What are the diagnostic criteria for autoimmune neutropenia?

Diagnostic Criteria for Autoimmune Neutropenia

Autoimmune neutropenia is diagnosed by demonstrating an absolute neutrophil count (ANC) <1,500 cells/µL (with severe neutropenia defined as ANC <500 cells/µL) in the presence of detectable granulocyte-specific autoantibodies, after excluding secondary causes such as medications, infections, malignancies, and other autoimmune diseases. 1, 2

Core Diagnostic Requirements

Essential Laboratory Findings

• Absolute neutrophil count <1,500 cells/µL is the fundamental hematologic criterion, with severe neutropenia defined as ANC <500 cells/µL 1, 3
• Detection of anti-neutrophil antibodies using granulocyte immunofluorescence testing or flow cytometric analysis is required to confirm the autoimmune etiology 4, 2, 5

Important Caveat on Antibody Testing

• Autoantibodies may not be detectable on initial testing and screening must be repeated multiple times until antibody detection succeeds, as antibodies are not always present in the patient's sera at every time point 2
• Approximately 35% of autoantibodies show preferential binding to granulocytes from NA1 and NA2 homozygous donors, which may affect detection 2

Bone Marrow Examination Findings

• Bone marrow aspiration typically reveals normocellular or hypercellular marrow with a variably diminished number of segmented granulocytes 2
• Bone marrow examination helps exclude other causes of neutropenia such as aplastic anemia, myelodysplastic syndrome, or infiltrative processes 4, 2

Classification: Primary vs. Secondary

Primary Autoimmune Neutropenia

• Predominantly occurs in infants and young children, typically diagnosed between 5-15 months of age but can occur as early as day 33 of life 2
• Presents as an isolated hematologic abnormality without other autoimmune diseases 1
• Generally self-limited with spontaneous remission in 95% of cases, usually within 7-24 months 2

Secondary Autoimmune Neutropenia

• More common in adults and associated with established autoimmune diseases, infections, malignancies, medications, or post-transplantation states 1, 5
• Requires thorough evaluation to identify the underlying condition 1

Exclusion Criteria

Before diagnosing autoimmune neutropenia, you must systematically exclude:

• Medication-induced neutropenia by reviewing all current and recent medications 1
• Infectious causes including viral infections (though parvovirus B19 has not shown significant association) 2
• Malignancies, particularly hematologic malignancies 1
• Other primary immunodeficiencies such as severe congenital neutropenia (SCN), cyclic neutropenia, or chronic granulomatous disease 6
• Autoimmune lymphoproliferative syndrome (ALPS) if lymphadenopathy or splenomegaly is present, which requires elevated CD3+TCRαβ+ CD4-CD8- double-negative T cells ≥1.5% of total lymphocytes 6, 7

Clinical Presentation Supporting Diagnosis

• Benign infections despite severe neutropenia in 90% of pediatric cases, which is characteristic of primary AIN 2
• Recurrent infections, particularly skin and upper respiratory tract infections, in the setting of documented neutropenia 3
• Absence of other cytopenias or systemic features that would suggest alternative diagnoses 1, 2

Diagnostic Algorithm Summary

1. Document ANC <1,500 cells/µL on complete blood count with differential
2. Perform bone marrow aspiration to assess cellularity and exclude other causes
3. Test for anti-neutrophil antibodies using flow cytometry or immunofluorescence (repeat if initially negative)
4. Exclude secondary causes through medication review, infectious workup, and screening for autoimmune diseases
5. In pediatric patients with typical presentation (age 5-15 months, benign infections, isolated neutropenia), diagnosis can be made with antibody detection without extensive investigations 2
6. In adults, more extensive workup is required to identify secondary causes before diagnosing primary AIN 1, 5