SARS-CoV-2 infections in children: Understanding diverse outcomes

Petter Brodin, Petter Brodin

Abstract

SARS-CoV-2 infections mostly lead to mild or even asymptomatic infections in children, but the reasons for this are not fully understood. More efficient local tissue responses, better thymic function, and cross-reactive immunity have all been proposed to explain this. In rare cases of children and young people, but very rarely in adults, post-infectious hyperinflammatory syndromes can develop and be serious. Here, I will discuss our current understanding of SARS-CoV-2 infections in children and hypothesize that a life history and energy allocation perspective might offer an additional explanation to mild infections, viral dynamics, and the higher incidence of rare multisystem inflammatory syndromes in children and young people.

Conflict of interest statement

Declaration of interests The authors declare no competing interests.

Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.

Figures

Figure 1
Figure 1
Immune responses in mild and severe COVID-19 Characteristic differences between patients developing mild versus severe COVID-19 disease with delayed and imbalanced IFN-I responses, lymphopenia, and uncontrolled viral replication. Typical signs of mild versus severe COVID-19 in terms of cytokine production, inflammasome activation, and coagulopathy, as seen a number of population studies (Carvalho et al., 2021).
Figure 2
Figure 2
Viral dynamics in the young and old Relative viral load (arbitrary units, a.u.) over time (days from diagnosis) as determined by PCR from either nasopharyngeal or stool samples. A schematic model summarizing the results of multiple studies showing prolonged shedding of viral nucleic acid from stool, particularly in children.
Figure 3
Figure 3
An energy allocation theory to explain mild COVID-19 and MIS-C in children based on disease tolerance and viral persistence (A) Energy requirement (kcal/kg) decrease with age in US children and is slightly higher in boys than girls (adapted from Torun, 2005). The fraction of asymptomatic children among SARS-CoV-2 PCR+ children across the indicated age groups (Leidman et al., 2021), MIS-C incidence in the US per 100,000 children across indicated age groups (Belay et al., 2021), and MIS-C incidence per 1 million cases of COVID-19 across the indicated age groups (Payne et al., 2021). (B) In growing children, the threshold for energy-expenditure on system inflammatory responses are higher, leading to disease tolerance in most cases and mild to asymptomatic COVID-19, while in the elderly, the obese, and individuals with inadequate type-I IFN-respones, systemic inflammation is triggered, driving bystander T cell activation and immunopathology.

References

    1. Abolhassani H., Vosughimotlagh A., Asano T., Landegren N., Boisson B., Delavari S., Bastard P., Aranda-Guillén M., Wang Y., Zuo F., et al. X-Linked TLR7 Deficiency Underlies Critical COVID-19 Pneumonia in a Male Patient with Ataxia-Telangiectasia. J. Clin. Immunol. 2021 doi: 10.1007/s10875-021-01151-y. Published online October 23, 2021.
    1. Abrams J.Y., Oster M.E., Godfred-Cato S.E., Bryant B., Datta S.D., Campbell A.P., Leung J.W., Tsang C.A., Pierce T.J., Kennedy J.L., et al. Factors linked to severe outcomes in multisystem inflammatory syndrome in children (MIS-C) in the USA: a retrospective surveillance study. Lancet Child Adolesc. Health. 2021;5:323–331.
    1. Addetia A., Crawford K.H.D., Dingens A., Zhu H., Roychoudhury P., Huang M.-L., Jerome K.R., Bloom J.D., Greninger A.L. Neutralizing Antibodies Correlate with Protection from SARS-CoV-2 in Humans during a Fishery Vessel Outbreak with a High Attack Rate. J. Clin. Microbiol. 2020;58:e02107-20.
    1. Arvin A.M., Fink K., Schmid M.A., Cathcart A., Spreafico R., Havenar-Daughton C., Lanzavecchia A., Corti D., Virgin H.W. A perspective on potential antibody-dependent enhancement of SARS-CoV-2. Nature. 2020;584:353–363.
