Diverse clinical features and diagnostic delay in monogenic inborn errors of immunity: A call for access to genetic testing.
cohort studies
delayed diagnosis
genetic testing
immunologic deficiency syndromes
primary immunodeficiency diseases
whole exome sequencing
Journal
Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology
ISSN: 1399-3038
Titre abrégé: Pediatr Allergy Immunol
Pays: England
ID NLM: 9106718
Informations de publication
Date de publication:
11 2021
11 2021
Historique:
revised:
19
05
2021
received:
19
01
2021
accepted:
31
05
2021
pubmed:
8
6
2021
medline:
8
1
2022
entrez:
7
6
2021
Statut:
ppublish
Résumé
Inborn errors of immunity (IEIs) are a group of conditions affecting immune system development and function. Due to their clinical heterogeneity and lack of provider awareness, patients suffer from long diagnostic delays that increase morbidity and mortality. Next-generation sequencing facilitates earlier diagnosis and treatment of IEIs, but too often patients are unable to see the benefit of this technology due to gaps in providers' knowledge regarding which patients to test and barriers to accessing sequencing. Here, we provide detailed clinical phenotyping and describe the impact of genetic sequencing on a cohort of 43 patients with monogenic IEIs seen in a tertiary care center from 2014 to 2019. Data were abstracted from a chart review, and a panel of clinical immunologists were consulted on the impact of genetic sequencing on their patients. We found that our patients had significant diagnostic delays, averaging 3.3 years; had diverse manifestations of immune system dysfunction; and had demonstrated highly complex medical needs, with on average 7.9 subspecialties involved in their care and 4.9 hospitalizations prior to definitive treatment. Our results also demonstrate the benefits of genetic testing, as it provided the majority of our patients with a diagnosis, and positively impacted their treatment, follow-up, and prognosis. This paper expands the paucity of literature on genetically confirmed IEIs in North America and supports the expansion of access to genetic testing for patients with clinical features suggesting IEI, such as those presented in our cohort.
Sections du résumé
BACKGROUND
Inborn errors of immunity (IEIs) are a group of conditions affecting immune system development and function. Due to their clinical heterogeneity and lack of provider awareness, patients suffer from long diagnostic delays that increase morbidity and mortality. Next-generation sequencing facilitates earlier diagnosis and treatment of IEIs, but too often patients are unable to see the benefit of this technology due to gaps in providers' knowledge regarding which patients to test and barriers to accessing sequencing.
METHODS
Here, we provide detailed clinical phenotyping and describe the impact of genetic sequencing on a cohort of 43 patients with monogenic IEIs seen in a tertiary care center from 2014 to 2019. Data were abstracted from a chart review, and a panel of clinical immunologists were consulted on the impact of genetic sequencing on their patients.
RESULTS
We found that our patients had significant diagnostic delays, averaging 3.3 years; had diverse manifestations of immune system dysfunction; and had demonstrated highly complex medical needs, with on average 7.9 subspecialties involved in their care and 4.9 hospitalizations prior to definitive treatment. Our results also demonstrate the benefits of genetic testing, as it provided the majority of our patients with a diagnosis, and positively impacted their treatment, follow-up, and prognosis.
CONCLUSION
This paper expands the paucity of literature on genetically confirmed IEIs in North America and supports the expansion of access to genetic testing for patients with clinical features suggesting IEI, such as those presented in our cohort.
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1796-1803Informations de copyright
© 2021 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.
