Vacinas COVID-19 e imunobiológicos
COVID-19 vaccines and immunobiological drugs
Faradiba Sarquis Serpa; Sérgio Duarte Dortas-Junior; Marta de Fátima Rodrigues da Cunha Guidacci; Filipe W. Sarinho; Eduardo Costa Silva; Nelson Augusto Rosario-Filho; João Negreiros Tebyriça; Norma de Paula M. Rubini; Aldo José Fernandes Costa; Régis de Albuquerque Campos
Resumo
Os medicamentos imunobiológicos têm sido frequentemente utilizados no tratamento das doenças alérgicas e de natureza imunológica. Esses agentes regulam a resposta imunológica do tipo 2 nas doenças alérgicas ou atuam em diversas vias de ativação alteradas nos erros inatos da imunidade. Com o surgimento da pandemia COVID-19 um crescente número de pacientes em uso de imunobiológicos para essas condições deverão ser vacinados contra o vírus SARS-CoV-2. Dessa forma, existe a necessidade de avaliar a segurança e eficácia destas vacinas nos pacientes em uso de imunobiológicos para asma, dermatite atópica, rinossinusite crônica com pólipos nasais, urticária crônica e erros inatos da imunidade. Foi realizada uma busca de literatura recente relevante sobre imunobiológicos e vacinas COVID-19 no PubMed. Existe um consenso de manutenção desses agentes durante a pandemia COVID-19, embora nas doenças alérgicas os mesmos devam ser suspensos durante a infecção ativa. Por outro lado, dados disponíveis em relação à segurança e eficácia das vacinas contra a COVID-19 nesse grupo de pacientes são escassos. Existem relatos do uso de outras vacinas inativadas em associação com alguns imunobiológicos demonstrando serem eficazes e seguras. Portanto, considerando o risco potencial da infecção COVID-19, especialmente nos pacientes portadores de erros inatos da imunidade, recomendamos que as vacinas contra a COVID-19 sejam utilizadas nos pacientes em uso de imunobiológicos. Desta forma, existe uma necessidade de estudos que avaliem estas questões haja vista que a terapia com diversos imunobiológicos tem sido amplamente utilizada nos pacientes com doenças alérgicas e de natureza imunológica.
Palavras-chave
Abstract
Immunobiological drugs have often been used to treat allergic and immunological diseases. These agents regulate the type 2 immune response in allergic diseases or act on different activation pathways altered in inborn errors of immunity. With the emergence of the COVID-19 pandemic, an increasing number of patients with these conditions using these agents should be vaccinated against the SARS-CoV-2 virus. Thus, there is a need to evaluate the safety and efficacy of these vaccines in patients using biologics for asthma, atopic dermatitis, chronic rhinosinusitis with nasal polyps, chronic urticaria, and inborn errors of immunity. A search for relevant recent literature on biologics and COVID-19 vaccines was conducted on PubMed. There is a consensus on maintaining the use of these agents during the COVID-19 pandemic, although in allergic diseases they must be suspended during active infection. Conversely, the available data regarding the safety and efficacy of the COVID-19 vaccines are scarce. There are reports of the use of other inactivated vaccines with some biologics proving to be effective and safe. Therefore, considering the potential risk of COVID-19 infection, especially in patients with inborn errors of immunity, we recommend that COVID-19 vaccines should be used in patients using biologics. Thus, there is a need for studies to assess these issues, given that therapy with several biologics has been widely used in patients with allergic and immunological diseases.
Keywords
References
1. Ter Haar NM, Frenkel J. Treatment of hereditary autoinflammatory diseases, Curr Opin Rheumatol. 2014; 26:252-8.
2. Solé D, Sano F, Rosário NA, Antilla M, Aranda C, Chong-Neto H et al. Guia prático de atualização: medicamentos biológicos no tratamento da asma, doenças alérgicas e imunodeficiências. Arq Asma Alergia Imunol. 2019;3:207-49.
3. Eyerich S, Metz M, Bossios A, Eyerich K. New biological treatment for asthma and skin allergies. Allergy. 2020;75:546-60.
4. Organização Mundial da Saúde. COVID-19 vaccines: Safety Surveillance Manual. Module: Introduction [Internet]. 2020. Disponível em: https://www.who.int/vaccine_safety/committee/Introduction.pdf?ua=1.
