitis, EBV, CMV, ANA and related tests from exposure and systemic phenotype rather than ordering indiscriminate panels.
- 06
Bone-marrow aspirate and trephine - Why
- Assess granulopoiesis and exclude failure, dysplasia or infiltration.
- Interpretation and limitations
- Indicated for persistent severe, unexplained or multilineage disease; cytogenetic and molecular studies accompany suspected clonal pathology.
- 07
Duffy phenotype or genotype - Why
- Support constitutional count interpretation when appropriate.
- Interpretation and limitations
- A Duffy-null result can explain a stable lower reference count but cannot excuse new fever, falling counts or other haematological abnormalities.
06Differential diagnosisRealistic alternatives and the features that help distinguish them.
Laboratory artefact
Sample delay, analyser flags or rare EDTA-dependent cell aggregation can produce a misleading result; repeat count and film verify an unexpected stable finding.
Acute leukaemia
Leukaemia can present with neutropenia, anaemia or thrombocytopenia despite no automated blast flag, requiring film and marrow assessment when clinical features persist.
Sepsis-associated leucopenia
Overwhelming infection may consume and redistribute neutrophils, so a low count can be consequence rather than pre-existing cause and indicates severe physiology.
Hypersplenism
Splenomegaly from liver, infective or haematological disease can sequester neutrophils with platelets and red cells, producing a multilineage peripheral cytopenia.
07ManagementImmediate care, first-line treatment, alternatives and escalation.
01Safety screenSeparate fever from a stable numberFirst stepA low neutrophil count is newly reported or found during illness.+
- 1Assess temperature, haemodynamics, mucosa, skin, lines, respiratory and perianal symptoms immediately and treat septic physiology through the acute pathway.
- 2Repeat count and film, retrieve prior values and grade depth and duration while taking cultures and giving antibiotics when fever or instability is present.
- 3Apply medicine-specific emergency rules, withholding a plausible culprit and coordinating essential-disease replacement with the responsible specialist.
02Cause definitionUse lineage, time and exposureNeutropenia persists after immediate infection risk is controlled.+
- 1Map whether the abnormality is isolated or multilineage and review medicines, infections, alcohol, nutrition, surgery, autoimmune symptoms, spleen and family history.
- 2Order targeted B12, folate, copper, viral, autoimmune or constitutional testing and avoid interpreting ancestry alone as a diagnosis.
- 3Arrange marrow examination for severe, progressive, unexplained or morphologically abnormal disease and communicate urgency if blasts or pancytopenia emerge.
03Recovery planRemove cause and protect the intervalDrug-induced, immune, congenital or treatment-related neutropenia is established.+
- 1AlternativeDocument and report a serious drug reaction, give patient-held avoidance information and agree an alternative for the condition that medicine treated.
- 2Use G-CSF only for a defined oncology or haematology indication, continuing antimicrobial treatment and source control during count recovery.
- 3Set count frequency, fever instructions and specialist follow-up from expected nadir and recovery time, investigating failure to recover for marrow disease.
Key medicines and prescribing safety2 treatments · regimens, roles and cautions+
Filgrastim
Haematology or oncology uses a weight-based subcutaneous regimen for a defined chemotherapy, congenital or severe drug-related indication, adjusting duration to neutrophil recovery and clinical context.Bone pain, splenic enlargement or rupture, leucocytosis, lung injury and sickle crisis are recognised; it does not replace antibiotics or source control in infection.
Culprit medicine withdrawal
Withhold further doses immediately under the product-specific agranulocytosis pathway and do not rechallenge unless a national monitoring service and senior specialist explicitly authorise it.Coordinate clozapine, antithyroid or seizure treatment alternatives urgently; document the reaction and avoid inadvertent exposure to the same or cross-reactive agent.
08ComplicationsImportant consequences, why they occur and why they matter clinically.
Bacterial sepsis
Gut, oral, skin and line organisms can invade rapidly, producing shock with minimal local signs when the absolute neutrophil count is profoundly reduced.
Invasive fungal infection
Prolonged profound neutropenia predisposes to mould and yeast disease, often presenting as persistent fever, pulmonary nodules or sinus findings despite antibiotics.
Mucosal injury
Painful oral ulceration, periodontal infection and perianal inflammation can impair nutrition and provide portals for bloodstream infection while examination signs remain subtle.
Treatment interruption
Stopping antipsychotic, antithyroid, cancer or immune therapy may destabilise the underlying illness, requiring coordinated substitution rather than an isolated laboratory instruction.
09Monitoring and follow-upTreatment response, safety checks and longer-term review.
- Repeat absolute neutrophil count at a frequency matched to depth, symptoms, culprit half-life and expected marrow recovery.
- During severe neutropenia monitor temperature, haemodynamics, mouth, skin, line, respiratory and perianal symptoms rather than relying on CRP alone.
- Trend haemoglobin, platelets and film morphology because evolution into multilineage cytopenia changes the marrow differential.
- For G-CSF record dose, count response, bone or splenic pain and respiratory symptoms and stop according to the specialist protocol.
- Confirm that a drug reaction is entered in prescribing, pharmacy, monitoring-service and patient-held records before discharge.
- In stable constitutional neutropenia, avoid repeated invasive testing but reopen assessment after a new count trajectory, infection burden or systemic feature.
10Special situationsVariants, exceptions and circumstances that change the usual approach.
No pus can mean danger
Profound neutropenia removes the cells that create local inflammation, so a deceptively quiet examination can coexist with invasive infection.
Duration modifies depth
A count below 0.5 for weeks after chemotherapy carries different fungal risk from a brief post-viral nadir.
Recent drugs still count
Immune agranulocytosis can present after exposure stops, making the preceding weeks as important as today's prescription chart.
Duffy-null is not disease
A healthy genetically determined reference range should prevent inequitable exclusion from treatment while retaining normal clinical vigilance.
11Common pitfallsFrequent interpretation and management errors.
- 01
Waiting for fever when septic physiology is present.
- 02
Looking only at today's medicine list.
- 03
Rechallenging a suspected agranulocytosis drug casually.
- 04
Equating ancestry with benign neutropenia without assessment.
- 05
Sending every stable mild case straight to marrow biopsy.
- 06
Using G-CSF instead of antibiotics during sepsis.