What are the causes of mild neutropenia?

Causes of Mild Neutropenia

Mild neutropenia (ANC 1000-1500 cells/mm³) is most commonly caused by medications, particularly antibiotics and immunosuppressive agents, followed by viral infections, nutritional deficiencies, and benign ethnic neutropenia. 1, 2

Primary Etiologic Categories

Drug-Induced Neutropenia (Most Common)

• Medications are the leading cause of acquired neutropenia in clinical practice, making detailed medication history essential 1
• Antibiotics, especially semisynthetic penicillins, typically cause neutropenia after 2 weeks or more of therapy through hypersensitivity reactions or dose-related bone marrow suppression 3
• Immunosuppressive agents used in rheumatoid arthritis and transplant patients frequently induce neutropenia, including methotrexate (check for concurrent folic acid deficiency), azathioprine, and mycophenolate 1, 4
• Valproic acid causes dose-related thrombocytopenia and can cause leukopenia, bone marrow suppression, pancytopenia, and agranulocytosis 5
• The mechanism involves either hypersensitivity reactions or toxic suppression of white blood cell precursors 3

Viral Infections

• Viral pathogens commonly cause transient neutropenia through increased peripheral destruction or bone marrow suppression 4
• Common viral causes include Herpes simplex virus, respiratory syncytial virus, influenza, and parainfluenza 6, 7, 8
• Viral-induced neutropenia is typically acute and self-limited 2, 9

Nutritional Deficiencies

• Folic acid deficiency should be routinely sought in patients taking methotrexate, as it can contribute to neutropenia 1
• Vitamin B12 deficiency can cause macrocytic anemia with associated neutropenia 4
• Copper deficiency is an underrecognized cause, particularly in patients with malabsorption or after gastric surgery 4

Benign Ethnic Neutropenia

• Constitutional neutropenia predominantly affects patients of African descent 1
• This is usually moderate (ANC 1000-1500 cells/mm³) and well tolerated without increased infection risk 1
• Represents a normal variant rather than pathologic condition 2

Autoimmune and Rheumatologic Causes

• Autoimmune neutropenia can occur as a primary disorder or secondary to rheumatoid arthritis 1
• Felty's syndrome (RA with splenomegaly and neutropenia) is accompanied by large granular lymphocytic leukemia in 40% of cases 1
• Systemic lupus erythematosus and other autoimmune conditions can cause immune-mediated neutrophil destruction 2

Bone Marrow Disorders

• Acquired disorders of myeloid progenitor cells represent less frequent causes of chronic neutropenia 9
• Myelodysplastic syndromes can present with isolated neutropenia or as part of multilineage cytopenias 9
• Lymphoproliferative infiltrates in transplant patients can cause neutropenia 4

Pathophysiologic Mechanisms

The three primary mechanisms underlying neutropenia are:

• Decreased bone marrow production - most common with drug toxicity and nutritional deficiencies 2
• Increased peripheral destruction - typical of autoimmune causes and viral infections 2, 9
• Splenic sequestration - seen with splenomegaly in Felty's syndrome and portal hypertension 1, 2

Clinical Approach

Immediate medication review is the critical first step, with discontinuation of any potentially causative drugs 1

• Obtain complete blood count with differential to confirm mild neutropenia (ANC 1000-1500 cells/mm³) and assess other cell lines 1, 2
• Review all medications, particularly antibiotics (especially if used >2 weeks), immunosuppressants, and anticonvulsants 1, 3
• Assess for viral symptoms (fever, respiratory symptoms, rash) suggesting acute viral infection 4
• Check nutritional markers: folate, vitamin B12, and copper levels, especially in patients on methotrexate or with malabsorption 1, 4
• Consider ethnic background for benign ethnic neutropenia in asymptomatic patients of African descent 1
• Examine for splenomegaly suggesting Felty's syndrome or portal hypertension 1

Most patients with mild neutropenia improve after discontinuation of the offending drug, typically within days to weeks 3