    1. Asano T., Boisson B., Onodi F., Matuozzo D., Moncada-Velez M., Maglorius Renkilaraj M.R.L., Zhang P., Meertens L., Bolze A., Materna M., et al. COVID Human Genetic Effort. COVID-STORM Clinicians. COVID Clinicians. Imagine COVID Group. French COVID Cohort Study Group. CoV-Contact Cohort. Amsterdam UMC Covid- Biobank. NIAID-USUHS COVID Study Group X-linked recessive TLR7 deficiency in ∼1% of men under 60 years old with life-threatening COVID-19. Sci. Immunol. 2021;6:eabl4348.
    1. Avanzato V.A., Matson M.J., Seifert S.N., Pryce R., Williamson B.N., Anzick S.L., Barbian K., Judson S.D., Fischer E.R., Martens C., et al. Case Study: Prolonged Infectious SARS-CoV-2 Shedding from an Asymptomatic Immunocompromised Individual with Cancer. Cell. 2020;183:1901–1912.
    1. Bartsch Y.C., Wang C., Zohar T., Fischinger S., Atyeo C., Burke J.S., Kang J., Edlow A.G., Fasano A., Baden L.R., et al. Humoral signatures of protective and pathological SARS-CoV-2 infection in children. Nat. Med. 2021;27:454–462.
    1. Bastard P., Rosen L.B., Zhang Q., Michailidis E., Hoffmann H.-H., Zhang Y., Dorgham K., Philippot Q., Rosain J., Béziat V., et al. Auto-antibodies against type I IFNs in patients with life-threatening COVID-19. Science. 2020;370:eabd4585.
    1. Bastard P., Orlova E., Sozaeva L., Lévy R., James A., Schmitt M.M., Ochoa S., Kareva M., Rodina Y., Gervais A., et al. Preexisting autoantibodies to type I IFNs underlie critical COVID-19 pneumonia in patients with APS-1. J. Exp. Med. 2021;218:e20210554.
    1. Bastard P., Gervais A., Voyer T.L., Rosain J., Philippot Q., Manry J., Michailidis E., Hoffmann H.-H., Eto S., Garcia-Prat M., et al. Autoantibodies neutralizing type I IFNs are present in ∼4% of uninfected individuals over 70 years old and account for ∼20% of COVID-19 deaths. Sci Immunol. 2021;6:eabl4340.
    1. Beccuti G., Ghizzoni L., Cambria V., Codullo V., Sacchi P., Lovati E., Mongodi S., Iotti G.A., Mojoli F. A COVID-19 pneumonia case report of autoimmune polyendocrine syndrome type 1 in Lombardy, Italy: letter to the. J. Endocrinol. Invest. 2020;43:1175–1177.
    1. Behnood S.A., Shafran R., Bennett S.D., Zhang A.X.D., O’Mahoney L.L., Stephenson T.J., Ladhani S.N., De Stavola B.L., Viner R.M., Swann O.V. Persistent symptoms following SARS-CoV-2 infection amongst children and young people: A meta-analysis of controlled and uncontrolled studies. J. Infect. 2021 doi: 10.1016/j.jinf.2021.11.011. Published online November 20, 2021.
    1. Belay E.D., Abrams J., Oster M.E., Giovanni J., Pierce T., Meng L., Prezzato E., Balachandran N., Openshaw J.J., Rosen H.E., et al. Trends in Geographic and Temporal Distribution of US Children With Multisystem Inflammatory Syndrome During the COVID-19 Pandemic. JAMA Pediatr. 2021;175:837–845.
    1. Brodin P. Why is COVID-19 so mild in children? Acta Paediatr. 2020;109:1082–1083.
    1. Brodin P. Immune determinants of COVID-19 disease presentation and severity. Nat. Med. 2021;27:28–33.
    1. Bucciol G., Tangye S.G., Meyts I. Coronavirus disease 2019 in patients with inborn errors of immunity: lessons learned. Curr. Opin. Pediatr. 2021;33:648–656.
