General Approach and Clinical Management for Adults with Primary Immunodeficiency Diseases

Mustafa İlker İNANa , Özgür KARTALa
aUniversity of Health Sciences Gülhane Training and Research Hospital, Clinic of Immunology and Allergy Diseases, Ankara, Türkiye

İnan Mİ, Kartal Ö. General approach and clinical management for adults with primary immunodeficiency diseases. Çölkesen F, ed. Primary Immunodeficiency Diseases in Adults. 1st ed. Ankara: Türkiye Klinikleri; 2024. p.1-9.

ABSTRACT
Primary immunodeficiency diseases (PIDs), recently called inborn errors of immunity, are a growing group of diseases. Increased susceptibility to all types of infections is the predominant clinic of all PIDs. However, a significant number of patients may also present with the manifestation of allergic diseases, autoimmune/autoinflammatory diseases and lymphoproliferative/malignant diseases without a history of infection. Immunoglobulin replacement therapy (IgRT) is the cornerstone of the treatment. Although it was shown that IgRT significantly reduces the infection rate and increases patient’s survival, it seems to be failed in controlling non-infectious complications. Thus, these complications should be actively investigated as a part of the diagnosis, patient phenotyping and in the course of the disease. Also a careful long-term follow-up is necessary for the management of complications. After the increased usage of genetic tests which are helping the understanding of underlying cause, new targeted treatment modalities are progressing and giving hope for a better prognosis.

Keywords: Primary immunodeficiency diseases; immunoglobulins, intravenous; complications; autoimmunity

Referanslar

  1. Tangye SG, Al-Herz W, Bousfiha A, Cunningham-Rundles C, Franco JL, Holland SM, et al. Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol. 2022;42(7):1473-507. [Crossref]  [PubMed]  [PMC]
  2. UpToDate [Internet]. Kathleen ES, Soma CJ. Inborn errors of immunity (primary immunodeficiencies): Classification. [Accessed August 28, 2023] Available from: [Link]
  3. UpToDate [Internet]. Micheal K. Inborn errors of immunity (primary immunodeficiencies): overview of management. [Accessed August 28, 2023] Available from: [Link]
  4. Bonilla FA, Khan DA, Ballas ZK, Chinen J, Frank MM, Hsu JT, et al.; Joint Task Force on Practice Parameters, representing the American Academy of Allergy, Asthma & Immunology; the American College of Allergy, Asthma & Immunology; and the Joint Council of Allergy, Asthma & Immunology. Practice parameter for the diagnosis and management of primary immunodeficiency. J Allergy Clin Immunol. 2015;136(5):1186-205.e1-78.
  5. Eades-Perner AM, Gathmann B, Knerr V, Guzman D, Veit D, Kindle G, et al.; ESID Registry Working Party. The European internet-based patient and research database for primary immunodeficiencies: results 2004-06. Clin Exp Immunol. 2007;147(2):306-12. [Crossref]  [PubMed]  [PMC]
  6. Kilic SS, Ozel M, Hafizoglu D, Karaca NE, Aksu G, Kutukculer N. The prevalences [correction] and patient characteristics of primary immunodeficiency diseases in Turkey--two centers study. J Clin Immunol. 2013;33(1):74-83. [Crossref]  [PubMed]
  7. García JM, Gamboa P, de la Calle A, Hernández MD, Caballero MT, García BE, et al.; Committee of Immunology of the Spanish Socierty of Allergology and Clinical Immunology. Diagnosis and management of immunodeficiencies in adults by allergologists. J Investig Allergol Clin Immunol. 2010;20(3):185-94.
