What causes low neutrophils (neutropenia)?

Causes of Low Neutrophils (Neutropenia)

Low neutrophils result primarily from chemotherapy-induced bone marrow suppression, drug-induced immune destruction, infections, autoimmune disorders, congenital genetic defects, or bone marrow infiltration by malignancy. 1, 2

Primary Mechanisms of Neutropenia

Neutropenia develops through three fundamental pathways that determine both etiology and clinical approach 2, 3:

• Decreased production from bone marrow suppression or failure 2, 3
• Increased destruction through immune-mediated mechanisms or consumption 2, 4
• Abnormal distribution including splenic sequestration 2, 5

Major Causes by Category

Chemotherapy and Cancer-Related Causes

Myelosuppressive chemotherapy is the most common cause of clinically significant neutropenia, particularly with regimens expected to cause neutropenia rates exceeding 50% 6, 7:

• High-risk regimens include lenalidomide plus alkylating agents or doxorubicin combinations 7
• Bone marrow infiltration by hematologic malignancies or metastatic solid tumors directly impairs neutrophil production 8
• Refractory hematologic malignancies cause marrow failure from disease itself and cumulative effects of multiple prior therapies 1

Drug-Induced Neutropenia

Drug-induced immune neutropenia occurs when drug-dependent antibodies target neutrophil membrane glycoproteins 4:

• Most commonly implicated drugs 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 annually for severe drug-induced neutropenia 4
• Mechanism involves hapten-induced antibody formation or autoantibodies against drug metabolites attached to neutrophil membranes 4

Infection-Related Neutropenia

Infections cause neutropenia through accelerated neutrophil consumption and bone marrow suppression 8, 2:

• Bacterial, viral, and fungal infections can all precipitate neutropenia 8
• Epstein-Barr virus particularly causes neutropenia in post-transplant settings 9
• Paradoxically, 50-60% of febrile neutropenic patients have underlying infections that both result from and potentially worsen the neutropenia 6, 8

Autoimmune and Immune-Mediated Causes

Autoimmune disorders cause neutropenia through antibody-mediated destruction 2, 4:

• Autoimmune diseases including systemic lupus erythematosus and rheumatoid arthritis produce anti-neutrophil antibodies 2
• Immune-mediated destruction reduces neutrophil survival in peripheral circulation 3

Congenital Neutropenia Syndromes

Genetic defects affecting neutrophil development cause chronic severe neutropenia 2, 5:

• Key genetic mutations include ELANE, HAX1, and SBDS genes affecting neutrophil precursor proliferation and maturation 2
• Mechanisms involve defects in membrane structures, secretory vesicles, mitochondrial metabolism, ribosome biogenesis, transcriptional regulation, and cytoskeletal dynamics 5
• Clinical significance includes increased risk for myelodysplasia and acute myeloid leukemia in certain congenital syndromes 5

Nutritional Deficiencies

Nutritional deficiencies impair neutrophil production 2:

• Vitamin B12 and folate deficiency cause megaloblastic changes affecting all hematopoietic cell lines including neutrophils 2
• Copper deficiency can cause isolated neutropenia 2

Clinical Risk Stratification

Severity Classification

Neutropenia severity directly correlates with infection risk 1, 6:

• Mild neutropenia: ANC 1000-1500/μL - minimal infection risk 2
• Moderate neutropenia: ANC 500-1000/μL - moderate infection risk 2
• Severe neutropenia: ANC <500/μL - high infection risk 1, 6
• Profound neutropenia: ANC <100/μL - greatest risk with 10-20% developing bloodstream infections 1, 6

Duration as Critical Factor

Duration of neutropenia is equally important as absolute count 1, 6:

• Prolonged neutropenia (>10 days) significantly increases infection risk and mortality 6
• Rate of decline and duration measure bone marrow reserve and correlate with severity of infection and clinical outcome 1

Common Pitfalls and Clinical Caveats

Do not assume all neutropenia in cancer patients is chemotherapy-related - consider drug-induced immune neutropenia, nutritional deficiencies, and infection as alternative or contributing causes 7, 2, 4.

Avoid using G-CSF prophylaxis indiscriminately - it should be reserved for regimens with >20% risk of febrile neutropenia or patients with additional risk factors, not for all neutropenic patients 1.

Remember that signs of infection are often absent or muted in neutropenic patients - fever may be the only indicator, requiring urgent empirical antibiotics within 2 hours 6.

Consider baseline ANC <1000/μL as an additional risk factor when assessing chemotherapy-related neutropenia risk, along with disease stage and previous treatments 7.