5. Wiersinga WJ, Rhodes A, Cheng AC, Peacock SJ, Prescott HC. Pathophysiology, transmission, diagnosis, and treatment of coronavirus Disease 2019 (COVID-19) a review. JAMA. 2020;324(8):782-93.
6. Sabogal Piñeros YS, Bal SM, Dijkhuis A, Majoor CJ, Dierdorp BS, Dekker T, et al. Eosinophils capture viruses, a capacity that is defective in asthma. Allergy. 2019;74(10):1898-909.
7. Skevaki C, Karsonova A, Karaulov A, Xie M, Renz H. Asthmaassociated risk for COVID-19 development. J Allergy Clin Immunol. 2020;146(6):1295-301.
8. Chaolin Hg, Yeming W, Xingwang L, Lili R, Jianping Z, Yi H, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506.
9. Rowe RK, Gill MA. Targeting antiviral pathways for treatment of allergic diseases. J Pediatric Infect Dis Soc. 2018;7(suppl2): S54‑S56.
10. Busse WW, Morgan WJ, Gergen PJ, Mitchell HE, Gern JE, Liu AH, et al. Randomized trial of omalizumab (anti-IgE) for asthma in inner-city children. N Engl J Med. 2011;364(11):1005-15.
11. Edwards MR, Strong K, Cameron A, Walton RP, Jackson DJ, Johnston SL. Viral infections in allergy and immunology: How allergic inflammation influences viral infections and illness. J Allergy Clin Immunol. 2017;140(4):909-20.
12. Vultaggio A, Agache I, Akdis CA, Akdis M, Bavbek S, Bossios A, et al. Considerations on biologics for patients with allergic disease in times of the COVID-19 pandemic: An EAACI statement. Allergy. 2020;75:2764-74.
13. Jackson DJ, Busse WW, Bacharier LB, Kattan M, O'Connor GT, Wood RA, et al. Association of respiratory allergy, asthma and expression of the SARS-CoV-2 receptor ACE2. J Allergy Clin Immunol. 2020;146:203-6.
14. Domínguez-Ortega J, López-Carrasco V, Barranco P, Ifim M, Luna JA, Romero D, et al. Early experiences of SARS-CoV-2 infection in severe asthmatics receiving biologic therapy. J Allergy Clin Immunol Pract. 2020;8(8):2784‑6.
15. Eger K, Hashimoto S, Braunstahl GJ et al. Poor outcome of SARSCoV-2 infection in patients with severe asthma on biologic therapy. Respir Med. 2021;177:106287.
16. Agência Nacional de Vigilância Sanitária. Relatório: Bases técnicas para decisão do uso emergencial, em caráter experimental de vacinas contra a COVID-19 [Internet]. 2021. Disponível em: https://www.gov.br/anvisa/pt-br/assuntos/noticias-anvisa/2021/confira-materiais-da-reuniao-extraordinaria-da-dicol/relatoriobases-tecnicas-para-decisao-do-uso-emergencial-final-4-1.pdf. Acessado em: 24/01/2021.
17. Kaur SP, Gupta V. COVID-19 Vaccine: A comprehensive status report. Virus Res. 2020;288:198114.
18. Prüß BM. Current state of the first COVID-19 vaccines. Vaccines (Basel). 2021;9(1):E30.
19. Zhao J, Zhao S, Ou J, Zhang J, Lan W, Guan W, et al. COVID19: Coronavirus Vaccine Development Updates. Front Immunol. 2020;11:602256.
20. Humbert M, Beasley R, Ayres J, Slavin R, Hébert J, Bousquet J, Surrey K. Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): INNOVATE. Allergy. 2005;60:309-16.
21. Buhl R. Anti-IgE antibodies for the treatment of asthma. Curr Opin Pulm Med. 2005;11:27.
22. Lin H, Boesel KM, Griffith DT, Prussin C, Foster B, Romero FA, et al. Omalizumab rapidly decreases nasal allergic response and FcεRI on basophils. J Allergy Clin Immunol. 2004;113:297‑302.
