Neurological manifestations of Kawasaki disease and multisystem inflammatory syndrome in children associated with COVID-19: A comparison of two different clinical entities.

Kawasaki disease (KD) is one of the most frequent idiopathic vasculitis in children, affecting medium- and small-sized vessels. Multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19 has recently emerged as a new systemic hyperinflammatory condition affecting children some weeks after an acute COVID-19 infection. KD and MIS-C share different aspects and differ in many others: patients affected by MIS-C are usually older, with prominent gastrointestinal manifestations, diffuse adenopathy, extensive conjunctivitis, myocardial damage, leukopenia, and thrombocytopenia at the laboratory exams. Both conditions can present neurological complications. The aim of this manuscript is to provide a narrative review of neurological involvement in KD and MIS-C. A comprehensive review literature has been performed, and the main clinical features have been analyzed, contributing to neurological differential diagnosis.

Neurological manifestations of Kawasaki disease and multisystem inflammatory syndrome in children associated with COVID-19: A comparison of two different clinical entities

Kawasaki disease (KD) is one of the most frequent idiopathic vasculitis in children, affecting medium- and small-sized vessels. Multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19 has recently emerged as a new systemic hyperinflammatory condition affecting children some weeks after an acute COVID-19 infection. KD and MIS-C share different aspects and differ in many others: patients affected by MIS-C are usually older, with prominent gastrointestinal manifestations, diffuse adenopathy, extensive conjunctivitis, myocardial damage, leukopenia, and thrombocytopenia at the laboratory exams. Both conditions can present neurological complications. The aim of this manuscript is to provide a narrative review of neurological involvement in KD and MIS-C. A comprehensive review literature has been performed, and the main clinical features have been analyzed, contributing to neurological differential diagnosis

Acute cardiac compromission in patients with MIS-C

Background and Aim: Multisystem inflammatory syndrome in chil-dren (MIS-C) is a late manifestation of SARS-CoV-2 infection. Cardiac involvement is common and presents as ventricular dys-function, shock, and coronary anomalies. The aim of the study is evaluate the influence of cardiac disfunction on clinical presen-tations and outcomes in a single center. Method(s): A retrospective study on patients diagnosed with MIS-C and referred to Buzzi Children's Hospital in Milan from November 2020 to February 2021. Patients were treated with intravenous immunoglobulins, corticosteroids and anti-throm-botic prophylaxis, in respect to our approved multidisciplinary protocol. According to the admission cardiac left ventricular ejec-tion fraction (LVEF), the patients were divided into group A (LVEF lt;45%) and group B (LVEF >=45%). Result(s): We collected 32 consecutive patients. Group A included 10 patients (9M/1F, aged 13 years [IQR 5-15]), and group B included 22 patients (15M/7M, aged 9 years [IQR 7-13]). At the presentation, significant differences were observed among shock (group A 6/10 vs group B 2/22, plt;0.01), gastrointestinal involvement (9/10 vs 11/22, p = 0.04) and duration of fever (5.3 vs 6.9 days, p = 0.02). All patients in group A required inten-sive care hospitalization (10/10 vs 12/22, p = 0.01). Interestingly, despite good cardiac function, two patients in group B presented with shock, probably due to vasoplegic/distributive cardiocircula-tory impairment secondary to the inflammatory state. Among biochemistry parameters, leukocytes, neutrophils, and CRP were significantly worse in group A (p = 0.001, p = 0.001 and p = 0.008, respectively). Pathological level of troponin T and NTproBNP were detected in all patients in group A and also in 33% and 77% of group B;with statistically significant higher median values in group A (Troponin T 72 [40-243] ng/L vs 22 [8-49] ng/L, p = 0.01;NTproBNP 14825 [11340-17810] ng/L vs 5921 [1114-11243] ng/L, p = 0.01). In group A, mitral regurgitation was more frequent (plt;0.01) and one patient had transient left main coronary dilation (Boston z-score +2.39). At the discharge, cardiac function normalized in all patients. Total length of hospital stay and cardiac recovery time were not statistically different between groups. Conclusion(s): If correctly diagnosed and early treated, all the MIS-C patients completely recovered, regardless of the initial cardiac involvement.