Références
Turvey SE, Bonilla FA, Junker AK. Primary immunodeficiency diseases: a practical guide for clinicians. Postgrad Med J. 2009;85(1010):660-666. https://doi.org/10.1136/pgmj.2009.080630
Bousfiha A, Jeddane L, Picard C, et al. Human inborn errors of immunity: 2019 update of the IUIS phenotypical classification. J Clin Immunol. 2020;40(1):66-81. https://doi.org/10.1007/s10875-020-00758-x
Ochs HD, Hagin D. Primary immunodeficiency disorders: general classification, new molecular insights, and practical approach to diagnosis and treatment. Ann Allergy, Asthma Immunol. 2014;112(6):489-495. https://doi.org/10.1016/j.anai.2014.04.007
Bonilla FA, Khan DA, Ballas ZK, et al. Practice parameter for the diagnosis and management of primary immunodeficiency. J Allergy Clin Immunol. 2015;136(5):1186-1205.e78. https://doi.org/10.1016/j.jaci.2015.04.049
Resnick ES, Bhatt P, Sidi P, Cunningham-Rundles C. Examining the use of ICD-9 diagnosis codes for primary immune deficiency diseases in New York State. J Clin Immunol. 2013;33(1):40-48. https://doi.org/10.1007/s10875-012-9773-1
Sokol K, Milner JD. The overlap between allergy and immunodeficiency. Curr Opin Pediatr. 2018;30(6):848-854. https://doi.org/10.1097/MOP.0000000000000697
Gennery A. Immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome. 2020. https://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=10440&Disease_Disease_Search_diseaseGroup=IPEX&Disease_Disease_Search_diseaseType=Pat&Disease(s)/groupofdiseases=Immune-dysregulation-polyendocrinopathy-enteropathy-X-linked-synd. Accessed August 27, 2020.
Jamee M, Zaki-Dizaji M, Lo B, et al. Clinical, immunological, and genetic features in patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) and IPEX-like syndrome. J Allergy Clin Immunol Pract. 2020;8(8):2747-2760.e7. https://doi.org/10.1016/j.jaip.2020.04.070
Bousfiha AA, Jeddane L, Ailal F, et al. Primary immunodeficiency diseases worldwide: more common than generally thought. J Clin Immunol. 2013;33(1):1-7. https://doi.org/10.1007/s10875-012-9751-7
Dupuis A, Hamilton D, Cole DEC, Corey M. Cystic fibrosis birth rates in Canada: a decreasing trend since the onset of genetic testing. J Pediatr. 2005;147(3):312-315. https://doi.org/10.1016/j.jpeds.2005.06.043
Casanova J-L, Conley ME, Seligman SJ, Abel L, Notarangelo LD. Guidelines for genetic studies in single patients: lessons from primary immunodeficiencies. J Exp Med. 2014;211(11):2137-2149. https://doi.org/10.1084/jem.20140520
Edgar JDM, Buckland M, Guzman D, et al. The United Kingdom Primary Immune Deficiency (UKPID) Registry: report of the first 4 years' activity 2008-2012. Clin Exp Immunol. 2014;175(1):68-78. https://doi.org/10.1111/cei.12172
Reda SM, El-Ghoneimy DH, Afifi HM. Clinical predictors of primary immunodeficiency diseases in children. Allergy Asthma Immunol Res. 2013;5(2):88-95. https://doi.org/10.4168/aair.2013.5.2.88
Sewell WAC, Khan S, Dore PC. Early indicators of immunodeficiency in adults and children: protocols for screening for primary immunological defects. Clin Exp Immunol. 2006;145(2):201-203. https://doi.org/10.1111/j.1365-2249.2006.03126.x
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. https://doi.org/10.1586/1744666X.2015.990440
MacGinnitie A, Aloi F, Mishra S. Clinical characteristics of pediatric patients evaluated for primary immunodeficiency. Pediatr Allergy Immunol. 2011;22(7):671-675. https://doi.org/10.1111/j.1399-3038.2011.01167.x
Aloi FP, Mishra SS, MacGinnitie AJ. Guidelines for “10 Warning Signs of Primary Immunodeficiency” neither sensitive nor specific. J Allergy Clin Immunol. 2007;119(1):S14. https://doi.org/10.1016/j.jaci.2006.11.070
