Autoimmune Polyendocrinopathy in a Pediatric Patient Presenting With Multisystem Inflammatory Syndrome in Children (MIS-C).

Multisystem inflammatory syndrome (MIS) is a well-known potential sequela of COVID-19 infection. Though prevalence is higher in certain populations, this syndrome is a rare occurrence in children. Beyond MIS, there has been increasing research into COVID infection and the subsequent onset of autoimmune conditions, such as diabetes. However, evidence of a poly-endocrinopathy developing after COVID infection is lacking, and evidence within the pediatric population is virtually nonexistent. In this case, we present the evolution of an autoimmune polyglandular syndrome (APS) type 2 phenotype, consisting of type 1 diabetes, Graves' disease, and adrenal insufficiency, after diagnosis of multisystem inflammatory syndrome of children (MIS-C) in a pediatric patient.  A 15-year-old biracial female without significant past medical history tested positive for COVID-19 and two weeks later presented with respiratory symptoms and other systemic signs. She was admitted for further evaluation and was found to have elevated inflammatory markers, EKG (electrocardiogram) abnormalities, and lab evidence of organ damage. The patient was diagnosed with MIS-C, and treatment was initiated with eventual discharge. One year after this initial visit, the patient returned to the hospital due to weight loss, difficulty breathing, polyuria, polydipsia, nausea, vomiting, and fatigue. A steroid course for MIS-C treatment had been completed three months prior. Exam and lab results confirmed diabetic ketoacidosis (DKA), and the patient was diagnosed with new-onset type 1 diabetes. Further testing determined that she was glutamic acid decarboxylase 65 (GAD-65) positive. DKA was managed in the hospital, and the patient was subsequently discharged with an insulin regimen and endocrine follow-up. A couple of months later, the patient returned to the emergency department (ED) due to two weeks of dyspnea on exertion and dizziness. Since her previous admission for DKA, the patient had contracted COVID-19 again and recovered from her respiratory symptoms. Physical exam and labs were grossly unremarkable; however, the patient had EKG abnormalities and an episode of severe bradycardia, prompting hospitalization. Thyroid workup revealed thyrotoxicosis due to Graves' disease. Due to intermittent hypotension, adrenal labs were obtained. She was found to have adrenal insufficiency as well, with a positive 21-hydroxylase antibody. Throughout these hospitalizations, the patient suffered from skin and hair changes as well, ultimately requiring dermatological intervention.

Multisystem inflammatory syndrome in children associated with COVID-19 presenting as cervical inflammation.

AIM: The major clinical manifestations multisystem inflammatory syndrome in children (MIS-C) are fever, gastrointestinal and cardiac. The aim of this study was to describe MIS-C in a series of patients who presented primarily with cervical manifestations. METHODS: We retrospectively reviewed medical records of all patients who met the Centers for Disease Control and Prevention and World Health Organization MIS-C diagnostic criteria treated at Hadassah-Hebrew University Medical Center between April 2020 and September 2021. RESULTS: Of 37 children diagnosed with MIS-C (median age: 10.2 years, range 1.5-18 years, 20 male) five, 13.5% (median age: 14.4 years, range 9.2-17.5 years) presented with cervical symptoms mimicking neck infections. One was hospitalised with a working diagnosis of retropharyngeal abscess, and four with acute cervical lymphadenitis that did not respond to early antibiotic treatment. All developed full MIS-C phenotype. CONCLUSION: MIS-C may present as cervical inflammation. An ill-appearing child with symptoms and/or signs of cervical inflammation should be evaluated for clinical and laboratory features of MIS-C, thereby facilitating prompt treatment of this potentially fatal disorder.

Immunological basis that supports the treatment of Multi-System Inflammatory Syndrome in Children (MIS-C/PIMS)

Pediatric inflammatory multisystemic syndrome temporarily associated with COVID-19 (MIS-C/PIMS) is a new post-infectious condition, secondary to SARS-CoV2 infection. It has been characterized by an inflammatory response with multisystem involvement, involving several mechanisms of immune damage such as an exaggerated increase in cytokines and epithelial damage. Immunomodulatory treatment is aimed at controlling the manifestations of hyperinflammation, to stabilize and prevent long-term sequelae. © 2023 Instituto Nacional de Pediatria. All rights reserved.

