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Chronic Granulomatous Disease

by James Fernandez, MD, PhD

Chronic granulomatous disease is characterized by WBCs that cannot produce activated O 2 compounds and by defects in phagocytic cell microbicidal function. Manifestations include recurrent infections; multiple granulomatous lesions of the lungs, liver, lymph nodes, and GI and GU tract; abscesses; lymphadenitis; hypergammaglobulinemia; elevated ESR; and anemia. Diagnosis is by assessing O 2 radical production in WBCs via a flow cytometric oxidative burst assay. Treatment is with antibiotics, antifungal drugs, and interferon-γ; granulocyte transfusions may be needed.

More than 50% of cases of chronic granulomatous disease (CGD) are inherited as an X-linked recessive trait and thus occur only in males; in the rest, inheritance is autosomal recessive. Common mutations responsible for CGD affect the GP91PHOX (X-linked form), p22phox, p47phox, and p67phox genes. In CGD, WBCs do not produce hydrogen peroxide, superoxide, and other activated O 2 compounds because nicotinamide adenine dinucleotide phosphate oxidase activity is deficient. Phagocytic cell microbicidal function is defective; thus, bacteria and fungi are not killed despite normal phagocytosis.

Symptoms and Signs

CGD usually begins with recurrent abscesses during early childhood, but in a few patients, onset is delayed until the early teens. Typical pathogens are catalase-producing organisms (eg, Staphylococcus aureus; Escherichia coli; Serratia, Klebsiella, and Pseudomonas sp; fungi). Aspergillus infections are the leading cause of death.

Multiple granulomatous lesions occur in the lungs, liver, lymph nodes, and GI and GU tract (causing obstruction). Suppurative lymphadenitis, hepatosplenomegaly, pneumonia, and hematologic evidence of chronic infection are common. Skin, lymph node, lung, liver, and perianal abscesses; stomatitis; and osteomyelitis also occur. Growth may be delayed.

Diagnosis

  • Flow cytometric oxidative (respiratory) burst assay

Diagnosis is by a flow cytometric oxidative (respiratory) burst assay to detect O 2 radical production using dihydrorhodamine 123 (DHR) or nitroblue tetrazolium (NBT). This test can also identify female carriers of the X-linked form and recessive forms. Genetic testing is done only in research settings and is not required to make the diagnosis. Siblings are usually screened using DHR shortly after the diagnosis.

Hypergammaglobulinemia and anemia can occur; ESR is elevated.

Treatment

  • Prophylactic antibiotics and usually antifungals

  • Usually interferon gamma

  • For severe infections, granulocyte transfusions

  • Bone marrow transplantation

Treatment is continuous prophylactic antibiotics, particularly trimethoprim/sulfamethoxazole 160/800 mg po bid. Oral antifungals are given as primary prophylaxis or are added if fungal infections occur even once; most useful are itraconazole po q 12 h (100 mg for patients < 13 yr; 200 mg for those 13 yr or weighing > 50 kg), voriconazole po q 12 h (100 mg for those weighing < 40 kg; 200 mg for those weighing 40 kg), or posaconazole (400 mg bid). Interferon gamma may reduce severity and frequency of infections and is usually included in the treatment regimen. Usual dose is 50 mcg/m 2 sc 3 times/wk.

Granulocyte transfusions can be lifesaving when infections are severe. When preceded by pretransplantation chemotherapy, HLA-identical sibling bone marrow transplantation is usually successful.

Gene therapy is under study.

Key Points

  • Suspect CGD if patients have recurrent abscesses during childhood (sometimes not until the early teens), particularly if the pathogen is a catalase-producing organism (eg, Staphylococcus aureus; Escherichia coli; Serratia, Klebsiella, or Pseudomonas sp; fungi).

  • Use the flow cytometric oxidative burst assay to diagnose CGD and identify carriers.

  • Treat most patients with prophylactic antibiotics, antifungals, and interferon gamma.

  • For severe infections, give granulocyte transfusions.

  • Consider bone marrow transplantation.

Drugs Mentioned In This Article

  • Drug Name
    Select Trade
  • VFEND
  • SPORANOX
  • No US brand name
  • NOXAFIL

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