Patients with common variable immunodeficiency who have granulomatous lesions in lymphoid tissues, solid organs, or skin have occasionally been described [10-13]. However, the actual frequency of granulomas in common variable immunodeficiency is uncertain. In one series [10], 3 of 40 patients (7.5%) had a sarcoid-like syndrome; in another [3], 5.4% of patients had granulomas. In a recent series [13], sarcoidosis was diagnosed in 10% of patients. We describe 17 hypogammaglobulinemic patients (from among a total of 189 patients with common variable immunodeficiency) who were found to have granulomas on one or more tissue biopsies. The clinical and immunologic characteristics of these patients and their current clinical status are discussed.

Methods

Top Methods Results Discussion Author & Article Info References

Blood studies were performed before intravenous immunoglobulin was infused. Serum immunoglobulin levels were quantitated by radial immunodiffusion or nephelometry. The extent of lymphocyte proliferation to mitogens (phytohemagglutinin, concanavalin A, and pokeweed mitogen) and antigens (Candida albicans and tetanus toxoid) was examined, and T and B lymphocytes were enumerated [2, 5]. Pathology slides were reviewed for the 11 patients for whom these slides were available. Levels of angiotensin-1-converting enzyme (ACE) were measured by using a standard spectrophotometric enzymatic assay (normal range, 8 to 52 U/L). Biopsies were performed in patients who had diffuse or nodular pulmonary disease, lymphadenopathy, or hepatic dysfunction.

Results

Top Methods Results Discussion Author & Article Info References

Patients

Seventeen of 189 patients (9.0%) with common variable immunodeficiency were found to have granulomas on biopsy of one or more tissue samples. The 17 patients ranged in age from 9 to 59 years; 12 of the 17 were female (Table 1 and Table 3). Although only 6 of 189 patients with common variable immunodeficiency were black (3.2%) and 3 were Hispanic (1.6%), 3 black patients (patients 1, 3, and 12) and 1 Hispanic patient (patient 10) had granulomas. In 7 of 17 patients, sarcoidosis was diagnosed before common variable immunodeficiency was diagnosed (Table 1 and Table 3). Four of these 7 patients had granulomas as shown by biopsy results and had pulmonary radiologic findings that suggested sarcoidosis; 3 had no pulmonary disease at the time when sarcoidosis was diagnosed. Eight patients were known to have hypogammaglobulinemia before granulomas were found.

Laboratory Tests and Immune Function

Five of 17 patients had decreased lymphocyte counts and CD4 cell counts; all but 3 of the 14 measured had a preserved ratio of CD4 to CD8 cells (Table 1 and Table 3). Sixteen of 17 patients had substantially decreased T-cell proliferation to mitogens, and proliferative responses to antigens were low in 9 of 13 patients (Table 1 and Table 3). Levels of ACE were elevated in 7 of 11 patients in whom these levels were measured (Table 2). For comparison, we tested the serum specimens of 12 patients with common variable immunodeficiency and 2 patients with X-linked agammaglobulinemia who were not known to have granulomas. Four patients with common variable immunodeficiency and both patients with X-linked agammaglobulinemia had elevated ACE levels.

Pathology

Biopsy tissue specimens were taken from the lung (7 patients), lymph nodes (7 patients), liver (7 patients), spleen (1 patient), parotid gland (1 patient), bone marrow (1 patient), and meninges (1 patient). The profusion of granulomas in lymph nodes varied from little to extensive replacement of the node. Granulomas of the liver were located in the lobular parenchyma, and 1 patient had histologic and clinical findings that suggested primary biliary cirrhosis. In patient 2, granulomas were diffusely scattered throughout the bone marrow. The three patients who underwent the Kveim test had negative results.

Clinical Outcome

Despite the institution of standard treatment with intravenous immunoglobulin in 14 of 17 patients, many patients developed serious illness (Table 2). Eleven of 17 patients received corticosteroids. For 7 patients, the length of time between the finding of granulomas with or without lung disease and the institution of treatment with intravenous immunoglobulin ranged from 2 to 17 years. During this time, patients 3, 6, 8, and 12 had recurrent episodes of bacterial pneumonia.

Four of 17 patients (patients 3, 6, 7, and 14) died of restrictive pulmonary disease; 1 of these patients died after bilateral lung transplantation. Lung disease was extensive in some patients: Patients 1, 13, and 16 had many infiltrates on chest radiography that were shown on computed tomography to be nodular and extensive. One patient developed granulomatous disease of the liver that led to ascites, portal hypertension, and hepatic encephalopathy. One patient underwent splenectomy for autoimmune hemolytic anemia, and 2 other patients continue to receive low-dose corticosteroid therapy to avoid splenectomy.