COVID 19 infection: Pediatric perspectives.

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread across the globe, causing innumerable deaths and a massive economic catastrophe. Exposure to household members with confirmed COVID-19 is the most common source of infection among children. Children are just as likely as adults to get infected with SARS-CoV-2. Most children are asymptomatic and when symptoms occur, they are usually mild. Infants <12 months old are at a higher risk for severe or critical disease. COVID-19 is diagnosed the same way in pediatric population as adults by testing specimen obtained from upper respiratory tract for nucleic acid amplification test (NAAT) using reverse transcriptase viral polymerase chain reaction (RT-PCR). The common laboratory findings in hospitalized patient include leukopenia, lymphopenia, and increased levels of inflammatory markers. Chest X-ray findings are variable and computed tomography scans of the chest may show ground glass opacities similar to adults or non-specific findings. Prevention is the primary intervention strategy. Recently the U.S. Food and Drug Administration (FDA) has provided emergency authorization of the Pfizer-BioNTech COVID-19 vaccine and many other vaccine candidates are in the investigational stage. There is limited data in children on the use of antivirals, hydroxychloroquine, azithromycin, monoclonal antibody, and convalescent plasma. Oxygen therapy is required in hypoxic children (saturation <92%). Similar to adults, other measures to maintain oxygenation such as high flow nasal cannula, CPAP, or ventilatory support may be needed. Ventilatory management strategies should include use of low tidal volumes (5-6 cc/kg), high positive expiratory pressure, adequate sedation, paralysis, and prone positioning. Recently, a new entity associated with COVID-19 called multisystem inflammatory syndrome in children (MIS-C) has emerged. Clinical, laboratory, and epidemiological criteria are the basis for this diagnosis. Management options include ICU admission, steroids, intravenous gamma globulin, aspirin, anakinra, and anticoagulants. Vasoactive-inotropic score (VIS) is used to guide vasopressor support.

Clinical and Laboratory Features of Patients with Multisystem Inflammatory Syndrome in Children (MIS-C): An Experience From Queen Rania Children's Hospital, Jordan.

Background Multisystem inflammatory syndrome in children (MIS-C) is a new clinical observation that emerged during the coronavirus pandemic of 2019 (COVID-19) and has similar manifestations to Kawasaki disease and toxic shock syndrome. In this study, we aim to describe the characteristics of MIS-C patients in a single center in Jordan. Methods A retrospective analysis of electronic medical records of pediatric patients diagnosed with MIS-C at the pediatric rheumatology division of Queen Rania Children's Hospital, Amman, Jordan, between January 2021 and December 2022. Data collected included age, gender, clinical and laboratory data on presentation, and treatment options, which were compared in two different age groups. Results A total of 80 patients were included in this cohort (53 males and 27 females). The mean age at presentation was 84.4 months (ranging between nine months and 16 years). The most common presenting symptoms included fever (100%), abdominal pain (76.2%), skin rash (75%), conjunctivitis (72.5%), and mucosal changes (62.5%). Lymphopenia was present in 66.2% of patients. The majority of patients (98.7%) showed elevated C-reactive protein (CRP); 72 patients showed elevated erythrocyte sedimentation rate (ESR) (92.5%); ferritin was elevated in 70% of patients; the median fibrinogen level was 390 (interquartile range (IQR) 0.6-20) mg/dL; and the D-dimer level was 3.9 (IQR 0.6-20) mg/dL. Pericardial effusion was present in 23.8% of patients, and five patients (6.3%) had coronary artery dilatation. Conclusion To the best of our knowledge, this study is the first large case series of MIS-C in Jordan, with a wide spectrum of clinical presentation and evidence of hyperinflammation.

Elevated cardiac biomarkers and outcomes in children and adolescents with acute COVID-19.