    1. Callow K.A., Parry H.F., Sergeant M., Tyrrell D.A.J. The time course of the immune response to experimental coronavirus infection of man. Epidemiol. Infect. 1990;105:435–446.
    1. Carvalho T., Krammer F., Iwasaki A. The first 12 months of COVID-19: a timeline of immunological insights. Nat. Rev. Immunol. 2021;21:245–256.
    1. Ceulemans L.J., Khan M., Yoo S.-J., Zapiec B., Van Gerven L., Van Slambrouck J., Vanstapel A., Van Raemdonck D., Vos R., Wauters E., et al. Persistence of SARS-CoV-2 RNA in lung tissue after mild COVID-19. Lancet Respir. Med. 2021;9:e78–e79.
    1. Cheng M.H., Zhang S., Porritt R.A., Noval Rivas M., Paschold L., Willscher E., Binder M., Arditi M., Bahar I. Superantigenic character of an insert unique to SARS-CoV-2 spike supported by skewed TCR repertoire in patients with hyperinflammation. Proc. Natl. Acad. Sci. USA. 2020;117:25254–25262.
    1. Consiglio C.R., Cotugno N., Sardh F., Pou C., Amodio D., Rodriguez L., Tan Z., Zicari S., Ruggiero A., Pascucci G.R., et al. The Immunology of Multisystem Inflammatory Syndrome in Children with COVID-19. Cell. 2020;183:968–981.
    1. Cotugno N., Ruggiero A., Pascucci G.R., Bonfante F., Petrara M.R., Pighi C., Cifaldi L., Zangari P., Bernardi S., Cursi L., et al. Pediatr Allergy Immu; 2021. Virological and immunological features of SARS-COV-2 infected children with distinct symptomatology.
    1. Delahoy M.J., Ujamaa D., Whitaker M., O’Halloran A., Anglin O., Burns E., Cummings C., Holstein R., Kambhampati A.K., Milucky J., et al. COVID-NET Surveillance Team. COVID-NET Surveillance Team Hospitalizations Associated with COVID-19 Among Children and Adolescents - COVID-NET, 14 States, March 1, 2020-August 14, 2021. MMWR Morb. Mortal. Wkly. Rep. 2021;70:1255–1260.
    1. Du W., Yu J., Liu X., Chen H., Lin L., Li Q. Persistence of SARS-CoV-2 virus RNA in feces: A case series of children. J. Infect. Public Health. 2020;13:926–931.
    1. Fallerini C., Daga S., Mantovani S., Benetti E., Picchiotti N., Francisci D., Paciosi F., Schiaroli E., Baldassarri M., Fava F., et al. GEN-COVID Multicenter Study Association of Toll-like receptor 7 variants with life-threatening COVID-19 disease in males: findings from a nested case-control study. eLife. 2021;10:e67569.
    1. Feldstein L.R., Tenforde M.W., Friedman K.G., Newhams M., Rose E.B., Dapul H., Soma V.L., Maddux A.B., Mourani P.M., Bowens C., et al. Overcoming COVID-19 Investigators Characteristics and Outcomes of US Children and Adolescents With Multisystem Inflammatory Syndrome in Children (MIS-C) Compared With Severe Acute COVID-19. JAMA. 2021;325:1074–1087.
    1. Ferré E.M.N., Schmitt M.M., Ochoa S., Rosen L.B., Shaw E.R., Burbelo P.D., Stoddard J.L., Rampertaap S., DiMaggio T., Bergerson J.R.E., et al. SARS-CoV-2 Spike Protein-Directed Monoclonal Antibodies May Ameliorate COVID-19 Complications in APECED Patients. Front. Immunol. 2021;12:720205.
