Increased breadth and neutralization of antibodies against SARS-CoV-2 variants after infection and vaccination: A serosurveillance study in pediatric patients of Southern Switzerland.

Little information is available about the nature of the immune response in children after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or vaccination. The aim of this study is to define the seroprevalence and the features of the antibody response in children of Southern Switzerland during the different waves of Coronavirus Disease 2019 (COVID-19) pandemic. By analyzing 756 sera collected from children aged 0 to 16 years admitted to the Institute of Pediatrics of Southern Switzerland during the prepandemic period (before March 2020) and the first four pandemic waves (between March 2020 and June 2022), we investigated binding titers, cross-reactivity, and neutralizing properties of the serum antibodies against SARS-CoV-2 variants. Seroprevalence varied from 6% during the first wave to 14% and 17% during the second and third waves, respectively, peaking at 39% during the fourth wave. The 96 seropositive cases were mostly asymptomatic (42.7%) or showed mild (20.8%) to moderate (32.3%) symptoms. Moderate symptoms and close contact with COVID-19-positive individuals were associated with a higher infection risk (P < 0.001). The antibody response was mainly driven by IgG directed to the receptor-binding domain (RBD) of Wuhan-1 SARS-CoV-2 Spike (S). Children infected in the first three waves produced antibodies with up to 11-fold and 5.5-fold reduction in binding and neutralizing titers, respectively, against different SARS-CoV-2 variants, including Beta, Delta, and Omicron BA.1, BA.2, and BA.5. Such reductions were less pronounced in children infected during the fourth wave, who showed the highest frequency and titers of neutralizing antibodies against the same variants. Compared to infection, vaccination with a Wuhan-1-based messenger RNA (mRNA) vaccine induced higher and heterogenous levels of antibodies cross-reacting to the different SARS-CoV-2 variants analyzed.   Conclusions: Despite the high burden of COVID-19 in Southern Switzerland, we observed an initial low seroprevalence of SARS-CoV-2 in children, which increased in the later waves. The antibody response was poor in the first three waves and improved in the fourth wave, when children produced higher levels of neutralizing antibodies after vaccination or infection with Delta and/or Omicron variants. What is Known: • Children were marginally affected by the initial SARS-CoV-2 variants. • The number of infected and hospitalized children increased after the appearance of the Omicron variants. What is New: • Seroprevalence of SARS-CoV-2 in children of Southern Switzerland increased overtime. • Children produced higher levels of neutralizing antibodies after vaccination or infection with Delta and/or Omicron variants in the fourth wave compared to children infected in the first three waves.

Autoimmune markers and vascular immune deposits in Finkelstein-Seidlmayer vasculitis: Systematic literature review.

Finkelstein-Seidlmayer vasculitis, also called acute hemorrhagic edema of young children or infantile immunoglobulin A vasculitis, is habitually a benign skin-limited small vessel leukocytoclastic vasculitis that mainly affects infants 24 months or less of age. Since this disease is commonly triggered by an infection, an immune-mediated origin has been postulated. To better appreciate the possible underlying immune mechanism of this vasculitis, we addressed circulating autoimmune markers and vascular immune deposits in patients contained in the Acute Hemorrhagic Edema BIbliographic Database, which incorporates all original reports on Finkelstein-Seidlmayer vasculitis. A test for at least one circulating autoimmune marker or a vascular immune deposit was performed in 243 cases. Subunits of complement system C4 resulted pathologically reduced in 4.7% and C3 in 1.4%, rheumatoid factor was detected in 6.1%, and antinuclear antibodies in 1.9% of cases. Antineutrophil cytoplasmic antibodies were never demonstrated. Immunofluorescence studies were performed on 125 skin biopsy specimens and resulted positive for complement subunits in 46%, fibrinogen in 45%, immunoglobulin A in 25%, immunoglobulin M in 24%, immunoglobulin G in 13%, and immunoglobulin E in 4.2% of cases. Infants testing positive for vascular immunoglobulin A deposits did not present a higher prevalence of systemic involvement or recurrences, nor a longer disease duration. In conclusion, we detected a very low prevalence of circulating autoimmune marker positivity in Finkelstein-Seidlmayer patients. Available immunofluorescence data support the notion that immune factors play a relevant role in this vasculitis. Furthermore, vascular immunoglobulin A deposits seem not to play a crucial role in this disease.