Cardiac involvement associated with multi-system inflammatory syndrome in children has been extensively reported, but the prevalence of cardiac involvement in children with SARS-CoV-2 infection in the absence of inflammatory syndrome has not been well described. In this retrospective, single centre, cohort study, we describe the cardiac involvement found in this population and report on outcomes of patients with and without elevated cardiac biomarkers. Those with multi-system inflammatory syndrome in children, cardiomyopathy, or complex CHD were excluded. Inclusion criteriaz were met by 80 patients during the initial peak of the pandemic at our institution. High-sensitivity troponin T and/or N-terminal pro-brain type natriuretic peptide were measured in 27/80 (34%) patients and abnormalities were present in 5/27 (19%), all of whom had underlying comorbidities. Advanced respiratory support was required in all patients with elevated cardiac biomarkers. Electrocardiographic abnormalities were identified in 14/38 (37%) studies. Echocardiograms were performed on 7/80 patients, and none demonstrated left ventricular dysfunction. Larger studies to determine the true extent of cardiac involvement in children with COVID-19 would be useful to guide recommendations for standard workup and management.

Short to midterm follow-up of multi-system inflammatory syndrome in children with special reference to cardiac involvement.

OBJECTIVES: We aim to describe the early and upto 16 months follow-up of post-coronavirus disease (COVID), multi-system inflammatory syndrome in children (MIS-C), with special reference to cardiac involvement. STUDY DESIGN: This cohort non-interventional descriptive study included patients <18 years admitted between May, 2020 and April, 2021. Based on underlying similarities, children were classified as post-COVID MIS-C with overlapping Kawasaki Disease, MIS-C with no overlapping Kawasaki Disease, and MIS-C with shock. Post-discharge, patients were followed at 1, 3, 6, 12, and 16 months. RESULTS: Forty-one patients predominantly males (73%), at median age of 7 years (range 0.2-16 years) fulfilled the World Health Organisation criteria for MIS-C. Cardiac involvement was seen in 15 (36.5%); impaired left ventricle (LV) function in 5 (12.2%), coronary artery involvement in 10 (24.4%), pericardial effusion in 6 (14.6%) patients, and no arrhythmias. There were two hospital deaths (4.9%), both in MIS-C shock subgroup (2/10, 20%). At 1 month, there was persistent LV dysfunction in 2/5, coronary artery abnormalities in 7/10, and pericardial effusion resolved completely in all patients. By 6 months, LV function returned to normal in all but coronary abnormalities persisted in two patients. At last follow-up (median 9.8 months, interquartile range 2-16 months), in 36/38 (94.7%) patients, coronary artery dilatation was persistent in 2 (20%) patients. CONCLUSIONS: Children with MIS-C have a good early outcome, though MIS-C with shock can be life-threatening subgroup in a resource-constrained country setting. On midterm follow-up, there is normalisation of LV function in all and recovery of coronary abnormalities in 80% of patients.

Timely Resolution of SARS-CoV-2-Related Multi-System Inflammatory Syndrome in Children.

Background: Multisystem inflammatory syndrome in children (MIS-C) is a severe, postinfectious manifestation of coronavirus disease 2019 (COVID-19) in the pediatric population. The disease is manifested by hyperinflammation and can result in cardiac dysfunction, coronary changes, and end-organ damage. Adequate timely treatment can prevent poor outcomes in the short term, but long-term data is lacking. Methods: A large single center MIS-C cohort was followed longitudinally after treatment with intravenous immunoglobulin (IVIG) ± glucocorticoids to determine the natural history of the disease and to describe improvement in laboratory markers and cardiac outcomes. Patient were stratified by disease severity and compared. Results: 137 patients were identified with demographics similar to previously described cohorts. Regardless of disease severity, when adequately treated, initial lab abnormalities rapidly improved by the 6-8 month follow-up period, with some resolved in as little as 1-2 weeks. Similarly, cardiac abnormalities improved quickly after treatment; all abnormalities resolved in this cohort by 1-2 months post-hospitalization. Conclusions: Although MIS-C is a serious sequela of COVID-19, when identified quickly and treated aggressively, laboratory abnormalities, coronary dilatation, and systolic dysfunction rapidly improve with minimal long-term morbidity or mortality.

