Neutrophil disorders

Name: Neutrophil disorders: Heme/Onc Board Review | HemeOncBuddy
Creator: Veli Bakalov, MD
License: https://creativecommons.org/licenses/by-nc-nd/4.0/

Benign Hematology

Neutrophil function

Ruler of absolute neutrophil count with profound below 100, severe below 500, neutropenia below 1,500 and a bracket for the 1,000 to 1,500 baseline of benign constitutional neutropenia. — ANC thresholds for neutropenia, and where benign constitutional neutropenia sits. Tap to enlarge.

Innate immunity: first responders to bacterial/fungal infection.
Functions: adhesion (selectins, integrins), chemotaxis, phagocytosis, oxidative burst (NADPH oxidase → ROS), degranulation, NETosis (neutrophil extracellular traps).
Neutropenia: ANC <1,500. Severe ANC <500. Profound <100.
Race-neutral cutoffs: benign constitutional / ethnic neutropenia common in Black and Middle Eastern populations; ANC 1,000 to 1,500 baseline; not pathologic.

Inherited neutrophil disorders

Pipeline from marrow production to degranulation, with each step linked to the inherited neutrophil disorder that breaks it, from severe congenital neutropenia to Chediak-Higashi syndrome. — Inherited neutrophil disorders mapped to the step of the neutrophil life cycle that fails. Tap to enlarge.

Inherited neutrophil disorders

Group	Disorder	Gene / mechanism	Key features
Neutropenia	Benign constitutional neutropenia (BCN) (formerly benign ethnic neutropenia)	Homozygous SNP in ACKR1 (Duffy antigen receptor for chemokines, DARC); linked to Duffy-negative RBCs	Partially protective against malaria (higher frequency in malaria-endemic ancestries) Relative shift of neutrophils from blood to tissues; not pathologic, no increased infection risk
	Severe congenital neutropenia (SCN)	Autosomal dominant ELANE (neutrophil elastase) mutation → misfolded protein accumulates → apoptosis Autosomal recessive Kostmann syndrome: HAX1 (mitochondrial protein) → membrane destabilization and apoptosis	BM: maturation arrest at the promyelocyte stage 20 to 25% develop AML from acquired CSF3R (G-CSF receptor) or RUNX1 mutations; G-CSF first-line, HSCT for G-CSF refractoriness/high requirement or clonal evolution (CNL also carries CSF3R mutation.)
	Cyclic neutropenia	Dominantly inherited; ELANE (ELA2) mutation in essentially 100% of cases	Neutropenia cycles every 15 to 35 days (nadir <200 up to >1K); BM shows myelocyte arrest during nadir Usually benign; G-CSF for severe infections NOT associated with increased AML risk; regular oscillations (classically ~21-day); may attenuate with age, but nadir does not reliably rise each cycle over time
	WHIM syndrome	Gain-of-function CXCR4 mutation → overactive CXCR4/CXCL12 signaling → retention of neutrophils in marrow (myelokathexis)	Warts, Hypogammaglobulinemia, Infections, Myelokathexis Peripheral neutropenia with hypercellular marrow rich in mature neutrophils Tx: IVIG, prophylactic antibiotics, plerixafor (and now mavorixafor, see below)
Neutrophil function	Chronic granulomatous disease (CGD)	X-linked (gp91phox) CYBB mutation (~65%) → dysfunctional NADPH oxidase (PHOX system) → ↓ respiratory (oxidative) burst and ROS	Recurrent infections with catalase-positive organisms (S. aureus, Nocardia, Serratia, Burkholderia, Aspergillus, Candida) Granulomatous colitis, restrictive lung disease, autoimmunity, MAS/HLH Abnormal DHR (dihydrorhodamine) test Tx: TMP-SMX, itraconazole, IFN-γ (~70% ↓ infections, no rise in oxidase), alloSCT, gene therapy
	Chediak-Higashi syndrome	LYST mutation → defective membrane fusion and granule trafficking → giant granules, ↓ granule release	Oculocutaneous albinism, recurrent bacterial infections, peripheral neuropathy Accelerated phase (often EBV-driven, HLH-like): hepatosplenomegaly, pancytopenia, death
	Leukocyte adhesion deficiency (LAD)	Type 1: β2-integrin (CD18) mutation Type 2: selectin-ligand defect Type 3: integrin-function genes (also platelet defect → bleeding) All → ↓ neutrophil chemotaxis and emigration from blood to infection sites	Delayed cord separation and delayed wound healing, recurrent bacterial infections without pus, marked neutrophilia Flow: LAD-I lacks CD18; LAD-II lacks CD15s (sialyl-Lewis X); LAD-III has normal integrin expression but defective activation Tx: alloSCT (5-yr OS ~75%)
	Hyper-IgE syndrome (HIES, Job syndrome)	Autosomal dominant (60 to 70%): STAT3 Autosomal recessive: DOCK8	Defective neutrophil chemotaxis and T-helper function, mild neutropenia, recurrent skin/sinus/lung infections, eczema, ↑ IgE, coarse facies, retained primary teeth DOCK8-HIES: severe atopy, cutaneous viral infections (HSV, HPV, molluscum), ↑ HPV squamous carcinoma and EBV-associated lymphoma; alloSCT curative and considered early