Tubulointerstitial nephritis and uveitis syndrome: a systematic review.

BACKGROUND: Tubulointerstitial nephritis and uveitis (TINU) syndrome is defined as the occurrence of tubulointerstitial nephritis (TIN) and uveitis in the absence of other systemic diseases. The most comprehensive review on this condition was published in 2001. METHODS: We conducted a systematic review of the literature for cases of TINU syndrome. MEDLINE and Embase databases were screened. Full-length articles or letters reporting cases with both TIN and uveitis were selected. We investigated differences between males and females and paediatric and adult cases. Multivariate analysis was performed to identify potential risk factors for chronic kidney disease (CKD) development. RESULTS: A total of 233 articles reporting 592 TINU cases were retained for the analysis. The median age of the included subjects was 17 years (interquartile range 13-46) with a female predominance (65%). Uveitis most frequently (52%) followed renal disease and was mostly anterior (65%) and bilateral (88%). Children tended to have more ocular relapses, while they were slightly less likely than adults to suffer from acute kidney injury and to develop CKD. Adult age as well as posterior or panuveitis were associated with an increased risk of developing CKD. CONCLUSIONS: TINU affects both children and adults, with some differences between these two categories. Adult age and the presence of a posterior uveitis or panuveitis appear to be associated with the development of CKD.

Skin Eruptions in Acute Hemorrhagic Edema of Young Children: Systematic Review of the Literature.

BACKGROUND: Acute hemorrhagic edema is a skin-limited small-vessel leukocytoclastic vasculitis, which affects infants 4 weeks to 2 years of age and remits within 3 weeks. The diagnosis is made clinically in not-ill appearing children with acute onset of raised annular or nummular eruptions and edema. In this vasculitis, type, distribution, and evolution of the rash have never been systemically investigated. To address this issue, we employed the data contained in the Acute Hemorrhagic Edema Bibliographic Database, which incorporates all reports on acute hemorrhagic edema. SUMMARY: Key features of rash were documented in 383 children. Annular eruptions in a strict sense, usually targetoid, were reported in 375 (98%) cases (many children also presented polycyclic or arciform eruptions). Nummular eruptions were also very common (n = 358; 93%). Purpuric eruptions and ecchymoses were reported in the vast majority of cases. Macules and wheals were described in a minority of cases. Edema, detected in all cases, was mostly painful, indurated and nonpitting. The following regions were affected, in decreasing order, by annular or nummular eruptions: legs, feet, face, arms, ears, trunk, and genitals. With the exception of feet, which were very often affected, the same distribution was reported for edema. The initial eruption was often a wheal or a macule that evolved into a nummular or an annular eruption. Nummular eruptions successively evolved into annular ones. KEY MESSAGE: This study carefully characterizes type, distribution, and evolution of skin eruption in acute hemorrhagic edema. The data help physicians to rapidly and noninvasively make the clinical diagnosis of this vasculitis.

Skin and Mucous Membrane Eruptions Associated with Chlamydophila Pneumoniae Respiratory Infections: Literature Review.

BACKGROUND: Mycoplasma pneumoniae pneumonia is sometimes associated with skin or mucous membrane eruptions. Available reviews do not address the association of Chlamydophila pneumoniae pneumonia with skin eruptions. We therefore conducted a systematic review of the literature addressing this issue. The National Library of Medicine, Excerpta Medica, and Web of Science databases were employed. SUMMARY: In two reports, skin lesions and especially urticaria were more common (p < 0.05) in atypical pneumonia caused by C. pneumoniae as compared with M. pneumoniae. We found 47 patients (<18 years, n = 16; ≥18 years, n = 31) affected by a C. pneumoniae atypical pneumonia, which was associated with erythema nodosum, erythema multiforme minus, erythema multiforme majus, isolated mucositis, or cutaneous vasculitis. We also found the case of a boy with C. pneumoniae pneumonia and acute generalized exanthematous pustulosis. We did not find any case of C. pneumoniae respiratory infection associated with either Gianotti-Crosti syndrome, pityriasis lichenoides et varioliformis acuta Mucha-Habermann, or varicella-like skin eruptions.

Nicolau syndrome caused by non-steroidal anti-inflammatory drugs: Systematic literature review.