Hepatitis of unknown etiology in children: Current evidence and association.

Two years after the coronavirus disease 2019 (COVID-19) pandemic, acute hepatitis of unknown etiology in children (AHUCD) began to be reported worldwide. The novel coronavirus and adenovirus were found in pathogen and antibody tests in AHUCD cases reported by the World Health Organization. Children are not exposed to the viruses that children are generally exposed to owing to COVID-19 infection preventive measures such as isolation and wearing masks; therefore, some researchers have speculated that this disease is related to reduced exposure to pathogens. Some scientists have also speculated that the disease is related to liver injury and adenoviral hepatitis, which are the sequelae of COVID-19. Some evidence also suggests a weak association between the disease and COVID-19 vaccination. Therefore, further research and investigation of the pathogenesis, preventive measures, and early treatment of hepatitis of unknown etiology are required. This study aimed to synthesize available evidence to further elucidate this disease in order to treat and prevent it effectively.

A Case of Steroid-Responsive Severe Pneumonia Following a Recent COVID-19 Infection in a Patient With Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infection.

A twenty-two-year-old woman with a history of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) on rituximab presented with fever, abdominal pain, and worsening shortness of breath requiring supplemental oxygen via nasal cannula one month after a severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection from which she was minimally symptomatic and had recovered. Radiographic studies revealed bilateral patchy consolidations interspersed with ground-glass opacities (GGO). She was started on antibiotics for presumed community-acquired pneumonia with no improvement. Echocardiography revealed preserved biventricular function and a suspected intracardiac mass. A cardiac magnetic resonance imaging (CMRI) revealed myocarditis and no intracardiac mass. Fever persisted and oxygen requirements increased from FiO2 0.4 to 1.0. Repeat CXR showed subtotal left hemithorax opacification. Bronchoscopic samples showed a negative Gram stain and an unremarkable cell count differential. In view of this and given her lack of response to antibiotics with worsening respiratory status, high-dose steroids were started. She improved rapidly, and six days later she was off oxygen. Transbronchial biopsies showed benign parenchyma with some intra-alveolar fibrin deposition with no definitive evidence of viral cytopathic effect, vasculitis, or diffuse alveolar damage (DAD). Follow-up imaging in the pulmonary clinic revealed improvement of prior airspace disease with some new migratory opacities that completely resolved after 12 weeks. Pulmonary function tests and repeat CMRI were normal three months after discharge. Multisystem inflammatory syndrome in adults (MISA), post-covid organizing pneumonia (OP), and immune reconstitution inflammatory syndrome (IRIS) are rare and potentially steroid-responsive causes of pneumonia, which were in our differential diagnosis. It is imperative to consider the rare possibility of steroid-responsive pneumonia-like MISA, post-COVID-OP, and IRIS in patients with worsening respiratory symptoms following a recent SARS-CoV 2 infection.

A global review of racial, ethnic and socio-economic disparities in multisystem inflammatory syndrome in children related to COVID-19.

With over 500 million confirmed cases and 6.2 million deaths worldwide, the novel coronavirus has highlighted the underlying disparities in healthcare, unpreparedness to deal with a new disease and the need for monitoring and surveillance for a post-infectious syndrome as well as complicated diseases. Initially, children were thought to be spared but reports of a new phenomenon manifesting as Kawasaki-like disease, toxic shock syndrome, and multi-system inflammatory syndrome, which developed after a few weeks of severe COVID-19 infection, emerged in the pediatric population. As the pandemic progressed, increased prevalence of multi-system inflammatory syndrome in children (MIS-C) related to COVID-19 was seen in non-Hispanic blacks, Asians, and Latinos as compared to the white population drawing attention to a possible role of ethnicity and socio-economic disparities. The CDC currently reports that 31% of MIS-C cases were seen in Black Non-Hispanics and 26% in Latinos, who were historically more affected in previous pandemics. Furthermore, MIS-C cases in developing countries showed higher mortality as compared to high-income countries, which points toward the role of social determinants of health and limitations in a low-resource set up in increasing the disease burden of MIS-C, which should be treated as a public health emergency. Our review highlights the role of ethnicity, socio-economic factors, comorbidities, and differences in populations affected by MIS-C in high-income vs. low- and middle-income countries.