23. Beck LA, Marcotte GV, MacGlashan D, Togias A, Saini S. Omalizumab-induced reductions in mast cell FcεRI expression and function. J Allergy Clin Immunol. 2004;114:527‑30.
24. Hanf G, Brachmann I, Kleine-Tebbe J, Seybold J, Kunkel G, Suttorp N, Noga O. Omalizumab decreased IgE-release and induced changes in cellular immunity in patients with allergic asthma. Allergy. 2006;61:1141-44.
25. Kaplan AP, Gimenez-Arnau AM, Saini SS. Mechanisms of action that contribute to efficacy of omalizumab in chronic spontaneous urticaria. Allergy. 2017;72: 519‑33.
26. Maggi L, Rossettini B, Montaini G, Matucci A, Vultaggio A, Mazzoni A, et al. Omalizumab dampens type 2 inflammation in a group of longterm treated asthma patients and detaches IgE from FcεRI. Eur J Immunol. 2018;48(12):2005‑14.
27. Teach SJ, Gill MA, Togias A, Sorkness CA, Arbes SJ Jr, Calatroni A, et al. Preseasonal treatment with either omalizumab or an inhaled corticosteroid boost to prevent fall asthma exacerbations. J Allergy Clin Immunol. 2015;136(6):1476‑85.
28. Esquivel A, Busse WW, Calatroni A, Togias AG, Grindle KG, Bochkov YA, et al. Effects of omalizumab on rhinovirus infections, illnesses, and exacerbations of asthma. Am J Respir Crit Care Med. 2017;196(8):985‑92.
29. Gill MA, Liu AH, Calatroni A, Krouse RZ, Shao B, Schiltz A, et al. Enhanced plasmacytoid dendritic cell antiviral responses after omalizumab. J Allergy Clin Immunol. 2018;141:1735‑43.
30. Bauer A, Dickel H, Jakob T, Kleinheinz A, Lippert U, Metz M, et al. Expert consensus on practical aspects in the treatment of chronic urticaria. Allergo J Int. 2021;30(2):64-75.
31. Pfaar O, Klimek L, Hamelmann E, Kleine-Tebbe J, Taube C, Wagenmann M, et al. COVID-19 vaccination of patients with allergiesand type-2 inflammation with concurrentantibody therapy (biologicals) – A Position Paper of the German Society of Allergology and Clinical Immunology (DGAKI) and the German Society for Applied Allergology (AeDA). Allergol Select. 2021;5:140‑7.
32. ANVISA: Consultas Medicamentos [site na Internet].Disponível em: https://consultas.anvisa.gov.br/#/medicamentos/25351189487201920/?nomeProduto=Dupixent. Acessado em: 06/03/21.
33. Wollenberg A, Barbarot S, Bieber T, Christen-Zaech S, Deleuran M, Fink-Wagner A, et al. Consensus-based European guidelines for treatment of atopic eczema (atopic dermatitis) in adults and children: part II. J Eur Acad Dermatol Venereol. 2018;32(6):850-78.
34. Thyssen JP, Vestergaard C, Barbarot S, de Bruin-Weller MS, Bieber T, Taieb A, et al. European Task Force on Atopic Dermatitis (ETFAD): position on vaccination of adult patients with atopic dermatitis against COVID-19 (SARS-CoV-2) being treated with systemic medication and biologics. J Eur Acad Dermatol Venereol. 2021;35:e308‑e352. https://doi.org/10.1111/jdv.17167.
35. Eichenfield LF, Bieber T, Beck LA, Simpson EL, Thaçi D, de BruinWeller M, et al. Infections in dupilumab clinical trials in atopic dermatitis: a comprehensive pooled analysis. Am J Clin Dermatol. 2019;20(3):443-56.
36. Wollenberg A, Flohr C, Simon D, Cork MJ, Thyssen JP, Bieber T, et al. European Task Force on Atopic Dermatitis (ETFAD) statement on severe acute respiratory syndrome coronavirus 2 (SARS-Cov2)-infection and atopic dermatitis. J Eur Acad Dermatol Venereol. 2020;34:e241-e242.
37. Jeyanathan M, Afkhami S, Smaill F, Miller MS, Lichty BD, Xing Z. Immunological considerations for COVID-19 vaccine strategies. Nat Rev Immunol. 2020;20:615‑32.