Acquired neutropenia

Drug-induced: chemotherapy (most common), antithyroid (PTU, methimazole/carbimazole), antipsychotics (clozapine), sulfasalazine, ticlopidine, ganciclovir, antibiotics (β-lactams, vancomycin, linezolid), DMARDs.
Drug-induced agranulocytosis: idiosyncratic, rare, sporadic, transient, but with significant morbidity and ~10% mortality. Eleven drugs cause ~50% of cases: carbimazole, clozapine, dapsone, dipyrone, methimazole, penicillin G, procainamide, propylthiouracil, rituximab, sulfasalazine, ticlopidine (plus prolonged vancomycin; and levamisole-adulterated cocaine/heroin). After most idiosyncratic drug-induced agranulocytosis (e.g., clozapine, thionamides) do not rechallenge; rituximab late-onset neutropenia is an exception, with rechallenge possible under monitoring; a lesser neutrophil drop may allow dose adjustment.
Infection: viral (HIV, HBV, HCV, EBV, parvovirus B19), bacterial sepsis, rickettsial, malaria.
Autoimmune: primary autoimmune neutropenia (mainly infants ~6 to 12 months; ~95% remit spontaneously over 2 years); SLE (leukopenia in ~50%, neutropenia in ~20 to 40%; marker of activity); Felty syndrome (RA + splenomegaly + neutropenia +/- Sjögren); LGL leukemia (shares features with Felty but is clonal/monoclonal; strong HLA-DR4 association in Felty and RA-associated T-LGL (not LGL leukemia generally)).
Marrow infiltration/replacement: leukemia, lymphoma. Marrow failure or ineffective production: aplastic anemia, MDS.
Nutritional: B12, folate, copper deficiency.
Hypersplenism: portal HTN, lymphoma.

Treatment of neutropenia

Flowchart for febrile neutropenia: broad-spectrum antibiotics within 1 hour, vancomycin only for listed indications, MASCC risk stratification with outpatient oral therapy for scores of 21 or more, and G-CSF prophylaxis thresholds. — Febrile neutropenia: empiric antibiotics within 1 hour, then MASCC risk stratification. Tap to enlarge.

Treat underlying cause; stop offending drugs.
GCSF (filgrastim, pegfilgrastim): severe congenital neutropenia, cyclic neutropenia, recovery from drug-induced neutropenia, chemo-induced neutropenia (primary prophylaxis if regimen ≥20% FN risk OR ≥10% with high-risk patient features). Often unnecessary in mild immune neutropenia; reserve for recurrent/serious infection. May flare joint disease in RA; contraindicated in sickle cell disease.
Autoimmune neutropenia: observe if well; G-CSF for recurrent/serious infection. Steroids not routine; IVIG transient. Treat any underlying autoimmune disease separately; LGL-associated: low-dose methotrexate.
Allo-HSCT: curative for severe congenital neutropenia; CGD (consider HSCT in suitable patients with a donor, ideally before irreversible organ damage).
Mavorixafor (Xolremdi): oral CXCR4 antagonist; FDA Apr 26, 2024 for WHIM syndrome ages ≥12, the first treatment for WHIM (4WHIM trial, Badolato, Blood 2024).
Antibiotic prophylaxis in CGD: TMP-SMX (bacterial), itraconazole (fungal); IFN-γ for selected patients.
Febrile neutropenia management: urgent antibiotics within 1 hour; broad-spectrum (cefepime, pip-tazo, or carbapenem); add vancomycin only for specific reasons (skin/soft tissue infection, hemodynamic instability, severe mucositis with FQ prophylaxis on ceftazidime, suspected catheter-related infection, MRSA/resistant gram-positive concern). MASCC ≥21 = low risk → consider outpatient oral ciprofloxacin + amoxicillin-clavulanate.

High yield (neutrophils)

CGD: catalase-positive organism infections (S. aureus, Aspergillus, Burkholderia, Serratia, Nocardia). Abnormal DHR test.
LAD: delayed cord separation + infections without pus + leukocytosis.
Chediak-Higashi: albinism + giant granules + neuropathy + accelerated phase HLH.
Job syndrome (hyper-IgE): STAT3; coarse facies, retained teeth, staph abscesses, ↑ IgE.
SCN (ELANE): promyelocyte arrest, AML risk; G-CSF first-line, HSCT for G-CSF refractoriness/high requirement, uncontrolled infection, or clonal evolution (MDS/AML); cyclic neutropenia (ELANE): 15 to 35 day cycles, no AML risk.
Felty syndrome: RA + splenomegaly + neutropenia.
Benign constitutional/ethnic neutropenia (ACKR1/Duffy): not pathologic; race-neutral cutoffs increasingly used.
Chemo neutropenia + fever: antibiotics within 1 hour; MASCC score for risk stratification.

Veli Bakalov MD, Board Review Notes 2026