Cardiac findings and short-term outcomes of multisystem inflammatory syndrome associated with COVID-19 single center experiences from turkiye

Background and Aim: Multi-system inflammatory syndrome in chil-dren (MISC) associated with COVID-19 has been described as a potentially life-threatening disease. In this study, we aimed to evaluate cardiovascular findings in children diagnosed with MISC at initial presentation and follow up. Method(s): Between November 2020 and November 2021, 35 children diagnosed with MISC based on WHO criteria were evaluated in this retrospective study.Cardiac markers, electrocardi-ography and echocardiography were performed in all cases at pre-sentation. Cardiac evaluation were repeated at the mean of 10th week after discharge(range:5 to 33weeks). Result(s): At this period, 633 children had positive PCR test of Covid-19. The freguency of MISC was 5.5% in our cohort. The median age was 9 years at diagnosis. Comorbid diseases were found in 20% cases, but none had preexisting heart disease. All patients had high grade fever and laboratory evidence of hyperin-flammation. Most cases had mild form disease, however 12 patients had been hospitalized in ICU median 6 day. 27 cases (77%) had cardiovascular involvement.Kawasaki-like findings were found in 10 patients and 5 cases were presented with shock(Figure-1) Echocardiography;Left ventricular (LV)systolic dysfunction (EFlt;57%) was detected in 11 cases (31.4%) and coronary artery (CA) dilatation(z scoregt;2)was found in five(14.2%) cases. Pericardial effusion was seen in 12 cases. Electrocardiography: Sinus tachycardia was the most common finding. 2 cases had pro-longed QTc interval and four cases had T wave alterations. Four cases had experienced complex ventricular arrhythmia. Cardiac markers:24 cases had high Pro-BNP level. 18 cases also had high Troponin T levels. Pro-BNP and Troponin T levels were not found to be correlated with LVEF. Only one adolescent boy who had severe cardiac dysfunction died during the acute period. Followup:There were two cases with persistent cardiac symptom, but no case had LV systolic dysfunction. The mean PR intervale was significantly lower than initial measurements. The mean of QT and QTc at follow up were not different from basal measurements.The mean LVEF was significantly higher than the initial levels. The basal CA z scores normalized at followup. Conclusion(s): MISC is characterized predominantly by cardio-vascular system involvement, but the children with MISC have good cardiac outcomes at short term follow up.

Severe Agitation as an Unusual Presentation of Multisystem Inflammatory Syndrome in Children.

Multisystem inflammatory syndrome in children (MIS-C) is a rare hyperinflammatory syndrome that mainly affects children after a primary infection with coronavirus disease 2019 (COVID-19), with the possibility of severe and lethal complications. We report a case of a unique presentation of MIS-C in a four-year-old boy who presented with severe agitation, muscle spasms, and two days of fever. Other findings consistent with MIS-C were revealed later, and he was managed with intravenous immunoglobulin (IVIG) and steroids. He showed a dramatic response of improvement and was discharged. This case report aimed to raise health professionals' awareness about the atypical presentations of MIS-C and the importance of early diagnosis, treatment, and follow-up MIS-C cases to avoid complications affecting children's lives.

A pediatric case of xanthogranulomatous pyelonephritis in the setting of Covid-19 and multi-system inflammatory syndrome (MIS-C).

Xanthogranulmatous pyelonephritis is a rare, chronic inflammatory pathology of the kidney. It most commonly arises in middle-aged females, but there are case reports and series described in the pediatric population. Here, we discuss the case of a 14 year old male who presented with xanthogranulomatous pyelonephritis in the setting of Covid-19 and multi-system inflammatory syndrome (MIS-C). As xanthogranulomatous pyelonephritis often mimics other diseases that are more prevalent in the pediatric population, our case was only definitively diagnosed with histopathology after surgical resection. This report is novel in that, to our knowledge, it is the first to describe xanthogranulomatous pyelonephritis in the setting of MIS-C.

