key: cord-0430677-yvruzl1k authors: Wang, Z.; Zhao, S.; Tang, Y.; Shi, Q.; Dang, X.; Gan, L.; Peng, S.; Li, W.; Zhou, Q.; Li, Q.; Mafiana, J. J.; Cortes, R. G.; Luo, Z.; Liu, E.; Chen, Y. title: Potentially effective drugs for the treatment of COVID-19 in children: a systematic review date: 2021-07-22 journal: nan DOI: 10.1101/2021.07.20.21260827 sha: f162bb9760d9e3eda809eefd20e3f12e12f5e42d doc_id: 430677 cord_uid: yvruzl1k Background: The efficacy and safety of using potential drugs such as remdesivir, glucocorticoid, and intravenous immunoglobulin (IVIG) in treating children and adolescents with COVID-19 is unclear. Methods: We searched seven databases, three preprint platform, ClinicalTrials.gov, and Google from December 1, 2019, to March 2, 2021, to collect evidence of remdesivir, glucocorticoid, and IVIG which were used in children and adolescents with COVID-19. Findings: A total of six cohort studies and one case series study were included in this systematic review. In terms of remdesivir, the meta-analysis of single-arm cohort studies have shown that, after the treatment, 37.1% (95%CI, 0.0% to 74.5%) experienced adverse events, 5.9% (95%CI, 1.5% to 10.2%) died, 37.2% (95%CI, 0% to 76.0%) needed extracorporeal membrane oxygenation (ECMO) or invasive mechanical ventilation (IMV). As for glucocorticoids, the results of the meta-analysis showed that the fixed-effect summary odds ratio (OR) for the association with mortality was 2.79 (95%CI, 0.13 to 60.87), and the mechanical ventilation rate was 3.12 (95%CI, 0.80 to 12.08) for glucocorticoids compared with the control group. In terms of IVIG, the two included cohort studies showed that for MIS-C patients with more severe clinical symptoms, IVIG combined with methylprednisolone could achieve better clinical efficacy than IVIG alone. Interpretation: Overall, the current evidence in the included studies is insignificant and of low quality, which does not adequately demonstrate the effectiveness and safety of using remdesivir, glucocorticoids, and IVIG in treating children and adolescents with COVID-19 or MIS-C. It is over a year and a half since the outbreak of coronavirus disease 2019 (COVID- 19) , and during this period, 72 studies on COVID-19 are continuously emerging [1, 2] . Researchers have paid much attention to drug therapy due 73 to the lack of safe and effective treatment to meet clinical needs [3] . Recent studies on COVID-19 drugs and 74 clinical guidelines have focused primarily on adult patients but less attention on children and adolescents. Although 75 children and adolescents with COVID-19 seem less susceptible and have milder symptoms once infected, they are 76 also at risks of advancing to severe stages [4] . Children and adults are known to have physiological differences 77 [5] ; thus, many effective COVID-19 drugs for adults may not suitable for children. Among these drugs, remdesivir, 78 glucocorticoids, and intravenous immunoglobulin (IVIG) in children and adolescents have been controversial. Remdesivir is a broad-spectrum antiviral medication that can integrate into the RNA strand of severe acute 80 respiratory syndrome coronavirus-2 (SARS-CoV-2) and prematurely terminate the ribonucleic acid (RNA) 81 replication process [6] . The World Health Organization (WHO) living guideline for COVID-19 [7] and the United States guideline for pediatric COVID-19 [8] have contradicting recommendations for the treatment of children and 83 adolescents, based on evidence from randomized controlled trials of adults. At the same time, the status of original 84 studies of remdesivir in children and adolescents with COVID-19 is unclear. Glucocorticoids are the most widely used and effective anti-inflammatory and immunosuppressive agents in 86 clinical practice. They have the potential to reduce the severity of lung inflammation in patients with severe 87 COVID-19 [9, 10] . Glucocorticoids are affordable, easy to administer, and readily available globally [11] . The 88 WHO living guidance on glucocorticoids for COVID-19 [12] recommends systemic glucocorticoids to treat adult 89 patients with severe COVID-19. However, the living guidance further suggests that the recommendation is 90 underrepresented in children and adolescents with COVID-19. IVIG is a recommended first-line therapy for Kawasaki disease because it produces anti-inflammatory effect, 92 which reduces coronary artery abnormalities and myocarditis in patients with Kawasaki disease [13] . MIS-C 93 (multi-system inflammatory syndrome in children) is a newly defined clinical syndrome associated with SARS- CoV-2 infection characterized by fever, systemic inflammation, and multiple organ dysfunction. Several case 95 definitions of this novel inflammatory condition have been published by the WHO [14] , the US Center for Disease 96 Control and Prevention (CDC) [15] , and the United Kingdom of Great Britain Royal College of Pediatrics and 97 Child Health (RCPCH) [16] . The clinical features of MIS-C are similar to those of Kawasaki disease, toxic shock 98 syndrome, sepsis, and macrophage activation syndrome [17] . Hence, the application of IVIG in the treatment of 99 MIS-C is a potential drug choice [18] , but the evidence of the application of IVIG in MIS-C treatment is still 100 unclear. Therefore, we aimed to determine the efficacy and safety of using: 1. remdesivir in treating children and All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The researchers in groups 1, 2, and 3 used "remdesivir," "corticosteroids," and "intravenous immunoglobulin," 121 and its derivatives as retrieval terms, respectively. The terms were also combined with "COVID-19" and its 122 derivatives using "AND". For question 3, "MIS-C" and its derivatives were added as retrieval terms and combined 123 with "AND" to improve the accuracy of the search. The search strategy can be found in Supplementary File 1. 153 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Cochrane's risk of bias tool [20] . Potential sources of bias are examined according to six domains (including seven 184 items): selection bias, performance bias, detection bias, attrition bias, reporting bias, and other biases. Each item 185 was assessed as "low risk of bias," "high risk of bias," or "unclear." The risk of bias of included non-randomized 186 controlled trials was assessed using the tool of ROBINS-I [21] , which contains seven items (confounding, selection 187 of participants into the study, classification of the intervention, deviations from intended interventions, missing 188 data, measurements of outcomes, and selections of the reported result), each of which was assessed as "low risk," 189 "moderate risk," "serious risk," "critical risk," and "no information". The Newcastle-Ottawa quality assessment 190 scale [22, 23] was used to assess the risk of bias of cohort studies. The scale contains eight items in three domains: 191 selection, comparability, and outcome. The items were rated with an asterisk. The Quality Appraisal Checklist for 192 Case Series Studies developed by the Institute of Health Economics was used to assess the risk of bias of case 193 series studies [24] . The checklist contains twenty items in eight domains: study objective, study population, 194 intervention and co-intervention, outcome measure, statistical analysis, results and conclusions, competing 195 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. interests and sources of support, and supplement. Each item was evaluated with "yes" or "no". 196 2.6. Data synthesis 197 A meta-analysis using the STATA14 software when the outcomes of included studies were highly consistent and 198 descriptive analyses when there was high heterogeneity of outcomes between the included studies. According to 199 Cochrane Handbook, when the meta-analysis was conducted, a random-effects meta-analysis for all outcomes was 200 presented [25] . For an included study with intervention group and control group, the odds ratios (ORs) and their 201 95% confidence interval (CI) were used to describe the effect of dichotomous variables while weighted mean 202 differences (WMD) and their 95% CI were used to describe the effect of continuous variables. However, for an 203 included study with only an intervention group, the effect sizes (ES) and their 95% CI were used to describe the 204 effect of dichotomous variables while mean differences (MD) and their 95% CI were used to describe the effect 205 of continuous variables. Statistical significance was set at <0.05 on both sides [26] . We used the chi-squared test 206 and I² statistic were used to assess the level of statistical heterogeneity between the included studies, with p<0.05 207 and I² of less than 50% representing heterogeneity [26] . When substantial heterogeneity was detected, subgroup 208 analyses by participant and study characteristics were used to compare pooled association estimates and 209 heterogeneity. Furthermore, sensitivity analysis was used to detect potential outliers by omitting one estimate at a 210 time and recalculating the pooled estimates. Publication bias was assessed through the funnel chart when the 211 studies included in the meta-analyses were more than five [26] . 