Quantitative analysis of preclinical ocular microvascular changes in Multisystemic Inflammatory Syndrome in Children (MIS-C) detected by optical coherence tomography angiography.

OBJECTIVES: To evaluate the macular and optic nerve head (ONH) vascular density, foveal avascular zone area, and outer retina and choriocapillaris flow in Multisystemic Inflammatory Syndrome in Children (MIS-C) using optical coherence tomography angiography (OCTA). METHODS: Thirty-four eyes of 34 patients with MIS-C and 36 age and sex-matched healthy controls were investigated in this prospective, cross-sectional study. The superficial capillary plexus (SCP) and deep capillary plexus (DCP), ONH, FAZ parameters, the flow area of the outer retina, and choriocapillaris were evaluated using OCTA. RESULTS: All VD parameters in SCP were significantly lower in MIS-C patients. There was no significant difference between the groups in VD parameters of both DCP and ONH, as well as FAZ area and FAZ perimeter. However, foveal density (FD-300) was significantly decreased in the MIS-C group. (p = 0.024). The outer retina flow area at 1 mm, 2 mm, and 3 mm radius and CC flow area at 1 mm and 2 mm radius were significantly lower in the MIS-C group than in the control group. Although CC flow area at 3 mm radius was decreased in the MIS-C group compared to healthy controls, the difference was not statistically significant. CONCLUSIONS: We demonstrated a decreased vessel density in SCP, choriocapillaris flow area, and outer retinal flow area in MIS-C patients. Hence, we proposed that OCTA could reveal retinal and choroidal microvascular changes in MIS-C patients who were completely healthy before the diagnosis of MIS-C.

Anakinra treatment in multisystemic inflammatory syndrome in children (MIS-C) associated with COVID-19.

Objective: The study aimed to report the efficacy and safety of anakinra treatment in patients with the refractory multisystemic inflammatory syndrome in children (MIS-C). Methods: This is a cross-sectional retrospective study consisting of pediatric patients diagnosed with MIS-C who were treated with anakinra. Results: Among the 378 patients diagnosed with MIS-C, 82 patients (21.6%) who were treated with anakinra were included in the study. The median age of patients was 115 (6-214) months. The median duration of hospitalization was 15 (6-42) days. Sixty patients (73.1%) were admitted to the pediatric intensive care unit. Patients were treated with a median dose of 2.7 mg/kg/day anakinra concomitant with IVIG and steroids. Intravenous anakinra was applied to 12 patients while 70 patients received it subcutaneously. Twenty-eight patients required high dose (4-10 mg/kg/day) anakinra. The median day of anakinra initiation was 2 (1-14) days and the median duration of anakinra use was 7 (1-41) days. No injection site reactions were observed while elevated transaminase levels were detected in 13 patients. Seventy-three patients (89.1%) were discharged without any sequela or morbidity. Seven patients (1.8%) died. Abnormal echocardiographic findings continued in two patients (2.4%) (coronary artery dilatation in one, low ejection fraction in one) at discharge and became normal on the 2nd month. Conclusion: Based on the results of the study, anakinra was associated with clinical improvements and was safe for most patients with refractory MIS-C.

The Multifaceted Presentation of the Multisystem Inflammatory Syndrome in Children: Data from a Cluster Analysis.

BACKGROUND: The aim of this study was to evaluate the outcomes of patients with the multisystem inflammatory syndrome in children (MIS-C) according to phenotypes of disease and define the prognostic factors for the severe course. METHODS: This cross-sectional study included 293 patients with MIS-C from seven pediatric rheumatology centers. A two-step cluster analysis was performed to define the spectrum of disease and their outcomes were compared between each group. RESULTS: Four subgroups were identified as follows: cluster I, predominantly Kawasaki-like features (n = 100); cluster II, predominantly MAS-like features (n = 34); cluster III, predominantly LV dysfunction (n = 47); cluster IV, other presentations (n = 112). The duration of fever was longer in cluster II and the length of hospitalization was longer in both clusters II and III. Laboratory findings revealed lower lymphocyte and platelet counts and higher acute phase reactants (APRs) in cluster II, while patients in cluster IV showed less inflammation with lower APRs. The resolution of abnormal laboratory findings was longer in clusters II and III, while it was shortest in cluster IV. Seven patients died. Among them, four belonged to cluster II, while three were labeled as cluster III. Patients with severe course had higher levels of neutrophil-lymphocyte ratio, mean platelet volume, procalcitonin, ferritin, interleukin-6, fibrinogen, D-Dimer, BNP, and troponin-I, and lower levels of lymphocyte and platelet counts. CONCLUSION: As shown, MIS-C is not a single disease presenting with various clinical features and outcomes. Understanding the disease spectrum will provide individualized management.

CXCL10/IP10 as a Biomarker Linking Multisystem Inflammatory Syndrome and Left Ventricular Dysfunction in Children with SARS-CoV-2.