Zhang Z-Y, An Y-F, Jiang L-P, et al. Distribution, clinical features and molecular analysis of primary immunodeficiency diseases in Chinese children. Pediatr Infect Dis J. 2013;32(10):1127-1134. https://doi.org/10.1097/INF.0b013e31829aa9e9
Wu J, Zhong W, Yin Y, Zhang H. Primary immunodeficiency disease: a retrospective study of 112 Chinese children in a single tertiary care center. BMC Pediatr. 2019;19(1):410. https://doi.org/10.1186/s12887-019-1729-7
Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)-A metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009;42(2):377-381. https://doi.org/10.1016/J.JBI.2008.08.010
Harris PA, Taylor R, Minor BL, et al. The REDCap consortium: Building an international community of software platform partners. J Biomed Inform. 2019;95:103208. https://doi.org/10.1016/J.JBI.2019.103208
Al-Herz W. Primary immunodeficiency disorders in Kuwait: first report from Kuwait National Primary Immunodeficiency Registry (2004-2006). J Clin Immunol. 2008;28(2):186-193. https://doi.org/10.1007/s10875-007-9144-5
Al-Tamemi S, Ur S, Naseem R, et al. Primary immunodeficiency diseases in Oman: 10-year experience in a Tertiary Care Hospital. J Clin Immunol. 2016;36(8):785-792. https://doi.org/10.1007/s10875-016-0337-7
Subbarayan A, Colarusso G, Hughes SM, et al. Clinical features that identify children with primary immunodeficiency diseases. Pediatrics. 2011;127(5):810-816. https://doi.org/10.1542/peds.2010-3680
Benjasupattananan P, Simasathein T, Vichyanond P, et al. Clinical characteristics and outcomes of primary immunodeficiencies in Thai children: an 18-year experience from a Tertiary Care Center. J Clin Immunol. 2009;29(3):357-364. https://doi.org/10.1007/s10875-008-9273-5
Gupta D, Thakral D, Kumar P, et al. Primary immunodeficiency disorders among north Indian children. Indian J Pediatrics. 2019;86(10):885-891. https://doi.org/10.1007/s12098-019-02971-y
Khalilzadeh S, Boloorsaz MR, Baghaie N, et al. Primary immunodeficiency in children: report of seven years study. Tanaffos. 2011;10 (2):38-43. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4153139/pdf/Tanaffos-10-038.pdf
Mellouli F, Ben MI, Ben KM, et al. Report of the Tunisian Registry of Primary Immunodeficiencies: 25-years of experience (1988-2012). J Clin Immunol. 2015;35(8):745-753. https://doi.org/10.1007/s10875-015-0206-9
Pirrone A, Markelj G, Piscianz E, et al. Clinical immunology Primary Immunodeficiency Diseases in two neighboring pediatric centers: registry data bring out a wide spectrum of diseases with complex clinical presentations. Cent Eur J Immunol. 2012;4(4):365-370. https://doi.org/10.5114/ceji.2012.32727
Zeng H, Tao Y, Chen X, et al. Primary immunodeficiency in South China: clinical features and a genetic subanalysis of 138 children. J Investig Allergol Clin Immunol. 2013;23 (5):302-308. http://www.jiaci.org/issues/vol23issue5/2.pdf
Yildirim M, Ayvaz DC, Konuskan B, et al. Neurologic involvement in primary immunodeficiency disorders. J Child Neurol. 2018;33(5):320-328. https://doi.org/10.1177/0883073817754176
Fattahi F, Badalzadeh M, Sedighipour L, et al. Inheritance pattern and clinical aspects of 93 Iranian patients with chronic granulomatous disease. J Clin Immunol. 2011;31(5):792-801. https://doi.org/10.1007/s10875-011-9567-x
McKinnon ML, Rozmus J, Fung S-Y, et al. Combined immunodeficiency associated with homozygous MALT1 mutations. J Allergy Clin Immunol. 2014;133(5):1458-1462.e7. https://doi.org/10.1016/j.jaci.2013.10.045
Kilic SS, Ozel M, Hafizoglu D, Karaca NE, Aksu G, Kutukculer N. The prevalances and patient characteristics of primary immunodeficiency diseases in Turkey-two centers study. J Clin Immunol. 2013;33(1):74-83. https://doi.org/10.1007/s10875-012-9763-3