BACKGROUND:The goal of this study was to identify symptoms that occur in children post-SARS-CoV-2 infection, their trajectory over the first-year post-enrollment, and relationship to age. METHODS:Longitudinal comparison of infected and uninfected cohorts. Participants (0-21 years) with laboratory-confirmed SARS-CoV-2 infection were enrolled as infected. The uninfected cohort was individuals without laboratory evidence of SARS-CoV-2 infection. Primary outcome was presence or absence of symptoms. RESULTS:852 participants (705 infected, 147 uninfected) completed baseline visits. Of those, 558 infected subjects completed a 12-month post-enrollment visit. Twenty symptoms were identified as more common in infected participants compared to uninfected, at either baseline or 12-months, with symptoms varying by age. Some symptoms in the infected were more frequent at baseline (e.g. fever, weight loss), whereas many symptoms persisted through 12-months. Several symptoms were more frequent at 12-months (e.g. dysmenorrhea, persistent headache). Presence of symptoms at 12-months was not significantly associated with the wave of circulating virus at original infection. CONCLUSIONS:Interim analysis at one-year post-enrollment identifies 20 symptoms that infected participants were more likely to report post SARS-CoV-2 infection compared to uninfected, at either visit. Type of symptoms varies by age. Ongoing longitudinal data up to 3-years post-enrollment will increase understanding of long-term symptoms of SARS-CoV-2 infection in children and their trajectory. CLINICAL TRIAL REGISTRATION:NCT04830852. IMPACT:Although most children recover fully from SARS-CoV-2 infection, some children experience a variety of prolonged symptoms following infection. Many studies attempting to characterize these symptoms and trajectory are not prospective nor longitudinal and lack comparison to uninfected controls. This longitudinal analysis identifies and characterizes post-COVID symptoms in children and adolescents and their trajectory through the first-year post enrollment compared to an uninfected cohort. 20 post-infection symptoms were identified as occurring more frequently in the infected as compared to uninfected cohort. Age played a critical role in the type and frequency of symptoms after SARS-CoV-2 infection. Gastrointestinal symptoms were prominent.

Radiologic findings associated with SARS-CoV-2 infection have been well described since its emergence. However, long-term clinical and radiologic complications of pediatric SARS-CoV-2 infection are less defined, including radiologic findings in children following recovery. This study compares chest radiographic (CXR) and low-dose chest computed tomography (CT) findings in pediatric participants; a longitudinal cohort of children who have recovered from SARS-CoV-2 infection and uninfected controls. Eight hundred forty-six children (700 laboratory confirmed SARS-CoV-2-infected children and 146 uninfected controls) completed a radiologic exam at the baseline visit, which occurred 9.8 months (mean) post-infection. CXR (n=485) and CT (n=362) images were evaluated by three radiologists for known radiologic manifestations of COVID-19 including various patterns of opacities (ground glass, reticular, consolidation), nodules, perihilar thickening, effusions, and/or cystic changes. Comparisons were made using generalized estimating equations with cohort (infected vs. uninfected) as the predictor. Overall, the incidence of radiologic abnormalities detected at baseline was 32.1 https://smart.servier.com/ ), licensed under CC BY 4.0 ( https://creativecommons.org/licenses/by/4.0/ ).

Most pandemic-associated chilblains (PAC) resolve spontaneously, but a subset of patients develops persistent or recurrent disease. We analyzed peripheral cytokine profiles in 17 patients with prolonged PAC and identified elevated IFN-γ, CXCL10, CX3CL1, IL-16, CCL22, and S100A8. In contrast to the transient type I interferon response described in acute PAC, prolonged disease was characterized by a type II interferon-skewed inflammatory signature with T-cell activation and endothelial involvement. Frequent autoimmune comorbidities suggest baseline immune dysregulation contributing to chronicity. These findings highlight potential therapeutic targets, including JAK inhibition and IFN-γ-directed therapies.

