Granulomatous disease in common variable immunodeficiency☆
Introduction
Common variable immunodeficiency (CVID) is characterized by hypogammaglobulinemia, defective antibody responses and recurrent infections [1], [2], [3], [4], [5]. Recurrent pulmonary infections especially for patients with delayed diagnosis or inadequate immune globulin replacement [6], [7], [8], [9], [10], can lead to bronchiectasis, respiratory failure and cor pulmonale, some of the most significant causes of both morbidity and mortality in this immune defect [1], [2], [3], [6], [7]. While hallmark of CVID is that of a B cell defect, many patients also have variable T cell abnormalities including cytokine defects, poor lymphocyte proliferation [1], [11], [12] and dendritic cell defects [13], [14], [15]. Mutations in selected genes are known to lead to the CVID phenotype, including the inducible co stimulator (ICOS) [16], [17], [18], [19] and CD19 [17], [18]. The role of mutations in the TNFRSF13B gene encoding TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor) although demonstrated in a significantly increased number (8%) of patients [20], [21] is somewhat less clear as the same mutations can be found in healthy family members [22], [23]. In order to classify CVID subjects, a number of reports have used various immunological characteristics, particularly B cell functions in response to selected activators in vitro. Most recently, enumeration of peripheral blood switched memory B cells has been used as an indictor of immunologic capacity also showing significant clinical relevance [24], [25], [26], [27], [28].
The developments of granulomatous disease or autoimmunity in CVID are two of the most problematic of clinical conditions, as some form of immune suppression may be required for adequate treatment. The granulomatous changes, or what is reported to be “sarcoidosis” is not infrequently diagnosed years prior to the recognition of hypogammaglobulinemia and in these cases, greatly delays the recognition of the immune defect and the revision of the diagnosis to CVID with granuloma [29], [30], [31], [32], [33]. Alternatively, those with known CVID may be found to have granulomata when a tissue is biopsied at a later date. Although granulomas can be found in many organ systems, lungs are the most prominent location [31], [33]. In some patients an intense lymphoid infiltration accompanies the granulomata leading what has been termed “granulomatous lymphocytic interstitial lung disease” (GLILD) [33], [34] the presence of which may be associated with a poorer outcome [34]. For unclear reasons, granulomatous disease is often found in associated with autoimmunity, in particular, immune thrombocytopenic purpura (ITP) or autoimmune hemolytic anemia (AIHA) [31]. These episodes may occur years before the discovery of granulomas in any tissues. Here we outline the clinical and immunological data of 37 CVID patients in whom granulomas were documented in one or more organ systems and compare the mortality of these subjects to other CVID subjects.
Section snippets
Patients
The clinical and immunologic information of a total cohort of 455 patients with CVID were surveyed. The diagnostic criteria for CVID included reduced serum IgG, IgA, and/or IgM by two or more confidence intervals below the normal ranges for ages and antibody deficiency, verified by lack of protective titers to vaccine antigens, based on laboratory reference values [1], [2], [4]. Subjects who had other causes of congenital or acquired hypogammaglobulinemia were excluded. Serum IgG, IgA and IgM
Patients and location of granulomas
Of the 455 subjects with CVID, 37 subjects (8.1%) had been found to have granulomas in one or more tissues. This group consisted of 29 (78%) Caucasian, 5 (14%) African American, 2 (5%) Hispanic and 1 (3%) Asian patients. For the group as a whole, 92% are Caucasian, 2.7% African American, 4% Hispanic and 1% are Asian patients. Of these, two had family history of CVID or IgA deficiency. The age of these patients at the time of diagnosis with CVID ranged between 2 and 59 years (median 26); 24 out
Discussion
Granulomatous disease occurs in between 8 and 22% of subjects with CVID [1], [30], [31], [33], [35] an association still not commonly recognized by physicians [29], [30], [31]. In fact when granulomas are discovered first, the diagnosis of CVID is often delayed as the patient is considered to have uncomplicated sarcoidosis. Tissue biopsy may be required not only for diagnosis of granulomas but also to differentiate these lesions from other complications such as lymphoid hyperplasia or lymphoma,
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This work was supported by grants from the National Institutes of Health, AI 101093, AI-467320, AI-48693 and NIAID Contract 03-22 to CCR.