38. Sahin U, Muik A, Derhovanessian E, Vogler I, Kranz LM, Vormehr M, et al. COVID-19 vaccine BNT162b1 elicits human antibody and T(H)1 T cell responses. Nature. 2020;586(7830):594-9.
39. Krings JG, McGregor MC, Bacharier LB, Castro M. Biologics for Severe Asthma: Treatment-Specific Effects Are Important in Choosing a Specific Agent. J Allergy Clin Immunol Pract. 2019;7(5):1379-92.
40. Rabe KF, Nair P, Brusselle G, Maspero JF, Castro M, Sher L et al. Efficacy and Safety of Dupilumab in Glucocorticoid Dependent Severe Asthma. N Engl J Med. 2018;378(26):2475-85.
41. Voysey M, Clemens SAC, Madhi SA, Weckx LY, Folegatti PM, Aley PK; Oxford COVID Vaccine Trial Group. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. Lancet. 2021;397(10269):99-111.
42. Blauvelt A, Simpson EL, Tyring SK, Purcell LA, Shumel B, Petro CD, et al. Dupilumab does not affect correlates of vaccine-induced immunity: A randomized, placebo-controlled trial in adults with moderate-to-severe atopic dermatitis. J Am Acad Dermatol. 2019;80(1):158-67.
43. Bhalla A, Mukherjee M, Radford K, Nazy I, Kjarsgaard M, Bowdish DME, et al. Dupilumab, severe asthma airway responses, and SARS-CoV-2 serology. Allergy. 2021;76:957-8.
44. Delgado J, Dávila IJ, Domínguez-Ortega J; Severe Asthma Group (SEAIC). Clinical Recommendations for the Management of Biological Treatments in Severe Asthma Patients: A Consensus Statement. J Investig Allergol Clin Immunol. 2021;31(1):36‑43.
45. Agache I, Beltran J, Akdis C, Akdis M, Canelo-Aybar C, Canonica GW, et al. Efficacy and safety of treatment with biologicals (benralizumab, dupilumab, mepolizumab, omalizumab and reslizumab) for severe eosinophilic asthma. A systematic review for the EAACI Guidelinesrecommendations on the use of biologicals in severe asthma. Allergy. 2020;75(5):1023-42.
46. Bousquet J, Jutel M, Akdis CA, Klimek L, Pfaar O, Nadeau KC, et al. ARIA-EAACI statement on asthma and COVID-19 (June 2, 2020). Allergy. 2021;76(3):689-97.
47. Klimek L, Jutel M, Akdis CA, Bousquet J, Akdis M, Torres-Jaen M, et al. ARIA-EAACI statement on asthma and COVID-19. Allergy. 2021;76(6):1624-8.
48. Klimek L, Pfaar O, Worm M. Use of Biologicals in allergic and type-2 inflammatory diseases during the current COVID-19 pandemic: position paper of Ärzteverband Deutscher Allergologen (AeDA), Deutsche Gesellschaft für Allergologie und Klinische Immunologie (DGAKI), Gesellschaft für Pädiatrische Allergologie und Umweltmedizin (GPA), Österreichische Gesellschaft für Allergologie und Immunologie (ÖGAI), Luxemburgische Gesellschaft für Allergologie und Immunologie (LGAI), Österreichische Gesellschaft für Pneumologie (ÖGP) in co-operation with the German, Austrian, and Swiss ARIA groups, and the European Academy of Allergy and Clinical Immunology (EAACI). Allergol Select. 2020;4:53-68.
49. Zhang JJ, Dong X, Cao YY, Yuan YD, Yang YB, Yan YQ, et al. Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China. Allergy. 2020 Jul;75(7):1730-41.
50. Du Y, Tu L, Zhu P. Clinical features of 85 fatal cases of COVID-19 from Wuhan. A retrospective observational study. Am J Respir Crit Care Med. 2020;201(11):1372‑9.
51. Lindsley AW, Schwartz JT, Rothenberg ME. Eosinophil responses during COVID-19 infections and coronavirus vaccination. J Allergy Clin Immunol. 2020;146(1):1-7.