    1. Fukuda S., Kaneta M., Miyake M., Ohya T., Miyakawa K., Iwamoto M., Ito S. A case of multisystem inflammatory syndrome in children in a Japanese boy: with discussion of cytokine profile. Mod Rheumatol Case Rep. 2021;5:442–447.
    1. Gaebler C., Wang Z., Lorenzi J.C.C., Muecksch F., Finkin S., Tokuyama M., Cho A., Jankovic M., Schaefer-Babajew D., Oliveira T.Y., et al. Evolution of antibody immunity to SARS-CoV-2. Nature. 2021;591:639–644.
    1. Gruber C.N., Patel R.S., Trachtman R., Lepow L., Amanat F., Krammer F., Wilson K.M., Onel K., Geanon D., Tuballes K., et al. Mapping Systemic Inflammation and Antibody Responses in Multisystem Inflammatory Syndrome in Children (MIS-C) Cell. 2020;183:982–995.
    1. Guan W.-J., Ni Z.-Y., Hu Y., Liang W.-H., Ou C.-Q., He J.-X., Liu L., Shan H., Lei C.-L., Hui D.S.C., et al. China Medical Treatment Expert Group for Covid-19 Clinical Characteristics of Coronavirus Disease 2019 in China. N. Engl. J. Med. 2020;382:1708–1720.
    1. Hamady A., Lee J., Loboda Z.A. Waning antibody responses in COVID-19: what can we learn from the analysis of other coronaviruses? Infection. 2021 doi: 10.1007/s15010-021-01664-z. Published online July 29, 2021.
    1. Hochberg Z. Evolutionary perspective in child growth. Rambam Maimonides Med. J. 2011;2:e0057.
    1. Hoste L., Roels L., Naesens L., Bosteels V., Vanhee S., Dupont S., Bosteels C., Browaeys R., Vandamme N., Verstaen K., et al. MIS-C Clinicians TIM3+ TRBV11-2 T cells and IFNγ signature in patrolling monocytes and CD16+ NK cells delineate MIS-C. J. Exp. Med. 2022;219:e20211381.
    1. Israelow B., Mao T., Klein J., Song E., Menasche B., Omer S.B., Iwasaki A. Adaptive immune determinants of viral clearance and protection in mouse models of SARS-CoV-2. Sci Immunol. 2021;6:eabl4509.
    1. Jayasooriya S., de Silva T.I., Njie-jobe J., Sanyang C., Leese A.M., Bell A.I., McAulay K.A., Yanchun P., Long H.M., Dong T., et al. Early virological and immunological events in asymptomatic Epstein-Barr virus infection in African children. PLoS Pathog. 2015;11:e1004746.
    1. Jones T.C., Biele G., Mühlemann B., Veith T., Schneider J., Beheim-Schwarzbach J., Bleicker T., Tesch J., Schmidt M.L., Sander L.E., et al. Estimating infectiousness throughout SARS-CoV-2 infection course. Science. 2021;373:eabi5273.
    1. Kahn R., Berg S., Berntson L., Berthold E., Brodin P., Bäckström F., Compagno M., Fasth A., Framme J.L., Horne A., et al. Population-based study of multisystem inflammatory syndrome associated with COVID-19 found that 36% of children had persistent symptoms. Acta Paediatr. 2021;111:354–362.
    1. Khanmohammadi S., Rezaei N., Khazaei M., Shirkani A. A Case of Autosomal Recessive Interferon Alpha/Beta Receptor Alpha Chain (IFNAR1) Deficiency with Severe COVID-19. J. Clin. Immunol. 2021 doi: 10.1007/s10875-021-01166-5. Published online October 28, 2021.
