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Chronic Granulomatous Disease (CGD)

By

James Fernandez

, MD, PhD, Cleveland Clinic Lerner College of Medicine at Case Western Reserve University

Last full review/revision Dec 2019| Content last modified Dec 2019
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Chronic granulomatous disease is characterized by white blood cells that cannot produce activated oxygen compounds and by defects in phagocytic cell microbicidal function. Manifestations include recurrent infections; multiple granulomatous lesions of the lungs, liver, lymph nodes, and gastrointestinal and genitourinary tracts; abscesses; lymphadenitis; hypergammaglobulinemia; elevated erythrocyte sedimentation rate; and anemia. Diagnosis is by assessing oxygen radical production in white blood cells via a flow cytometric oxidative burst assay. Treatment is with antibiotics, antifungal drugs, and interferon gamma; granulocyte transfusions may be needed.

Chronic granulomatous disease (CGD) is a primary immunodeficiency disorder that involves phagocytic cell defects. More than 50% of cases of 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 gp91 phox (X-linked form), p22phox, p47phox, and p67phox genes.

In CGD, white blood cells (WBCs) do not produce hydrogen peroxide, superoxide, and other activated oxygen 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

Chronic granulomatous disease 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, Pseudomonas, fungi). Aspergillus infections are the leading cause of death.

Multiple granulomatous lesions occur in the lungs, liver, lymph nodes, and gastrointestinal and genitourinary tracts (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.

X-linked carriers of gp91 phox chronic granulomatous disease may be asymptomatic or develop various usually less severe symptoms, including joint pain with a lupus-like syndrome, aphthous ulcers, chorioretinal lesions, and photosensitivity (1).

Symptoms and signs reference

  • 1. Battersby AC, Braggins H, Pearce MS, et al: Inflammatory and autoimmune manifestations in X-linked carriers of chronic granulomatous disease in the United Kingdom. J Allergy Clin Immunol 140:628–630, 2017.

Diagnosis

  • Flow cytometric oxidative (respiratory) burst assay

Diagnosis of chronic granulomatous disease is by a flow cytometric oxidative (respiratory) burst assay to detect oxygen 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. In these forms, the assay using DHR demonstrates 2 populations of phagocytes, normal and affected.

Genetic testing is done to confirm the genetic defect but is not required to make the diagnosis. Siblings are usually screened using DHR shortly after the diagnosis.

Hypergammaglobulinemia and anemia can occur; erythrocyte sedimentation rate is elevated.

Treatment

  • Prophylactic antibiotics and usually antifungals

  • Usually interferon gamma

  • For severe infections, granulocyte transfusions

  • Hematopoietic stem cell transplantation

Treatment of chronic granulomatous disease is continuous prophylactic antibiotics, particularly trimethoprim/sulfamethoxazole 160/800 mg orally twice a day. Oral antifungals are given as primary prophylaxis or are added if fungal infections occur even once; most useful are

  • Itraconazole orally every 12 hours (100 mg for patients < 13 years, 200 mg for those ≥ 13 years or weighing > 50 kg)

  • Voriconazole orally every 12 hours (100 mg for patients weighing < 40 kg; 200 mg for those weighing ≥ 40 kg)

  • Posaconazole (400 mg orally twice a day)

Interferon gamma may reduce severity and frequency of infections and is usually included in the treatment regimen. Usual dose is 50 mcg/m2 subcutaneously 3 times a week.

Granulocyte transfusions can be lifesaving when infections are severe.

When preceded by pretransplantation chemotherapy, hematopoietic stem cell transplantation from an HLA (human leukocyte antigen)-identical sibling is usually successful.

Gene therapy is under study.

Key Points

  • Suspect chronic granulomatous disease (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, 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 hematopoietic stem cell transplantation.

Drugs Mentioned In This Article

Drug Name Select Trade
No US brand name
SPORANOX
NOXAFIL
VFEND
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