Neutrophil Dysfunction

Neutrophil Dysfunction

 

Numerous disorders may cause neutropenia, which is defined as an absolute reduction in the number of circulating neutrophils.

Epidemiology

  • Incidence – each individual disorder is rare except for autoimmune disorders
  • Age – most often discovered before 1 year old
  • Gender – no gender preference except for X-linked disorders

Classification

  • Congenital
    • Cyclic hematopoiesis (cyclic neutropenia)
    • Severe chronic neutropenia
    • Familial benign neutropenia
    • Myelokathexis
  • Immune-mediated
    • Autoimmune neutropenia of infancy (ANI)
    • Immune-mediated neutropenia in the neonate
  • Complex syndromes
    • Chronic granulomatous disease
    • Primary immunodeficiencies (X-linked hyper IgM syndrome, hyper IgE syndrome)
    • Chédiak-Higashi syndrome
    • Shwachman-Diamond syndrome
    • Cartilage hair hypoplasia (onychotrichodysplasia)
    • Metabolic disorders – glycogen storage disease
    • Reticular dysgenesis
    • Fanconi anemia

Specific Diseases

  • Cyclical neutropenia
    • Genetics – autosomal dominant
    • Clinical presentation – recurring fever, mucosal ulcers and occasional life-threatening infections
    • Diagnosis – CBC (cyclical changes every 21 days in neutrophil counts)
  • Severe chronic neutropenia (Kostmann syndrome)
    • Genetics
      • Autosomal dominant, autosomal recessive, sporadic
    • Clinical presentation
      • Early onset of severe neutropenia and life-threatening infections
        • Cellulitis, omphalitis, stomatitis, sepsis, meningitis
        • Common organisms include S. aureus, E. coli and Pseudomonas spp
      • Late developing myelodysplastic syndrome and acute myelogenous leukemia
    • Diagnosis
      • Serial CBC testing will generally be adequate for initial diagnosis
      • Bone marrow reveals myeloid hyperplasia with maturation arrest
      • Genotyping confirms the diagnosis
  • Autoimmune neutropenia of infancy (ANI)
    • Clinical presentation
      • Later onset of mild to severe infections (8-10 months old)
        • Pyoderma, URIs, otitis media
    • Diagnosis
      • CBC shows non-cyclical neutropenia
      • Antineutrophil antibodies are present for >6 months
        • Antibodies are not found in severe chronic neutropenia or for >6 months in immune neutropenia of the neonate
  • Immune-mediated neutropenia in the neonate
    • Clinical Presentation
      • Similar to ANI
    • Diagnosis
      • Neutrophil antibody testing – antibodies are not present after 6 months
  • Hyper IgE syndrome (Jobs syndrome)
    • Clinical Presentation
      • Recurrent boils
      • Coarse facies
      • Impaired resorption of primary teeth
      • Recurrent mucocutaneous candida infections
    • Diagnosis
      • Immunoglobulin testing
        • IgE levels – elevated
        • All other levels – normal
      • Chemotaxis studies which need to include Candida-specific IgE neutrophil chemotaxis – abnormal
  • Chédiak-Higashi
    • Genetics – autosomal recessive
    • Clinical Presentation
      • Partial albinism
      • Severe infections – particularly with encapsulated organisms
      • Defective platelets
    • Diagnosis
      • CBC with differential testing
        • Peripheral smear demonstrates large cytoplasmic granules in the neutrophils and lymphocytes
        • Defective chemotaxis and intracellular killing
  • Shwachman-Diamond syndrome
    • Genetics – autosomal recessive
    • Clinical Presentation
      • Pancreatic insufficiency, neutropenia, chronic eczema and metaphyseal dysostosis
  • Onychotrichodysplasia
    • Genetics – autosomal recessive
    • Clinical Presentation
      • Hypoplastic nails
      • Neutropenia
      • Sparse hair
    • Diagnosis
      • CBC testing
        • Presence of neutropenia and lymphopenia
        • Clinical presentation with persistent neutropenia
  • Glycogen storage disease type 1b (GSD 1b)
    • Clinical Presentation (identical to von Gierke type [GSD 1a])
      • Hypoglycemia, hyperlipidemia and lactic acidosis
      • Hepatomegaly
      • Recurrent infections – oral and perianal abscesses
    • Diagnosis
      • CBC testing
      • Clinical presentation with neutropenia
  • Reticular dysgenesis
    • Clinical Presentation
      • Lymphoid and thymic hypoplasia with severe combined immune deficiency
      • Overwhelming infections in the first two weeks of life
    • Diagnosis
      • CBC shows neutropenia and lymphopenia
      • Lymphocyte subsets show severe deficiency of all types of lymphocytes

See Also