  8. Rosenberg E, Dent PB, Denburg JA. Primary Immune Deficiencies in the Adult: A Previously Underrecognized Common Condition. J Allergy Clin Immunol Pract. 2016;4(6):1101-7. [Crossref]  [PubMed]
  9. Bousfiha AA, Jeddane L, Ailal F, Benhsaien I, Mahlaoui N, Casanova JL, et al. Primary immunodeficiency diseases worldwide: more common than generally thought. J Clin Immunol. 2013;33(1):1-7. [Crossref]  [PubMed]
  10. Özdemir Ö. Günlük Klinik Rutinde Sık Kullanılan Basit Laboratuvar Testlerinden (Primer) İmmün Yetmezlik Hastalığına Yaklaşım. Güncel Pediatri. 2019;17(1):151-69.
  11. Abolhassani H, Rezaei N, Mohammadinejad P, Mirminachi B, Hammarstrom L, Aghamohammadi A. Important differences in the diagnostic spectrum of primary immunodeficiency in adults versus children. Expert Rev Clin Immunol. 2015;11(2):289-302. [Crossref]  [PubMed]
  12. Muşabak UH. Geç Başlangıçlı Primer İmmün Yetmezlikler: Ülkemizde ve Dünyadaki Durum. Turkiye Klinikleri J Immun Allergy-Special Topics. 2017;10(2):49-53.
  13. Mahlaoui N, Warnatz K, Jones A, Workman S, Cant A. Advances in the Care of Primary Immunodeficiencies (PIDs): from Birth to Adulthood. J Clin Immunol. 2017;37(5):452-60. [Crossref]  [PubMed]  [PMC]
  14. Grammatikos A, Bright P, Bhatnagar R, Johnston S. How to investigate a suspected immune deficiency in adults. Respir Med. 2020;171:106100. [Crossref]  [PubMed]
  15. Litzman J. Primary immunodeficiencies in adults. Vnitr Lek. 2019;65(2):109-116. English. [Crossref]  [PubMed]
  16. Sanges S, Wallet F, Blondiaux N, Theis D, Vérin I, Vachée A, et al. Diagnosis of primary antibody and complement deficiencies in young adults after a first invasive bacterial infection. Clin Microbiol Infect. 2017;23(8):576.e1-576.e5. [Crossref]  [PubMed]
  17. Gathmann B, Mahlaoui N; CEREDIH; Gérard L, Oksenhendler E, Warnatz K, Schulze I, Kindle G, Kuijpers TW; et al.; European Society for Immunodeficiencies Registry Working Party. Clinical picture and treatment of 2212 patients with common variable immunodeficiency. J Allergy Clin Immunol. 2014;134(1):116-26. [Crossref]  [PubMed]
  18. Audemard-Verger A, Descloux E, Ponard D, Deroux A, Fantin B, Fieschi C, et al. Infections Revealing Complement Deficiency in Adults: A French Nationwide Study Enrolling 41 Patients. Medicine (Baltimore). 2016;95(19):e3548. [Crossref]  [PubMed]  [PMC]
  19. Agarwal S, Cunningham-Rundles C. Gastrointestinal Manifestations and Complications of Primary Immunodeficiency Disorders. Immunol Allergy Clin North Am. 2019;39(1):81-94. [Crossref]  [PubMed]  [PMC]
  20. Giorgio F, Principi M, Losurdo G, Piscitelli D, Iannone A, Barone M, et al. Seronegative Celiac Disease and Immunoglobulin Deficiency: Where to Look in the Submerged Iceberg? Nutrients. 2015;7(9):7486-504. [Crossref]  [PubMed]  [PMC]
  21. European Society for Immunodeficiencies [Internet].The 6 ESID warning signs for ADULT primary immunodeficiency diseases. [Accessed August 28, 2023] Available from: [Link]
  22. Hill AT, Sullivan AL, Chalmers JD, De Soyza A, Elborn SJ, Floto AR, et al. British Thoracic Society Guideline for bronchiectasis in adults. Thorax. 2019;74(Suppl 1):1-69. [Crossref]  [PubMed]
  23. Litzman J, Stikarovska D, Pikulova Z, Pavlik T, Pesak S, Thon V, et al. Change in referral diagnoses and diagnostic delay in hypogammaglobulinaemic patients during 28 years in a single referral centre. Int Arch Allergy Immunol. 2010;153(1):95-101. [Crossref]  [PubMed]
  24. Staels F, Collignon T, Betrains A, Gerbaux M, Willemsen M, Humblet-Baron S, et al. Monogenic Adult-Onset Inborn Errors of Immunity. Front Immunol. 2021;12:753978. [Crossref]  [PubMed]  [PMC]