    1. Kim G.B. Reality of Kawasaki disease epidemiology. Korean J. Pediatr. 2019;62:292–296.
    1. Koch C.M., Prigge A.D., Anekalla K.R., Shukla A., Do-Umehara H.C., Setar L., Chavez J., Abdala-Valencia H., Politanska Y., Markov N.S., et al. Immune response to SARS-CoV-2 in the nasal mucosa in children and adults. medRxiv. 2021 doi: 10.1101/2021.01.26.21250269.
    1. Kosmicki J.A., Horowitz J.E., Banerjee N., Lanche R., Marcketta A., Maxwell E., Bai X., Sun D., Backman J.D., Sharma D., et al. Regeneron Genetics Center. UKB Exome Sequencing Consortium Pan-ancestry exome-wide association analyses of COVID-19 outcomes in 586,157 individuals. Am. J. Hum. Genet. 2021;108:1350–1355.
    1. Lei X., Dong X., Ma R., Wang W., Xiao X., Tian Z., Wang C., Wang Y., Li L., Ren L., et al. Activation and evasion of type I interferon responses by SARS-CoV-2. Nat. Commun. 2020;11:3810.
    1. Leidman E., Duca L.M., Omura J.D., Proia K., Stephens J.W., Sauber-Schatz E.K. COVID-19 Trends Among Persons Aged 0-24 Years - United States, March 1-December 12, 2020. MMWR Morb. Mortal. Wkly. Rep. 2021;70:88–94.
    1. Lemarquis A., Campbell T., Aranda-Guillén M., Hennings V., Brodin P., Kämpe O., Blennow K., Zetterberg H., Wennerås C., Eriksson K., et al. J Allergy Clin Immun; 2021. Severe COVID-19 in an APS1 patient with interferon autoantibodies treated with plasmapheresis.
    1. Loske J., Röhmel J., Lukassen S., Stricker S., Magalhães V.G., Liebig J., Chua R.L., Thürmann L., Messingschlager M., Seegebarth A., et al. Pre-activated antiviral innate immunity in the upper airways controls early SARS-CoV-2 infection in children. Nat. Biotechnol. 2021 doi: 10.1038/s41587-021-01037-9. Published online August 18, 2021.
    1. Mateus J., Grifoni A., Tarke A., Sidney J., Ramirez S.I., Dan J.M., Burger Z.C., Rawlings S.A., Smith D.M., Phillips E., et al. Selective and cross-reactive SARS-CoV-2 T cell epitopes in unexposed humans. Science. 2020;370:89–94.
    1. McArdle A.J., Vito O., Patel H., Seaby E.G., Shah P., Wilson C., Broderick C., Nijman R., Tremoulet A.H., Munblit D., et al. BATS Consortium Treatment of Multisystem Inflammatory Syndrome in Children. N. Engl. J. Med. 2021;385:11–22.
    1. Medzhitov R., Schneider D.S., Soares M.P. Disease tolerance as a defense strategy. Science. 2012;335:936–941.
    1. Meyts I., Bucciol G., Quinti I., Neven B., Fischer A., Seoane E., Lopez-Granados E., Gianelli C., Robles-Marhuenda A., Jeandel P.-Y., et al. IUIS Committee of Inborn Errors of Immunity Coronavirus disease 2019 in patients with inborn errors of immunity: An international study. J. Allergy Clin. Immunol. 2021;147:520–531.
    1. Moreews M., Gouge K.L., Khaldi-Plassart S., Pescarmona R., Mathieu A.-L., Malcus C., Djebali S., Bellomo A., Dauwalder O., Perret M., et al. Polyclonal expansion of TCR Vbeta 21.3+ CD4+ and CD8+ T cells is a hallmark of Multisystem Inflammatory Syndrome in Children. Sci Immunol. 2021;6:eabh1516.
    1. Morone G., Palomba A., Iosa M., Caporaso T., De Angelis D., Venturiero V., Savo A., Coiro P., Carbone D., Gimigliano F., et al. Incidence and Persistence of Viral Shedding in COVID-19 Post-acute Patients With Negativized Pharyngeal Swab: A Systematic Review. Front. Med. (Lausanne) 2020;7:562.