AIM: Intramuscular or, more rarely, local drug injection is occasionally followed by immediate local pain, livedoid skin lesions and, some days later, the development of ischemic lesions. This very uncommon but potentially severe reaction, termed Nicolau syndrome, is traditionally associated with bismuth and ß-lactam antimicrobials. The aim of this report was to review the literature associating Nicolau syndrome with the administration of non-steroidal anti-inflammatory drugs. METHODS: The National Library, Excerpta Medica, Web of Science and Cochrane library databases were used. RESULTS: Sixty-two cases (40 females and 22 males aged from 13 to 81, median 57 years) of Nicolau syndrome were published after 1992. Fifty-three cases occurred after diclofenac. The remaining nine cases were associated with ketoprofen (N = 2), ketorolac (N = 2), phenylbutazone (N = 2), etofenamate (N = 1), ibuprofen (N = 1) and piroxicam (N = 1). CONCLUSION: Although Nicolau syndrome is extremely uncommon, physicians must be aware of this complication after intramuscular administration of non-steroidal anti-inflammatory drugs and should avoid unnecessary injections.

Immune deposits in skin vessels of patients with acute hemorrhagic edema of young children: A systematic literature review.

BACKGROUND: Acute hemorrhagic edema of young children is a benign skin-limited vasculitis mainly affecting children 2 to 24 months of age, which is often considered the infantile variant of immunoglobulin A vasculitis (Henoch-Schönlein purpura). In most cases, the diagnosis is made on a clinical basis without a skin biopsy. METHODS: A systematic review of the literature was performed to examine the reported prevalence of vascular immune deposits in skin biopsies of patients with acute hemorrhagic edema of young children. RESULTS: Testing for vascular immune deposits was performed in 75 cases (64 boys and 11 girls aged from 3.5 to 72, median 11 months) published between 1970 and 2018. Vessel wall deposition of complement C3 was seen in 40 cases. Immunoglobulin M (N = 24), immunoglobulin A (N = 21), immunoglobulin G (N = 13), and immunoglobulin E (N = 3) were less frequently detected. Gender, age, clinical features, and disease duration were not statistically different in cases with and without vessel wall deposition of immunoglobulin A. CONCLUSION: Immune deposits in skin vessels, most frequently complement C3, are common in subjects with acute hemorrhagic edema of young children, providing furhter evidence that acute hemorrhagic edema, immunoglobulin A vasculitis, and pauci-immune vasculitides are different entities.

Classification criteria for autoinflammatory recurrent fevers.

BACKGROUND: Different diagnostic and classification criteria are available for hereditary recurrent fevers (HRF)-familial Mediterranean fever (FMF), tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS), mevalonate kinase deficiency (MKD) and cryopyrin-associated periodic syndromes (CAPS)-and for the non-hereditary, periodic fever, aphthosis, pharyngitis and adenitis (PFAPA). We aimed to develop and validate new evidence-based classification criteria for HRF/PFAPA. METHODS: Step 1: selection of clinical, laboratory and genetic candidate variables; step 2: classification of 360 random patients from the Eurofever Registry by a panel of 25 clinicians and 8 geneticists blinded to patients' diagnosis (consensus ≥80%); step 3: statistical analysis for the selection of the best candidate classification criteria; step 4: nominal group technique consensus conference with 33 panellists for the discussion and selection of the final classification criteria; step 5: cross-sectional validation of the novel criteria. RESULTS: The panellists achieved consensus to classify 281 of 360 (78%) patients (32 CAPS, 36 FMF, 56 MKD, 37 PFAPA, 39 TRAPS, 81 undefined recurrent fever). Consensus was reached for two sets of criteria for each HRF, one including genetic and clinical variables, the other with clinical variables only, plus new criteria for PFAPA. The four HRF criteria demonstrated sensitivity of 0.94-1 and specificity of 0.95-1; for PFAPA, criteria sensitivity and specificity were 0.97 and 0.93, respectively. Validation of these criteria in an independent data set of 1018 patients shows a high accuracy (from 0.81 to 0.98). CONCLUSION: Eurofever proposes a novel set of validated classification criteria for HRF and PFAPA with high sensitivity and specificity.

Ultrasound changes in synovial abnormalities induced by treatment in juvenile idiopathic arthritis.

