Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a novel pathogen that emerged in December of 2019 and has since infected people of all ages around the world. Children with acute SARS-CoV-2 infection are largely spared of the severe disease seen in adults. However, a life-threatening, post-viral inflammatory condition known as Multisystem Inflammatory Syndrome – Children (MIS-C) develops in a small fraction of children four to six weeks after either past SARS-CoV-2 infection or exposure and is characterized by high fevers, significant gastrointestinal symptoms and severe cardiac complications. Little is known about the lasting immune profiles of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection in children, let alone the long-term effects of the disease in this population. This study presents clinical features and serologic immune profiles of forty-nine pediatric patients (ages 12.4 ± 6.7 years) enrolled in the Massachusetts General Hospital Pediatric COVID-19 Biorepository with previous diagnoses of SARS-CoV-2 infection or the COVID-19-related MIS-C. Thirty-two children ages 0-22 years completed a questionnaire which captured lingering clinical symptoms of COVID-19 and MIS-C at the follow-up timepoint. This questionnaire study revealed significant on-going symptoms in both cohorts, including respiratory, gastrointestinal, neurologic and cardiovascular symptoms. To characterize lasting immune responses following the acute presentation, serum antibodies to S, RBD and N proteins of SARS-CoV-2 were quantified at the follow-up timepoint in forty-nine pediatric patients with past COVID-19 or MIS-C at a mean follow-up timepoint of 6.56 ± 1.75 months. Serologic signatures against SARS-CoV-2 in COVID-19 and severe MIS-C patients were compared at acute illness and at follow-up timepoints. Anti-SARS-CoV-2 antibodies remained elevated over time showing adequate seroconversion. Interestingly, anti-SARS-CoV-2 IgA remained elevated in the vast majority of individuals at follow-up, suggesting continued antigen exposure and mucosal inflammation. This research elucidates whether children maintain antibody levels to SARS-CoV-2 over time and speaks to the differences in antibody recovery to baseline in COVID-19 and MIS-C patients. It also highlights the lingering symptoms in both the COVID-19 and MIS-C cohorts, and suggests the need for significant long-term follow-up in children months, or even years after resolution of acute illness or disease. In total, this study addresses the substantial gap in understanding of the recovery of the adaptive immune system after SARS-CoV-2 infection in children. / 2023-11-09T00:00:00Z

INTRODUCTION: With the emergence of the COVID 19 pandemic, a new disease, Multisystem Inflammatory Syndrome in Children (MIS-C), had evolved. Increasing number of children are being reported to have MIS-C in the U.S. & worldwide. In the U.S. there are currently 2617 MISC cases reported. MIS-C & Kawasaki Disease (KD), have almost the same presentation, making clinical differentiation difficult. This study aims at differentiating KD & MIS-C which could assist clinicians to determine which one they could be dealing with in their practices. METHODS: Clinical features & laboratory values were collected from published studies found by queries on PubMed & other websites. Reported values were selected from published systemic reviews, meta-analyses, & large retrospective chart studies. RESULTS: In KD, the most prevalent clinical features are fever (100%) & the 5 KD-defining clinical features: oral mucosal changes (96.5%), rash (96%), non-purulent conjunctivitis (89%), extremity changes (75.6%), and cervical lymphadenopathy (62.7%). MIS-C also presents with fever (100%) but has lower prevalence of oral mucosal changes (23%), rash (38.2%), non-purulent conjunctivitis (44.0%), extremity changes (2.5%), & cervical lymphadenopathy (4%). MIS-C leads to higher rates of ventricular dysfunction (39.3%), myocarditis (23%), & shock. For cardiac biomarkers, MIS-C has elevated troponin I (x6 normal) & Beta Natriuretic Peptide (BNP) (x414 normal), while KD has elevations of troponin I (x1.9 normal) & BNP (x15 normal). MIS-C has higher elevations in ESR, CRP, and D-Dimer at x6, x30, and x40 from the normal values, respectively, while KD has elevations of x2.8, x2.1, x7.3 from the normal values, respectively. MIS-C is associated with neutrophilia, thrombocytopenia, & anemia in 22% of cases. KD is associated with mild neutrophilia & anemia. KD has thrombocytosis in the subacute phase (x1.46 normal). CONCLUSION: Our results demonstrated that there are overlaps & differences in clinical and laboratory features. Fever is present in both KD & MIS-C, however the 5 KD defining clinical features of KD are less frequent in MIS-C. MIS-C induces higher levels of troponin I & BNP, findings that could potentially explain for higher rates of ventricular dysfunction & myocarditis. MIS-C causes higher elevations in inflammatory markers & D-Dimers compared to KD. Uniquely, thrombocytopenia is commonly present in MISC rather than in KD. Differentiating KD & MIS-C can be challenging, but by focusing closely on the clinical & laboratory features, clinicians may be able to distinguish between the two &, therefore, deliver the most appropriate care to patients in their practices.