    1. Morparia K., Park M.J., Kalyanaraman M., McQueen D., Bergel M., Phatak T. Abdominal Imaging Findings in Critically Ill Children With Multisystem Inflammatory Syndrome Associated With COVID-19. Pediatr. Infect. Dis. J. 2021;40:e82–e83.
    1. Nakajima Y., Ogai A., Furukawa K., Arai R., Anan R., Nakano Y., Kurihara Y., Shimizu H., Misaki T., Okabe N. Prolonged viral shedding of SARS-CoV-2 in an immunocompromised patient. J. Infect. Chemother. 2021;27:387–389.
    1. Nalbandian A., Sehgal K., Gupta A., Madhavan M.V., McGroder C., Stevens J.S., Cook J.R., Nordvig A.S., Shalev D., Sehrawat T.S., et al. Post-acute COVID-19 syndrome. Nat. Med. 2021;27:601–615.
    1. Niessl J., Sekine T., Lange J., Konya V., Forkel M., Maric J., Rao A., Mazzurana L., Kokkinou E., Weigel W., et al. Identification of resident memory CD8+ T cells with functional specificity for SARS-CoV-2 in unexposed oropharyngeal lymphoid tissue. Sci Immunol. 2021;6:eabk0894.
    1. Palmer S., Cunniffe N., Donnelly R. COVID-19 hospitalization rates rise exponentially with age, inversely proportional to thymic T-cell production. J. R. Soc. Interface. 2021;18:20200982.
    1. Payne A.B., Gilani Z., Godfred-Cato S., Belay E.D., Feldstein L.R., Patel M.M., Randolph A.G., Newhams M., Thomas D., Magleby R., et al. Incidence of Multisystem Inflammatory Syndrome in Children Among US Persons Infected With SARS-CoV-2. JAMA Netw Open. 2021;4:e2116420.
    1. Pierce C.A., Sy S., Galen B., Goldstein D.Y., Orner E., Keller M.J., Herold K.C., Herold B.C. Natural mucosal barriers and COVID-19 in children. JCI Insight. 2021;6:e148694.
    1. Porritt R.A., Paschold L., Rivas M.N., Cheng M.H., Yonker L.M., Chandnani H., Lopez M., Simnica D., Schultheiß C., Santiskulvong C., et al. HLA class I-associated expansion of TRBV11-2 T cells in multisystem inflammatory syndrome in children. J. Clin. Invest. 2021;131:e146614.
    1. Pou C., Nkulikiyimfura D., Henckel E., Olin A., Lakshmikanth T., Mikes J., Wang J., Chen Y., Bernhardsson A.K., Gustafsson A., et al. The repertoire of maternal anti-viral antibodies in human newborns. Nat. Med. 2019;25:591–596.
    1. Povysil G., Butler-Laporte G., Shang N., Wang C., Khan A., Alaamery M., Nakanishi T., Zhou S., Forgetta V., Eveleigh R.J.M., et al. Rare loss-of-function variants in type I IFN immunity genes are not associated with severe COVID-19. J. Clin. Invest. 2021;131:e147834.
    1. Preston L.E., Chevinsky J.R., Kompaniyets L., Lavery A.M., Kimball A., Boehmer T.K., Goodman A.B. Characteristics and Disease Severity of US Children and Adolescents Diagnosed With COVID-19. JAMA Netw. Open. 2021;4:e215298.
    1. Raja M.A., Mendoza M.A., Villavicencio A., Anjan S., Reynolds J.M., Kittipibul V., Fernandez A., Guerra G., Camargo J.F., Simkins J., et al. COVID-19 in solid organ transplant recipients: A systematic review and meta-analysis of current literature. Transplant. Rev. (Orlando) 2021;35:100588.
