Inflammatory responses in SARS-CoV-2 associated Multisystem Inflammatory Syndrome and Kawasaki Disease in children: An observational study.

Multisystem Inflammatory Syndrome in Children (MIS-C) is a severe inflammatory disease in children related to SARS-CoV-2 with multisystem involvement including marked cardiac dysfunction and clinical symptoms that can resemble Kawasaki Disease (KD). We hypothesized that MIS-C and KD might have commonalities as well as unique inflammatory responses and studied these responses in both diseases. In total, fourteen children with MIS-C (n=8) and KD (n=6) were included in the period of March-June 2020. Clinical and routine blood parameters, cardiac follow-up, SARS-CoV-2-specific antibodies and CD4+ T-cell responses, and cytokine-profiles were determined in both groups. In contrast to KD patients, all MIS-C patients had positive Spike protein-specific CD3+CD4+ T-cell responses. MIS-C and KD patients displayed marked hyper-inflammation with high expression of serum cytokines, including the drug-targetable interleukin (IL)-6 and IFN-γ associated chemokines CXCL9, 10 and 11, which decreased at follow-up. No statistical differences were observed between groups. Clinical outcomes were all favourable without cardiac sequelae at 6 months follow-up. In conclusion, MIS-C and KD-patients both displayed cytokine-associated hyper-inflammation with several high levels of drug-targetable cytokines.

Uniting Global Efforts on Pediatric Long-COVID: Results of the International Post- COVID Condition in Children Collaboration (IP4C)

RATIONALE4,4-44,4% of children suffer from post-COVID syndrome, commonly known as long- COVID, after an acute SARS-CoV-2 infection. However, an uniform clinical definition, and guidelines to diagnose or treat children suspected of long-COVID are lacking. Multiple careprograms have been initiated worldwide. In this study, we aimed to assess the currently available pediatric international long-COVID care programs and explore the characteristics of their patient cohorts.METHODSWe established an international network (IP4C) and performed a crosssectional analysis from aggregated data collected by its members using a survey. Topics included: the used definition for long-covid in children, the organization of pediatric long-COVID clinics and long-COVID patients characteristics. Descriptive analysis of the aggregated data was used to summarize and compare each of these categories across countries. RESULTSWe included data concerning organization of care from 17 cohorts based in 13 different countries. A wide range of definitions for long COVID was used, which differed mostly in duration of symptoms and the necessity of microbiologically proven SARS-COV-2 infection. 66,6-100% of patients in the long- COVID cohorts suffered from complaints for more than twelve weeks, and 49,5-97,3% of patients had a positive RT-PCR or serology for SARS-CoV-2. Most long-COVID care programs consisted of real-life visits with multidisciplinary teams, consisting of general pediatricians, pediatric lung specialists, cardiologists and infectiologist, a physiotherapist and psychologist. The type of investigations performed at the long-COVID clinics ranged from assessment of medical history (100%) and standardized questionnaires (91%) to in depth evaluation of organ functioning (e.g. spirometry performed in 0-100% of patients). Aggregated data of 431 long-COVID patients from 11 dedicated long-COVID care programs were analyzed. Mean age of patients ranged from 6,5-16,4 years old. Girls were overrepresented in most cohorts (20-65%). 28-81,8% of patient had a positive medical history, most commonly atopic syndrome, asthma and prematurity. Most patients (90- 100%) suffered from asymptomatic or mild acute COVID-19. Frequent long-COVID symptoms were fatigue, headaches, concentration difficulties, dyspnea and sleep disturbances. 5-37% of patients had severe limitations in daily life. CONCLUSIONSThis is the first study to describe the organization of pediatric long-COVID care. It demonstrates that pediatric long-COVID is recognized worldwide as a multisystemic disease, but its definition and care programs for pediatric long- COVID patients differ between cohorts. A clear definition of pediatric long-COVID is needed to improve international scientific collaboration and patient care. Our international network will facilitate further collaboration in investigation pathophysiology and therapeutic interventions in order to provide evidence based medical care for these patients.