Neutropenia

Neutropenia is a deficiency in the number of neutrophils, also known as polymorphonuclear leukocytes, or PMNs. Neutropenia is generally defined as an absolute neutrophil count <1,500/mL. Counts of <500/mL represent severe, life-threatening deficiency. Neutropenia often accompanies other disorders, but here we describe neutropenia when it occurs in isolation or as the predominant characteristic of disease. Most cases are acquired due to increased destruction of neutrophils (eg, from infections, drugs, immune defects) or decreased production of neutrophils (eg, from nutritional defects, malignancies). Chemotherapeutic treatment is a common cause of neutropenia. Some congenital disorders are also associated with neutropenia and vary in severity, from mild conditions such as benign familial or constitutional neutropenia, which may not lead to infections, to severe congenital disorders that result in serious chronic infections (Gibson, 2014). Infection-related neutropenia in children may be caused by a virus (Gibson, 2014). Laboratory testing for neutropenia includes CBC, immunoglobulin evaluation, flow cytometry, and genetic testing.

Quick Answers for Clinicians

Diagnosis

Indications for Testing

  • In neonates – recurrent bacterial infections
  • In older children, adolescents, adults
    • Low neutrophil count as incidental finding on CBC
    • Recurrent infections, oral ulcerations, or delayed healing
    • Acute febrile illness or sepsis
    • Existing ​neutropenia, which must be monitored for severity

Laboratory Testing

  • Initial testing
    • CBC
      • At least three CBCs recommended to demonstrate persistent neutropenia
    • Blood smear
    • Lymphocyte flow cytometry panel testing – to rule out cellular defects
  • Other testing based on clinical presentation
    • Neutrophil antibody testing
    • Rheumatic disorder testing (eg, antinuclear antibodies [ANAs])
    • Nutritional assessment (eg, B12)
    • Bone marrow biopsy and aspirate
    • Genetic testing – may be necessary to confirm specific disorder

Differential Diagnosis

Background

Epidemiology

  • Neutropenia
    • Increased prevalence in African Americans; less common in Caucasian and Mexican Americans (Hsieh, 2007)
  • Congenital neutrophil disorders
    • Incidence – rare (3-8/million) (Donadieu, 2013)
    • Age – more severe disorders usually discovered before 1 year; less severe disorders may be discovered later
    • Sex – M:F, equal (except for X-linked disorders)

Clinical Presentation

  • Clinical presentation and severity vary based on etiology (Gibson, 2014)
    • Benign familial or constitutional neutropenia
      • Typically not associated with clinical sequelae; no follow-up is needed after diagnosis is established
    • Congenital neutropenia
      • Recurrent infections – omphalitis, septicemia, abscess formation early in life
      • Those who survive infancy frequently show progressive periodontitis
      • May occur as part of a syndrome (eg, Chediak-Higashi syndrome, Shawchman-Diamond, or cartilage hair hypoplasia; see Specific Diseases below)
    • Cyclic neutropenia
      • Congenital disease – neutropenic episodes occur every 2-5 weeks
      • Typically mild, but infections or mouth ulcers can develop during neutropenic period
    • Drug-induced agranulocytosis (absence of granulocytes)
      • Acute febrile illness or sepsis
    • Primary autoimmune neutropenia
      • Typically occurs during infancy (first year)
      • May be severe, with serious infections, but usually resolves within 2 years
    • Secondary autoimmune neutropenia
      • Typically in adults in connection with systemic autoimmune disease
      • Recurrent infections and neutrophil count <500/mL
    • Felty’s syndrome
    • Large granular lymphocyte leukemia-associated neutropenia
    • Chronic idiopathic neutropenia
      • Unknown pathogenesis
      • Diagnosis of exclusion
      • Often benign but occasionally results in recurrent infections

Pathophysiology

  • Immunologic and hematologic parameters are diverse (see Specific Diseases below)
  • Congenital neutropenias
    • Exact molecular pathogenesis varies by genetic defect, but all lead to maturation arrest of precursor myeloid cells due to increased apoptosis
    • Increased apoptosis might be caused by the unfolded protein response due to accumulation of misfolded proteins (eg, ELANE, G6PC3), mitochondrial membrane potential (HAX1), or defective mitosis and cytokinesis (WAS)

Genetics

Autosomal recessive (AR), autosomal dominant (AD), or X-linked (XL) inheritance (see Specific Diseases below)

Specific Diseases

The following tables are based on the International Union of Immunological Societies 2017 Primary Immunodeficiencies report (Picard, 2018)

ARUP Lab Tests

Identify the presence of neutropenia

Use to assist in evaluation of neutropenia

Use to rule out cellular defects

Support the diagnosis of immune neutropenia in various autoimmune disorders

A positive result is not definitive for specific antineutrophil antibodies; anti-HLA antibodies and immune complexes may also cause a positive result; the results of this test should be correlated to clinical history and other data

Related Tests

Preferred genetic test for individual with clinical phenotype of primary antibody deficiency (eg, hyper-IgM syndrome, agammaglobulinemia, or common variable immunodeficiency)

For hyper-IgM syndrome genetic testing, refer to the hyper-IgM sequencing and deletion/duplication panel

For agammaglobulinemia genetic testing, refer to the agammaglobulinemia sequencing and deletion/duplication panel

Refer to Test Fact Sheet for a complete list of the genes tested and test limitations

Preferred test for evaluating vitamin B12 deficiency in individuals with macrocytic or unexplained anemia, or unexplained neurologic disease

Aid in detection of vitamin B12 and folate deficiency in individuals with macrocytic or unexplained anemia, or unexplained neurologic disease

Medical Experts

Contributor

Delgado

Julio Delgado, MD, MS
Professor of Clinical Pathology, University of Utah
Chief, Division of Clinical Pathology, University of Utah and ARUP Laboratories
Chief Medical Officer and Director of Laboratories at ARUP Laboratories
Contributor

References

Additional Resources
Resources from the ARUP Institute for Clinical and Experimental Pathology®