CHARACTERIZATION of HIV and SARS-CoV-2 COINFECTION: ROLE of IL-10

Background: Interaction between HIV and SARS-CoV-2 infection has not yet been fully characterized. To this purpose, an in-vitro HIV/SARS-CoV-2 coinfection assay was set up. Furthermore, the results obtained in the in-vitro model were verified in a cohort of HIV/SARS-CoV-2 coinfected young individuals. Methods: We designed an in-vitro SARS-CoV-2/HIV coinfection. We challenged PBMCs derived from 10 healthy volunteers with 1 ng/1×106 cells of HIV-1BaL and subsequently co-cultured them with a human lung epithelial cell line (CaLu3) infected with SARS-CoV-2 at 0.015 MOI. At 96 hours post HIV-1 infection, both PBMCs and CaLu3 cells were harvested for mRNA expression and proteomic analysis. Furthermore, we enrolled 85 ART-treated HIV-vertically transmitted patients (mean age 22.4 years) followed at the Unit of Pediatric Infectious Diseases, Sacco Hospital in Milan, Italy. Real-time PCR was performed to detect SARS-CoV-2 and plasma samples were tested for anti-SARS-CoV-2-specific IgG (Euroimmun Kit). The subjects who contracted SARS-CoV-2 infection (H+/S+) were compared to the HIV-positive, SARS-CoV-2 negative ones (H+/S-) and to a cohort of SARS-CoV-2 positive, HIV-negative age-matched patients (H-/S+, mean age 22.8 years). We evaluated mRNA expression of factors involved in the anti-viral immune response on PBMCs upon stimulation with SARS-CoV-2 antigens (Quantigene Plex assay) and secreted cytokines/chemokines on plasma (Multiplex Cytokine Array). Results: We observed a significant reduction of SARS-CoV-2 replication on CaLu3 cells when exposed to HIV-pre-infected PBMCs in-vitro. IL-10 expression and production were significantly higher in the coinfected condition, in both CaLu3 cells and PBMCs. The upregulation of IL-10 was associated to higher expression levels of STAT3. In the HIV-vertically transmitted cohort, 4 out of 85 subjects contracted SARS-CoV-2 infection (H+/S+). All H+/S+ patients were asymptomatic. Similarly to the data obtained in-vitro, a significant increase in both expression and production of IL-10 emerged in comparison to H+/S-and H-/S+. Conclusion: In-vitro, a dampening in SARS-CoV-2 replication, along with a higher IL-10 mRNA expression and production, have been observed in the HIV/SARS-CoV-2 coinfected condition. Presumably, IL-10 exerted its activity through the STAT3 pathway. These results were confirmed in HIV/SARS-CoV-2 coinfected subjects in which an upregulation of IL-10 was observed. Our data might be useful defining HIV/SARS-CoV-2 coinfected young individuals pathogenesis.

Long-term cardiac outcome in patients with multisystem inflammatory syndrome in children (MIS-C)

Introduction: Multisystem Inflammatory Syndrome in children (MISC) was initially described during the first phase of COVID-19 pandemic as a severe clinical condition with systemic inflammation and multi-organ involvement. Many patients show features of Kawasaki Disease. Cardiac involvement, from myocarditis to coronary abnormalities, is a key feature of the syndrome, but there are still little data concerning the long-term outcome in these patients. Objectives: The aim of our study was to evaluate long-term cardiac outcome in patients diagnosed with MIS-C during the first phase of COVID-19 pandemic in Italy. Methods: We previously published the results of the Italian multicenter survey of MIS-C, launched by the Rheumatology Study Group of Italian Pediatric Society during the first wave of COVID-19 pandemic. For each patient who received MIS-C diagnosis, we collected demographic, clinical, laboratory data, imaging findings, and treatment information in an online anonymized database (RedCAP). Data collection included all the admission period and all follow/up visits. For the purpose of this study, we analyzed all patients with at least 3months of follow/up mainly focusing on heart involvement. Results: Fifty-three patients who received MIS-C diagnosis between February 1st and May 31st 2020 were included in our study. The median age at diagnosis was 7 years (IQR 4,5-11). Forty-one patients showed cardiac involvement during the course of the disease. Treatment with IVIG was reported in 66% of patients at diagnosis and glucocorticoids in 56,6%. Four patients received treatment with IL-1 receptor antagonist (anakinra) and one with hydroxychloroquine. Use of vasoactive agents was reported in 20,8% of patients. No case of death was reported in our population. Data on cardiac outcome were available for 33 patients after a median time of follow-up of 6 months (IQR 7.2- 4.08). Twenty-eight out of 33 patients presented a cardiac involvement during hospitalization for MIS-C: 17 had myocarditis, 5 had pericarditis, 3 coronary artery abnormalities, 8 heart failure, 9 valvular insufficiency, 11 shock or hypotension. For each patient cardiac outcome was assessed by heart ultrasonography. At the end of our follow-up period only four patients still had heart abnormalities: all of them presented mild valvular insufficiency and 2 patients still had ultrasonographic signs of hypokinesia. None of them was on medication. Conclusion: MIS-C is an emerging inflammatory condition that spreads among the pediatric population in parallel to SARS-CoV2 pandemic. The disease is frequently complicated by cardiological involvement but, differently to Kawasaki disease, myocarditis and shock are the most common complications. As we reported in our previous study, short-term outcome is usually good in children with MIS- C and heart involvement. With this study we also provide a long-term cardiac follow-up and we showed that only a minority of patients with previous cardiac involvement presented minor heart abnormalities. Furthermore, no patients developed new heart disease during follow-up.

