PULMONARY PATHOLOGIES AND MANAGEMENT STRATEGIES IN PRIMARY IMMUNODEFICIENCIES

pulmonary_pathologies_kapak

GRANULOMATOUS AND LYMPHOCYTIC INTERSTITIAL LUNG DISEASE (GLILD), AUTOIMMUNE PULMONARY MANIFESTATIONS, AND MANAGEMENT

Fatma Arzu Akkuş

Konya City Hospital, Department of Immunology and Allergic Diseases, Konya, Türkiye

Akkuş FA. Granulomatous and Lymphocytic Interstitial Lung Disease (GLILD), Autoimmune Pulmonary Manifestations, and Management. In: Arslan Ş editor. Pulmonary Pathologies and Management Strategies in Primary Immunodeficiencies. 1st ed. Ankara: Türkiye Klinikleri; 2025. p.73-87.

ABSTRACT

Primary immunodeficiencies (PIDs) are a heterogeneous group of disorders caused by genetic abnormalities that affect one or more components of the immune system. In these disorders, in addition to increased susceptibility to infections, various systemic complications such as immune dysregulation, autoimmunity, and malignancies may also occur. Among the most commonly encountered issues in patients with PIDs are pulmonary complications. Pulmonary complications are a major cause of morbidity and mortality in patients with PIDs. The impact of PIDs on the lungs can be broadly categorized into infectious and non-infectious manifestations. Recurrent respiratory tract infections often present as the initial manifestation. These infections can typically be managed with immunoglobulin replacement therapy and antibiotics. However, there is a growing recognition of non-infectious pulmonary complications, driven by factors such as autoimmunity, immune dysregulation, and aberrant inflammation. These complications may result in findings such as interstitial lung diseases, which can lead to parenchymal fibrosis, and can also cause structural damage to the bronchial airways, ultimately resulting in bronchiectasis. Granulomatous and lymphocytic interstitial lung disease (GLILD) is a serious condition observed in certain PID subtypes, particularly common variable immunodeficiency (CVID), and is characterized by granuloma formation, lymphocytic infiltration, and fibrotic changes in the lung parenchyma. The diagnosis of these conditions is often delayed, as clinical findings are non-specific and typically require a combination of radiological imaging, pulmonary function tests, and, when necessary, histopathological evaluation. Treatment involves the use of immunomodulatory drugs, corticosteroids, biologic agents, and supportive therapies. Although early diagnosis and appropriate treatment may not completely prevent non-infectious pulmonary complications, they can help slow disease progression. A multidisciplinary approach to managing pulmonary complications in patients with PIDs significantly improves both quality of life and prognosis.

Keywords: Primary immunodeficiency; Interstitial lung disease; Pulmonary fibrosis; Autoimmunity; Granuloma