52. Azim A, Pini L, Khakwani Z, Kumar S, Howarth P. Severe acute respiratory syndrome coronavirus 2 infection in those on mepolizumab therapy. Ann Allergy Asthma Immunol. 2021;126(4):438-40.
53. Bleecker ER, FitzGerald JM, Chanez P, Papi A, Weinstein SF, Barker P, et al. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting beta2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet. 2016;388:2115‑27.
54. Zeitlin PL, Leong M, Cole J, Mallory RM, Shih VH, Olsson RF, Goldman M, ALIZE study investigators. Benralizumab does not impair antibody response to seasonal influenza vaccination in adolescent and young adult patients with moderate to severe asthma: results from the Phase IIIb ALIZE trial. J Asthma Allergy. 2018;11:181-92.
55. Tangye SG, Al-Herz W, Bousfiha A, Chatila T, Cunningham-Rundles C, Etzioni A, et al. Human inborn errors of immunity:2019 update on the Classification from the International Union ofImmunological Societies Expert Committee. J Clin Immunol. 2020;40(1):24‑64.
56. Kilic SS, Kilicbay F. Interferon-alpha treatment of molluscum contagiosum in a patient with hyperimmunoglobulin E syndrome. Pediatrics. 2006;117:1253-5.
57. Al-Zahrani D, Raddadi A, Massaad M, Keles S, Jabara HH, Chatila TA, et al. Successful interferon-alpha 2b therapy for unremitting warts in a patient with DOCK8 deficiency. Clin Immunol. 2014;153:104‑8.
58. Alangari AA, Al-Zamil F, Al-Mazrou A, Al-Muhsen S, Boisson-Dupuis S, Awadallah S, et al. Treatment of disseminated mycobacterial infection with high-dose IFN-gamma in a patient with IL-12Rbeta1 deficiency. Clin Dev Immunol. 2011;201:691956.
59. A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease. The International Chronic Granulomatous Disease Cooperative Study Group. N Engl J Med. 1991;324:509‑16.
60. Orange JS, Roy-Ghanta S, Mace EM, Maru S, Rak SGD, Sanborn KB, et al. IL-2 induces a WAVE2-dependent pathway for actin reorganization that enables WASP-independent human NK cell function. J Clin Invest. 2011;121:1535-48.
61. Yilmaz-Demirdag Y, Wilson B, Lowery-Nordberg M, Bocchini Jr JA, Bahna SL. Interleukin-2 treatment for persistent cryptococcal meningitis in a child with idiopathic CD4(+) T lymphocytopenia. Allergy Asthma Proc. 2008; 29:421-4.
62. Yashiro S, Fujino Y, Tachikawa N, Inamochi K, Oka S. Longterm control of CMV retinitis in a patient with idiopathic CD4+ T lymphocytopenia. J Infect Chemother. 2013:19:316-20.
63. Cunningham-Rundles C, Bodian C, Ochs HD, Martin S, ReiterWong M, Zhuo Z. Long-term low-dose IL-2 enhances immune function in common variable immunodeficiency, Clin Immunol. 2001;100:181‑90.
64. Janczar S, Zalewska-Szewczyk B, BaBOL-Pokora K, PaSnik J, Zeman K, MŁynarski W. Vaccination in children with chronic severe neutropenia - review of recommendations and a practical approach. Cent Eur J Immunol. 2020;45(2):202-5.
65. Feldmann M, Maini RN. Lasker clinical medical research award. TNF defined as a therapeutic target for rheumatoid arthritis and other autoimmune diseases. Nat Med. 2003;9:1245‑50.
66. Scheinfeld N. A comprehensive review and evaluation of the side effects of the tumor necrosis factor blockers etanercept, infliximab and adalimumab. J Dermatolog Treat. 2004;15(5):280‑94.
67. Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J, Schwieterman WD, et al. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med. 2001;345(15):1098‑104.
68. Tragiannidis A, Kyriakidis I, Zündorf I, Groll AH. Invasive fungal infections in pediatric patients treated with tumor necrosis alpha (TNF-α) inhibitors. Mycoses. 2016; 60(4):222‑9.
69. Mansouri B, Horner ME, Menter A. Tumor necrosis factor-α inhibitor use in psoriasis patients with a first-degree relative with multiple sclerosis. J Drugs Dermat. 2015;14(8):876‑8.
