Autoantibodies Detected in MIS-C Patients due to Administration of Intravenous Immunoglobulin (preprint)

The autoantibody profile associated with known autoimmune diseases in patients with COVID-19 or multisystem inflammatory syndrome in children (MIS-C) remains poorly defined. Here we show that adults with COVID-19 had a moderate prevalence of autoantibodies against the lung antigen KCNRG, and SLE-associated Smith autoantigen. Children with COVID-19 rarely had autoantibodies; one of 59 children had GAD65 autoantibodies associated with acute insulin-dependent diabetes. While autoantibodies associated with SLE/Sjogren syndrome (Ro52, Ro60, and La) and/or autoimmune gastritis (gastric ATPase) were detected in 74% (40/54) of MIS-C patients, further analysis of these patients and of children with Kawasaki disease (KD), showed that the administration of intravenous immunoglobulin (IVIG) was largely responsible for detection of these autoantibodies in both groups of patients. Monitoring in vivo decay of the autoantibodies in MIS-C children showed that the IVIG-derived Ro52, Ro60, and La autoantibodies declined to undetectable levels by 45-60 days, but gastric ATPase autoantibodies declined more slowly requiring >100 days until undetectable. Together these findings demonstrate that administration of high-dose IVIG is responsible for the detection of several autoantibodies in MIS-C and KD. Further studies are needed to investigate autoantibody production in MIS-C patients, independently from IVIG administration.

Multi-omics approach identifies novel age-, time- and treatment-related immunopathological signatures in MIS-C and pediatric COVID-19 (preprint)

Pediatric COVID-19 (pCOVID-19) is rarely severe, however a minority of SARS-CoV-2-infected children may develop MIS-C, a multisystem inflammatory syndrome with significant morbidity. In this longitudinal multi-institutional study, we used multi-omics to identify novel time- and treatment-related immunopathological signatures in children with COVID-19 (n=105) and MIS-C (n=76). pCOVID-19 was characterized by enhanced type I IFN responses, and MIS-C by type II IFN- and NF-{kappa}B dependent responses, matrisome activation, and increased levels of Spike protein. Reduced levels of IL-33 in pCOVID-19, and of CCL22 in MIS-C suggested suppression of Th2 responses. Expansion of TRBV11-2 T-cell clonotypes in MIS-C was associated with inflammation and signatures of T-cell activation, and was reversed by glucocorticoids. The association of MIS-C with the combination of HLA A*02, B*35, C*04 alleles suggests genetic susceptibility. MIS-C B cells showed higher mutation load. Use of IVIG was identified as a confounding factor in the interpretation of autoantibody levels.

Severe Gastrointestinal Features in Children with Covid-19: A Multicenter Retrospective Cohort Study (preprint)

Background: Severe gastrointestinal (GI) involvement has been occasionally reported in children with SARS-CoV-2 infection or among those with multisystem inflammatory syndrome (MIS-C). We aimed to investigate the clinical, radiological and histopathological GI characteristics in order to identify factors associated with severe outcome. Methods: In this multicenter retrospective nationwide cohort study, symptomatic children with laboratory confirmed SARS-CoV-2 infection or MIS-C were enrolled. Children who received a diagnosis of acute abdomen, appendicitis, intussusception, pancreatitis, diffuse adeno-mesenteritis or abdominal fluid collections requiring surgical consultation and temporally correlated with SARS-CoV-2 infection were classified as having a severe GI involvement. Logistic regression models were used to estimate odds ratios (OR [95% confidence intervals]) between potential explanatory factors and severe outcome. Findings: 685 children were enrolled between February 2020 and January 2021. The presence of GI symptoms was associated with a higher chance of hospital admission (OR 2·64 [1·89–3·69]) and of intensive care support (OR 3·90 [1·98–7·68]). Overall, 65 children (9.5%) showed a severe GI involvement featuring atypical presentations including disseminated adeno-mesenteritis (39·6%), appendicitis (33·5%), abdominal fluid collections (21·3%), pancreatitis (6·9%) or ileal intussusception (4·6%). Twenty-seven (42%) of these children underwent surgery, and remarkably only half of clinically suspected appendicitis were histologically confirmed. Children aged 5-10 years (OR 8·33 [2·62–26·5]) or > 10 years of age (OR 6·37 [2·12-19·1]) had a higher chance of severe outcome, compared to preschool-age children. Severe GI outcomes were more frequent in patients with abdominal pain (aOR 34·5 [10·1–118]), lymphopenia (aOR 8·93 [3·03-26·3]) or MIS-C (aOR 6·28 [1·92–20·5]). Diarrhea was associated with a higher chance of adeno-mesenteritis (aOR 3·13 [1·08–9·12]) and abdominal fluid collections (aOR 3·22 [1·03-10]). Interpretation: About 10% of symptomatic children with COVID-19 may have severe GI involvement, frequently associated with MIS-C. Early identification of at-risk patients can improve the management of serious complications.Funding Information: SARS-CoV-2, gastrointestinal tract, gut, COVID-19, children, MIS-CDeclaration of Interests: All authors declare no competing interests.Ethics Approval Statement: This study was undertaken in accordance with good clinical practice guidelines and the Declaration of Helsinki. Written informed consent was obtained from parents/caregivers, and the patient if appropriate. The study protocol was approved by the Ethical Committee of the coordinating center (protocol number 0031296) as well as by independent ethics committees and/or institutional review boards of any single enrolling center.