BACKGROUND: To investigate the diagnostic accuracy of CXCL10/IP10 for left ventricular (LV) dysfunction in multisystemic inflammatory syndrome (MIS-C). METHODS: This cross-sectional, longitudinal study included 36 patients with MIS-C. Patients were classified as follows: (1) patients presenting with Kawasaki-like features (group I = 11); (2) patients presenting with LV systolic dysfunction (group II = 9); and (3) other presentations (group III = 3). CXCL10/IP10 levels were measured upon admission and on days 3 and 7 of treatment. RESULTS: Twenty patients were male and 16 were female. The median age of patients at diagnosis was 7.5 (1.5-17) years. All patients had a fever lasting for a median of 4 (2-7) days. Ten patients had LV systolic dysfunction. The duration of hospitalization was longer in group II. Lymphocyte and platelet counts were lower, whereas NT-pro-BNP, troponin-I, D-dimer, and CXCL10/IP10 levels were higher in group II. Baseline levels of CXCL10/IP10 were weakly negatively correlated with ejection fraction (r = -0.387, p = 0.022). Receiver operator characteristic curve analysis yielded a cutoff value of CXCL10/IP10 to discriminate patients with LV dysfunction was 1839 pg/mL with sensitivity 88% and specificity 68% (Area under curve (AUC) = 0.827, 95% CI 0.682-0.972, p = 0.003). CONCLUSION: Having a good correlation with cardiac function, CXCL10/IP10 is a potential biomarker to predict LV dysfunction in MIS-C patients.

Exploring the attitudes, concerns, and knowledge regarding COVID-19 vaccine by the parents of children with rheumatic disease: Cross-sectional online survey.

BACKGROUND: Vaccination programs are effective strategies in preventing infectious diseases and controlling epidemics. Vaccination against SARS-CoV-2 in children has not yet been approved globally, and it is unclear what attitude families will take when it is approved in children. We aimed to investigate the underlying causes of vaccine acceptance, hesitation, and refusal, as well as concerns about the acceptability of the COVID-19 vaccine by parents of children with rheumatic diseases. METHODS: Parents of children followed up with a diagnosis of rheumatic disease in the pediatric rheumatology outpatient clinic of a university hospital were included in the study. We applied a closed web-based online survey conducted cross-sectionally and sent to the participants via mobile smartphones. RESULTS: For fathers, mothers, and their children, acceptance rates for a COVID-19 vaccine were 64.2%, 57.7%, and 41.8%, respectively. In the multivariate analysis, factors affecting parents' acceptance of vaccines for their children were as follows: "Receiving antirheumatic medications regularly (AOR 5.40, 95% CI 1.10-26.33, p = 0.03), the previous history of getting special recommended vaccines (AOR 4.12, 95% CI 1.12-27.85, p = 0.03), relying on vaccines for ending pandemic (AOR 8.84, 95% CI 2.80-27.85, p = 0.001), complying with the pandemic measures entirely (AOR 5.24, 95% CI 1.46-18.74, p = 0.01)". The two most common reasons for vaccine rejection were fear of the side effects of the vaccine and its possible interaction with rheumatic drugs used by children. CONCLUSION: According to our survey, parents were more likely to accept a COVID-19 vaccine for themselves than their children. The success of COVID-19 vaccination programs sources highly on people's willingness to accept the vaccine. It is crucial to vaccinate children for achieving herd immunity and in terms of avoiding vaccine hesitancy. Larger data examining the causes of concerns in parents of both healthy children and children with chronic diseases should be delineated.

The clinical course of SARS-CoV-2 infection among children with rheumatic disease under biologic therapy: a retrospective and multicenter study.

The effects of biological disease-modifying antirheumatic drugs (bDMARDs) in the clinical course of COVID-19 on children with underlying rheumatologic diseases have not been fully demonstrated. To evaluate the course of COVID-19 infection in patients with rheumatic disease receiving bDMARD treatment. This was a retrospective, multicenter study conducted in pediatric patients infected by SARS-CoV-2 and under bDMARDs therapy. The study population consisted of 113 patients (72 female/41 male). The mean age of the patients was 12.87 ± 4.69 years. The primary diagnosis of the cohort was as follows: 63 juvenile idiopathic arthritis, 35 systemic autoinflammatory diseases, 10 vasculitides, and five cases of connective tissue diseases. The mean duration of the primary disease was 4.62 ± 3.65 years. A total of 19 patients had additional comorbid diseases. Thirty-five patients were treated with canakinumab, 25 with adalimumab, 18 with etanercept, 10 with infliximab, nine with tocilizumab, six with rituximab, four with anakinra, three with tofacitinib, and one with abatacept. The median exposure time of the biological drug was 13.5 months. Seventy-one patients had symptomatic COVID-19, while 42 were asymptomatic. Twenty-four patients required hospitalization. Five patients presented with MIS-C. The hospitalized patients were younger and had a shorter duration of rheumatic disease compared to ambulatory patients, although the difference was not statistically significant. Steroid usage, presence of fever, and dyspnea were more common among the hospitalized patients. A worsening in the course of both COVID-19 and current disease was not noticed under bDMARDs, however, to end with a strong conclusion multicentric international studies are required.

Differences and similarities of multisystem inflammatory syndrome in children, Kawasaki disease and macrophage activating syndrome due to systemic juvenile idiopathic arthritis: a comparative study.