OBJECTIVES: To investigate the capacity of ultrasound (US) to detect improvement of synovial abnormalities induced by treatment in juvenile idiopathic arthritis (JIA). METHODS: Eighty-three joints (33 knees, 22 tibiotalar, 10 wrists, 9 elbows, 9 subtalar joints) of 33 patients with new-onset JIA were assessed by US at study entry and 6 months after a therapeutic intervention. Each joint was scored for grey-scale (GS) and power Doppler (PD) abnormalities according to a 4-point semiquantitative scale. Pre- and post-treatment US scores were compared and the sensitivity to change of GSUS and PDUS was estimated. Clinical response was assessed using the ACR paediatric (ACRp) response criteria. RESULTS: Seventeen patients (51.5%) underwent intra-articular corticosteroid injection (IACI) only, 15 (45.5%) were given IACI and systemic medications, and 1 (3.0%) was started with systemic therapy alone. Both GSUS and PDUS scores improved significantly (p<0.0001) from baseline to follow-up. US revealed strong sensitivity to change with standardised response mean for GSUS and PDUS of 2.44 and 1.23, respectively. At the follow-up visit, 13/20 (65.0%) joints with residual US abnormalities were judged in remission on clinical grounds. Six/21 (28.6%) patients who were ACRp90 responders did not display complete resolution of synovial abnormalities on US. CONCLUSIONS: US is a sensitive tool to assess therapeutic response in patients with JIA. Subclinical disease on US is common in joints with clinically-defined remission. An ACRp90 response may not be coupled with complete resolution of synovial abnormalities on US. Further studies are needed to establish the impact of US on therapeutic decision-making in JIA.

The Swiss French version of the Juvenile Arthritis Multidimensional Assessment Report (JAMAR).

The Juvenile Arthritis Multidimensional Assessment Report (JAMAR) is a new parent/patient reported outcome measure that enables a thorough assessment of the disease status in children with juvenile idiopathic arthritis (JIA). We report the results of the cross-cultural adaptation and validation of the parent and patient versions of the JAMAR in the Swiss French language. The reading comprehension of the questionnaire was tested in ten JIA parents and patients. Each participating centre was asked to collect demographic, clinical data, and the JAMAR in 100 consecutive JIA patients or all consecutive patients seen in a 6-month period and to administer the JAMAR to 100 healthy children and their parents. The statistical validation phase explored descriptive statistics and the psychometric issues of the JAMAR: the three Likert assumptions, floor/ceiling effects, internal consistency, Cronbach's alpha, interscale correlations, test-retest reliability, and construct validity (convergent and discriminant validity). A total of 98 JIA patients (3.1% systemic, 43.9% oligoarticular, 16.3% RF negative polyarthritis, 36.7% other categories), and 64 healthy children were enrolled in a paediatric rheumatology centre. The JAMAR components discriminated well healthy subjects from JIA patients. All JAMAR components revealed good psychometric performances. In conclusion, the Swiss French version of the JAMAR is a valid tool for the assessment of children with JIA and is suitable for use both in routine clinical practice and clinical research.

[Kawasaki disease: an update]. / Maladie de Kawasaki : mise à jour.

The cause of Kawasaki disease (KD) is still unknown, but an infectious origin and genetic susceptibility have been suggested. The American Heart Association has changed the guidelines for diagnosis and treatment of KD in 2017. One goal is to better identify patients most at risk, particularly young children with « incomplete ¼ KD. In case of intravenous immunoglobulin resistance, alternative treatments to the traditional use of corticosteroids, such as TNF-alpha inhibitors have been proposed. For all patients with coronary aneurisms, regular assessment of myocardial perfusion is recommended, either with stress echocardiography, MRI, scintigraphy or PET-scan.

Bien que la cause de la maladie de Kawasaki (MK) reste à ce jour inconnue, les hypothèses actuelles suggèrent une origine infectieuse ainsi qu'une susceptibilité génétique. Les recommandations pour le diagnostic et la prise en charge de la MK ont été modifiées en 2017 par l'American Heart Association. Un des buts est de mieux identifier les patients à risque, en particulier les jeunes enfants avec une MK « incomplète ¼. En cas de résistance au traitement par immunoglobulines intraveineuses, des alternatives thérapeutiques aux corticostéroïdes utilisés traditionnellement sont proposées, incluant les inhibiteurs du TNFα. Chez tout patient avec des anévrismes coronariens, il est conseillé d'avoir une évaluation régulière de la perfusion myocardique, au moyen d'une échocardiographie, d'une IRM ou d'une scintigraphie de stress, ou d'un PET-scan.

Biologics in juvenile idiopathic arthritis: a narrative review.