In a subset of children and adolescents, SARS-CoV-2 infection induces a severe acute hyperinflammatory shock1 termed multisystem inflammatory syndrome in children (MIS-C) at four to eight weeks after infection. MIS-C is characterized by a specific T cell expansion2 and systemic hyperinflammation3. The pathogenesis of MIS-C remains largely unknown. Here we show that acute MIS-C is characterized by impaired reactivation of virus-reactive memory T cells, which depends on increased serum levels of the cytokine TGFβ resembling those that occur during severe COVID-19 (refs. 4,5). This functional impairment in T cell reactivity is accompanied by the presence of TGFβ-response signatures in T cells, B cells and monocytes along with reduced antigen-presentation capabilities of monocytes, and can be reversed by blocking TGFβ. Furthermore, T cell receptor repertoires of patients with MIS-C exhibit expansion of T cells expressing TCRVβ21.3, resembling Epstein-Barr virus (EBV)-reactive T cell clones capable of eliminating EBV-infected B cells. Additionally, serum TGFβ in patients with MIS-C can trigger EBV reactivation, which is reversible with TGFβ blockade. Clinically, the TGFβ-induced defect in T cell reactivity correlates with a higher EBV seroprevalence in patients with MIS-C compared with age-matched controls, along with the occurrence of EBV reactivation. Our findings establish a connection between SARS-CoV-2 infection and COVID-19 sequelae in children, in which impaired T cell cytotoxicity triggered by TGFβ overproduction leads to EBV reactivation and subsequent hyperinflammation.

BackgroundPECOS is an ongoing study aimed to characterize long-term outcomes following pediatric SARS-CoV-2 infection.MethodsThis is a cross-sectional analysis of infected and uninfected cohorts at baseline. Participants (0-21 years) with laboratory-confirmed SARS-CoV-2 infection were enrolled as infected. Uninfected were defined as individuals without history or laboratory evidence of SARS-CoV-2 infection. Outcome measures included demographics, medical history, review of symptoms, physical exam, cardiopulmonary evaluation and validated psychological and developmental surveys. Primary outcomes were cohort comparisons for abnormalities on all measures.Results654 participants (541 infected, 113 uninfected) completed baseline visits by June 30, 2023. Infected participants were more likely to report constitutional (OR: 2.24), HEENT (OR: 3.74); respiratory (OR: 2.41), or gastrointestinal (OR: 2.58) symptoms. Infected had worse scores in domains of Pain, Fatigue, Global Health, Physical and Cognitive functioning, Mobility and Sleep disturbances when compared to uninfected controls using Patient Reported Outcomes. Cardiopulmonary findings were similar among cohorts.ConclusionsThe first report of this ongoing longitudinal study demonstrates that infected participants were more likely to report symptoms compared to uninfected controls, which may affect performance and quality of life of these individuals. Longitudinal data will increase understanding of long-term effects of SARS-CoV-2 infection in children. ClinicalTrials.gov Identifier: NCT04830852ImpactThis study establishes a large, diverse, prospective, longitudinal, multi-center cohort of children with history of SARS-CoV-2 infection compared to an uninfected cohort to be followed for 3 years.Cross-sectional cohort analysis at study entry showed infected participants were more likely to report constitutional, respiratory, and GI symptoms compared to uninfected controls.Infected participants were more likely to have significantly worse parent-reported performance in 6 of 10 Patient Reported Outcome Measures domains.Continued study of this cohort will help identify clinical sequelae of COVID-19, characterize the immune response to SARS-CoV-2 infection, and identify potential genetic/immunologic factors associated with long-term outcomes.

OBJECTIVES:Patients with chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature/proteasome-associated autoinflammatory syndrome (CANDLE/PRAAS) respond to the janus kinase inhibitor 1/2 inhibition with baricitinib at exposures higher than in rheumatoid arthritis. Baricitinib dose reductions to minimise exposure triggered disease flares which we used to develop 'flare criteria'. METHODS:Of 10 patients with CANDLE/PRAAS treated with baricitinib in an open-label expanded-access programme, baricitinib doses were reduced 14 times in 9 patients between April 2014 and December 2019. Retrospective data analysis of daily diary scores and laboratory markers collected before and after the dose reductions were used to develop 'clinical' and 'subclinical' flare criteria. Disease flare rates were compared among patients with <25% and >25% dose reductions and during study visits when patients received recommended 'optimized' baricitinib doses (high-dose visits) versus lower than recommended baricitinib doses (low-dose visits) using two-sided χ2 tests. RESULTS:In the 9/10 patients with CANDLE with dose reduction, 7/14 (50%) times the dose was reduced resulted in a disease flare. All four dose reductions of >25% triggered a disease flare (p <0.05). Assessment of clinical and laboratory changes during disease flares allowed the development of disease flare criteria that were assessed during visits when patients received high or low doses of baricitinib. Disease flare criteria were reached during 43.14% of low-dose visits compared with 12.75% of high-dose visits (p <0.0001). Addition of an interferon score as an additional flare criterion increased the sensitivity to detect disease flares. CONCLUSION:We observed disease flares and rebound inflammation with baricitinib dose reductions and proposed flare criteria that can assist in monitoring disease activity and in designing clinical studies in CANDLE/PRAAS.