Referanslar

  1. Rodriguez JA, Bang TJ, Restrepo CS, Green DB, Browne LP, Vargas D. Imaging Features of Primary Immunodeficiency Disorders. Radiology Cardiothoracic imaging. Apr 2021;3(2):e200418. [Crossref]  [PubMed]  [PMC]
  2. Gutierrez MJ, Nino G, Sun D, Restrepo-Gualteros S, Sadreameli SC, Fiorino EK, et al. The lung in inborn errors of immunity: From clinical disease patterns to molecular pathogenesis. The Journal of allergy and clinical immunology. Dec 2022;150(6):1314-1324. [Crossref]  [PubMed]  [PMC]
  3. Restrepo-Gualteros S, Nino G, Gutierrez MJ. The lung in inborn errors of immunity. Pediatric pulmonology. Mar 2025;60 Suppl 1:S29-s31. [Crossref]
  4. Wijsenbeek M, Suzuki A, Maher TM. Interstitial lung diseases. Lancet (London, England). Sep 3 2022;400(10354):769786. [Crossref]  [PubMed]
  5. Feghali-Bostwick CA, Tsai CG, Valentine VG, Kantrow S, Stoner MW, Pilewski JM, et al. Cellular and humoral autoreactivity in idiopathic pulmonary fibrosis. Journal of immunology (Baltimore, Md : 1950). Aug 15 2007;179(4):2592-9. [Crossref]  [PubMed]
  6. Hurst JR, Warnatz K. Interstitial lung disease in primary immunodeficiency: towards a brighter future. The European respiratory journal. Apr 2020;55(4) [Crossref]  [PubMed]
  7. Sullivan NP, Maniam N, Maglione PJ. Interstitial lung diseases in inborn errors of immunity. Current opinion in allergy and clinical immunology. Dec 1 2023;23(6):500-506. [Crossref]  [PubMed]
  8. Buso H, Discardi C, Bez P, Muscianisi F, Ceccato J, Milito C, et al. Sarcoidosis versus Granulomatous and Lymphocytic Interstitial Lung Disease in Common Variable Immunodeficiency: A Comparative Review. Biomedicines. Jul 6 2024;12(7) [Crossref]  [PubMed]  [PMC]
  9. Yazdani R, Abolhassani H, Asgardoon MH, Shaghaghi M, Modaresi M, Azizi G, et al. Infectious and Noninfectious Pulmonary Complications in Patients With Primary Immunodeficiency Disorders. Journal of investigational allergology & clinical immunology. 2017;27(4):213-224. [Crossref]  [PubMed]
  10. Jesenak M, Banovcin P, Jesenakova B, Babusikova E. Pulmonary manifestations of primary immunodeficiency disorders in children. Frontiers in pediatrics. 2014;2:77. [Crossref]  [PubMed]  [PMC]
  11. Casal A, Riveiro V, Suárez-Antelo J, Ferreiro L, Rodríguez-Núñez N, Lama A, et al. Pulmonary Manifestations of Primary Humoral Deficiencies. Canadian respiratory journal. 2022;2022:7140919. [Crossref]  [PubMed]  [PMC]
  12. Pac M, Bielecka T, Grzela K, Komarnicka J, Langfort R, Koltan S, et al. Interstitial Lung Disease in Children With Selected Primary Immunodeficiency Disorders-A Multicenter Observational Study. Frontiers in immunology. 2020;11:1950. [Crossref]  [PubMed]  [PMC]
  13. Rao N, Mackinnon AC, Routes JM. Granulomatous and lymphocytic interstitial lung disease: a spectrum of pulmonary histopathologic lesions in common variable immunodeficiency--histologic and immunohistochemical analyses of 16 cases. Human pathology. Sep 2015;46(9):1306-14. [Crossref]  [PubMed]  [PMC]
  14. Lamers OAC, Smits BM, Leavis HL, de Bree GJ, Cunningham-Rundles C, Dalm V, et al. Treatment Strategies for GLILD in Common Variable Immunodeficiency: A Systematic Review. Frontiers in immunology. 2021;12:606099. [Crossref]  [PubMed]  [PMC]
  15. Baumann U, Routes JM, Soler-Palacín P, Jolles S. The Lung in Primary Immunodeficiencies: New Concepts in Infection and Inflammation. Frontiers in immunology. 2018;9:1837. [Crossref]  [PubMed]  [PMC]
  16. Hurst JR, Verma N, Lowe D, Baxendale HE, Jolles S, Kelleher P, et al. British Lung Foundation/United Kingdom Primary Immunodeficiency Network Consensus Statement on the Definition, Diagnosis, and Management of Granulomatous-Lymphocytic Interstitial Lung Disease in Common Variable Immunodeficiency Disorders. The journal of allergy and clinical immunology In practice. Jul-Aug 2017;5(4):938945. [Crossref]  [PubMed]
  17. Galant-Swafford J, Catanzaro J, Achcar RD, Cool C, Koelsch T, Bang TJ, et al. Approach to diagnosing and managing granulomatous-lymphocytic interstitial lung disease. EClinicalMedicine. Sep 2024;75:102749. [Crossref]  [PubMed]  [PMC]