Severe Gastrointestinal Features in Children with COVID-19: A Multicenter Retrospective Cohort Study (preprint)

Background: Severe gastrointestinal (GI) involvement has been occasionally reported in children with SARS-CoV-2 infection or among those with multisystem inflammatory syndrome (MIS-C). We aimed to investigate the clinical, radiological and histopathological GI characteristics in order to identify factors associated with severe outcome.Methods: In this multicenter retrospective nationwide cohort study, symptomatic children with laboratory confirmed SARS-CoV-2 infection or MIS-C were enrolled. Children who received a diagnosis of acute abdomen, appendicitis, intussusception, pancreatitis, diffuse adeno-mesenteritis or abdominal fluid collections requiring surgical consultation and temporally correlated with SARS-CoV-2 infection were classified as having a severe GI involvement. Logistic regression models were used to estimate odds ratios (OR [95% confidence intervals]) between potential explanatory factors and severe outcome.Findings: 685 children were enrolled between February 2020 and January 2021. The presence of GI symptoms was associated with a higher chance of hospital admission (OR 2·64 [1·89–3·69]) and of intensive care support (OR 3·90 [1·98–7·68]).Overall, 65 children (9.5%) showed a severe GI involvement featuring atypical presentations including disseminated adeno-mesenteritis (39·6%), appendicitis (33·5%), abdominal fluid collections (21·3%), pancreatitis (6·9%) or ileal intussusception (4·6%). Twenty-seven (42%) of these children underwent surgery, and remarkably only half of clinically suspected appendicitis were histologically confirmed. Children aged 5-10 years (OR 8·33 [2·62–26·5]) or > 10 years of age (OR 6·37 [2·12-19·1]) had a higher chance of severe outcome, compared to preschool-age children. Severe GI outcomes were more frequent in patients with abdominal pain (aOR 34·5 [10·1–118]), lymphopenia (aOR 8·93 [3·03-26·3]) or MIS-C (aOR 6·28 [1·92–20·5]). Diarrhea was associated with a higher chance of adeno-mesenteritis (aOR 3·13 [1·08–9·12]) and abdominal fluid collections (aOR 3·22 [1·03-10]).Interpretation: About 10% of symptomatic children with COVID-19 may have severe GI involvement, frequently associated with MIS-C. Early identification of at-risk patients can improve the management of serious complications.Funding Statement: None.Declaration of Interests: All authors declare no competing interests.Ethics Approval Statement: The study protocol was approved by the Ethical Committee of the coordinating center (protocol number 0031296) as well as by independent ethics committees and/or institutional review boards of any single enrolling center.

Tele-Medicine Provides an Effective Tool for the Management of COVID-19 in Children (preprint)

