key: cord-0825606-4nqnda3x authors: Kundu, Anusrita; Maji, Swagata; Kumar, Suchismita; Bhattacharya, Shreya; Chakraborty, Pallab; Sarkar, Joy title: Clinical aspects and presumed etiology of multisystem inflammatory syndrome in children (MIS-C): A review date: 2022-02-03 journal: Clin Epidemiol Glob Health DOI: 10.1016/j.cegh.2022.100966 sha: 802f6dd1634d6403bbc272b6856e8d4a32b1d582 doc_id: 825606 cord_uid: 4nqnda3x The COVD-19 outbreak sparked by SARS-CoV-2, begat significant rates of malady worldwide, where children with an abnormal post-COVID ailment called the Multisystem Inflammatory Syndrome (MIS-C), were reported by April 2020. Here we have reviewed the clinical characteristics of the pediatric patients and the prognosis currently being utilized. A vivid comparison of MIS-C with other clinical conditions has been done. We have addressed the probable etiology and fundamental machinery of the inflammatory reactions, which drive organ failure. The involvement of androgen receptors portrays the likelihood of asymptomatic illness in children below adolescence, contributing to the concept of antibody-dependent enhancement.  Many studies have found that MIS-C has a significant impact on African American, African/Afro-Caribbean, and Hispanic youngsters. African/Afro-Caribbean children constituted the largest fraction of the cases in European research with relevant race/ethnicity data, ranging from 38 % to 62 Obesity and a history of asthma have been the most frequent comorbidities in individuals who did possess past medical issues across studies, with autoimmune illness, long-term lung ailment, diabetes, cancer, congenital heart disease, and neurological disorders as fundamental detections 4, 14, 15, 18, [21] [22] [23] 28 . The World Health Organization (WHO) has published the case-definition MIS-C, where the following six criteria are to be fulfilled. iii. Cardiac disability, pericardial inflammation, coronary anomalies, or valvulitis (including echocardiographic findings or elevated troponin/brain natriuretic peptide) iv. Presence of coagulopathy (prolonged prothrombin time or PTT; amplified D-dimer) v. Acute gastrointestinal symptoms (diarrhoea, vomiting, or abdominal pain) 4. Inflammation markers that are elevated (namely, erythrocyte sedimentation rate, Creactive protein, or procalcitonin). 5. Other microbiological causes of inflammation, like bacterial sepsis and staphylococcal/streptococcal toxic shock syndromes are not identified. 6. Reports testing positive for present or past SARS-CoV-2 pathogenesis by RT-PCR, antibody, or antigen test; or interaction with a person infected with COVID-19 1, 4, [11] [12] [13] 27 . CDC also has a separate case definition that focuses on evidence of clinical symptoms involving several organs 4,27,29 . Knowledge revolving around the clinical condition of MIS-C patients is unfolding day by day 11 . As a significant percentage of SARS-CoV-2 infections has escaped diagnosis, the overall population of children residing in the danger for MIS-C is unclear, owing to the possibility of asymptomatic or paucisymptomatic infections 4 . Based on a temporal link of SARS-CoV-2 invasion with MIS-C, the average time between primary infection and the incidence of MIS-C symptoms, in children with a recorded history of confirmed or suspected COVID-19 infection, is two to six weeks 4,29 . The establishment of a severe inflammatory state is one of the major symptoms of MIS-C including, spiking and persistent fever (>39°C-40°C) with severe asthenia for a few couples of days, myalgia, swollen hands or feet, and multisystem damage ( Figure 1 ) 3,4,6,9,11,14,27-29 . Patients initially felt chest pain, with an average delay of 6 days between the outset of clinical symptoms and the outset of heart failure symptoms. They experienced cardiogenic shock upon their entry to the pediatric intensive care unit (PICU) and were provided with inotropic support 11,20,30 . All of the investigations found cardiac abnormalities using echocardiography or electrocardiography, highlighting the appearance of myocardial dysfunction 4 . Echocardiography revealed depressed systolic function, with left ventricular ejection fraction J o u r n a l P r e -p r o o f (LVEF) of <55% (moderate dysfunction) and sometimes <30% (severe dysfunction) 19,21,30 , pericarditis (pericardial effusion) and myocarditis, atrioventricular valve regurgitation, cardiac dysrhythmia, coronary dilation, or aneurysms with a medial z score range of 2.0 -2.8 indicating small aneurysm and rarely giant