Reduction in cell counts - neutropenia
Description
- Neutrophils <1.5 x10^9/L
| Grade | Neutrophils (x10^9/L) | Infection risk |
|---|---|---|
| Mild | 1.0-1.5 | Negligible |
| Moderate | 0.5-1.0 | Modest |
| Severe | <0.5 | High |
| Profound | <0.2 | Very high, endogenous flora |
- *Duration matters as much as depth* - >7 days of severe neutropenia is the threshold for invasive fungal risk
- Agranulocytosis = <0.2 with an otherwise preserved count, usually drug-induced
- Benign ethnic (Duffy-null associated) neutrophil count
- Common in people of African, Middle Eastern and West Indian ancestry; ~4.5% of Australians of African ancestry
- ACKR1/Duffy-null promoter variant - marginated rather than reduced neutrophil mass
- Normal marrow, normal infection risk. Do not investigate, do not withhold chemotherapy or clozapine on it alone
- Infection risk is modified by mucosal barrier integrity, steroid exposure, and central lines - not by the number alone
Epidemiology
- Drug-induced idiosyncratic agranulocytosis: ~3-12 per million/yr; mortality ~5%, rising with age and comorbidity
- Chemotherapy-induced neutropenia: the commonest cause in hospital practice
- Duffy-null associated neutrophil count: the commonest cause of an incidental low neutrophil count worldwide
- Severe congenital neutropenia ~1-2 per million births; cyclic neutropenia rarer
Aetiopathogenesis
1. Reduced production
- Marrow failure - aplastic anaemia, MDS, marrow infiltration (leukaemia, lymphoma, myeloma, solid tumour, fibrosis)
- Cytotoxic chemotherapy and radiotherapy - predictable, dose-dependent, nadir day 7-14
- Nutritional - B12, folate, copper, severe protein-energy malnutrition, anorexia nervosa
- Infection - viral marrow suppression (HIV, EBV, CMV, hepatitis, parvovirus), overwhelming bacterial sepsis, TB, brucella, leishmania
- Alcohol
- Congenital - severe congenital neutropenia (ELANE, HAX1/Kostmann), Shwachman-Diamond, Chediak-Higashi, WHIM, GATA2 deficiency, glycogen storage disease Ib
2. Increased destruction / peripheral consumption
- Autoimmune - primary autoimmune neutropenia (children), SLE, RA (Felty), Sjogren
- Large granular lymphocytic (LGL) leukaemia - T-cell clone, neutropenia out of proportion, strongly associated with RA
- Hypersplenism - sequestration
- Sepsis - consumption exceeding production
3. Drug-induced
The single most examinable list. Two mechanisms: dose-dependent marrow suppression, and idiosyncratic immune destruction.
- Antithyroid: carbimazole, propylthiouracil - warn every patient; sore throat/fever = urgent FBE
- Clozapine - mandatory count monitoring
- Sulfonamides (incl. co-trimoxazole), dapsone
- Anti-epileptics - carbamazepine, phenytoin, valproate
- NSAIDs, metamizole
- Captopril, procainamide, ticlopidine
- Rituximab - late-onset neutropenia 2-3 months after the last dose (often missed - the drug is long finished)
- Chloramphenicol, vancomycin, beta-lactams (high dose, prolonged), linezolid
- Methotrexate, azathioprine, mycophenolate, colchicine
- Immune checkpoint inhibitors
4. Pseudo-neutropenia (redistribution, not loss)
- Haemodialysis - complement activation on the membrane -> neutrophil margination onto pulmonary endothelium
- Transient nadir ~15-30 min into dialysis, recovers by 1 h
- Blood drawn during dialysis can show apparently severe neutropenia with no true reduction in neutrophil mass
- Duffy-null associated neutrophil count (as above)
- Endotoxin, complement activation, acute haemodialysis-like circuits
Cyclic neutropenia
- ELANE mutation, autosomal dominant
- Regular oscillation, period ~14-35 days (classically ~21 days), consistent within an individual
- Nadir accompanied by mouth ulcers, fever, pharyngitis, cervical adenopathy
- *No somatic abnormalities and no leukaemia risk (unlike severe congenital neutropenia*)
- Attenuates with age; occasionally fatal (clostridial sepsis, necrotising enteritis)
- Regular G-CSF raises the nadir and reduces infections
Diagnosis
First questions
- Isolated, or with other cytopenias? (isolated -> drug, autoimmune, ethnic; multiple -> marrow)
- Acute or long-standing? *Find old blood counts - this answers the question faster than any test*
- Drug and supplement history, including drugs stopped in the last 3 months
- Ancestry (Duffy-null), family history, ulcers/infections since childhood
- Recurrent oral ulceration and periodontal disease -> chronic neutropenia
Tests
- FBE + film (blasts, dysplasia, hypersegmentation, LGLs), reticulocytes
- Serial counts 2-3x/week for 6 weeks if cyclic neutropenia suspected - the only way to demonstrate the cycle
- B12, folate, copper, LFT, HIV/hepatitis serology, EBV/CMV, ANA, RF, immunoglobulins
- Anti-neutrophil antibodies - poor sensitivity and specificity, rarely changes management