The antibody profile against autoantigens previously associated with autoimmune diseases and other human proteins in patients with COVID-19 or multisystem inflammatory syndrome in children (MIS-C) remains poorly defined. Here we show that 30% of adults with COVID-19 had autoantibodies against the lung antigen KCNRG, and 34% had antibodies to the SLE-associated Smith-D3 protein. Children with COVID-19 rarely had autoantibodies; one of 59 children had GAD65 autoantibodies associated with acute onset of insulin-dependent diabetes. While autoantibodies associated with SLE/Sjögren’s 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. Further testing of IgG and/or IgA antibodies against a subset of potential targets identified by published autoantigen array studies of MIS-C failed to detect autoantibodies against most (16/18) of these proteins in patients with MIS-C who had not received IVIG. However, Troponin C2 and KLHL12 autoantibodies were detected in 2 of 20 and 1 of 20 patients with MIS-C, respectively. Overall, these results suggest that IVIG therapy may be a confounding factor in autoantibody measurements in MIS-C and that antibodies against antigens associated with autoimmune diseases or other human proteins are uncommon in MIS-C.

Pediatric Coronavirus Disease 2019 (pCOVID-19) is rarely severe; however, a minority of children infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might develop multisystem inflammatory syndrome in children (MIS-C), with substantial morbidity. In this longitudinal multi-institutional study, we applied multi-omics (analysis of soluble biomarkers, proteomics, single-cell gene expression and immune repertoire analysis) to profile children with COVID-19 ( n = 110) and MIS-C ( n = 76), along with pediatric healthy controls (pHCs; n = 76). pCOVID-19 was characterized by robust type I interferon (IFN) responses, whereas prominent type II IFN-dependent and NF-κB-dependent signatures, matrisome activation and increased levels of circulating spike protein were detected in MIS-C, with no correlation with SARS-CoV-2 PCR status around the time of admission. Transient expansion of TRBV11-2 T cell clonotypes in MIS-C was associated with signatures of inflammation and T cell activation. The association of MIS-C with the combination of HLA A*02, B*35 and C*04 alleles suggests genetic susceptibility. MIS-C B cells showed higher mutation load than pCOVID-19 and pHC. These results identify distinct immunopathological signatures in pCOVID-19 and MIS-C that might help better define the pathophysiology of these disorders and guide therapy.

Objective Autoinflammatory type I interferonopathies, chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature/proteasome-associated autoinflammatory syndrome (CANDLE/PRAAS), stimulator of interferon genes (STING)-associated vasculopathy with onset in infancy (SAVI) and Aicardi-Goutières syndrome (AGS) are rare and clinically complex immunodysregulatory diseases. With emerging knowledge of genetic causes and targeted treatments, a Task Force was charged with the development of ‘points to consider’ to improve diagnosis, treatment and long-term monitoring of patients with these rare diseases. Methods Members of a Task Force consisting of rheumatologists, neurologists, an immunologist, geneticists, patient advocates and an allied healthcare professional formulated research questions for a systematic literature review. Then, based on literature, Delphi questionnaires and consensus methodology, ‘points to consider’ to guide patient management were developed. Results The Task Force devised consensus and evidence-based guidance of 4 overarching principles and 17 points to consider regarding the diagnosis, treatment and long-term monitoring of patients with the autoinflammatory interferonopathies, CANDLE/PRAAS, SAVI and AGS. Conclusion These points to consider represent state-of-the-art knowledge to guide diagnostic evaluation, treatment and management of patients with CANDLE/PRAAS, SAVI and AGS and aim to standardise and improve care, quality of life and disease outcomes.