In the past years, pediatric rheumatology has seen a revolution in the treatments for rheumatic diseases, particularly juvenile idiopathic arthritis. Even if nonsteroidal anti-inflammatory drugs (NSAID), intra-articular corticosteroids (IAC) injections, and methotrexate remain the mainstay of the treatment for JIA patients, in aggressive disease, these treatments may be not sufficient to reach disease remission and to prevent long-term disability. Comprehension of immunological mechanisms involved in the pathogenesis of the diseases allowed to conceive new drugs targeting specific steps of the immune response. Several cytokines, like TNF alpha and IL-1, represent a very interesting target for biologic therapies. Due to the efficacy of these therapies, nowadays, "disease remission" in pediatric rheumatology is more and more frequent, especially in juvenile idiopathic arthritis patients, and the long-term outcomes have been significantly improved. Crucial to these advancements have been multicenter controlled clinical trials and long-term safety monitoring. CONCLUSIONS: Research in pediatric rheumatology has resulted in dramatic advances in diseases management. Biologic treatments have improved physical and functional outcomes and quality of life of patients with rheumatic disease. What is Known: • NSAID, intra-articular injection of corticoids, and methotrexate are the mainstay in treatment of JIA. • In aggressive JIA, these treatments may be not sufficient to reach disease remission and to prevent long term disability. What is New: • In recent years, management of JIA has significantly improved with the development of biologic therapies that allowed children with arthritis to reach a normal growth and to achieve a good long-term functional outcome.

Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis (PFAPA) Syndrome: a Review of the Pathogenesis.

PFAPA syndrome represents the most common cause of recurrent fever in children in European populations, and it is characterized by recurrent episodes of high fever, pharyngitis, cervical adenitis, and aphthous stomatitis. Many possible causative factors have been explored so far, including infectious agents, immunologic mechanisms and genetic predisposition, but the exact etiology remains unclear. Recent findings demonstrate a dysregulation of different components of innate immunity during PFAPA flares, such as monocytes, neutrophils, complement, and pro-inflammatory cytokines, especially IL-1ß, suggesting an inflammasome-mediated innate immune system activation and supporting the hypothesis of an autoinflammatory disease. Moreover, in contrast with previous considerations, the strong familial clustering suggests a potential genetic origin rather than a sporadic disease. In addition, the presence of variants in inflammasome-related genes, mostly in NLRP3 and MEFV, suggests a possible role of inflammasome-composing genes in PFAPA pathogenesis. However, none of these variants seem to be relevant, alone, to its etiology, indicating a high genetic heterogeneity as well as an oligogenic or polygenic genetic background.

Reporting the Location and Extent of Pain in Adolescents: A Test-Retest Reliability Study.

BACKGROUND: A pain drawing is a self-administered assessment that requires the patient to shade in on a body chart the areas in which he or she experiences pain, regardless of the intensity. Pain drawings have already been validated in several adult populations. OBJECTIVES: The aim of this study is to establish adolescents' test-retest reliability in reporting the extent and location of their pain using a paper-based pain drawing. STUDY DESIGN: A one-day test-retest reliability study was set up. SETTING: The study took place in 2 separate locations-a pediatric hospital and a private physiotherapy practice in Ticino, in the southern part of Switzerland. This reliability study was approved by the local ethics committee of Ticino (2021-00492 CE 3832). METHODS: Adolescents with musculoskeletal pain (aged 11-16 years) were included. All participants were asked to shade the areas in which they experienced pain over the previous week. After the administration of a questionnaire and the acquisition of further personal data, the pain drawing was administered again. The pain drawings were then scanned and analyzed using a digital platform, which allowed the extraction of pain extent and location values. The test-retest reliability was evaluated on these data. The intraclass correlation coefficient and Bland-Altman analysis were used to assess the reliability of the reporting of the pain extent, whereas the Jaccard similarity coefficient was used to calculate the reliability of the reporting of the pain location. RESULTS: The reporting of the pain extent was observed to have excellent test-retest reliability: ICC2,1: 0.959 (95% CI: 0.925-0.978). The Bland-Altman analysis showed a mean difference close to 0: -0.010% (limits of agreements -0.962 to 0.942). The reliability of the reporting of pain location was also supported by the Jaccard index mean score of 0.82 (± 0.19). LIMITATIONS: Reliability of reporting may vary depending on the nature of the pain, its duration, or the type of disorder and body areas involved. CONCLUSIONS: Adolescents complaining musculoskeletal pain showed reliability in reporting pain extent and location using pain drawings.