To compare the clinical and laboratory findings of multisystem inflammatory syndrome in children (MIS-C), patients with Kawasaki disease (KD) and with macrophage activating syndrome due to systemic juvenile idiopathic arthritis (sJIA-MAS) on real-life data. Patients diagnosed with MIS-C, KD, and sJIA-MAS from 12 different centers in Turkey who were followed for at least 6 months were included in the study. Demographic, clinical, and laboratory findings of all patients were analyzed. A total of 154 MIS-C, 59 KD, and 31 sJIA-MAS patients were included. The median age of patients with MIS-C were higher than those with KD while lower than those with sJIA-MAS (8.2, 3, 12 years, respectively). Myalgia (39.6%), cardiac (50.6%), gastrointestinal (72.7%), and neurological (22.1%) involvements were more common in patients with MIS-C compared to others. MIS-C patients had lower levels of lymphocyte (950 vs 1700 cells/µl) and thrombocyte (173,000 vs 355,000 cells/µl) counts and higher pro-BNP (1108 vs 55 pg/ml) levels than KD. Ferritin levels were higher in patients with MIS-C compared to patients with KD while they were lower than patients with sJIA-MAS (440, 170, 10,442 ng/ml, respectively). Patients with MIS-C had a shorter duration of hospitalization than sJIA-MAS (p = 0.02) while they required intensive care unit admission more frequently (55 vs 8 patients, p < 0.001). The median MAS/sJIA score of MIS-C patients was - 1.64 (- 5.23 to 9.68) and the median MAS/sJIA score of sJIA-MAS patients was -2.81 ([- 3.79] to [- 1.27]). MIS-C patients displayed certain differences in clinical and laboratory features when compared to KD and sJIA-MAS. Definition of the differences and similarities between MIS-C and the other intense inflammatory syndromes of childhood such as KD and MAS will help the clinicians while making timely diagnosis.

Multisystemic inflammatory syndrome in children associated with COVID-19: a single center experience in Turkey.

OBJECTIVE: Multisystem inflammatory syndrome in children (MIS-C) associated with the coronavirus disease 2019 (COVID-19) is a new concern emerging as a severe presentation of COVID-19 in children. We aimed to describe the characteristics and short-term outcomes of children diagnosed with MIS-C. MATERIAL AND METHODS: A retrospective study was conducted on 24 patients who were diagnosed with MIS-C between June 1, 2020 and December 1, 2020. A total of 24 (14 male and 10 female) patients were included in the study. RESULTS: The median age at the diagnosis was 111 (10-180) months. A total of 17 patients had a history of contact with a patient with COVID-19. Among the 24 patients, the most common findings were gastrointestinal involvement (n=20), followed by conjunctivitis (n=12), erythematous rash (n=11), and oral changes (n=10). Cardiovascular involvement was detected in 12 patients, of whom six had systolic dysfunction, four had mild coronary artery involvement, four had pericardial effusion, and three had mitral insufficiency. All patients received intravenous immunoglobulin, and 14 patients were treated with methylprednisolone in addition. Anti-interleukin-1 was given to two patients. The median duration of hospitalization was 8 (5-15) days. A total of 23 patients were discharged and evaluated on the median of 68.5 (52-140) days after discharge. The remaining one patient with dilated cardiomyopathy died after 2 months in the intensive care unit. CONCLUSION: Increasing the knowledge on MIS-C will provide clinicians with information on early recognition, evaluation, and management of these patients.

Does immunosuppressive treatment entail an additional risk for children with rheumatic diseases? A survey-based study in the era of COVID-19.

The aim of the research was to further extend current knowledge of whether severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) disease 2019 (COVID-19) entails a risk for children with various rheumatic diseases under immunosuppressive treatment. Telephone survey was administered by conducting interviews with the parents from May 1, 2020 to May 20, 2020. A message containing a link to the actual questionnaire was sent to their phones simultaneously. The medical records of the patients were reviewed for gathering information about demographic data, clinical follow-up, and treatments. Patients who were followed-up under immunosuppressive treatment (n = 439) were attempted to be contacted. The diagnostic distribution of patients (n = 414) eligible for the study was as follows: juvenile idiopathic arthritis (JIA) (n = 243, 58.7%), autoinflammatory diseases (n = 109, 26.3%), connective tissue diseases (n = 51, 12.3%), and vasculitis (n = 11, 2.7%). In the entire cohort, the mean age was 12 ± 4.7 years, and 54.1% (n = 224) were female. Nine patients have attended the hospital for COVID-19 evaluation, 6 of whom were in close contact with confirmed cases. One patient with seronegative polyarticular JIA, previously prescribed methotrexate and receiving leflunomide during pandemic was identified to be diagnosed with COVID-19. None, including the confirmed case, had any severe symptoms. More than half of the patients with household exposure did not require hospitalization as they were asymptomatic. Although circumstances such as compliance in social distancing policy, transmission patterns, attitude following contact may have influenced the results, immunosuppressive treatment does not seem to pose an additional risk in terms of COVID-19.