Original article
Systemic immune disorders
Pulmonary radiologic findings in common variable immunodeficiency: clinical and immunological correlations

https://doi.org/10.1016/j.anai.2014.04.024Get rights and content

Abstract

Background

It remains unclear whether interstitial lung disease (ILD) in common variable immunodeficiency (CVID) is a consequence of chronic infection or a manifestation of dysregulated lymphoid proliferation found in those with this condition.

Objective

To increase understanding of CVID-associated lung disease by comparing clinical and immunologic associations in those with bronchiectasis, ILD, or no lung disease observed on chest computerized tomography (CT).

Methods

Retrospective review of electronic medical records of 61 patients with CVID was used to identify clinical and laboratory correlates of bronchiectasis, ground glass opacity, and pulmonary nodules on CT scan.

Results

Significant clinical and immunologic associations were identified for common CT scan findings in CVID. Bronchiectasis was strongly correlated with a CD4+ T-cell count lower than 700 cells/μL and was associated with a history of pneumonia and older age. Pulmonary nodular disease was correlated with increased CD4+:CD8+ T-cell ratios, a history of autoimmune hemolytic anemia or immune thrombocytopenic purpura, elevated IgM, and younger age. Ground glass opacity had similar clinical and laboratory characteristics as those for nodular lung disease but was associated with elevated monocyte counts and the presence of liver disease.

Conclusion

CT findings of bronchiectasis or ILD, including ground glass opacity and extensive pulmonary nodules, were correlated with selected clinical and laboratory characteristics. These results suggest divergent processes of CVID lung disease, with bronchiectasis more strongly associated with infection and T-cell lymphopenia and ILD more strongly linked with autoimmunity and lymphoproliferation.

Introduction

Common variable immunodeficiency (CVID) is the most prevalent symptomatic primary immunodeficiency1 and is characterized by predisposition to sinopulmonary infections and susceptibility to noninfectious complications such as autoimmunity and malignancy.2 Chronic lung disease is among the most common complications of CVID, affecting 29% to 58% of patients, depending on the study population.[3], [4], [5] Ten years previously, it was established by Bates et al6 that interstitial lung disease (ILD) significantly worsens survival in CVID. However, established CVID lung disease has proved difficult to treat and is not reversed by conventional immunoglobulin replacement therapy in most patients,7 although it may improve pulmonary function testing.[8], [9]

Radiologic evaluation of lungs in CVID discloses different chronic pulmonary findings, including air trapping, bronchial wall thickening, bronchiectasis, emphysema, ground glass opacities, parenchymal consolidation, pulmonary nodules, and/or scarring or fibrosis.[7], [10], [11], [12] Lung pathology may show ILD with manifestations of pulmonary lymphoid hyperplasia (PLH), which includes follicular bronchiolitis, lymphocytic interstitial pneumonitis (LIP), and nodular lymphoid hyperplasia.[6], [13], [14], [15] In addition, granulomatous lung disease is found in many cases[16], [17], [18] and organizing pneumonia (OP) in some.[19], [20], [21] Granulomatous-lymphocytic interstitial lung disease has been used as an encompassing term for this combination of pathologic findings in CVID.6

The pathogenesis of lung disease in CVID is not well understood. Although as many as 50% of patients with CVID reportedly develop bronchiectasis, not all have or progress to ILD.11 Development of lung disease in patients with CVID has been associated with a low CD4+:CD8+ T-cell ratio in bronchoalveolar lavage,22 decreases in peripheral CD8+ T cells,6 and fewer numbers of IgM-IgD-CD27+ isotype-switched and IgM+CD27+ memory B cells[23], [24] in some, but not all, studies.25 Epstein-Barr virus may be associated with PLH,26 as in patients with human immunodeficiency virus,27 but Epstein-Barr virus has not been found in lung biopsies from patients with CVID and PLH.13 Similarly, human herpesvirus-8 was associated with granulomatous-lymphocytic interstitial lung disease in 1 study,28 although this has not been confirmed. Noninfectious pathogenic mechanisms for the development of CVID lung disease also have been proposed, including aberrant B-cell lymphoproliferation29 and T-cell–driven autoimmunity.14 Through retrospective chart review, the authors found bronchiectasis to be associated with a history of pneumonia and decreased CD4+ T cells in CVID. In contrast, patients with computed tomographic (CT) evidence of ILD shared clinical and radiologic characteristics that differed from those with bronchiectasis alone or no chest CT findings. In addition, the presence of numerous pulmonary nodules was linked to autoimmunity, elevation of IgM, and increased CD4+:CD8+ T-cell ratio, whereas progression to ground glass opacity was associated with elevated peripheral monocytes and increased prevalence of liver disease.

Section snippets

Study Design

This study was conducted through retrospective review of electronic medical records from Mount Sinai Hospital (New York, New York). Electronic medical records and supplemental material are available for patient encounters from January 2003 until the present. Patients with the International Classification of Diseases, Ninth Revision code for CVID (279.06) who had a CT scan of the chest or tissue biopsy pathology report in the medical record were selected. One hundred twenty-six patients were

Radiologic Studies

Of the 61 patients with CVID in this study, 34 were women and 27 were men. The age range of the patients was 14 to 89 years, with a median age of 47 years. Baseline IgG, averaged IgA, IgM, post-treatment IgG values, and medical complications are listed in Table 1. Ten of these patients did not have CT abnormalities. For the 51 patients with radiologic findings, 34 (67%) had at least 5 pulmonary nodules, 22 (43%) had bronchiectasis, and 18 (37%) had ground glass opacity (Fig 1A). For

Discussion

The authors analyzed a group of 61 patients with CVID who had a chest CT scan to seek clinical and/or laboratory correlations with specific radiologic findings. Because CT scan of the chest was not routinely obtained in all patients with CVID, there may have been a bias toward more severe disease in this study because many patients had imaging performed for clinical symptoms. Many patients are referred to the authors' institution because of abnormal CT chest scans in the setting of CVID,

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    Disclosures: Dr. Maglione received research grants from Thrasher Research Fund and the Clinical Immunology Society. The other authors have nothing to disclose.

    Funding: Supported by the Thrasher Research Fund Early Career Award, Baxter-Clinical Immunology Society Senior Fellowship Award, Jeffrey Modell Foundation, National Institutes of Health grants AI 048693 and AI 061093, and the David S. Gottesman Immunology Chair.

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