What are the causes of severe neutropenia?

Causes of Severe Neutropenia

Severe neutropenia (absolute neutrophil count <500 cells/µL) results primarily from chemotherapy-induced bone marrow suppression, congenital disorders affecting neutrophil production, drug-induced immune destruction, and bone marrow infiltration by malignancy. 1

Primary Etiologic Categories

Chemotherapy-Induced Neutropenia (Most Common)

• Myelosuppressive chemotherapy is the leading cause of severe neutropenia in cancer patients, with 70-100% of patients developing febrile episodes after intensive chemotherapy 1
• High-risk regimens include 3-drug combinations with lenalidomide plus alkylating agents or doxorubicin, with expected neutropenia rates >50% 2
• The severity depends on chemotherapy dose intensity, duration of treatment, and baseline bone marrow reserve 1
• Both the rate of neutrophil decline and duration of neutropenia are critical determinants of infection risk and clinical outcomes 1

Congenital Severe Chronic Neutropenia (SCN)

• ELANE gene mutations are the most common genetic cause of congenital neutropenia, presenting with autosomal dominant, recessive, or X-linked inheritance patterns 1, 3
• Infants typically present with recurrent bacterial infections within the first 6 months of life, affecting respiratory, digestive, and skin systems 3
• SCN carries an 11% cumulative risk of progression to MDS/AML at a median age of 16.2 years, often preceded by CSF3R and RUNX1 somatic mutations 1
• Other genetic causes include cyclic neutropenia and idiopathic neutropenia, which generally respond to lower G-CSF doses (1-3 mcg/kg/d) compared to congenital forms requiring 3-10 mcg/kg/d 1

Drug-Induced Immune Neutropenia (DIIN)

• Drug-dependent antibodies form against neutrophil membrane glycoproteins causing rapid neutrophil destruction 4
• High-risk medications include dipyrone, diclofenac, ticlopidine, antithyroid drugs (propylthiouracil), carbamazepine, sulfamethoxazole-trimethoprim, β-lactam antibiotics, clozapine, and vancomycin 4
• Incidence ranges from 1.6 to 15.4 cases per million population per year for non-chemotherapy drugs 4
• Presents acutely with fever, chills, and severe infections that can be fatal if untreated 4

Bone Marrow Disorders

Malignant Infiltration:

• Direct bone marrow infiltration by hematologic malignancies or metastatic solid tumors impairs neutrophil production 5
• Myelodysplastic syndromes (MDS) cause ineffective hematopoiesis with qualitative and quantitative neutrophil defects 1

Inherited Bone Marrow Failure Syndromes:

• Shwachman-Diamond syndrome (SDS) presents with pancreatic exocrine insufficiency, skeletal abnormalities, and neutropenia due to defective ribosome biogenesis 1
• SAMD9/SAMD9L mutations cause severe neutropenia with high MDS/AML risk, often with monosomy 7 or uniparental disomy 7q 1
• Diamond-Blackfan anemia (DBA) involves ribosomal protein gene mutations (RPS19, RPL5, RPS24) with macrocytic anemia and MDS risk 1
• GATA2 deficiency causes MonoMAC syndrome with severe infections and high progression risk to MDS/AML 1

Emerging Genetic Predispositions

• ERCC6L2 mutations (autosomal recessive) affect DNA repair pathways and predispose to bone marrow failure and myeloid malignancies 1
• MBD4, MECOM, and ERG variants are newly recognized causes with variable MDS/AML risk 1

Critical Clinical Considerations

Infection Risk Stratification

• Risk is inversely proportional to neutrophil count, with greatest danger when ANC <100 cells/µL 1, 6
• Duration of neutropenia >10 days significantly amplifies infection risk 6
• Approximately 10-20% of patients with ANC <100 cells/µL develop bloodstream infections 1, 6
• 50-60% of febrile neutropenic patients have established or occult infections 1, 6

Common Pitfalls

• Do not overlook drug-induced causes: A thorough medication history is essential, as DIIN can be rapidly fatal if the offending agent is not discontinued 4
• Congenital neutropenia requires genetic testing and long-term surveillance for MDS/AML transformation, particularly in patients requiring high-dose G-CSF 1
• Corticosteroids and lymphocyte-depleting agents (fludarabine) blunt fever and mask infection signs, delaying diagnosis 1
• Monosomy 7 in SAMD9/SAMD9L patients may spontaneously resolve in preschool children, making HSCT timing decisions challenging 1

Diagnostic Approach Priorities

• Confirm severe neutropenia with ANC <500 cells/µL and examine peripheral blood smear for morphologic abnormalities 7
• Review complete medication history including over-the-counter drugs and recent exposures 4, 7
• Obtain bone marrow aspirate/biopsy with cytogenetics when chronic neutropenia is present or malignancy is suspected 7
• Consider genetic testing for congenital causes in children with recurrent infections, family history, or syndromic features 1, 3
• Evaluate for anatomic factors: tumor obstruction causing postobstructive pneumonia, genitourinary/hepatobiliary obstruction, or colonic mucosal invasion 1