216 by outcome [27, 28] . Under the GRADE system, RCTs were initially assessed as high quality and observational 217 studies as low quality. However, they were downgraded for reasons such as the risk of bias, inconsistency, 218 indirectness, imprecision, publication bias, or upgraded for reasons such as the large magnitude of effect, dose-219 response gradient, and plausible confounding [29] [30] [31] [32] [33] [34] . Thus, the quality of studies was rated as "high," "medium," 220 "low," and "very low," reflecting the extent to which we are confident in the effect estimates. Due to the peculiarity and public health significance of COVID-19, this study was not registered on the 222 international registration platform PROSPERO. For clinical question 1, a total of 5020 records were retrieved from the databases and other methods. A total of 226 three cohort studies were included, one of them was included from the database and two of them were unpublished 227 studies obtained by data request [35] [36] [37] . For clinical question 2, 3937 records were retrieved. A cohort [38] and 228 case series [39] study was included by reading the title, abstract, and full text. (Table 1) . All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. One hundred and twelve patients in 3 single-arm cohort studies [35] [36] [37] reported the efficacy and safety of remdesivir in treating children and adolescents with COVID-19. The results from a published study showed (n=8) [35] that 75% of the patients were admitted to the Pediatric Intensive Care Unit (PICU), 62.5% were on mechanical ventilation, and 12.5% were on noninvasive ventilation or high-flow oxygen. In another study (n=77) [37] , all the patients were diagnosed with severe COVID-19, among which 50.6% were treated with mechanical ventilation and 26.0% with noninvasive ventilation or high-flow oxygen. In another study (n=27) [ and Anemia (3%, 2/77) [37] . There were 16·2% (95%CI, 1·8% to 30·5%, very low-quality evidence) of them experienced serious adverse events, 5·9% (95%CI, 1·5% to 10·2%) died, 37·2% (95%CI, 0% to 76·0%, very low-quality evidence) needed extra-corporeal membrane oxygenation (ECMO) or invasive mechanical ventilation (IMV). A retrospective cohort and case series studies [38, 39] comprising of 69 children or adolescents (age 7·41±5·08) with severe COVID-19 treated with glucocorticoids were included. There was no statistically significant association between glucocorticoids therapy and mortality (OR= 2·79, 95% CI, 0·13 to 60·87, very low-quality evidence), mechanical ventilation rate (OR = 3·12, 95% CI, 0·80 to 12·08, very low-quality evidence) or the duration of PICU admission (WMD = 2·0, 95% CI, -0·95 to 4·95, very low-quality evidence). One cohort study [40] consisting of 96 MIS-C patients reported the effectiveness and safety of IVIG (32 patients were in the IVIG and methylprednisolone group while 64 in the IVIG group after propensity score matching). Patients who received IVIG alone as first-line therapy had a treatment success rate of 62% (treatment failure defined as the persistence of fever two days after introducing first-line therapy or recrudescence of fever within seven days after the first-line therapy). Patients with more severe initial clinical presentation (initial acute left ventricular dysfunction, initial PICU care, and hemodynamic support requirement) received a combination of IVIG and methylprednisolone as first-line therapy. The result showed that IVIG combined with methylprednisolone could decrease the treatment failure (OR=0·25, 95%CI, 0.09 to 0.70, low-quality evidence), second-line treatment (OR=0·19, 95%CI, 0·06 to 0·61, low-quality evidence), hemodynamic support (OR=0·21, 95%CI, 0·06 to 0·76, low-quality evidence), the occurrence of secondary acute left ventricular dysfunction (OR=0·20, 95%CI, 0·06 to 0·66, low-quality evidence), and duration of PICU stay (4 vs. 6, p=0·005). In the other cohort study [41] , 22 MIS-C patients received a combination of IVIG (2 g/kg) and methylprednisolone (0·8 mg/kg/d for 5d). They had a shorter recovery time from left ventricle ejection fraction (2·9d vs 5·4 d, p=0·002), isovolumic relaxation time (6·4d vs 