What could be the cause of chronic neutropenia in a 43-year-old adult with well-controlled type 2 diabetes mellitus (T2DM) on metformin (biguanide), without any constitutional symptoms?

Chronic Neutropenia in a Well-Controlled Type 2 Diabetic on Metformin

The most likely causes of chronic neutropenia in this 43-year-old patient are autoimmune/idiopathic neutropenia, benign ethnic neutropenia, or rarely, metformin-induced immune-mediated neutropenia, and the diagnostic approach should focus on excluding secondary causes through peripheral smear examination, antineutrophil antibody testing, and bone marrow evaluation if severe.

Primary Diagnostic Considerations

The absence of constitutional symptoms (fever, weight loss, night sweats) makes malignancy, active infection, and severe systemic disease less likely 1, 2.

Most Common Causes in This Age Group

• Chronic idiopathic neutropenia (CIN) or autoimmune neutropenia (AIN) are the most frequent causes of chronic neutropenia in adults without obvious secondary causes 3.
• These conditions are immune-mediated, often overlapping, and typically present with mild-to-moderate neutropenia without systemic symptoms 3.
• Unlike in children where spontaneous remission occurs in 3-5 years, adult CIN rarely remits and tends to persist 3.

Benign Ethnic Neutropenia

• Certain populations (African, Middle Eastern, West Indian descent) have constitutionally lower neutrophil counts (ANC 1.0-1.5 × 10⁹/L) without increased infection risk 1.
• This is a diagnosis of exclusion but should be considered early in the appropriate ethnic background 1.

Metformin as a Potential Cause

While metformin-induced neutropenia is rare, it has been documented as an immune-mediated phenomenon:

• A case report demonstrated severe neutropenia with bone marrow maturation arrest at the promyelocyte stage, with detectable anti-neutrophil autoantibodies specific to metformin 4.
• The neutropenia reversed within one week of metformin discontinuation, with neutrophil counts rising from 0.283 g/L to 1.9 g/L 4.
• Critical pitfall: This is exceptionally rare and should not be the first consideration, but temporal relationship to metformin initiation should be assessed 4.

Essential Diagnostic Workup

Initial Laboratory Assessment

• Peripheral blood smear examination to assess for dysplastic changes, abnormal cell morphology, large granular lymphocytes, or immature cells 5, 2.
• Complete blood count with differential to determine the absolute neutrophil count (ANC) and assess for other cytopenias 6.
• Antineutrophil antibody testing (direct and indirect granulocyte immunofluorescence), though its clinical utility remains uncertain in CIN/AIN 3.

Severity Classification and Risk Assessment

• Mild neutropenia: ANC 1.0-1.5 × 10⁹/L - minimal infection risk 6.
• Moderate neutropenia: ANC 0.5-1.0 × 10⁹/L - intermediate risk 6.
• Severe neutropenia: ANC <0.5 × 10⁹/L - high infection risk requiring intervention 6, 2.

When to Pursue Bone Marrow Evaluation

• Bone marrow aspirate and biopsy with cytogenetics are indicated if: 2
  • Severe neutropenia (ANC <0.5 × 10⁹/L) persists
  • Other cytopenias are present
  • Peripheral smear shows dysplastic or abnormal cells
  • History suggests congenital or intrinsic marrow disorder

Secondary Causes to Exclude

Autoimmune and Inflammatory Conditions

• Large granular lymphocyte (LGL) syndrome presents with chronic neutropenia and should be evaluated with flow cytometry if lymphocytosis or atypical lymphocytes are present 1.
• HIV, hepatitis, and other chronic viral infections require serologic testing 1.
• Rheumatologic conditions (lupus, rheumatoid arthritis) may present with isolated neutropenia before other manifestations 1.

Nutritional and Metabolic Factors

• Vitamin B12, folate, and copper deficiency can cause neutropenia, though these typically present with macrocytic anemia and elevated reticulocyte counts if marrow is responding 5.
• In a diabetic patient, nutritional assessment is reasonable but less likely given good glycemic control 5.

Management Approach Based on Severity

For Mild-to-Moderate Neutropenia (ANC >0.5 × 10⁹/L)

• Observation without prophylactic treatment is appropriate if the patient has no recurrent infections, fevers, or inflammatory symptoms 3.
• No prophylactic antibiotics or G-CSF are indicated 3.
• Regular monitoring every 3-6 months is sufficient 3.

For Severe Neutropenia (ANC <0.5 × 10⁹/L) with Recurrent Infections

• G-CSF (filgrastim) at low doses (1-3 mcg/kg/day subcutaneously) on an intermittent basis (daily, alternate-day, or thrice-weekly) is effective 7.
• Doses should be adjusted to maintain neutrophil levels in the normal or low-normal range 7.
• Treatment is reserved for patients with both severe neutropenia AND evidence of recurrent infections 3.

Critical Pitfalls to Avoid

• Do not assume metformin is the cause without temporal correlation - metformin-induced neutropenia is exceedingly rare and typically occurs shortly after drug initiation or reintroduction 4.
• Do not treat mild neutropenia prophylactically - most patients with ANC >0.5 × 10⁹/L do not require G-CSF or antibiotics 3.
• Do not overlook LGL syndrome - this can present identically to CIN/AIN but requires different long-term monitoring due to clonal nature 1.
• Do not use pegfilgrastim in chronic neutropenia - its long-acting nature prevents dose adjustment needed for chronic management 8.

Practical Algorithm

1. Confirm true neutropenia with repeat CBC and calculate ANC 6.
2. Review peripheral smear for morphologic abnormalities 5, 2.
3. Assess infection history - recurrent bacterial infections, oral ulcers, skin infections suggest functional significance 2.
4. Screen for secondary causes - HIV, hepatitis, autoimmune markers, B12/folate 1.
5. If ANC >0.5 × 10⁹/L and no infections: observe with periodic monitoring 3.
6. If ANC <0.5 × 10⁹/L or recurrent infections: proceed to bone marrow evaluation and consider G-CSF 3, 2.