ALLERGIC AND IMMUNOLOGIC CONDITIONS

Chronic Granulomatous Disease (CGD)

Classification: Primary phagocyte-killing defect caused by impaired NADPH oxidase respiratory burst (Kishiyama et al., 2019).

Key diagnostic discriminator: Recurrent deep abscesses or pneumonia caused by characteristic catalase-positive organisms, granuloma formation, and functional evidence of defective phagocyte oxidative metabolism (Kishiyama et al., 2019).

Clinical priority: Fever, focal pain, respiratory symptoms, neurologic symptoms, or hepatic tenderness may represent invasive fungal or deep bacterial infection even when external findings are limited (Kishiyama et al., 2019).

Etiology and risk factors

  • Most cases are X-linked; autosomal recessive forms occur. The causal genes encode components of the phagocyte NADPH oxidase complex (Kishiyama et al., 2019).
  • Presentation often occurs in childhood, but residual oxidase activity can delay recognition. Family history, unusual infections, and inflammatory bowel-like disease increase concern (Kishiyama et al., 2019).

Pathophysiology

  • Neutrophils ingest organisms normally but cannot generate an effective superoxide/hydrogen-peroxide respiratory burst. Intracellular killing is impaired (Kishiyama et al., 2019).
  • Catalase-positive organisms degrade their own peroxide, removing a substrate that CGD phagocytes might otherwise use. Persistent organisms trigger granulomas and dysregulated inflammation that can obstruct hollow organs (Kishiyama et al., 2019).

Clinical manifestations

  • Recurrent pneumonia, lymphadenitis, skin or liver abscess, osteomyelitis, bacteremia, poor wound healing, and granulomatous obstruction (Kishiyama et al., 2019).
  • High-yield organisms include Staphylococcus aureus, Serratia marcescens, Burkholderia cepacia complex, Nocardia species, and Aspergillus species. Colitis resembling inflammatory bowel disease can occur (Kishiyama et al., 2019).

Findings that argue against or redirect

  • Normal phagocyte oxidative metabolism on a valid functional study argues strongly against CGD (Kishiyama et al., 2019).
  • Low neutrophil number suggests neutropenia rather than a qualitative killing defect. Delayed cord separation with marked neutrophilia and little pus suggests leukocyte-adhesion deficiency (Kishiyama et al., 2019).
  • Normal bacterial killing does not exclude other phagocyte or immune disorders (Kishiyama et al., 2019).

Diagnostic evaluation

  • Test phagocyte oxidative metabolism to demonstrate the defective respiratory burst, then use genetic testing to classify the responsible NADPH oxidase defect and inheritance pattern (Kishiyama et al., 2019).
  • Culture and image suspected infection aggressively. Evaluate inflammatory bowel-like disease and granulomatous obstruction and assess at-risk relatives after confirmation (Kishiyama et al., 2019).

Expected diagnostic and laboratory findings

  • Functional testing shows absent or reduced stimulated phagocyte oxidative metabolism. Some X-linked carriers show mixed normal and abnormal cell populations (Kishiyama et al., 2019).
  • A pathogenic variant in an NADPH oxidase component confirms the subtype in the appropriate clinical and functional phenotype (Kishiyama et al., 2019).
  • The neutrophil count may be normal between episodes and can rise during infection (Kishiyama et al., 2019).

Differential diagnosis

  • Leukocyte-adhesion deficiency: delayed cord separation, neutrophilia, impaired pus formation, and abnormal leukocyte adhesion (Kishiyama et al., 2019).
  • Myeloperoxidase deficiency: a different phagocyte-enzyme defect with a generally milder infection pattern (Kishiyama et al., 2019).
  • Cystic fibrosis: recurrent respiratory infection plus characteristic pulmonary and gastrointestinal disease (Kishiyama et al., 2019).
  • Hyper-IgE syndrome: eczema, very high IgE, staphylococcal abscesses, and skeletal or dental features (Kishiyama et al., 2019).

Treatment and management

  • Long-term antibacterial and antifungal prophylaxis and interferon-gamma are commonly used. Treat suspected infection early with organism- and site-directed therapy; drainage may be required (Kishiyama et al., 2019; Norris, 2020).
  • Hematopoietic stem-cell transplantation can be curative. Avoid unnecessary immunosuppression, but inflammatory complications sometimes require specialist-directed anti-inflammatory treatment (Kishiyama et al., 2019; Norris, 2020).

Additional complications and red flags

  • Granulomas can obstruct the gastrointestinal or genitourinary tract (Kishiyama et al., 2019).

Content last reviewed:

References

Kishiyama, J. L., Chang, J. J., & Donovan, S. M. (2019). Disorders of the immune system. In G. D. Hammer & S. J. McPhee (Eds.), Pathophysiology of disease: An introduction to clinical medicine (8th ed.). McGraw-Hill Education.

Norris, T. L. (2020). Porth’s essentials of pathophysiology (5th ed.). Wolters Kluwer.