Çocuklarda Covid 19 İlişkili Multisistem İnflamatuar Sendrom Patofizyolojisi

Öz

Koronavirüs hastalığı 2019 (COVID-19) salgını ilk kez Asya'da rapor edildiğinde ve ardından tüm dünyaya yayıldığında, ilk bulgular enfeksiyonun çocuklarda daha hafif semptomlarla görüldüğü şeklindeydi. Ancak Nisan 2020 ortalarında önce İngiltere, ardından İtalya, İspanya, Amerika olmak üzere bir çok ülkeden çoklu organ yetmezliği bulgularıyla başvuran hastalar rapor edildi ve yeni bir hiperinflamatuar sendrom olan çocuklarda multisistem inflamatuar sendrom (MIS-C) tanımlandı. MIS-C’nin erişkinlerdeki şiddetli akut respiratuvar sendromu koronavirüsü 2 (SARS-CoV-2) piklerinden 4-6 hafta sonra görülme sıklığı artması nedeniyle bir enfeksiyon sonrası süreç olduğu düşünülmektedir. MIS-C Kawasaki hastalığı, sitokin salınım sendromu, makrofaj aktivasyon sendromu ile benzerlikleri olsa da ayrı bir immün fenotipe sahiptir. MIS-C patofizyolojisi ve neden bazı çocuklarda gelişip diğerlerinde gelişmediği net bilinmemektedir. Çocuklarda genellikle asemptomatik veya hafif semptomlarla geçen erken enfeksiyon, makrofaj aktivasyonuna ve ardından yardımcı T hücrelerin uyarılmasına neden olur. Bunun sonucunda tümör nekrozis faktör (TNF), interlökin (IL)-6, IL-1β, IL-4, IL-23, IL-18, IL-12 ve interferon (IFN) gibi sitokinlerin salınımına/fırtınasına, makrofajların, nötrofillerin ve monositlerin uyarılmasına neden olur. MIS-C patogenezini anlamak ve COVID-19 pandemisi yeni piklerle devam ederken tedavisine ve önlenmesine rehberlik etmek için daha fazla araştırma yapılması zorunludur.

Anahtar Kelimeler

• MIS-C
• Multisistem inflamatuar sendrom
• çocuklar
• SARS-CoV-2
• COVID-19
• patofizyoloji
• immün yanıt
• interlökin

Pathophysıology of Covıd 19 Related Multisystem Inflammatory Syndrome in Children

Öz

When the coronavirus disease 2019 (COVID-19) outbreak was first reported in Asia and then spread worldwide, the initial findings showed that the infection was milder in children. However, in mid-April 2020, patients from many countries, first in England, then Italy, Spain, and United States of America, were reported with multiple organ failure symptoms, and multisystem inflammatory syndrome (MIS-C) was identified in children as a new hyperinflammatory syndrome. MIS-C is thought to be a post-infection process due to its increased incidence 4-6 weeks after the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) peaks in adults. Although it has similarities with Kawasaki disease, cytokine release syndrome and macrophage activation syndrome have a separate immune phenotype. The pathophysiology of MIS-C and why it develops in some children and not in others is not clear. Early infection, usually asymptomatic or with mild symptoms in children, causes macrophage activation followed by stimulation of helper T cells. This causes the release of cytokines such as tumor necrosis factor (TNF), interleukin (IL)-6, IL-1β, IL-4, IL-23, IL-18, IL-12, and interferon (IFN) and stimulation of macrophages, neutrophils, and monocytes. Further research is imperative to understand the pathogenesis of MIS-C and to guide its treatment and prevention as the COVID-19 pandemic continues with new peaks.

Anahtar Kelimeler

• MIS-C
• Multisystem inflammatory syndrome
• children
• SARS-CoV-2
• COVID-19
• pathogenesis
• immune response
• interleukin

Kaynakça

1. Riphagen S, Gomez X, Gonzalez-Martinez C, Wilkinson N, Theocharis P. Hyperinflammatory shock in children during COVID-19 pandemic. Lancet 2020;395, 1607–1608.
2. Verdoni L, Mazza A, Gervasoni A, et al. An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study. Lancet 2020; 395:1771.
3. Cabrero-Hernández M. et al. Severe SARS-CoV-2 infection in children with suspected acute abdomen: a case series from a tertiary hospital in Spain. Pediatr Infect Dis J. 2020 Aug;39(8):e195-e198.
4. Chiotos, K. et al. Multisystem inflammatory syndrome in children during the COVID-19 pandemic: a case series. J Pediatric Infect Dis Soc. 2020 Jul 13;9(3):393-398. PMID:32463092
5. Rowley AH. Understanding SARS-CoV-2-related multisystem inflammatory syndrome in children. Nat Rev Immunol. 2020 Aug;20(8):453-454. PMID: 32546853
6. CDC Multisystem Inflammatory Syndrome in Children (MIS-C). Centers for Disease Control and Prevention. https ://www.cdc.gov/mis-c/hcp/. Accessed 11 Aug 2020.
7. Multisystem inflammatory syndrome in children and adolescents with COVID-19 Scientific brief: World Health Organisa-tion. https ://www.who.int/publi catio ns-detai l/multi syste m-inflammato ry-syndr ome-in-child ren-andad olesc ents-with-covid -19. Accessed 15 May 2020.
8. Feldstein LR, Rose EB, Horwitz SM, et al. Multisystem Inflammatory Syndrome in U.S. Children and Adolescents. N Engl J Med 2020; 383:334.