    1. Ramaswamy A., Brodsky N.N., Sumida T.S., Comi M., Asashima H., Hoehn K.B., Li N., Liu Y., Shah A., Ravindra N.G., et al. Immune dysregulation and autoreactivity correlate with disease severity in SARS-CoV-2-associated multisystem inflammatory syndrome in children. Immunity. 2021;54:1083–1095.
    1. Reyman M., Clerc M., van Houten M.A., Arp K., Chu M.L.J.N., Hasrat R., Sanders E.A.M., Bogaert D. Microbial community networks across body sites are associated with susceptibility to respiratory infections in infants. Commun Biol. 2021;4:1233.
    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.
    1. Rodriguez L., Pekkarinen P.T., Lakshmikanth T., Tan Z., Consiglio C.R., Pou C., Chen Y., Mugabo C.H., Nguyen N.A., Nowlan K., et al. Systems-level immunomonitoring from acute to recovery phase of severe COVID-19. Cell Reports Medicine. 2020;1:100078.
    1. Röltgen K., Nielsen S.C.A., Arunachalam P.S., Yang F., Hoh R.A., Wirz O.F., Lee A.S., Gao F., Mallajosyula V., Li C., et al. mRNA vaccination compared to infection elicits an IgG-predominant response with greater SARS-CoV-2 specificity and similar decrease in variant spike recognition. medRxiv. 2021 10/1101/2021.04.05.21254952.
    1. Sagar M., Reifler K., Rossi M., Miller N.S., Sinha P., White L.F., Mizgerd J.P. Recent endemic coronavirus infection is associated with less-severe COVID-19. J. Clin. Invest. 2021;131:131.
    1. Sancho-Shimizu V., Brodin P., Cobat A., Biggs C.M., Toubiana J., Lucas C.L., Henrickson S.E., Belot A., Tangye S.G., Milner J.D., et al. MIS-C@CHGE SARS-CoV-2-related MIS-C: A key to the viral and genetic causes of Kawasaki disease? J. Exp. Med. 2021;218:e20210446.
    1. Shulman S.T., Rowley A.H. Kawasaki disease: insights into pathogenesis and approaches to treatment. Nat. Rev. Rheumatol. 2015;11:475–482.
    1. Smith C., Odd D., Harwood R., Ward J., Linney M., Clark M., Hargreaves D., Ladhani S.N., Draper E., Davis P.J., et al. Deaths in children and young people in England after SARS-CoV-2 infection during the first pandemic year. Nat. Med. 2021 doi: 10.1038/s41591-021-01578-1. Published online November 11, 2021.
    1. Stearns S.C. The Evolution of Life Histories. Oxford University Press; 1992.
    1. Thabet F., Chehab M., Bafaqih H., Al Mohaimeed S. Middle East respiratory syndrome coronavirus in children. Saudi Med. J. 2015;36:484–486.
    1. Thai K.T.D., Nishiura H., Hoang P.L., Tran N.T.T., Phan G.T., Le H.Q., Tran B.Q., Nguyen N.V., de Vries P.J. Age-specificity of clinical dengue during primary and secondary infections. PLoS Negl. Trop. Dis. 2011;5:e1180.
    1. Torun B. Energy requirements of children and adolescents. Public Health Nutr. 2005;8:968–993.
    1. Toubiana J., Poirault C., Corsia A., Bajolle F., Fourgeaud J., Angoulvant F., Debray A., Basmaci R., Salvador E., Biscardi S., et al. Outbreak of Kawasaki disease in children during COVID-19 pandemic: a prospective observational study in Paris, France. medRxiv. 2020 doi: 10.1101/2020.05.10.20097394.
    1. Tregoning J.S., Schwarze J. Respiratory viral infections in infants: causes, clinical symptoms, virology, and immunology. Clin. Microbiol. Rev. 2010;23:74–98.