Non-thyroidal illness syndrome and SARS-CoV-2-associated multisystem inflammatory syndrome in children.

PURPOSE: COVID-19 disease may result in a severe multisystem inflammatory syndrome in children (MIS-C), which in turn may alter thyroid function (TF). We assessed TF in MIS-C, evaluating its impact on disease severity. METHODS: We retrospectively considered children admitted with MIS-C to a single pediatric hospital in Milan (November 2019-January 2021). Non-thyroidal illness syndrome (NTIS) was defined as any abnormality in TF tests (FT3, FT4, TSH) in the presence of critical illness and absence of a pre-existing hormonal abnormality. We devised a disease severity score by combining severity scores for each organ involved. Glucose and lipid profiles were also considered. A principal component analysis (PCA) was performed, to characterize the mutual association patterns between TF and disease severity. RESULTS: Of 26 (19 M/7F) patients, median age 10.7 (IQR 5.8-13.3) years, 23 (88.4%) presented with NTIS. A low FT3 level was noted in 15/23 (65.3%), while the other subjects had varying combinations of hormone abnormalities (8/23, 34.7%). Mutually correlated variables related to organ damage and inflammation were represented in the first dimension (PC1) of the PCA. FT3, FT4 and total cholesterol were positively correlated and characterized the second axis (PC2). The third axis (PC3) was characterized by the association of triglycerides, TyG index and HDL cholesterol. TF appeared to be related to lipemic and peripheral insulin resistance profiles. A possible association between catabolic components and severity score was also noted. CONCLUSIONS: A low FT3 level is common among MIS-C. TF may be useful to define the impact of MIS-C on children's health and help delineate long term follow-up management and prognosis.

The impact of COVID-19 on type 1 diabetes and ketoacidosis incidence in pediatric age

Introduction: The COVID-19 pandemic has had a significant impact the region of Lombardy, causing more than 16,000 deaths. Fortunately, children, including those with type 1 diabetes (T1DM), were only slightly affected. It is debated as to whether COVID-19 infection may increase the incidence of T1DM in children and whether the conditions during and following lockdown may have led to an increased number of diabetic ketoacidosis (DKA) at onset. Objectives: To assess the impact of COVID-19 on T1DM and DKA incidence. Methods: A network of 11 regional pediatric T1DM clinics collected data in children of ages 0-18 years during the time period between March 1-May 31 in the years 2017-2020. Given that all T1DM children are hospitalized at onset and rarely escape this network of regional clinics, it was possible to define a minimal incidence of T1DM without a secondary source, Results: Number of onsets was stable (2017: 206 cases/year, 2018: 199 cases/year, 2019: 233 cases/year, 2020: 105 cases/5 months). DKA at onset varied between 36 and 40% of new onsets. By comparing the cases in the period March 1-May 302,017-2020, an increase in DKA incidence at onset from 11 to 24/1.7 million (p < 003) was found. The minimum regional incidence of T1DM showed a slight increase from 11.7 to 13.7 cases/100000 (0-18 years of age), comparable to previously collected regional data from 2008. Conclusion: These data suggest that COVID-19 infection in Lombardy was not correlated with an in increased T1DM incidence. Furthermore, the minimum regional incidence of TIDM in ages 0-18 years seems stable in the last 10 years. However, a significant increase in the number of DKA at onset was found, many of which were reported to be severe and probably consequent to delayed hospital presentation due to lockdown restrictions and fear of infection, emphasizing the indirect deleterious impact of pandemics on potentially lifethreatening conditions such as DKA.