Purpose To investigate the relationship between the risk of pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) in children and the predominance of different SARS-CoV-2 variants of concern (VOC) over time. Methods In relation to the Alpha, Delta, and Omicron VOC phases of the pandemic, the risk of developing PIMS-TS was calculated by analyzing data for rtPCR-confirmed SARS-CoV-2 infections reported to the German statutory notification system, along with data captured by a separate, national PIMS-TS registry. Both overall infection rates and age group-specific ratios of PIMS-TS during the different pandemic phases were calculated using the Alpha period as the baseline. Results The PIMS-TS rate changed significantly over time. When the Alpha VOC was dominant [calendar week (CW) 11 in March–CW 31 in August 2021], the PIMS-TS rate was 6.19 [95% confidence intervals (95% CI) 5.17, 7.20]. When Delta prevailed (CW 32 in August 2021–CW 4 in January 2022), the rate decreased to 1.68 (95% CI 1.49, 1.87). During the Omicron phase (CW 5 in January–CW 16 in April 2022), the rate fell further to 0.89 (95% CI 0.79, 1.00). These changes correspond to a decreased PIMS-TS rate of 73% (rate ratio 0.271, 95% CI 0.222; 0.332) and 86% (rate ratio 0.048, 95% CI 0.037; 0.062), respectively, in comparison to the Alpha period. Rate ratios were nearly identical for all age groups. Conclusion The data strongly suggest an association between the risk for PIMS-TS and the prevailing VOC, with highest risk related to Alpha and the lowest to Omicron. Given the uniformity of the decreased risk across age groups, vaccination against SARS-CoV-2 does not appear to have a significant impact on the risk of children developing PIMS-TS.

Health is often defined in terms of absence of disease or pathological processes, but this is a definition of exclusion and incomplete. For example, SARS-CoV-2 viral load does not reliably predict disease severity, and so individuals must vary in their ability to control inflammation and maintain normal tissue homeostasis. This host defense strategy is called disease tolerance, and better understanding of disease tolerance mechanisms could change the way that we treat disease and work to maintain health. The first project presented in this dissertation found that after accounting for effects of age and sex, innate lymphoid cells (ILCs), but not T cells, were lower in adults and children sick with COVID-19 or MIS-C, independent of lymphopenia. Furthermore, abundance of ILCs, but not of T cells, correlated inversely with disease severity. These blood ILCs were shown to produce amphiregulin, a protein implicated in disease tolerance and tissue homeostasis, and the percentage of amphiregulin-producing ILCs was lower in males. These results suggest that, by promoting disease tolerance, homeostatic ILCs decrease morbidity and mortality associated with SARS-CoV-2 infection, and that lower ILC abundance accounts for increased COVID-19 severity with age and in males. The second project describes a novel mouse model of epigenetic inheritance wherein paternal influenza A virus (IAV) infection results in less severe influenza disease in IAV infected offspring. This offspring phenotype was not attributable to differences in viral load, indicating a possible difference in disease tolerance. Paternal caloric deprivation decreased, and influenza B virus infection increased, offspring influenza disease severity, and in vitro fertilization demonstrated sperm are sufficient to transfer IAV-associated epigenetic inheritance phenotypes. These findings represent a foundation for further work that, by continuing to elucidate the mechanisms of disease tolerance and epigenetic inheritance, could provide novel therapeutic interventions to help promote and maintain health.