  25. Dhalla F, Misbah SA. Secondary antibody deficiencies. Curr Opin Allergy Clin Immunol. 2015;15(6):505-13. [Crossref]  [PubMed]
  26. European Society for Immunodeficiencies [Internet]. Differential Diagnosis of Hypogammaglobulinemia. [Accessed August 28, 2023] Available from: [Link]
  27. Perez EE, Orange JS, Bonilla F, Chinen J, Chinn IK, Dorsey M, et al. Update on the use of immunoglobulin in human disease: A review of evidence. J Allergy Clin Immunol. 2017;139(3S):S1-S46. [Crossref]  [PubMed]
  28. UpToDate [Internet]. Jordan SO. Immune globulin therapy in inborn errors of immunity. [Accessed August 28, 2023] Available from: [Link]
  29. UpToDate [Internet]. Charlotte CR. Treatment and prognosis of common variable immunodeficiency. [Accessed August 28, 2023] Available from: [Link]
  30. UpToDate [Internet]. Stephen J. Subcutaneous and intramuscular immune globulin therapy. [Accessed August 28, 2023] Available from: [Link]
  31. Shrestha P, Karmacharya P, Wang Z, Donato A, Joshi AY. Impact of IVIG vs. SCIG on IgG trough level and infection incidence in primary immunodeficiency diseases: A systematic review and meta-analysis of clinical studies. World Allergy Organ J. 2019;12(10):100068. [Crossref]  [PubMed]  [PMC]
  32. Berger M. Incidence of infection is inversely related to steady-state (trough) serum IgG level in studies of subcutaneous IgG in PIDD. J Clin Immunol. 2011;31(5):924-6. [Crossref]  [PubMed]
  33. Lee JL, Mohamed Shah N, Makmor-Bakry M, Islahudin FH, Alias H, Noh LM, et al. A Systematic Review and Meta-regression Analysis on the Impact of Increasing IgG Trough Level on Infection Rates in Primary Immunodeficiency Patients on Intravenous IgG Therapy. J Clin Immunol. 2020;40(5):682-98. [Crossref]  [PubMed]
  34. Milito C, Pulvirenti F, Cinetto F, Lougaris V, Soresina A, Pecoraro A, et al. Double-blind, placebo-controlled, randomized trial on low-dose azithromycin prophylaxis in patients with primary antibody deficiencies. J Allergy Clin Immunol. 2019;144(2):584-93.e7. [Crossref]  [PubMed]
  35. Smits BM, Kleine Budde I, de Vries E, Ten Berge IJM, Bredius RGM, van Deuren M, et al. Immunoglobulin Replacement Therapy Versus Antibiotic Prophylaxis as Treatment for Incomplete Primary Antibody Deficiency. J Clin Immunol. 2021;41(2):382-92. [Crossref]  [PubMed]  [PMC]
  36. Sobh A, Bonilla FA. Vaccination in Primary Immunodeficiency Disorders. J Allergy Clin Immunol Pract. 2016;4(6):1066-75. [Crossref]  [PubMed]
  37. UpToDate [Internet]. Craig D Platt. Immunizations in patients with inborn errors of immunity. [Accessed August 28, 2023] Available from: [Link]
  38. Neven B, Leroy S, Decaluwe H, Le Deist F, Picard C, Moshous D, et al. Long-term outcome after hematopoietic stem cell transplantation of a single-center cohort of 90 patients with severe combined immunodeficiency. Blood. 2009;113(17):4114-24. [Crossref]  [PubMed]
  39. Chiesa R, Wang J, Blok HJ, Hazelaar S, Neven B, Moshous D, et al. Hematopoietic cell transplantation in chronic granulomatous disease: a study of 712 children and adults. Blood. 2020;136(10):1201-11. [Crossref]  [PubMed]
  40. Wehr C, Gennery AR, Lindemans C, Schulz A, Hoenig M, Marks R, et al.; Inborn Errors Working Party of the European Society for Blood and Marrow Transplantation and the European Society for Immunodeficiency. Multicenter experience in hematopoietic stem cell transplantation for serious complications of common variable immunodeficiency. J Allergy Clin Immunol. 2015;135(4):988-97.e6.