Pediatric systemic multi-inflammatory diseases in Italy during SARS-COV-2 epidemic: From Kawasaki disease to Kawacovid

Introduction: Italy was affected by the SARS-CoV-2 epidemic after its outbreak in China. With a 4-weeks delay after the peak in adults, we observed an abnormal number of patients with characteristics of a multi-inflammatory disease and similarities with Kawasaki Disease (KD). Others reported similar cases, defined PIMS-TS or MIS-C.1,2 Objectives: To better characterize clinical features and treatment response of PIMS-TS and to explore its relationship with KD. Methods: We conducted an observational, retrospective, multicenter study. On April 24th-2020 the Rheumatology Study Group of the Italian Pediatric Society launched a national online survey, to enroll patients diagnosed with KD or with a multisystem inflammatory disease between February 1st 2020 and May 31st. The population was then divided into two different groups: 1) Classical and incomplete KD, named Kawasaki Disease Group (KDG);2) KD-like multi-inflammatory syndrome, named KawaCOVID (KCG). An expert panel of pediatric rheumatologists re-analyzed every single patient to ensure appropriate classification. Data were collected with an online database. Results: 149 cases were studied, 96 with KDG and 53 with KCG. The two population significantly differed for clinical characteristics (see table 1). Lymphopenia, higher CRP levels, elevated Ferritin and Troponin-T characterized KCG such as lower WBC and platelets (all p values<0,05). KDG received more frequently immunoglobulins (IVIG) and acetylsalicylic acid (ASA) (81,3% vs 66%;p=0.04 and 71,9% vs 43,4%;p=0.001 respectively) as KCG more often received glucocorticoids (56,6% vs 14,6%;p<0.0001). SARS-CoV-2 assay more often resulted positive in KCG than in KDG (75,5% vs 20%;p<0.0001). Short-term follow data on KCG showed minor complications while on KDG a majority of patients had persistence of CAA. Comparing KDG with a KD-Historical Italian cohort (598 patients), no statistical difference was found in terms of clinical manifestations and laboratory data between the two groups Conclusion: Our study would suggest that SARS-CoV-2 infection might determine two distinct inflammatory diseases in children: KD, possibly triggered by SARS-CoV-2, and PIMS-TS. Older age at onset and clinical peculiarities, like the occurrence of myocarditis, characterize this multiinflammatory syndrome. Our patients had an optimal response to treatments and a good outcome, with few complications and no deaths.

SARS-COV-2: Its implications in the paediatric population

By the end of December 2019 there was an outbreak of polmonitis of a new coronavirus named SARS-CoV-2. Until now there have been 76,727 cases, 2,247 deaths and 18,562 healed patients in China and less than 1,200 cases in the rest of the world. Few data are available regarding the epidemiology and the clinical manifestations in the paediatric population, nonetheless the virus seems to be affecting this population way less severely than the adults. This data may be due to an understatement of children's involvement, since they seem to have very scarce symptoms. The question that arises is: Can those mildly symptomatic or asymptomatic paediatric cases infect others therefore enhancing the virus transmission?.

Vaginal delivery in SARS-CoV-2-infected pregnant women in Northern Italy: a retrospective analysis.

OBJECTIVE: To report mode of delivery and immediate neonatal outcome in women infected with COVID-19. DESIGN: Retrospective study. SETTING: Twelve hospitals in northern Italy. PARTICIPANTS: Pregnant women with COVID-19-confirmed infection who delivered. EXPOSURE: COVID 19 infection in pregnancy. METHODS: SARS-CoV-2-infected women who were admitted and delivered from 1 to 20 March 2020 were eligible. Data were collected from the clinical records using a standardised questionnaire on maternal general characteristics, any medical or obstetric co-morbidity, course of pregnancy, clinical signs and symptoms, treatment of COVID 19 infection, mode of delivery, neonatal data and breastfeeding. MAIN OUTCOME AND MEASURES: Data on mode of delivery and neonatal outcome. RESULTS: In all, 42 women with COVID-19 delivered at the participating centres; 24 (57.1%, 95% CI 41.0-72.3) delivered vaginally. An elective caesarean section was performed in 18/42 (42.9%, 95% CI 27.7-59.0) cases: in eight cases the indication was unrelated to COVID-19 infection. Pneumonia was diagnosed in 19/42 (45.2%, 95% CI 29.8-61.3) cases: of these, 7/19 (36.8%, 95% CI 16.3-61.6) required oxygen support and 4/19 (21.1%, 95% CI 6.1-45.6) were admitted to a critical care unit. Two women with COVID-19 breastfed without a mask because infection was diagnosed in the postpartum period: their newborns tested positive for SARS-Cov-2 infection. In one case, a newborn had a positive test after a vaginal operative delivery. CONCLUSIONS: Although postpartum infection cannot be excluded with 100% certainty, these findings suggest that vaginal delivery is associated with a low risk of intrapartum SARS-Cov-2 transmission to the newborn. TWEETABLE ABSTRACT: This study suggests that vaginal delivery may be associated with a low risk of intrapartum SARS-Cov-2 transmission to the newborn.