(See also Overview of Immunodeficiency Disorders Overview of Immunodeficiency Disorders Immunodeficiency disorders are associated with or predispose patients to various complications, including infections, autoimmune disorders, and lymphomas and other cancers. Primary immunodeficiencies... read more and Approach to the Patient With an Immunodeficiency Disorder Approach to the Patient With Suspected Immunodeficiency Immunodeficiency typically manifests as recurrent infections. However, recurrent infections are more likely to have causes other than immunodeficiency (eg, inadequate treatment, resistant organisms... read more .)
Chronic granulomatous disease (CGD) is a primary immunodeficiency disorder Primary Immunodeficiencies Immunodeficiency disorders are associated with or predispose patients to various complications, including infections, autoimmune disorders, and lymphomas and other cancers. Primary immunodeficiencies... read more that involves phagocytic cell defects Phagocytic cell defects Immunodeficiency disorders are associated with or predispose patients to various complications, including infections, autoimmune disorders, and lymphomas and other cancers. Primary immunodeficiencies... read more . 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 gp91phox (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 of CGD
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 gp91phox 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 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... read more ).
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 of CGD
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.
Hypergammaglobulinemia and anemia can occur; erythrocyte sedimentation rate is elevated.
Treatment of CGD
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 sulfamethoxazole/trimethoprim 800/160 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 once a day (100 mg capsule for patients < 13 years or weighing < 50 kg; 200 mg tablet for those ≥ 13 years or weighing > 50 kg)
Voriconazole orally every 12 hours (9 mg/kg oral suspension for patients 2 to 12 years or weighing < 40 kg; 200 mg tablet for those weighing ≥ 40 kg)
Posaconazole 300 mg delayed-release tablet orally twice a day on day 1, then 300 mg once daily; weight-based dosing for patients weighing < 40 kg
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 Hematopoietic Stem Cell Transplantation Hematopoietic stem cell (HSC) transplantation is a rapidly evolving technique that offers a potential cure for hematologic cancers ( leukemias, lymphomas, myeloma) and other hematologic disorders... read more from an HLA (human leukocyte antigen)-identical sibling is usually successful.
Gene therapy is under study.
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,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|
|Primsol, Proloprim, TRIMPEX|
|ONMEL, Sporanox, TOLSURA|