Pediatric patients with immune-mediated diseases on immunosuppressants have low risk of severe COVID-19 and no increase in flare rate after SARS CoV-2 exposure

Abstract

•Pediatric patients on immunosuppressive drugs had mild COVID-19.•Risk of flare related to SARS CoV-2 exposure in rheumatic disease patients was similar to baseline.•Seroprevalence survey identified high asymptomatic infection rate. In response to the publication by Zsigmond et al. we report the very low risk of severe COVID-19 in immunosuppressed children in Romania.1Zsigmond B Breathnach AS Mensah A Ladhani SN. Very low rates of severe COVID-19 in children hospitalised with confirmed SARS-CoV-2 infection in London, England.J Infect. 2022; (S0163-4453(22)00203-1)Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar Children are prone to asymptomatic or mild infection. In the first pandemic year, reported deaths for children and young adults from England attributed to SARS CoV-2 infection were two per million.2Smith C Odd D Harwood R et al.Deaths in children and young people in England after SARS-CoV-2 infection during the first pandemic year.Nat Medicine. 2022; 28: 185-192Crossref PubMed Scopus (24) Google Scholar During the Delta and Omicron variants surge, the hospitalization rate in children increased especially for those aged <4 years without an increase in mortality rate,3Hospitalizations of children and adolescents with laboratory-confirmed COVID-19 COVID-NET, 14 States, July 2021–January 2022. Centers for disease control and prevention. Weekly report February 18, 2022. https://www.cdc.gov/mmwr/volumes/71/wr/mm7107e4.htm.Google Scholar but remained ten times lower compared to flu-associated-hospitalization from the 2017 to 2018 season.4Estimated Flu-Related Illnesses, Medical visits, hospitalizations, and deaths in the United States — 2017–2018 Flu Season. Centers for disease control and prevention. Updated September 30, 2021. https://www.cdc.gov/flu/about/burden/2017-2018.htm.Google Scholar Severe SARS CoV-2 infection in children is rare but unveiling risk factors for worse outcomes can help identify high-risk groups and impose protective measures. According to CDC, use of corticosteroids and other immunosuppressive drugs includes these patients in high risk group for severe COVID-19.5Underlying Medical Conditions Associated with Higher Risk for Severe COVID-19. Centers for disease control and prevention. Updated February 15, 2022. https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/underlyingconditions.html.Google Scholar However, there is controversy among risk-reporting studies in immunosuppressed children with conditions ranging from autoimmunity to malignancy.6Harwood R Yan H Da Camara NT et al.Which children and young people are at higher risk of severe disease and death after hospitalisation with SARS-CoV-2 infection in children and young people: a systematic review and individual patient meta-analysis.EClinicalMedicine. 2022; 44101287Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar, 7Bailey AJM Kirkham AM Monaghan M et al.A portrait of SARS-CoV-2 infection in patients undergoing hematopoietic cell transplantation: a systematic review of the literature.Curr Oncol. 2022; 29 (13): 337-349Crossref PubMed Scopus (3) Google Scholar, 8Chappell H Patel R Driessens C Tarr AW Irving WL Tighe PJ Jackson HJ Harvey-Cowlishaw T Mills L Shaunak M Gbesemete D Leahy A Lucas JS Faust SN de Graaf H. Immunocompromised children and young people are at no increased risk of severe COVID-19.J Infect. 2022; 84: 31-39Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar, 9Williams N Radia T Harman K Agrawal P Cook J Gupta A. COVID-19 Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children and adolescents: a systematic review of critically unwell children and the association with underlying comorbidities.Eur J Pediatr. 2021; 180: 689-697Crossref PubMed Scopus (42) Google Scholar Apart from infection severity, virus exposure increased concerns about medium term flare-ups in rheumatic-disease patients due to both treatment discontinuation and COVID-19-related distress.10Maldonado D Tu E Mahmood SN Wahezi DM Darapaneni R Sima N Curiel-Duran L Pattison LM Gabbay V Bauman LJ Broder A Rubinstein TB. Association of medication access difficulty and COVID-19-related distress with disease flares in rheumatology patients during the COVID-19 pandemic.Arthritis Care Res. 2021; 73: 1162-1170Crossref PubMed Scopus (9) Google Scholar,11Hügle B Krumrey-Langkammerer M Haas JP. Infection with SARS-CoV-2 causes flares in patients with juvenile idiopathic arthritis in remission or inactive disease on medication.Pediatr Rheumatol Online J. 2021; 19: 163Crossref PubMed Scopus (4) Google Scholar We investigated the rate of severe outcomes related to COVID-19 in a cohort of pediatric patients diagnosed with immune-mediated diseases and treated with immunosuppressive medication. Secondly, we estimated the rate of asymptomatic infection through a seroprevalence survey and determined the risk of disease flare-up after virus exposure. We enrolled pediatric patients aged <19 years diagnosed with immune-mediated diseases in a tertiary care center, Department of Clinical Immunology, National Institute of Mother and Child, Bucharest, Romania. The study was conducted between July 1, 2021 and March 30, 2022. We included patients with a defined diagnosis of immune-mediated disease and continuous treatment with immunosuppressive medication three months before enrollment. We collected data regarding demographics, disease activity, treatment, and clinical features of past confirmed SARS CoV-2 infection by real time PCR (RT-PCR) or rapid antigen test on the nasal-pharyngeal swab during regular face-to-face evaluations. Qualitative detection of antibodies against spike protein from serum sample of each subject was assayed by fluorescence immunoassay using the FRENDTM COVID-9 IgG/IgM Duo. The flow diagram of the study is presented in Fig. 1. Subjects were divided into two groups based on their exposure to the SARS CoV-2 virus:(i) Exposed: previously confirmed infection by RT-PCR or rapid antigen on the nasal-pharyngeal swab material or positive anti spike antibodies at first or second evaluation during the first five months of the study.