Discussion

Top Methods Results Discussion Author & Article Info References

The occurrence of noncaseating granulomatous lesions in patients with common variable immunodeficiency is well recognized [10-13]. Previous studies [3, 10-13] have found a 5.4% to 10% incidence of granulomas in common variable immunodeficiency, but the actual incidence of granulomas remains uncertain. Seven patients in our study had granulomas that were diagnosed 2 to 17 years before hypogammaglobulinemia was diagnosed. In some of these patients, a history of recurrent bacterial pneumonia suggests that hypogammaglobulinemia was present for many years before it was diagnosed. In the recent report by Fasano and colleagues [13], hypogammaglobulinemia was documented in 5 of 8 patients 3 to 19 years after sarcoidosis was diagnosed; during this time interval, these 5 patients had recurrent bronchitis, sinusitis, pneumonia, and sepsis and one episode of meningitis. This suggests that hypogammaglobulinemia may have been present during these years.

Sarcoidosis is a chronic multisystem disease characterized by noncaseating epithelial granulomas; depressed cellular immunity; and an exaggerated T-helper lymphocytic process in affected organs, most often the lung [14]. Hyperglobulinemia is also common. Although patients with common variable immunodeficiency may also have poor cellular immunity, hypogammaglobulinemia and poor to absent production of antibodies are the cardinal manifestations. This important difference led to intermittent debate about whether the presence of noncaseating granulomatous lesions in common variable immunodeficiency should be considered sarcoidosis [3, 10-13]. Because radiologic evidence of diffuse or more localized pulmonary disease with or without hilar adenopathy is common in patients with common variable immunodeficiency, chest radiography alone is of uncertain value for confirming a diagnosis of sarcoidosis in common variable immunodeficiency. Some authors use the term "sarcoid" or "sarcoid-like" to describe granulomas in patients with common variable immunodeficiency; others simply state that "granulomas were present" [3, 10-13]. Some authors [15] have concluded that true sarcoidosis may exist in some patients with common variable immunodeficiency, but other patients may only have a sarcoid-like illness. Results of the Kveim test have been negative in many patients with common variable immunodeficiency with granulomas, but a positive result has been reported in some patients [11]. In one study [13], 3 of 9 patients with common variable immunodeficiency had negative results on the Kveim test; 3 of our patients who were tested had negative results. Combining all of the available data (including that from our study), 12 patients with common variable immunodeficiency and granulomas had positive results on Kveim tests and 14 had negative results.

Although granulomatous lesions have been viewed as characteristic of some patients with common variable immunodeficiency, such lesions are not found in X-linked agammaglobulinemia. A characteristic of common variable immunodeficiency is T-cell dysfunction, as manifested by poor proliferative responses to mitogens and antigens [5, 16]. Because patients with X-linked agammaglobulinemia are not anergic and have normal in vitro T-cell function, it has been tempting to suggest that T-cell deficiencies, antigen processing defects, or imbalanced production of cytokines (perhaps by activated macrophages) in common variable immunodeficiency may lead to the abnormal sequestration of antigen and the subsequent formation of granulomas. Consistent with this hypothesis, 16 of 17 hypogammaglobulinemic patients with granulomas in our study had moderately to severely abnormal proliferative responses to mitogens or antigens.

Increased serum levels of ACE are not a specific diagnostic marker for sarcoidosis; high levels are found in other inflammatory diseases and are usually attributed to monocyte activation [17]. Levels of ACE were elevated in 7 of 11 patients in whom these levels were measured, as has been noted in other patients with common variable immunodeficiency and granulomas [11, 13]. In granulomatous lung diseases, including sarcoidosis, the amount of ACE messenger RNA produced has been correlated with the burden of granuloma [18]. The incidence of elevated ACE levels in common variable immunodeficiency has not been previously reported; we found that 4 of 12 other randomly chosen patients with common variable immunodeficiency who were not known to have granulomatous lesions had increased serum ACE levels, as did two patients with X-linked agammaglobulinemia (Unpublished data). We do not know whether this finding implies that granulomas are present in these patients, but it shows that ACE levels are often elevated in common variable immunodeficiency.

Although 28% of our 189 patients with common variable immunodeficiency had some type of autoimmune disorder [2], 9 of the 17 patients (53% [95% CI, 29% to 77%]) with granulomas had frank autoimmune disease. In a review of 30 patients with common variable immunodeficiency and granulomatous disease [13], 5 had hemolytic anemia, 1 had pernicious anemia, and 1 had primary biliary cirrhosis. The increased prevalence of autoimmune disease in patients with common variable immunodeficiency and granulomas suggests that a connection between deficient or abnormal T-cell function and cytokine production may help explain the apparent link between these phenomena.

The pathogenic connection between granulomas and increased illness in patients with common variable immunodeficiency is uncertain. However, it is important to diagnose hypogammaglobulinemia in patients with granulomas because untreated antibody deficiency can lead to continued, perhaps irreversible organ damage.

Dr. Dikman: Division of Clinical Pathology, Mount Sinai School of Medicine, 1452 Madison Avenue, New York, NY 10029.