Lung Disease in Primary Antibody Deficiencies

Abstract

Primary antibody deficiencies (PADs) are the most common form of primary immunodeficiency and predispose to severe and recurrent pulmonary infections, which can result in chronic lung disease including bronchiectasis. Chronic lung disease is among the most common complications of PAD and a significant source of morbidity and mortality for these patients. However, the development of lung disease in PAD may not be solely the result of recurrent bacterial infection or a consequence of bronchiectasis. Recent characterization of monogenic immune dysregulation disorders and more extensive study of common variable immunodeficiency have demonstrated that interstitial lung disease (ILD) in PAD can result from generalized immune dysregulation and frequently occurs in the absence of pneumonia history or bronchiectasis. This distinction between bronchiectasis and ILD has important consequences in the evaluation and management of lung disease in PAD. For example, treatment of ILD in PAD typically uses immunomodulatory approaches in addition to immunoglobulin replacement and antibiotic prophylaxis, which are the stalwarts of bronchiectasis management in these patients. Although all antibody-deficient patients are at risk of developing bronchiectasis, ILD occurs in some forms of PAD much more commonly than in others, suggesting that distinct but poorly understood immunological factors underlie the development of this complication. Importantly, ILD can have earlier onset and may worsen survival more than bronchiectasis. Further efforts to understand the pathogenesis of lung disease in PAD will provide vital information for the most effective methods of diagnosis, surveillance, and treatment of these patients.

Keywords: Bronchiectasis; CVID; Common variable immunodeficiency; Granulomatous interstitial lung disease; Interstitial lung disease; Primary antibody deficiency.

Figure 1. Radiologic findings of lung disease in PAD

A. Bronchiectasis (marked by white arrows) in a patient with CVID. B. CVID patient with bilateral pulmonary nodules and mediastinal lymphadenopathy. C. CVID patient with innumerable nodular opacities, bronchiectasis, and mediastinal lymphadenopathy. D. Patient with IgA/IgG2 deficiency (IgA < 10 mg/dL, IgG 997 mg/dL, IgG2 < 16 mg/dL) demonstrating multiple non-calcified lung nodules.

Figure 2. Therapeutic approach for bronchiectasis in PAD

Treatment algorithm for management of bronchiectasis in PAD patients. LABA, long-acting β-agonist.

Figure 3. Pulmonary pathology from CVID ILD patients

A. Lymphoid follicle (black circle) near the airway with minimal involvement of other parenchyma indicating follicular bronchiolitis (200X). B. Follicular bronchiolitis (black circle) noted with lymphocytes in the interstitium and expanding the alveolar septum characteristic of LIP (black arrows, 200X). C. Granulomatous inflammation with circumscribed granuloma (black arrow) and ectopic lymphoid follicle (black circle, 200X). D. Well-demarcated lymphoid follicles characteristic of nodular lymphoid hyperplasia (100X).

Figure 4. PLH contains ectopic lymphoid follicles in CVID

Wedge biopsy from CVID patient with LIP demonstrating diffuse lymphocytic infiltrate (H&E) with ectopic B cell follicles (CD20) circumscribed by T cells (CD3) and containing follicular dendritic cells (CD23), a germinal center marker (Bcl-6), and proliferating cells (Ki67).

Figure 5. Therapeutic approach for ILD in PAD

Treatment algorithm for management of ILD in PAD patients. AZA, azathioprine; LABA, long-acting β-agonist; MMF, mycophenolate mofetil; RTX, rituximab; 6MP, 6-mercaptopurine.