Cutaneous and hepatic granulomas in a young woman with common variable immunodeficiency

S ir, Common variable immunodeficiency (CVID) is a disorder characterized by hypogammmaglobulinaemia and recurrent infections of the respiratory and gastrointestinal tract caused by encapsulated bacteria and Giardia lamblia.1 This disease has been associated with autoimmune and lymphoproliferative disorders and recently with the occurrence of non‐infectious cutaneous and visceral granulomas. We report a patient with cutaneous and hepatic granulomas 1 year after the diagnosis of CVID. A 17‐year‐old woman presented with a 7‐month history of an erythematous, infiltrated and well‐defined plaque, 4 cm in diameter, on her right cheek ( Fig. 1a). She had no cutaneous disease except herpes labialis. Because of the presence of sinus and pulmonary infections (pneumonia and bronchiectasias) and gastrointestinal infections (colitis caused by Clostridium difficile and G. lamblia), she had been fully investigated for an immunological deficiency 1 year previously. Results of laboratory investigation revealed decreased levels of IgM and IgG, and negligible levels of IgA. She also had an abnormal T‐cell count with an increased percentage of CD8 cells and natural killer cells and a decreased percentage of CD4 cells. Response of lymphocytes on culture with mitogens and antigens was diminished. On the basis of these results, she was diagnosed as having CVID. She received intravenous gammaglobulin once a month, vitamins and gentamicin by aerosol. When seen in our department, she was healthy with no lymphadenopathy or hepatosplenomegaly. Owing to an initial suspicion of infection (even though cutaneous infections are infrequent in this disease) by opportunist agents, i.e. mycobacteria, a skin biopsy was performed. This showed a dense infiltrate of non‐caseating epithelioid granulomas with occasional giant multinucleated cells and sparse lymphocytes in the mid‐dermis with periappendageal distribution (Fig. 1b). Ziehl–Nielsen, periodic acid–Schiff and silver stains were all negative and no fungi, mycobacteria or bacteria grew in specific cultures of biopsy material. (a) A well‐defined erythematous plaque, 4 cm in diameter, is evident on the right cheek. (b) Photomicrograph of lesional skin showing a dense infiltrate of non‐caseating epithelioid granulomas with occasional giant multinucleated cells and sparse lymphocytes in the mid‐dermis with periappendageal distribution (haematoxylin and eosin; original magnification, × 40). Five months later, she developed elevation of liver enzymes, although serological tests for hepatotrophic viruses, Brucella, Coxiella and a tuberculin test were all negative. Liver biopsies revealed a chronic hepatitis with lymphoid hyperplasia and numerous non‐caseating epithelioid granulomas. Fungal, mycobacterial and bacterial cultures of hepatic biopsy material were all negative. At the time of writing, the patient is not receiving any systemic treatment but is being closely observed at regular intervals. In the literature, we found 20 cases of non‐infectious granuloma in patients with CVID,2–6 as in our patient. Skin lesions coincide to be erythematous, indurated papules and plaques with central scaling and atrophy, showing a characteristic acral distribution and histological changes from sarcoid‐like to caseating granulomas.2 These lesions have been described in patients with other immunodeficiencies.3 Chronic granulomatous disease (a primary neutrophil defect) is most commonly associated with visceral granulomas, and cutaneous granulomas are uncommon.4 The immunodeficiencies associated with these lesions are combined B/T‐cell defects, e.g. severe combined immunodeficiency, Wiskott–Aldrich syndrome, ataxia and telangiectasia, as well as CVID, and some authors suggest that granulomas are a manifestation of a functional imbalance of cellular immunity.4 These lesions often undergo spontaneous regression without therapy. In most cases no treatment is necessary, but occasionally the process is aggressive and results in tissue destruction, in which case systemic corticosteroids (1–2 mg/kg per day) can be helpful.4, 5 Interleukin 24 and cyclosporin6 have been reported to be useful. Standard therapy for CVID consists of intravenously administered immunoglobulin to reduce the number of infections and improve the quality of life. However, there is no relationship between this treatment and the occurrence of lesions.5 Topical corticosteroids did not improve the lesions in the published cases, but our patient was treated with diflucortolone valerate 0.1% cream for 2 months and the infiltration diminished. Some authors have noted similarities between this syndrome and sarcoidosis.4, 6 An association with CVID is rare but well‐recognized and many cases of granulomatosis in immunodeficiencies (including our patient) show sarcoid‐like granulomas on histology. In spite of the morphology of the lesion, the histology and the decreased CD4/CD8 ratio, our patient did not have organomegaly or lymph node enlargement, and a chest X‐ray was normal. Her serum calcium and angiotensin‐converting enzyme levels were normal. A Kveim test was not performed because it is usually negative in CVID patients because of anergy, and is therefore considered unhelpful.6 There was no definite evidence of sarcoidosis in our patient.Topical corticosteroids did not improve the lesions in the published cases, but our patient was treated with diflucortolone valerate 0.1% cream for 2 months and the infiltration diminished. Some authors have noted similarities between this syndrome and sarcoidosis.4, 6 An association with CVID is rare but well‐recognized and many cases of granulomatosis in immunodeficiencies (including our patient) show sarcoid‐like granulomas on histology. In spite of the morphology of the lesion, the histology and the decreased CD4/CD8 ratio, our patient did not have organomegaly or lymph node enlargement, and a chest X‐ray was normal. Her serum calcium and angiotensin‐converting enzyme levels were normal. A Kveim test was not performed because it is usually negative in CVID patients because of anergy, and is therefore considered unhelpful.6 There was no definite evidence of sarcoidosis in our patient.