Acute Aseptic Meningitis Temporally Associated with Intravenous Polyclonal Immunoglobulin Therapy: A Systematic Review.

An acute aseptic meningitis has been occasionally observed on intravenous polyclonal human immunoglobulin therapy. Since case reports cannot be employed to draw inferences about the relationships between immunoglobulin therapy and meningitis, we conducted a systematic review and meta-analysis of the literature. Eligible were cases, case series, and pharmacovigilance studies. We found 71 individually documented cases (36 individuals ≤ 18 years of age) of meningitis. Ninety percent of cases presented ≤ 3 days after initiating immunoglobulin therapy and recovered within ≤ 7 days (with a shorter disease duration in children: ≤ 3 days in 29 (94%) cases). In 22 (31%) instances, the authors noted a link between the onset of meningitis and a rapid intravenous infusion of immunoglobulins. Cerebrospinal fluid analysis revealed a predominantly neutrophilic (N = 46, 66%) pleocytosis. Recurrences after re-exposure were observed in eight (N = 11%) patients. Eight case series addressed the prevalence of meningitis in 4089 patients treated with immunoglobulins. A pooled prevalence of 0.6% was noted. Finally, pharmacovigilance data revealed that meningitis temporally associated with intravenous immunoglobulin therapy occurred with at least five different products. In conclusion, intravenous immunoglobulin may cause an acute aseptic meningitis. The clinical features remit rapidly after discontinuing the medication.

Individual and environmental determinants associated with longer times to access pediatric rheumatology centers for patients with juvenile idiopathic arthritis, a JIR cohort study.

BACKGROUND: Despite guidelines, poor access to appropriate care for juvenile idiopathic arthritis (JIA) patients remains a global issue. Prompt referral to a pediatric rheumatology (PR) center and effective care is known to be critical for changing the natural history of the disease and improving long-term prognosis. This project assesses socio-economic factors of delayed referral to a pediatric rheumatologist (PRst) for JIA patients in France and Switzerland within the Juvenile Inflammatory Rheumatism (JIR) Cohort. METHODS: All patients diagnosed with JIA, presenting at one center of the JIRcohort in France or Switzerland with additional data on referral pathway were included. Patient characteristics at first visit to the PR center, dates of visits to healthcare providers during referral, and parent characteristics were extracted from the JIRcohort database. RESULTS: Two hundred fifty children were included. The overall median time to first PR assessment was 2.4 months [1.3; 6.9] and ranged widely across the JIA subtypes, from 1.4 months [0.6; 3.8] for children with systemic juvenile idiopathic arthritis (sJIA) to 5.3 months [2.0; 19.1] for children with enthesitis-related arthritis (ERA). A diagnosis of ERA and an appointment with an orthopedist during the referral pathway were significantly associated with a longer time before the first PR visit (hazard ratio HR 0.50 [95% CI: 0.29; 0.84]) and HR 0.68 [95% CI: 0.49; 0.93], respectively) in multivariable analysis. Having a mother with a post-graduate educational attainment level was tendentially associated with a shorter time before the first PR visit, (HR 1.32 [95% CI: 0.99; 1.78]). CONCLUSIONS: Time to first PRst visit was most often short compared to other studies and close to the British recommendations. However, this time remained too long for many patients. We observed no social inequities in access to a PRst, but we show the need to improve effective pathway and access to a PR center for JIA patients.

Methylprednisolone versus intravenous immunoglobulins in children with paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS): an open-label, multicentre, randomised trial.