20·6d, p＜0·0001) , and duration of PICU stay (3·4d vs 5·3d, p＜0·05), in comparison with the 18 patients that received only IVIG (2 g/kg) as first-line therapy (Very low quality evidence). All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 22, 2021. ; https://doi.org/10.1101/2021.07.20.21260827 doi: medRxiv preprint 4. Discussion A total of six cohort studies and one case series study were included in this systematic review. In terms of remdesivir, there was no controlled study to prove its efficacy and safety in treating children and adolescents with COVID-19. Single-arm cohort studies have shown that the incidence of adverse reactions, mortality, and mechanical ventilation rate in patients treated with remdesivir are relatively low. As for glucocorticoids, the meta-analysis results showed no statistically significant difference in the improvement of mortality and mechanical ventilation rate between the intervention and control group. In terms of IVIG, the two included cohort studies showed that for MIS-C patients with more severe clinical symptoms, IVIG combined with methylprednisolone could achieve better clinical efficacy than IVIG alone. OR = 1·29 (95% CI 1·03-1·60); 5-day remdesivir versus control: OR = 1·80 (95% CI 1·31-2·48)] of patients treated for 5 and 10 days were higher than placebo. Nevertheless, there was no significant improvement in mortality [42] . Other systematic reviews of adult patients have reached similar conclusions [43] . Based on this, on October 22, 2020, the U.S. Food and Drug Administration (FDA) approved Veklury (remdesivir) for the treatment of COVID-19 in children and adolescents aged at least 12 years and weighing at least 40 kg requiring hospitalization [44] . It also approved an emergency use authorization of remdesivir to treat suspected or laboratory-confirmed COVID-19 in hospitalized pediatric patients weighing at least 3·5 kg but being either aged less than 12 years or weighing less than 40 kg [45] . The results of this systematic review showed that most of the children and adolescents included in this study had severe or underlying diseases, and the adverse events, mechanical ventilation rate, and mortality of the patients after treatment with remdesivir were low, but there was a lack of control group; thus, the quality of evidence was low. As of April 26, 2021, 24 clinical studies included children with COVID-19 treated with remdesivir and registered at ClinicalTrials.gov, but few studies focused only on children or adolescents [46] . The effectiveness of glucocorticoids in the treatment of adult patients with COVID-19 has been confirmed. The The New England Journal of Medicine, and the results of the study showed that among patients hospitalized with COVID-19, the use of dexamethasone resulted in lower 28-days mortality [9] . The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) working group published a systematic review based on seven RCTs The results showed that systemic glucocorticoids administered to critically ill COVID-19 patients were associated with 28-days lower mortality than usual care or placebo [47] . Based on the systematic review evidence, the WHO developed a living guideline on glucocorticoids to recommend systemic glucocorticoids in treating patients with severe COVID-19 [12] . The recommendation was intended for the average patient population. However, the evidence that supported the recommendation was unclear for the under-represented population, such as children in the considered trials, which supported the meta-analysis of the systematic review. We have also searched ClinicalTrials.gov to find registered clinical trials on the effectiveness of glucocorticoids in the treatment of COVID-19. No registered clinical trials have included or specifically targeted children or adolescents except for the RECOVERY trial. Most children with COVID-19 have only mild symptoms [5, 48] , so it may be challenging to recruit critically ill children or adolescents to participate in clinical trials. The two All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 22, 2021. ; https://doi.org/10.1101/2021.07.20.21260827 doi: medRxiv preprint studies included in this systematic review were observational studies with a small sample [38, 39] which found that glucocorticoids could not reduce the death rate in children or adolescents with critical COVID-19. Nevertheless, high-quality randomized controlled trials are recommended to confirm the effectiveness of