    1. van der Made C.I., Simons A., Schuurs-Hoeijmakers J., van den Heuvel G., Mantere T., Kersten S., van Deuren R.C., Steehouwer M., van Reijmersdal S.V., Jaeger M., et al. Presence of Genetic Variants Among Young Men With Severe COVID-19. JAMA. 2020;324:663–673.
    1. Verdoni L., Mazza A., Gervasoni A., Martelli L., Ruggeri M., Ciuffreda M., Bonanomi E., D’Antiga L. An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study. Lancet. 2020;395:1771–1778.
    1. Wang E.Y., Mao T., Klein J., Dai Y., Huck J.D., Jaycox J.R., Liu F., Zhou T., Israelow B., Wong P., et al. Yale IMPACT Team Diverse functional autoantibodies in patients with COVID-19. Nature. 2021;595:283–288.
    1. Whittaker E., Bamford A., Kenny J., Kaforou M., Jones C.E., Shah P., Ramnarayan P., Fraisse A., Miller O., Davies P., et al. PIMS-TS Study Group and EUCLIDS and PERFORM Consortia Clinical Characteristics of 58 Children With a Pediatric Inflammatory Multisystem Syndrome Temporally Associated With SARS-CoV-2. JAMA. 2020;324:259–269.
    1. Wölfel R., Corman V.M., Guggemos W., Seilmaier M., Zange S., Müller M.A., Niemeyer D., Jones T.C., Vollmar P., Rothe C., et al. Virological assessment of hospitalized patients with COVID-2019. Nature. 2020;581:465–469.
    1. Xing Y.H., Ni W., Wu Q., Li W.J., Li G.J., Wang W.D., Tong J.N., Song X.F., Wong G.W.K., Xing Q.S. Prolonged viral shedding in feces of pediatric patients with coronavirus disease 2019. J Microbiol Immunol Infect. 2020;53:473–480.
    1. Yonker L.M., Gilboa T., Ogata A.F., Senussi Y., Lazarovits R., Boribong B.P., Bartsch Y.C., Loiselle M., Rivas M.N., Porritt R.A., et al. Multisystem inflammatory syndrome in children is driven by zonulin-dependent loss of gut mucosal barrier. J. Clin. Invest. 2021;131:e149633.
    1. Zang R., Castro M.F.G., McCune B.T., Zeng Q., Rothlauf P.W., Sonnek N.M., Liu Z., Brulois K.F., Wang X., Greenberg H.B., et al. TMPRSS2 and TMPRSS4 promote SARS-CoV-2 infection of human small intestinal enterocytes. Sci Immunol. 2020;5:eabc3582.
    1. Zhang Q., Bastard P., Liu Z., Pen J.L., Moncada-Velez M., Chen J., Ogishi M., Sabli I.K.D., Hodeib S., Korol C., et al. Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science. 2020:eabd4570.
    1. Zhang Q., Bastard P., Bolze A., Jouanguy E., Zhang S.-Y., Cobat A., Notarangelo L.D., Su H.C., Abel L., Casanova J.L., COVID Human Genetic Effort Life-Threatening COVID-19: Defective Interferons Unleash Excessive Inflammation. Med (N Y) 2020;1:14–20.
    1. Zhang Q., Cobat A., Bastard P., Notarangelo L.D., Su H.C., Abel L., Casanova J.-L., COVID Human Genetic Effort (CHGE) Association of rare predicted loss-of-function variants of influenza-related type I IFN genes with critical COVID-19 pneumonia. J. Clin. Invest. 2021;131:e152474.
    1. Zhong N.-S., Wong G.W.K. Epidemiology of severe acute respiratory syndrome (SARS): adults and children. Paediatr. Respir. Rev. 2004;5:270–274.
    1. Zimmermann P., Curtis N. Why is COVID-19 less severe in children? A review of the proposed mechanisms underlying the age-related difference in severity of SARS-CoV-2 infections. Arch. Dis. Child. 2020;106:429–439.

Source: PubMed

3
Tilaa