The Lung in Primary Immunodeficiencies: New Concepts in Infection and Inflammation

Abstract

Immunoglobulin replacement therapy (IGRT) has contributed critically to the management of primary antibody deficiencies (PAD) and the decrease in pneumonia rate. However, despite adequate IGRT and improved prognosis, patients with PAD continue to experience recurrent respiratory tract infections, leading to bronchiectasis and continuing decline in lung function with a severe impact on their quality of life. Moreover, non-infectious inflammatory and interstitial lung complications, such as granulomatous-lymphocytic interstitial lung disease, contribute substantially to the overall morbidity of PAD. These conditions develop much more often than appreciated and represent a major therapeutic challenge. Therefore, a regular assessment of the structural and functional condition of the lung and the upper airways with appropriate treatment is required to minimize the deterioration of lung function. This work summarizes the knowledge on lung complications in PAD and discusses the currently available diagnostic tools and treatment options.

Keywords: bronchiectasis; comorbidity; granulomatous-lymphocytic interstitial lung disease; immunoglobulin; lung complications; lung computed tomographic scan; primary immunodeficiency; pulmonary functional tests.

Figure 1

Development of immunoglobulin replacement therapy and infection rates since 1990s. Data for immunoglobulin (Ig) trough levels (top left) and infection rates (top right) are from a cohort of 115 patients with common variable immunodeficiency (CVID) or X-linked agammaglobulinemia reported by Lucas et al. (1). A combined analysis of data on the percentage of patients experiencing pneumonia and recurrent respiratory tract infections (bottom left) is shown in three large series of CVID patients in 1999, 2008, and 2011 (two from the same cohort in the United States 12 years apart, 248 and 252 patients, and one from a French cohort, 473 patients); reproduced with kind permission from 2014 British Society for Immunology, Clinical and Experimental Immunology, 178: 67–69 (2). Mortality data (bottom right) for 1971 are from Healy et al. (6); those for 1999 and 2012 are from a single cohort follow up reported by Resnick et al. (7). DEFI, a French national study. Abbreviation: PAD, primary antibody deficiencies.

Figure 2

Infectious and non-infectious complications in primary antibody deficiencies. Abbreviations: GLILD, granulomatous-lymphocytic interstitial lung disease; IgA, immunoglobulin A; LIP, lymphocytic interstitial pneumonitis.

Figure 3

Prevalence of chronic lung disease before and during immunoglobulin replacement therapy (IGRT). Prevalence before and during IGRT is shown. Data for chronic lung disease are from Plebani et al. (XLA) (39) and Quinti et al. (CVID) (40). Abbreviations: CVID, common variable immunodeficiency; XLA, X-linked agammaglobulinemia.

Figure 4

Morphology and prevalence of bronchiectasis. (A) Schematic presentation of normal bronchi and bronchi with bronchiectasis. The upper airways (blue) are more exposed to pathogens compared with the lower airways (orange). (B) Types of bronchiectasis. (C) Prevalence of bronchiectasis before and during IGRT. Data are from Quinti et al. (24).

Figure 5

Histologic features of granulomatous-lymphocytic interstitial lung disease. (A) Lymphocytic interstitial pneumonitis. Diffuse, lymphocytic interstitial infiltrates obliterating the alveolar spaces in some areas (100×). (B) Follicular bronchiolitis. Nodular, lymphoid peribronchiolar aggregates (100×). (C) Non-necrotizing granuloma with multinucleated giant cells (arrow; 200×). Hematoxylin and eosin staining.

Figure 6

Granulomatous-lymphocytic interstitial lung disease diagnostic algorithm. All patients with common variable immunodeficiency should have a high-resolution computed tomography (HRCT) of the chest to screen for pulmonary disease. If there is significant interstitial lung disease (ground glass abnormalities, nodules, and areas of consolidation), one should consider lung biopsy by video-assisted thoracoscopic surgery (VATS) for definitive diagnosis. It may be worth considering if a more easily accessible organ such as a lymph node could be useful for detection of granulomas.

Figure 7

Diagnosis of granulomatous-lymphocytic interstitial lung disease (GLILD). (A) PET-CT before and 3 months after rituximab and mycophenolate treatment. Whole body images were acquired at 90 min following 285 MBq 2-[(18)F]-fluoro-2-deoxy-d-glucose (tracer). Maximum intensity projection whole body images before treatment show widespread abnormal uptake of tracer in the lung parenchyma and lymph nodes above and below the diaphragm (A); images following treatment show near resolution of all the areas of abnormal tracer uptake (B). (C,D) Axial fused positron emission tomography–computed tomography (PET–CT) images at the mid-thoracic level. The level of tracer uptake is represented by the intensity of color superimposed upon the CT image. There is a combination of interstitial septal thickening and ill-defined tracer-avid peri-bronchovascular nodules before treatment (C); post-treatment image shows improvement of the nodularity with near resolution of tracer uptake (D). Images at the level of the carina show an enlarged lymph node exhibiting intense abnormal tracer uptake prior to treatment (E), and a normalized lymph node with no abnormal tracer uptake following treatment (F). Pre-treatment images through the abdomen at the level of the right renal hilum demonstrate numerous enlarged tracer-avid retroperitoneal lymph nodes (G) which reduce in size and tracer uptake following treatment (H). Reproduced with kind permission from 2016 British Society for Immunology, Clinical and Experimental Immunology, 187: 138–145 (100). (B) Radiographic features of GLILD versus sarcoidosis. GLILD is characterized by macronodular (yellow circles) disease that is located predominantly in the lower lung zones. In contrast, micronodular (yellow circles) disease located in the upper lung zones and frequently accompanied by marked hilar adenopathy (stars) is characteristic of sarcoidosis. Reproduced from Ref. (101) with kind permission from European Respiratory Society.