A 4-year-old boy presents with a recent history of persistent pneumonia. A detailed past medical history reveals several recurrent infections including pneumonia and lymph node abscesses growing Staphylococcus aureus and Burkholderia cepacia. His parents claim that he has been prescribed multiple courses of antibiotics over the last month with no improvement in his respiratory symptoms. There is no family history of immunodeficiency. Examination of the child revealed mild subcostal retractions and diffuse rales bilaterally. A chest x-ray demonstrated bilateral infiltrates of the upper and middle lung fields and a CT showed multifocal pneumonia (Figure 220-1). Diagnostic bronchoalveolar lavage and serological tests confirmed the presence of invasive pulmonary aspergillosis and the patient was placed on appropriate antifungal treatment. Because of the history and types of infection, a work-up for immunodeficiency was undertaken and the child was found to have chronic granulomatous disease.

Chronic granulomatous disease (CGD) is the result of impaired intracellular microbial killing by phagocytes leading to formation of granulomata and recurrent infections with bacteria and fungi. Phagocytes are unable to kill the microbes they ingest secondary to a defect in a system of enzymes that produce reactive oxygen compounds. The most common and severe form of CGD is the X-linked type (~70% of all CGD cases) seen only in boys.

CGD, Chronic Dysphagocytosis, Chronic Familial Granulomatosis, Septic Progressive Granulomatosis, Fatal Granulomatosis of Childhood, Impotent Neutrophil Syndrome, Congenital Dysphagocytosis, Bridges-Good syndrome, and Quie syndrome.

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  CGD affects around 1:200,000 people in the US.¹

  
  
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  The frequency of CGD is equal across ethnic and racial groups with disease presentation ranging from infancy into late adulthood.

  
  
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  Most patients receive a diagnosis as toddlers.

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  Normal phagocytes utilize NADPH oxidase to generate reactive oxygen compounds like superoxide, which is essential for direct killing of certain catalase-positive bacteria and fungi.

  
  
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  The enzyme that catalyzes the respiratory burst, NADPH oxidase, is a complex made up of subunits. One of 4 subunits may be defective in CGD.²

  
  
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  Approximately 2/3 of CGD cases result from defects in the X-linked gene encoding the gp91phox subunit. The autosomal recessive forms of CGD are caused by mutations in the remaining subunits p22phox, p47phox, and p67phox. A recently discovered fifth subunit, p40phox, has been found to contribute to the autosomal recessive form of CGD as well.³

  
  
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  Mutations leading to a loss or functional inactivation of one of these subunits leads to susceptibility of infection from any number of microorganisms (most commonly Staphylococci, Aspergillus, Serratia, Nocardia, and Burkholderia).

The following factors increase the risk of developing CGD:

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  Parents who are carriers of the recessive gene and thus can transmit the gene to their offspring in an autosomal recessive manner.

  
  
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  Male gender, as most mutations are X-linked.

  
  
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  A family history of unexplained recurrent or chronic infections.

  
  
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  Rare cases may be due to spontaneous mutations.⁴

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  Median age at diagnosis is 2.5 to 3 years.⁵

  
  
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  Diagnosis may be delayed as a result of broad spectrum antibiotic use or if the manifestations are less severe (as in the autosomal recessive forms of the disease).

  
  
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  Carrier females can exhibit some symptoms due to high degree of lyonization of the functional gene creating a mosaic pattern. This can create a discoid lupus appearance (Figure 220-2).⁶ Most female carriers are asymptomatic.

Clinical Features

Infection

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  Recurrent or unusually severe bacterial and fungal infections most often manifesting as pneumonia, abscesses, suppurative adenitis (Figure 220-3), osteomyelitis (Figure 220-4), bacteremia/fungemia, superficial skin infections, and organ abscesses (liver, spleen, brain; Figure 220-5).

  
  
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  Typical bacteria found in US and European patients include S. aureus and Burkholderia. Fungi isolated in CGD are Aspergillus and Nocardia species.⁷