9. Son MBF, Friedman K. COVID-19: Multisystem inflammatory syndrome in children (MIS-C) clinical features, evaluation, and diagnosis. https://www.uptodate.com/contents/covid-19-multisystem-inflammatory-syndrome-in-children-mis-c-clinical-features-evaluation-and-diagnosis?
10. Whittaker E, Bamford A, Kenny J, et al. Clinical Characteristics of 58 Children With a Pediatric Inflammatory Multisystem Syndrome Temporally Associated With SARS-CoV-2. JAMA 2020; 324:259.
11. Carter MJ, Fish M, Jennings A, et al. Peripheral immunophenotypes in children with multisystem inflammatory syndrome associated with SARS-CoV-2 infection. Nat Med 2020; 26:1701.
12. Lee PY, Day-Lewis M, Henderson LA, et al. Distinct clinical and immunological features of SARS-CoV-2-induced multisystem inflammatory syndrome in children. J Clin Invest 2020; 130:5942.
13. Godfred-Cato S, Bryant B, Leung J, et al. COVID-19-Associated Multisystem Inflammatory Syndrome in Children - United States, March-July 2020. MMWR Morb Mortal Wkly Rep 2020; 69:1074.
14. Nakra NA, Blumberg DA, Herrera-Guerra A, Lakshminrusimha S. Multi-System Inflammatory Syndrome in Children (MIS-C) Following SARS-CoV-2 Infection: Review of Clinical Presentation, Hypothetical Pathogenesis, and Proposed Management. Children (Basel). 2020 Jul 1;7(7):69. PMID: 32630212
15. Pang J, Boshier FAT, Alders N, et al. SARS-CoV-2 Polymorphisms and Multisystem Inflammatory Syndrome in Children. Pediatrics 2020; 146.
16. Bunyavanich S, Do A, Vicencio A. Nasal gene expression of angiotensin-converting enzyme 2 in children and adults. JAMA 2020 Jun 16;323(23):2427-2429.
17. Giamarellos-Bourboulis EJ, Netea MG, Rovina N, Akinosoglou K, Antoniadou A, et al. Complex immune dysregulation in COVID-19 patients with severe respiratory failure. Cell Host Microbe 2020 Jun 10;27(6):992-1000.e3. doi: 10.1016/j.chom.2020.04.009. Epub 2020 Apr 21. [CrossRef]
18. Gruber C, Patel R, Trachman R, Lepow L, Amanat F, Krammer F, et al. Mapping systemic inflammation and antibody responses in multisystem inflammatory syndrome in children (MIS-C). medRxiv. 2020;2020.07.04.20142752. 91.
19. Consiglio CR, Cotugno N, Sardh F, Pou C, Amodio D, Rod-riguez L, et al. The Immunology of multisystem inflammatory syndrome in children with COVID-19. Cell 2020;S0092–8674(20):31157.
20. Kulhankova K, Kinney KJ, Stach JM, Gourronc FA, Grumbach IM, Klingelhutz AJ, et al. The superantigen toxic shock syndrome toxin 1 alters human aortic endothelial cell function. Infect Immun 2018;86:e00848–17. doi: 10.1128/IAI.00848-17
21. Lee Y, Wakita D, Dagvadorj J, Shimada K, Chen S, Huang G, et al. IL-1 signaling is critically required in stromal cells in kawasaki disease vasculitis mouse model: role of both IL-1a and IL-1b. Arterioscler Thromb Vasc Biol 2015;35:2605–16. doi: 10.1161/ATVBAHA.115.306475
22. Dinarello CA. Overview of the IL-1 family in innate inflammation and acquired immunity. Immunol Rev 2018; 281:8–27. doi: 10.1111/imr.12621
23. Gaudino SJ, Kumar P. Cross-talk between antigen presenting cells and T cells impacts intestinal homeostasis, bacterial infections, and tumorigenesis. Front Immunol 2019;10:360. doi: 10.3389/fimmu.2019.00360
24. Yasuda K, Nakanishi K, Tsutsui H. Interleukin-18 in health and disease. Int J Mol Sci 2019;20:649. doi: 10.3390/ijms20030649
25. Cheung EW, Zachariah P, Gorelik M, Boneparth A, Kernie SG, Orange JS, et al. Multisystem inflammatory syndrome related to COVID-19 in previously healthy children and adolescents in New York city. JAMA 2020;324:259–69. doi: 10.1001/jama.2020.10374
26. McMurray JC, May JW, Cunningham MW, Jones OY. Multisystem Inflammatory Syndrome in Children (MIS-C), a Post-viral Myocarditis and Systemic Vasculitis-A Critical Review of Its Pathogenesis and Treatment. Front Pediatr 2020 Dec 16;8:626182. doi: 10.3389/fped.2020.626182. eCollection 2020. PMID: 33425823
27. Onouchi Y, Ozaki K, Burns JC, Shimizu C, Terai M, Hamada H, et al. A genome-wide association study identifies three new risk loci for Kawasaki disease. Nat Genet 2012;44:517–21. doi: 10.1038/ng.2220
28. Xu M, Jiang Y, Wang J, Liu J, Liu C, Liu D, et al. Distinct variations of antibody secreting cells and memory B cells during the course of Kawasaki disease. BMC Immunol 2019;20(1):16.
29. Kabeerdoss J, Pilania RK, Karkhele R, Kumar TS, Danda D, Singh S. Severe COVID‑19, multisystem inflammatory syndrome in children, and Kawasaki disease: immunological mechanisms, clinical manifestations and management. Rheumatol Int. 2021 Jan;41(1):19-32. PMID: 33219837
30. Park A, Iwasaki A. Type I and type III interferons — induction, signaling, evasion, and application to combat COVID-19. Cell Host Microbe 2020;27: 870–878.
31. Blanco-Melo D, et al. Imbalanced host response to SARS-CoV-2 drives development of COVID-19. Cell 2020; 181:1036–1045.e9
32. Beverley PC. Immunology of vaccination. Br. Med. Bull 2002;62: 15–28.