  41. Catak MC, Akcam B, Bilgic Eltan S, Babayeva R, Karakus IS, Akgun G, et al. Comparing the levels of CTLA-4-dependent biological defects in patients with LRBA deficiency and CTLA-4 insufficiency. Allergy. 2022;77(10):3108-23. [Crossref]  [PubMed]
  42. Rich AL, Le Jeune IR, McDermott L, Kinnear WJ. Serial lung function tests in primary immune deficiency. Clin Exp Immunol. 2008;151(1):110-3. [Crossref]  [PubMed]  [PMC]
  43. UpToDate [Internet]. James V. Pulmonary complications of primary immunodeficiencies. [Accessed August 28, 2023] Available from: [Link]
  44. UpToDate [Internet]. Nima R, Payam M, Atefeh Z, Hassan A. Gastrointestinal manifestations in primary immunodeficiencies. [Accessed August 28, 2023 Available from: [Link]
  45. Azizi G, Ziaee V, Tavakol M, Alinia T, Yazdai R, Mohammadi H, et al. Approach to the Management of Autoimmunity in Primary Immunodeficiency. Scand J Immunol. 2017;85(1):13-29. [Crossref]  [PubMed]
  46. Rizvi FS, Zainaldain H, Rafiemanesh H, Jamee M, Hossein-Khannazer N, Hamedifar H, et al. Autoimmunity in common variable immunodeficiency: a systematic review and meta-analysis. Expert Rev Clin Immunol. 2020;16(12):1227-35. [Crossref]  [PubMed]
  47. Fischer A, Provot J, Jais JP, Alcais A, Mahlaoui N; members of the CEREDIH French PID study group. Autoimmune and inflammatory manifestations occur frequently in patients with primary immunodeficiencies. J Allergy Clin Immunol. 2017;140(5):1388-93.e8.
  48. Walter JE, Farmer JR, Foldvari Z, Torgerson TR, Cooper MA. Mechanism-Based Strategies for the Management of Autoimmunity and Immune Dysregulation in Primary Immunodeficiencies. J Allergy Clin Immunol Pract. 2016;4(6):1089-100. [Crossref]  [PubMed]  [PMC]
  49. Mortaz E, Tabarsi P, Mansouri D, Khosravi A, Garssen J, Velayati A, et al. Cancers Related to Immunodeficiencies: Update and Perspectives. Front Immunol. 2016;7:365. [Crossref]  [PubMed]  [PMC]
  50. Salavoura K, Kolialexi A, Tsangaris G, Mavrou A. Development of cancer in patients with primary immunodeficiencies. Anticancer Res. 2008;28(2B):1263-9.
  51. Mayor PC, Eng KH, Singel KL, Abrams SI, Odunsi K, Moysich KB, et al. Cancer in primary immunodeficiency diseases: Cancer incidence in the United States Immune Deficiency Network Registry. J Allergy Clin Immunol. 2018;141(3):1028-35. [Crossref]  [PubMed]  [PMC]
  52. Chapel H, Lucas M, Lee M, Bjorkander J, Webster D, Grimbacher B, et al. Common variable immunodeficiency disorders: division into distinct clinical phenotypes. Blood. 2008;112(2):277-86. [Crossref]  [PubMed]
  53. UpToDate [Internet]. Payam M, Hassan A. Malignancy in primary immunodeficiencies. [Accessed August 28, 2023] Available from: [Link]