  18. Fernández Pérez ER. Granulomatous lymphocytic interstitial lung disease. Immunology and allergy clinics of North America. Nov 2012;32(4):621-32. [Crossref]  [PubMed]
  19. Schussler E, Beasley MB, Maglione PJ. Lung Disease in Primary Antibody Deficiencies. The journal of allergy and clinical immunology In practice. Nov-Dec 2016;4(6):10391052. [Crossref]  [PubMed]  [PMC]
  20. Wheat WH, Cool CD, Morimoto Y, Rai PR, Kirkpatrick CH, Lindenbaum BA, et al. Possible role of human herpesvirus 8 in the lymphoproliferative disorders in common variable immunodeficiency. The Journal of experimental medicine. Aug 15 2005;202(4):479-84. [Crossref]  [PubMed]  [PMC]
  21. Arnold DF, Wiggins J, Cunningham-Rundles C, Misbah SA, Chapel HM. Granulomatous disease: distinguishing primary antibody disease from sarcoidosis. Clinical immunology (Orlando, Fla). Jul 2008;128(1):18-22. [Crossref]  [PubMed]  [PMC]
  22. Bates CA, Ellison MC, Lynch DA, Cool CD, Brown KK, Routes JM. Granulomatous-lymphocytic lung disease shortens survival in common variable immunodeficiency. The Journal of allergy and clinical immunology. Aug 2004;114(2):415-21. [Crossref]  [PubMed]
  23. Cereser L, Girometti R, d'Angelo P, De Carli M, De Pellegrin A, Zuiani C. Humoral primary immunodeficiency diseases: clinical overview and chest high-resolution computed tomography (HRCT) features in the adult population. Clinical radiology. Jul 2017;72(7):534-542. [Crossref]  [PubMed]
  24. Torigian DA, LaRosa DF, Levinson AI, Litzky LA, Miller WT, Jr. Granulomatous-lymphocytic interstitial lung disease associated with common variable immunodeficiency: CT findings. Journal of thoracic imaging. Aug 2008;23(3):162-9. [Crossref]  [PubMed]
  25. Bintalib HM, van de Ven A, Jacob J, Davidsen JR, Fevang B, Hanitsch LG, et al. Diagnostic testing for interstitial lung disease in common variable immunodeficiency: a systematic review. Frontiers in immunology. 2023;14:1190235. [Crossref]  [PubMed]  [PMC]
  26. Perlman DM, Sudheendra MT, Racilla E, Allen TL, Joshi A, Bhargava M. Granulomatous-Lymphocytic Interstitial Lung Disease Mimicking Sarcoidosis. Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG. 2021;38(3):e2021025.
  27. Mongkonsritragoon W, Srivastava R, Seth D, Navalpakam A, Poowuttikul P. Non-infectious Pulmonary Complications in Children with Primary Immunodeficiency. Clinical medicine insights Pediatrics. 2023;17:11795565231196431. [Crossref]  [PubMed]  [PMC]
  28. Shah KK, Pritt BS, Alexander MP. Histopathologic review of granulomatous inflammation. Journal of clinical tuberculosis and other mycobacterial diseases. May 2017;7:1-12. [Crossref]  [PubMed]  [PMC]
  29. Henrickson SE, Jongco AM, Thomsen KF, Garabedian EK, Thomsen IP. Noninfectious Manifestations and Complications of Chronic Granulomatous Disease. Journal of the Pediatric Infectious Diseases Society. May 9 2018;7(suppl_1):S18-s24. [Crossref]  [PubMed]  [PMC]
  30. Carrington JM, Hershberger DM. Pulmonary Alveolar Proteinosis. In, eds. StatPearls. ed. StatPearls Publishing Copy right © 2025, StatPearls Publishing LLC.; 2025: https:// www.ncbi.nlm.nih.gov/books/NBK482308
  31. Borie R, Danel C, Debray MP, Taille C, Dombret MC, Aubier M, et al. Pulmonary alveolar proteinosis. European respiratory review : an official journal of the European Respiratory Society. Jun 2011;20(120):98-107. [Crossref]  [PubMed]  [PMC]
  32. Deng K, Lu G. Immune dysregulation as a driver of bronchiolitis obliterans. Frontiers in immunology. 2024;15:1455009. [Crossref]  [PubMed]  [PMC]
  33. Aguilar PR, Michelson AP, Isakow W. Obliterative Bronchiolitis. Transplantation. Feb 2016;100(2):272-83. [Crossref]  [PubMed]
  34. Krishna R, Anjum F, Oliver TI. Bronchiolitis Obliterans. In, eds. StatPearls. ed. StatPearls Publishing Copyright © 2025, StatPearls Publishing LLC.; 2025.
  35. Barbosa M, Chalmers JD. Bronchiectasis. Presse medicale (Paris, France: 1983). Sep 2023;52(3):104174. [Crossref]  [PubMed]