Overcrowding, the unavailability of personal protective equipment, and transmission between health care workers are the main causes of the rapid spread of coronavirus disease 2019 (COVID-19) in hospital settings. Because children have less severe symptoms than adults, we used tele-medicine (TM) as the main approach to managing subjects younger than 14 years who contacted their primary care paediatrician (PCP). A TM program for suspected paediatric COVID-19 cases was developed by the COVID-19 paediatric referral centre and PCPs in the Campania Region, Italy. A total of 269 cases of suspected COVID-19 were discussed through tele-consultation between PCPs and paediatric infectious disease specialists. The main reason for the initiation of tele-consultation by PCPs was the need for case management advice (n=206, 77%). A total of 203 children were tested for COVID-19, and 139 were positive (73 males, aged 5 years [IQR 1-10]), of whom 103 were managed at home with phone/video monitoring, 17 received a direct medical visit and discharged to home, and 19 were admitted to the COVID-19 unit. The main symptoms were fever (45%) and cough (25%). Thirty-five percent were asymptomatic and detected in family clusters. None had severe clinical outcomes.ConclusionTM is a reliable tool to limit the spread of COVID-19 and might reduce the number of unnecessary visits and hospital admissions. Through tele-consultation with an expert, PCPs can identify at-risk children who need testing and manage most cases remotely. However, standardization of the TM approach and criteria for hospital admission are needed.

Epidemiology, Clinical Features and Prognostic Factors of Pediatric SARS-CoV-2 Infection: Results from an Italian Multicenter Study (preprint)

Background: Many aspects of SARS-CoV-2 infection in children and adolescents remain unclear and optimal treatment is debated. The objective of our study was to investigate epidemiological, clinical and therapeutic aspects of SARS-CoV-2 infection in infants, children and adolescents, focusing on risk factors for complicated and critical disease.Methods: The present study is a multicenter Italian study promoted by the Italian Society of Pediatric Infectious Diseases, involving both pediatric hospitals and general pediatricians/family doctors. All subjects under 18 years of age with documented SARS-CoV-2 infection and referred to the coordinating center were enrolled starting from March 2020. An adequate follow-up to outline outcome was required (at least 2 weeks).Findings: As of 15 September 2020, 759 children were enrolled (median age 7.2 years, IQR 1.4;12.4). Among the 688 symptomatic children, fever was the most common symptom (81.9%). Barely 47% of children were hospitalized for COVID-19, with a median hospital stay of 6 days (IQR 4;10). Age was inversely related to hospital admission (p Mycoplasma pneumoniae co-infections, underlying clinical conditions, age between 5 and 9 years and lymphopenia were statistically related to ICU admission (p< 0.05). Multisystem inflammatory syndrome temporarily related to COVID-19 (MIS-C) was diagnosed in 30 children (3.9%). All but three children recovered.Interpretation: Complications of COVID-19 in children are related to the presence of co-morbidities. The length of hospital stay and the risk of complications increase with age. Viral co-infections are additional risk factors for disease progression and high CRP levels and lymphopenia may be predictive markers of severe clinical pictures. MIS-C is a risk factor for ICU admission. Outside MIS-C, most children with COVID-19 require only supportive therapy.Funding Statement: None.Declaration of Interests: None.Ethics Approval Statement: The study received ethical approval on 24 March 2020 (protocol number 0031296) and data collection was allowed by written consent of at least one parent.

Health-care organization for the management and surveillance of SARS-CoV-2 infection in children during pandemic in Campania Region, Italy (preprint)

Background: In comparison with adults, severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection in children has a milder course. The management of children with suspected or confirmed coronavirus disease (COVID-19) needs to be appropriately targeted.Methods: We designed a hub-and-spoke system to provide healthcare indications based on the use of telemedicine and stringent admission criteria, coordinate local stakeholders and disseminate information.Result: Between March 24th and September 24th 2020, the Hub Centre managed a total of 208 children (52% males, median age, 5.2, IQR 2-9.6 years) with suspected or confirmed COVID-19. Among them, 174 were managed in cooperation with family pediatricians and 34 with hospital-based physicians. One hundred-four (50%) received a final diagnosis of SARS-CoV-2 infection. Application of stringent criteria for hospital admission based on clinical conditions, risk factors and respect of biocontainment measures, allowed to manage the majority of cases (74, 71.1%) through telemedicine. Thirty children (28%) were hospitalized (median length 10 days, IQR 5-19 days), mainly due to the presence of persistent fever, mild respiratory distress or co-infection occurring in infant or children with underlying conditions. However, the reasons for admission slightly changed over time.Conclusion: An hub-and-spoke system is effective in coordinate territorial health-care structures involved in management paediatric COVID-19 cases through telemedicine and the definition of stringent hospital admission criteriaThe management of children with COVID-19 should be based on clinical conditions, assessed on a case-by-case critical evaluation, as well as on isolation measures, but may vary according to local epidemiological changes.