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.

ObjectiveTo identify novel heterozygousLPIN2mutations in a patient with Majeed syndrome and characterize the pathomechanisms that lead to the development of sterile osteomyelitis.MethodsTargeted genetic analysis and functional studies assessing monocyte responses, macrophage differentiation, and osteoclastogenesis were conducted to compare the pathogenesis of Majeed syndrome to interleukin‐1 (IL‐1)–mediated diseases including neonatal‐onset multisystem inflammatory disease (NOMID) and deficiency of the IL‐1 receptor antagonist (DIRA).ResultsA 4‐year‐old girl of mixed ethnic background presented with sterile osteomyelitis and elevated acute‐phase reactants. She had a 17.8‐kb deletion on the maternalLPIN2allele and a splice site mutation, p.R517H, that variably spliced out exons 10 and 11 on the paternalLPIN2allele. The patient achieved long‐lasting remission receiving IL‐1 blockade with canakinumab. Compared to controls, monocytes and monocyte‐derived M1‐like macrophages from the patient with Majeed syndrome and those with NOMID or DIRA had elevated caspase 1 activity and IL‐1β secretion. In contrast, lipopolysaccharide‐stimulated, monocyte‐derived, M2‐like macrophages from the patient with Majeed syndrome released higher levels of osteoclastogenic mediators (IL‐8, IL‐6, tumor necrosis factor, CCL2, macrophage inflammatory protein 1α/β, CXCL8, and CXCL1) compared to NOMID patients and healthy controls. Accelerated osteoclastogenesis in the patient with Majeed syndrome was associated with higher NFATc1 levels, enhanced JNK/MAPK, and reduced Src kinase activation, and partially responded to JNK inhibition and IL‐1 (but not IL‐6) blockade.ConclusionWe report 2 novel compound heterozygous disease‐causing mutations inLPIN2in an American patient with Majeed syndrome.LPIN2deficiency drives differentiation of proinflammatory M2‐like macrophages and enhances intrinsic osteoclastogenesis. This provides a model for the pathogenesis of sterile osteomyelitis which differentiates Majeed syndrome from other IL‐1–mediated autoinflammatory diseases.

AbstractPediatric 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-κB 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.

BACKGROUND:Monogenic autoinflammatory diseases (AID) are caused by mutations in innate immune genes. The effects of these mutations on allergic inflammation are unknown. OBJECTIVES:We investigated allergic, immunological and clinical phenotypes in FMF (familial Mediterranean fever), CAPS (cryopyrin-associated periodic syndrome), TRAPS (tumour necrosis factor receptor-associated periodic syndrome), HIDS (hyper-IgD syndrome), PAPA (pyogenic arthritis, pyoderma gangrenosum and acne), DADA2 (deficiency of adenosine deaminase 2), HA20 (haploinsufficiency of A20), CANDLE (chronic atypical neutrophilic dermatosis, lipodystrophy, elevated temperature) and SAVI (STING-associated vasculopathy of infancy). METHODS:In this cross-sectional study, clinical data were assessed in 425 patients with AID using questionnaires and chart reviews. Comparator data were obtained from public databases. Peripheral blood mononuclear cells obtained from 55 patients were stimulated and CD4+ cytokine production assessed. RESULTS:Clinical laboratory features of Type 2 immunity were elevated in CAPS but reduced in most AID, particularly DADA2. Physician-diagnosed allergic diseases were prevalent in multiple AID, including CAPS and DADA2. T helper 2 (Th2) cells were expanded in CAPS, TRAPS and HIDS; Th9 cells were expanded in HA20. CONCLUSIONS:CAPS is characterised by an enhanced Type 2 signature, whereas FMF and CANDLE are associated with reduced Type 2 responses. DADA2 is associated with reduced Type 2 responses but a high rate of physician-diagnosed allergy. Therefore, NLRP3-driven autoinflammation may promote Type 2 immunity, whereas AID like DADA2 may manifest clinical phenotypes that masquerade as allergic disorders. Further investigations are needed to determine the contribution of autoinflammation to allergic clinical and immunological phenotypes, to improve the treatment of patients with AID.