70. Cavalli G, Dinarello CA. Treating rheumatological diseases and co-morbidities with interleukin-1 blocking therapies. Rheumatology. 2015;54:2134-44.
71. Settas D, Tsimirikas G, Vosvotekas G, Triantafyllidou E, Nicolaides P. Reactivation of pulmonary tuberculosis in a patient with rheumatoid arthritis during treatment with IL-1 receptor antagonists (anakinra). J Clin Rheumatology. 2007;13:219-20.
72. Jeyanathan M, Afkhami S, Smaill F, Miller MS, Lichty BD, Xing Z. Immunological considerations for COVID-19 vaccine strategies. Nat Rev Immunol. 2020;10:615-32.
73. Canedo-Marroquín G, Saavedra F, Andrade CA, Berrios RV, Rodríguez-Guilarte L, Opazo MC, et al. SARS-CoV-2: immune response elicited by infection and development of vaccines and treatments. Front Immunol. 2020;11:569760. doi: 10.3389/ fimmu.2020.
74. Lederer K, Castaño D, Gómez Atria D, Oguim TH 3rd, Wang S, Manzoni TB, et al. SARS-CoV-2 mRNA vaccines foster potent antigen specific germinal center responses associated with neutralizing antibody generation. Immunity. 2020;53(6):1281‑95.
75. Kennedy NA, Goodhand JR, Bewshea C, Nice R, Chee D, Lin S, et al. Anti-SARS-CoV-2 antibody responses are attenuated in patients with IBD treated with infliximab. Gut. 2021;70(5):865-75.
76. Eleftheriou D, Brogan PA. Genetic interferonopathies: An overview. Best Practice & Research Clinical Rheumatology. 2017;31:441‑59.
77. Higgins E, Al Shehri T, McAleer MA, Conlon N, Feighery C, Lilic D, et al. Use of ruxolitinib to successfully treat chronic mucocutaneous candidiasis caused by gain-of-function signal transducer and activator of transcription 1 (STAT1) mutation, J Allergy Clin Immunol. 2015;135:551-3.
78. Weinacht KG, Charbonnier LM, Alroqi F, Plant A, Qiao Q, Wu H, et al. Ruxolitinib reverses dysregulated T helper cell responses and controls autoimmunity caused by a novel signal transducer and activator of transcription 1 (STAT1) gain-of-function mutation. J Allergy Clin Immunol. 2017;139:1629-40.
79. Zimmerman O, Rosler B, Zerbe CS, Rosen LB, Hsu AP, Uzel G, et al. Risks of Ruxolitinib in STAT1 Gain-of-Function-Associated Severe Fungal Disease. Open Forum Infect Dis. 2017;4ofx202.
80. Gobert D, Bussel JB, Cunningham-Rundles C, Galicier L, Dechartres A, Berezne A, et al. Efficacy and safety of rituximab in common variable immunodeficiency-associated immune cytopenias: a retrospective multicentre study on 33 patients. Br J Haematol. 2011;155:498-508.
81. Hennig C, Baumann U, Ilginus C, Horneff G, Foell J, Hansen G. Successful treatment of autoimmune and lymphoproliferative complications of patients with intrinsic B-cell immunodeficiencies with Rituximab. Br J Haematol. 2010;148:445-8.
82. Chase NM, Verbsky JW, Hintermeyer MK, Waukau JK, TomitaMitchell A, Casper JT, et al. Use of combination chemotherapy for treatment of granulomatous and lymphocytic interstitial lung disease (GLILD) in patients with common variable immunodeficiency (CVID). J Clin Immunol. 2013; 33:30-9.
83. Bindl L, Torgerson T, Perroni L, Youssef N, Ochs HD, Goulet O, et al. Successful use of the new immune-suppressor sirolimus in IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome). J Pediatr. 2005;147;256-9.
84. Lucas CL, Kuehn HS, Zhao F, Niemela JE, Deenick EK, Palendira U, et al. Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110delta result in T cell senescence and human immunodeficiency. Nat Immunol. 2014;15:88-97.
Submitted date:
03/15/2021
Accepted date:
03/26/2021