Short-term Cardiovascular Complications of Multi-system Inflammatory Syndrome in Children (MIS-C) in Adolescents and Children.

PURPOSE OF REVIEW: We provide the readers with a review of cardiac complications in children with multi-system inflammatory syndrome in children (MIS-C) and its short-term outcomes. RECENT FINDINGS: Recent reports described the acute cardiac manifestations of MIS-C in children and provided a glimpse of the short-term outcomes. SUMMARY: Children with MIS-C have been reported to acutely have variable degrees of cardiac findings including abnormal cardiac enzymes, abnormal electrocardiographs, decreased systolic function, coronary artery abnormalities from coronary dilation to giant aneurysms, mitral valve regurgitation, tricuspid valve regurgitation, aortic valve insufficiency, pericardial effusion, diastolic dysfunction, abnormal cardiac strain, and abnormal cardiac MRI. The majority of these abnormalities resolved during short-term follow-up. Further studies are needed to assess if transient or persistent cardiac complications are associated with long-term adverse cardiac events in children with MIS-C. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40124-021-00258-5.

Spectrum of SARS-CoV-2-Related Clinical Syndromes in Children: A Year in the Life.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a wide pediatric clinical spectrum. Initial reports suggested that children had milder symptoms compared with adults; then diagnosis of multisystem inflammatory syndrome in children (MIS-C) emerged. We performed a retrospective cohort study of hospitalized patients at a children's hospital over 1 year. Our objectives were to study the demographic and clinical profile of pediatric SARS-CoV-2-associated diagnoses. Based on the clinical syndrome, patients were classified into coronavirus disease 2019 (COVID-19; non-MIS-C) and MIS-C cohorts. Among those who tested positive, 67% were symptomatic. MIS-C was diagnosed in 24 patients. Both diagnoses were more frequent in Caucasians. Both cohorts had different symptom profiles. Inflammatory markers were several-fold higher in MIS-C patients. These patients had critical care needs and longer hospital stays. More COVID-19 patients had respiratory complications, while MIS-C cohort saw cardiovascular involvement. Health care awareness of both syndromes is important for early recognition, diagnosis, and prompt treatment.

A case report of multi-system inflammatory syndrome in adults (MIS-A) associated with heart failure.

BACKGROUND: Multi-system inflammatory syndrome in children (MIS-C) is a systemic inflammatory condition where various body organs, such as the heart, kidney, gastrointestinal organs, become inflamed. Several cases have been reported in children linking MIS-C with novel corona virus disease-2019 (COVID-19); however, few cases have been reported in adults [multi-system inflammatory syndrome in adults (MIS-A)]. CASE SUMMARY: A case of a 20-year-old male patient with a history of COVID-19 infection 2 months before presentation who presented with fever and acute right lower quadrant pain. Workup revealed right-sided mesenteric lymphadenopathy and mild colitis that was non-responsive to antibiotics. The patient was found to have significantly elevated inflammatory markers. He also developed myocarditis resulting in acute systolic heart failure with reduced ejection fraction. The diagnosis of MIS-A was made by exclusion. The patient showed improvement with intravenous immunoglobulin and pulse steroids. Based on the available literature, MIS-C was defined till the age of 21; however, we think it is a misnomer for adults more than 18. Hence, we prefer to use MIS-A for our patient. CONCLUSION: It is essential to diagnose and treat patients with the multi-system inflammatory syndrome at an early stage; the management of these patients, especially with heart disease, should include immune-modulatory therapy as well as guideline-directed therapy.

Acute Appendicitis Associated With Multisystem Inflammatory Syndrome in Children.

Multisystem inflammatory syndrome in children (MIS-C) has been reported to cause significant gastrointestinal symptoms. In this case series, we present four patients with MIS-C with documented acute appendicitis, which strengthens the association between SARS-CoV-2, MIS-C, and acute appendicitis.