glucocorticoids in the treatment of critically ill children or adolescents with COVID-19. MIS-C is a unique complication in children and adolescents with COVID-19, which has similar characteristics to those of Kawasaki disease. Admittedly, IVIG generally produces anti-inflammatory effects, mitigates coronary artery abnormalities, and serves as first-line therapy of Kawasaki disease [49] . MIS-C is theorized to be a delayed immunological response after SARS-CoV-2 infection, but based on the limited evidence, the immunopathology of MIS-C remains a challenge [50] . Several MIS-C guidelines are published, and the treatment therapy is based chiefly on Kawasaki disease, where IVIG is recommended empirically as the first-line treatment [46] [47] [48] . Besides, IVIG combined with glucocorticoids is also suggested as adjuvant therapy for severe patients or intensive therapy for patients with refractory diseases [51] . Two cohort studies included in this study showed that IVIG combined with glucocorticoids had better efficacy in MIS-C treatment than IVIG alone. In one cohort study, IVIG combined with glucocorticoids was associated with greater efficacy and safety in children with more severe symptoms than IVIG alone. The result is in agreement with the guideline recommendation of the use of IVIG in children and adolescents with COVID-19. Current guidelines also indicate a lack of high-quality studies comparing IVIG with glucocorticoids in MIS-C [51, 54] . Although the two cohort studies included in this study were of high quality, the results could not be combined due to the difference in their outcome indicators. As of April 26, 2021, 11 MIS-C clinical studies were registered on ClinicalTrials.gov, but there no study investigated the efficacy of IVIG as a therapeutic agent [55]. This study is the first systematic review accessing the remdesivir, glucocorticoids and IVIG in treating children and adolescents with COVID-19. The study highlights the current status of evidence, identifies research gaps and proffer recommendations for developing clinical practice guidelines in treating children and adolescents with COVID-19. However, there are also some limitations: 1) All the studies using remdesivir in treating children with were low-quality single-arm cohort studies; thus, its efficacy and safety could not be clearly ascertained. 2) Due to the small sample size in the studies using glucocorticoids as treatment included in the study, the results of meta-analysis may be biased to some extent, and 3) Quantitative analysis of studies on the treatment of MIS-C by IVIG was not feasible due to the heterogeneity of their outcome indicators. Based on the results of this systematic review, we recommend 1) high-quality randomized controlled trials of potentially effective drugs for children with COVID-19; 2) develop better guidelines based on substantial current evidence, provide a timely guide for clinical workers, and update them in real-time according to the evidence situation. Overall, the current evidence in the included studies is insignificant and of low quality, which does not adequately demonstrate the effectiveness and safety of using remdesivir, glucocorticoids, and IVIG in treating children and adolescents with COVID-19 or MIS-C. Therefore, it is recommended to conduct high-quality randomized controlled trials to provide substantial evidence for the development of guidelines. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 22, 2021. ; https://doi.org/10.1101/2021.07.20.21260827 doi: medRxiv preprint All authors have completed the ICMJE uniform disclosure form, and have no conflicts of interest to declare. This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors. The datasets used and analyzed during this study are available from the corresponding author on reasonable request. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 22, 2021. ; https://doi.org/10.1101/2021.07.20.21260827 doi: medRxiv preprint Pandemic publishing: Medical journals strongly speed up their publication process for COVID-19 Meeting public health needs in emergencies-World Health Organization guidelines Efficacy of the current investigational drugs for the treatment of COVID-19: a scoping review Clinical characteristics of children with COVID-19: a rapid review and meta-analysis Diagnosis, treatment, and prevention of 2019 novel coronavirus infection in children: experts' consensus statement To investigate the application value of remdesivir in the treatment of COVID-19 patients A living WHO guideline on drugs for covid-19 Multicenter Interim Guidance on Use of Antivirals for Children With Coronavirus Disease 2019/Severe Acute Respiratory Syndrome Coronavirus 2 Dexamethasone in Hospitalized Patients with Covid-19 Pulmonary post-mortem findings in a series of COVID-19 cases from northern Italy: a two-centre descriptive study Coronavirus disease (COVID-19): Dexamethasone. Available from World Health Organization. Corticosteroids for COVID-19: living guidance Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association Multisystem inflammatory syndrome in children and adolescents with COVID-19 Emergency preparedness and response: health alert network Guidance: paediatric multisystem inflammatory syndrome temporally associated with COVID-19 COVID-19 associated Multisystem Inflammatory Syndrome in Children (MIS-C) guidelines; a Western New York approach No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted The Cochrane Collaboration's tool for assessing risk of bias in randomised trials ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions Newcastle-Ottawa Quality Assessment Scale--Case Control Studies The ROBINS-I and the NOS had similar reliability but differed in applicability: A random sampling observational studies of systematic reviews/meta-analysis A principal component analysis is conducted for a case series quality appraisal checklist Random-effects model for meta-analysis of clinical trials: an update Cochrane Handbook for Systematic Reviews of Interventions version 6 GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables GRADEpro Guideline Development Tool Available from: www. gradepro.org GRADE guidelines: 4. Rating the quality of evidence-study limitations (risk of bias) GRADE guidelines: 5. Rating the quality of evidencepublication bias GRADE guidelines 6. Rating the quality of evidence-imprecision GRADE guidelines: 7. Rating the quality of evidenceinconsistency GRADE guidelines: 8. Rating the quality of evidence-indirectness GRADE guidelines: 9. Rating up the quality of evidence Compassionate use of remdesivir in children with COVID-19 Safety and Efficacy of Remdesivir in a Pediatric COVID-19 Population. Virtual CROI 2021 Compassionate Use of Remdesivir in Children With Severe COVID-19 Severe manifestations of SARS-CoV-2 in children and adolescents: from COVID-19 pneumonia to multisystem inflammatory syndrome: a multicentre study in pediatric intensive care units in Spain Clinical features of severe pediatric patients with coronavirus disease 2019 in Wuhan: a single center's observational study No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted Addition of Corticosteroids to Immunoglobulins Is Associated With Recovery of Cardiac Function in Multi-Inflammatory Syndrome in Children Clinical efficacy and safety of remdesivir in patients with COVID-19: a systematic review and network meta-analysis of randomized controlled trials Update: Remdesivir for Adults With COVID-19 : A Living Systematic Review and Meta-analysis for the American College of Physicians Practice Points FDA Approves First Treatment for COVID-19 Veklury (remdesivir) EUA Fact Sheet for Healthcare Providers Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis Clinical Characteristics of Children With COVID-19: A Meta-Analysis. Front Pediatr Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association The immune roadmap for understanding multi-system inflammatory syndrome in children: opportunities and challenges American College of Rheumatology Clinical Guidance for Multisystem Inflammatory Syndrome in Children Associated With SARS-CoV-2 and Hyperinflammation in Pediatric COVID-19: Version 2 A national consensus management pathway for paediatric inflammatory multisystem syndrome temporally associated with COVID-19 (PIMS-TS): results of a national Delphi process Multisystem Inflammatory Syndrome in Children (MIS-C) Interim Guidance infections/clinical-guidance/multisystem-inflammatory-syndrome-in-children-mis-c-interimguidance Childhood multisystem inflammatory syndrome associated with COVID-19 (MIS-C): a diagnostic and treatment guidance from the Rheumatology Study Group of the Italian Society of Pediatrics All rights reserved. No reuse allowed without permission.(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint this version posted July 22, 2021. ; https://doi.org/10.1101/2021.07.20.21260827 doi: medRxiv preprint