Beware Adult Onset CGD in Subjects with Pulmonary or Extrapulmonary Granulomas but Negative AFB & Tuberculous Culture

 Chronic Granulomatous Disease (CGD) is rare and affects 1 in 200,000 live births. While 75% have the X-linked form (and thus presenting in boys) due to a protein subunit of NADPH oxidase called gp91phox, the rest have an autosomal recessive form due to other protein subunits of the same enzyme, namely p22phox, p47phox, and p67 phox. Of these, p47phox is the second commonest and can present during adulthood occasionally. The involved gene is that of NCF-1 (Neutrophil Cytosolic Factor-1). The average age for presentation of the X-linked form is 3 years, and for the autosomal recessive forms, 8 years.

When CGD presents in adulthood, it is often confused with tuberculosis due to a pulmonary involvement (the most commonly affected organ in CGD), and presence of granulomas on biopsy. These granulomas are however, non-necrotising, and obviously without detectable AFB and yield negative cultures for M.tuberculosis. They are therefore sometimes diagnosed as pulmonary sarcoidosis, given the geographical setting and demographics.

Sputum or bronchoscopic washings growing the following 6 genus in a subject with pulmonary granuloma should lead to a suspicion of CGD- Aspergillus, Candida, Staphylococcus, Serratia, Burkholderia or Nocardia.

These patients often have hyperglobulinemia, with raised Ig levels, but this is not invariable. 

CGD can affect other areas, and thus cause abscesses or cellulitis in the skin, gingivitis (but not periodontitis, unlike leucocyte adhesion defects) Crohn's like granulomas in the intestines, and spinal abscesses. Granulomas can cause obstructive lesions in the urogenital & GI tracts. Delayed wound healing is often a notable feature.

Unlike LAD, which can also rarely present in adulthood, the neutrophil count tends to be normal between infectious episodes. Just for context, there are two forms of LAD, including LAD-1, caused by a defect of CD18, which is a part of the heterodimeric beta-integrins, and LAD-2, caused by a defect in fucosylation, and thus an absence of Sialyl Lewis-X , the latter being necessary for neutrophils to roll on endothelial cells prior to adhesion and diapedesis. Subjects with LAD tend to have severe periodontitis and perpetually high neutrophil counts. LAD-2 is associated with developmental abnormalities such as stunted growth.

The most convenient diagnostic test for CGD is flow cytometry with Dihydrorhodamine 123. Absence of fluorescent staining indicates abrogation of oxidative burst in neutrophils, which is characteristic of CGD. An alternative test is the Nitroblue tetrazolium test (NBT).

The only curative treatment is allogeneic BMT. Symptoms can be improved by treatment with gamma-interferon, and prophylactic administration of co-trimoxazole and itraconazole. Infective episodes should be treated with specific antibiotics.