- Flow cytometry + TCR gene rearrangement for LGL leukaemia
- Marrow aspirate/trephine + cytogenetics if: other cytopenias, abnormal film, splenomegaly, no explanation, or persistent severe neutropenia
- Genetic panel (ELANE, HAX1, SBDS, GATA2, WAS) if childhood onset or family history
Management
A. Febrile neutropenia - a medical emergency
- Definition: temperature >=38.0 C sustained or >=38.5 C once, with neutrophils <0.5 (or <1.0 and falling)
- *Empirical broad-spectrum IV antibiotics within 60 minutes of presentation. Do not wait for cultures or the count.*
- Piperacillin-tazobactam (or cefepime) first line in Australia
- Add vancomycin only for specific indications - suspected line infection, skin/soft tissue, haemodynamic instability, known MRSA colonisation
- Add gentamicin for shock or suspected resistant Gram negatives
- Blood cultures peripherally and from every lumen of any central line; urine, CXR, sputum, swabs of any focus
- MASCC or CISNE score to identify low-risk patients suitable for oral therapy or early discharge
- Persistent fever >4-7 days -> investigate for invasive fungal infection (CT chest, galactomannan, beta-D-glucan) and consider empirical antifungal
B. Reversing the cause
- Stop the culprit drug immediately - and record it as an allergy. Most idiosyncratic agranulocytosis recovers in 1-3 weeks
- Replace B12/folate/copper; treat HIV, alcohol, underlying malignancy
- Felty/LGL: methotrexate is first line; ciclosporin, cyclophosphamide; splenectomy rarely and only if refractory
- Autoimmune neutropenia: usually observation; corticosteroid or rituximab only if recurrent infection
C. G-CSF (filgrastim, pegfilgrastim)
- Primary prophylaxis if the regimen's febrile neutropenia risk >=20%, or 10-20% with patient risk factors (age >65, poor performance status, prior FN, marrow involvement)
- Secondary prophylaxis after a prior episode where dose intensity must be maintained
- Severe congenital and cyclic neutropenia - regular G-CSF
- *Not routinely for established febrile neutropenia* - shortens neutropenia but does not improve mortality
- Avoid in the 24 h before or after cytotoxic chemotherapy; causes bone pain and can produce a leukaemoid reaction and splenic enlargement
D. Prophylaxis and prevention in prolonged neutropenia
- Antibacterial (fluoroquinolone), antifungal (posaconazole in AML/MDS induction; fluconazole after transplant), antiviral (aciclovir if HSV seropositive), PJP prophylaxis with prolonged steroid or purine analogue
- Hand hygiene, avoid rectal examinations and suppositories; the neutropenic diet has been abandoned - no benefit
- Vaccination before treatment; no live vaccines during
- *Patients on carbimazole or clozapine need an explicit rule: fever or sore throat -> stop the drug and get an urgent FBE*
Associations
- Felty syndrome - seropositive RA + neutropenia + splenomegaly
- Splenomegaly present in only ~25%; occurs in ~1% of RA, usually longstanding, often "burnt-out" seropositive disease with nodules and high-titre RF; autoimmune basis
- Overlaps clinically with T-cell LGL leukaemia - check for an LGL clone in any RA patient with neutropenia
- SLE, Sjogren, sarcoidosis
- HIV, hepatitis B/C, EBV, parvovirus B19
- MDS, aplastic anaemia, PNH, hairy cell leukaemia, myelofibrosis
- Duffy-null (ACKR1) associated neutrophil count
- GATA2 deficiency - monocytopenia, atypical mycobacteria, MDS/AML
- WHIM syndrome (warts, hypogammaglobulinaemia, infections, myelokathexis)
- Shwachman-Diamond (exocrine pancreatic insufficiency, skeletal dysplasia), Chediak-Higashi, glycogen storage disease Ib
Natural history & complications
- Depends entirely on the cause and duration
- Drug-induced agranulocytosis: recovery in 1-3 weeks after withdrawal; mortality ~5%
- Chemotherapy-induced: predictable nadir day 7-14, recovery by day 21-28
- Benign ethnic and cyclic neutropenia: normal life expectancy
What determines infection risk
- Depth (<0.5) and duration (>7 days)
- Mucosal barrier injury, central venous catheter, corticosteroid, prior colonisation
Typical organisms
- Early: *Gram negatives incl. Pseudomonas*** (the reason for antipseudomonal empirical cover), coagulase-negative staphylococci, viridans streptococci
- Prolonged: **Candida, Aspergillus, mucormycosis**
- *Signs of infection are muted - no pus, minimal infiltrate on CXR. Fever may be the only sign*
Complications
- Septic shock, neutropenic enterocolitis (typhlitis), perianal sepsis, invasive fungal disease
- Severe congenital neutropenia: ~20% cumulative risk of MDS/AML, particularly with acquired CSF3R mutations
- Cyclic neutropenia carries no such risk
- Chronic oral ulceration, gingivitis, tooth loss
- Dose reductions and treatment delays compromising cancer cure
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