BACKGROUND: The emergence of paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) led to the widespread use of anti-inflammatory treatments in the absence of evidence from randomised controlled trials (RCTs). We aimed to assess the effectiveness of intravenous methylprednisolone compared with intravenous immunoglobulins. METHODS: This is an open-label, multicentre, two-arm RCT done at ten hospitals in Switzerland in children younger than 18 years hospitalised with PIMS-TS (defined as age <18 years; fever and biochemical evidence of inflammation, and single or multiorgan dysfunction; microbiologically proven or putative contact with SARS-CoV-2; and exclusion of any other probable disease). Patients were randomly assigned 1:1 to intravenous methylprednisolone (10 mg/kg per day for 3 days) or intravenous immunoglobulins (2 g/kg as a single dose). The primary outcome was length of hospital stay censored at day 28, death, or discharge. Secondary outcomes included proportion and duration of organ support. Analyses were done by intention-to-treat. The study was registered with Swiss National Clinical Trials Portal (SNCTP000004720) and ClinicalTrials.gov (NCT04826588). FINDINGS: Between May 21, 2021, and April 15, 2022, 75 patients with a median age of 9·1 years (IQR 6·2-12·2) were included in the intention-to-treat population (37 in the methylprednisolone group and 38 in the intravenous immunoglobulins group). The median length of hospital stay was 6·0 days (IQR 4·0-8·0) in the methylprednisolone group and 6·0 days (IQR 5·0-8·8) in the intravenous immunoglobulins group (estimated effect size -0·037 of the log10 transformed times, 95% CI -0·13 to 0·065, p=0·42). Fewer patients in the methylprednisolone group (ten [27%] of 37) required respiratory support compared with the intravenous immunoglobulin group (21 [55%] of 38, p=0·025). Need and duration of inotropes, admission to intensive care units, cardiac events after baseline, and major bleeding and thrombotic events were not significantly different between the study groups. INTERPRETATION: In this RCT, treatment with methylprednisolone in children with PIMS-TS did not significantly affect the length of hospital stay compared with intravenous immunoglobulins. Intravenous methylprednisolone could be an acceptable first-line treatment in children with PIMS-TS. FUNDING: NOMIS Foundation, Vontobel Foundation, and Gaydoul Foundation.

[New therapies in pediatric rheumatology]. / Nouvelles thérapies en rhumatologie pédiatrique.

Biotherapies are recent treatments, which target molecules implicated in the pathogenesis of inflammatory diseases. In pediatric rheumatology, we use anti-TNF-alpha and abatacept in JIA patients with polyarticular involvement, whereas anti-IL-6 and anti-IL-1 blockers are efficacious in the systemic form of JIA and other auto-inflammatory conditions. These new treatments have significantly improved the control of articular and systemic inflammation and the prognosis of rheumatic diseases. Their effect and their safety on the long-term need to be assessed on large cohorts of patients. Due to the impact of these chronic illnesses on the young patient and its family, and the required specific knowledge, the care of these children should be provided by a multidisciplinary team linked to a centre of competence.

Multicenter Randomized Trial of Methylprednisolone vs. Intravenous Immunoglobulins to Treat the Pediatric Inflammatory Multisystem Syndrome-Temporally Associated With SARS-CoV-2 (PIMS-TS): Protocol of the Swissped RECOVERY Trial.

Introduction: In 2020, a new disease entitled Pediatric Inflammatory Multisystem Syndrome temporally associated with COVID-19 (PIMS-TS), or Multisystem Inflammatory Syndrome in Children (MIS-C), emerged, with thousands of children affected globally. There is no available evidence based on randomized controlled trials (RCT) to date on the two most commonly used immunomodulatory treatments, intravenous immunoglobulins (IVIG) and corticosteroids. Therefore, the Swissped RECOVERY trial was conducted to assess whether intravenous (IV) methylprednisolone shortens hospital length of stay compared with IVIG. Methods and Analysis: Swissped RECOVERY is an ongoing investigator-initiated, open-label, multicenter two-arm RCT in children and adolescents <18 years hospitalized with a diagnosis of PIMS-TS. The trial is recruiting at 10 sites across Switzerland. Patients diagnosed with PIMS-TS are randomized 1:1 to methylprednisolone IV (10 mg/kg/day for 3 days) or IVIG (2 g/kg as a single dose). The primary outcome is hospital length of stay censored at day 28, death, or discharge (whichever is first). The target total sample size is ~80 patients 1:1 randomized to each study arm. Ancillary and exploratory studies on inflammation, vaccination acceptance and coverage, long-term outcomes, and healthcare costs are pre-planned. Significance: Currently, robust trial evidence for the treatment of PIMS-TS is lacking, with a controversy surrounding the use of corticosteroids vs. IVIG. This trial will provide evidence for the effectiveness and safety of these two treatments. Ethics and Dissemination: The study protocol, which was designed based on the U.K. RECOVERY trial, the patient information and consent forms, and other study-specific study documents were approved by the local ethics committees (Project ID: 2021-00362). Registration Details: The study is registered on the Swiss National Clinical Trials Portal (SNCTP000004720) and Clinicaltrials.gov (NCT04826588).