(ii) Unexposed: negative anti spike antibodies after one or two consecutive tests performed in the first five months of the study. Our primary outcomes were: need of hospitalization, intensive care unit (ICU) admission and mortality rate in immunosuppressed children with COVID-19. Our secondary outcomes were: seroprevalence survey and incidence of flare-ups in exposed versus unexposed subjects. A total of 117 patients were enrolled, female to male ratio of 1.6, median age at inclusion time 11.1 years (range 1-18). Three patients were excluded from the study: two received Comirnaty COVID-19 vaccine and one patient was transferred to adult care facility. 68% of included patients had juvenile idiopathic arthritis (JIA). The most frequent immunosuppressive drug was methotrexate prescribed in 96 patients (84%), either as monotherapy or in association with other synthetic or biologic disease-modifying-anti-rheumatic-drugs (DMARDs). A total of 20 patients (17.5%) had a confirmed SARS CoV-2 infection and four amongst them tested positive after two previous negative anti spike protein measures. Only one patient required hospitalization in the 14th day after confirmation date for bacterial pneumonia. The mortality rate was null in our cohort and none of our patients required ICU admission or oxygen supplementation. Immunosuppressive treatment in confirmed subjects included monotherapy with synthetic DMADRs, double or triple therapy with synthetic and biologic DMARDs and corticosteroids, with duration of therapy detailed in Supplementary Table 1. All 20 patients experienced minor symptoms (low-grade fever, rhinorrhea, cough or gastrointestinal symptoms) for up to seven days. According to confirmation date, four patients got infected during the pre-Delta variant period, when Alpha/Beta variants were predominant. Seven patients got infected during the Delta wave, classified as variant of concern (VOC) by CDC due to increased transmissibility and disease severity. Finally, nine patients got infected after January 2022, when the predominant variant was Omicron. None of the patients disrupted their chronic medication during acute infection. As of month five of our study, 54 included subjects tested positive for Ig G antibodies to spike protein: 48 with positive serology at first measurement and 6 at second evaluation, three to four months distance. Nine (18%) subjects had a documented direct contact with a positive case, but no history of symptomatic infection. 50 subjects had negative Ig G antibodies to spike protein: 27 with two sequential negative serology tests three months apart and 23 with one negative serology test. 64 patients were included in the exposed group: ten with confirmed infection up to December 2021 and 54 with at least one positive serology test. 50 patients were included in the unexposed group: negative serology up to December 2021. The differences between groups in terms of age, gender, immune-related disease, type and duration of immunosuppressive therapy were not statistically significant (Supplementary Table 2). We assessed flare-ups retrospectively for COVID-19 confirmed cases (follow-up for maximum six months starting confirmation date) and prospectively for subjects without history of a positive SARS CoV-2 test. During the median follow-up of four months (range two to six months), a total of 13 (11%) subjects flared. The risk of flare in the exposed and unexposed group was 9% and 14%, respectively (p = 0.45, Log Rank test, Fig. 2). Those who flared were more likely to be female, receive higher doses of corticosteroids and have monotherapy with synthetic DMARDs, p < 0.05 (Supplementary Table 2). Multivariate analysis using Cox model showed that only female gender was associated with an increased risk of flare-up (Supplementary Table 3). The final seroprevalence survey results from March 2022 showed that 63% (62/99 patients) of immunosuppressed children in our cohort had previous asymptomatic infection (Supplementary Table 4). This is the first report of clinical outcomes, seroprevalence survey and risk of flare related to SARS CoV-2 infection in a cohort of pediatric patients with rheumatic diseases from Romania. All subjects with confirmed infection had mild COVID-19 and none required medication interruption. Previous exposure to SARS CoV-2 virus did not seem to increase flare-ups on a medium term. Seroprevalence survey identified high asymptomatic infection, reinforcing previous clinical observations that risk of severe COVID-19 in immunosuppressed pediatric patients with rheumatic diseases is minimal. This cohort study involving human participants was conducted in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The ethics committee of our center approved the study protocol (approval date 16/06/2021). All authors have contributed sufficiently to the scientific work and, therefore, share collective responsibility and accountability for the results. All authors have read and approved the final manuscript. AVC and AI contributed to the study conception and design, revised the manuscript for important intellectual content, performed data analysis and data interpretation, and drafted the manuscript; OMF gathered medical data and revised the manuscript. The authors have no financial interests that impact this study. We also certify that there are no actual or potential conflicts of interest in relation to this article. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. We thank our colleague Delia Corina Elena, our biochemist, for her help with serology assays. 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