aneurysm were reported 3,4,10,12-14,21,27,29-31 . In adolescents with vasodilatory shock, cardiac magnetic resonance imaging (MRI) revealed signs of myocardial edema, necessitating fluid resuscitation 13,29 . Cardiac involvement is an extensive factor to differentiate MIS-C from COVID-19 10 . Though COVID-19-like respiratory complaints are not often associated with MIS-C, difficulties in breathing like tachypnoea, cough, hypoxia, have been disclosed so far. Chest radiographs showed pulmonary edema, basilar opacities suggestive of atelectasis, either dependent or coercive as a consequence of pleural effusion, pulmonary infiltrates, pneumothorax, pulmonary hemorrhage, and bronchospasm, requiring the utility of bronchodilators continuously. Critical pulmonary infection, such as acute respiratory distress syndrome (ARDS), was uncommon in children who needed supplemented oxygen or a ventilator for breathing support 4,6,10,11,21,27,29,31,32 . The youngsters have been observed with various neurologic issues. Headaches, hearing & visual problems, amnesia, meningitis, irritability, apathy, and lassitude are some of the symptoms. Encephalopathy, stroke or abrupt intracranial hemorrhage, uveitis, coma, seizures, demyelinating disease, aseptic meningoencephalitis (strengthening pro-inflammatory CNS feedback) 31 , and brain death were among the profound neurologic findings seen in specific cases. Rare instances reported ischemic brain infarction, acute cerebral edema, and Guillain-Barre syndrome 4,10,11,20,27,29,31 . Gastrointestinal involvement was usually the most apparent attribute of MIS-C, reported in maximum patients often resembling abdominal infections 4,11,12 . Abdominal cramps, diarrhoea, and vomiting were among the prominent symptoms 4,11,12,14,27,29 . Abdominal ultrasonography and computed tomography of the abdomen and pelvis disclosed grave results like appendicitis, gall bladder hydrops, ascites, mesenteric adenopathy, pleural effusions, J o u r n a l P r e -p r o o f enterocolitis, in certain cases terminal ileitis and colitis, all leading to hypovolemia. The pancreatic images reported pancreatomegaly, and those of the liver reported hepatomegaly, and biliary sludge, while increased renal echogenicity, lead to acute kidney failure 4,9,10,21,29,32 . The mucocutaneous results were heterogeneous. Morbilliform, urticarial, scarlatiniform, and reticulated forms were among the morphologic features of exanthemas 26 . The area of the skin affected also differed where certain individuals were with restricted acrofacial inclusion while others harbored more extensive outbreaks 26 . Some studies have also revealed a strong age bias in the advent of symptoms 26 . The prevailing cutaneous records were conjunctivitis, hyperemia, periorbital swelling and erythema, and strawberry tongue. A few dermatological findings were whereas malar rashes, facial edema, palmar erythema, lip cracks, and lip hyperemia causing redness and swelling 4,10,11,21,26,29,32 . In a special case, a skin biopsy presented lymphocytic infiltrate as the root of skin lesion 26 . MIS-C patients were found with several thrombotic events where activation of coagulation lead to deep vein thrombosis, intracardiac thrombosis, cerebral venous sinus thrombosis(CVST), subarachnoid hemorrhage (SAH) bringing about ischemic brain death 10,13,20,27,33 . A prothrombotic coagulopathy may be enhanced by MIS-C's hyperinflammatory condition in conjunction with COVID-19 triggering pulmonary embolism 6,33 . Additional hematologic abnormalities comprise lymphopenia, neutrophilia, haematolysis, hypoxemia, ischemia, anemia, pancytopenia, and hemolytic uremic syndrome (HUS) 10,11,33 . Swollen lymph node often called adenopathy has been noted as a common sign of inflammation in MIS-C-affected children encompassing distinct organs like mesenteric lymphadenitis and mediastinal and hilar lymphadenopathy which have been observed through thoracic imaging 6,11,32 . The common feature found in every MIS-C patient is an extremely elevated level of inflammatory and cardiac indicators 4 . Inflammatory indicators like CRP (C-reactive protein), J o u r n a l P r e -p r o o f (Table-1) . There exist no definitive therapeutic guidelines for the treatment of MIS-C at this time, but few current administration and therapy options are available. Most of these treatment strategies have yielded a positive result 4 . IVIG and corticosteroids have been proven to be effective in various studies as a remedy for inflammation, leading to a quick recovery 4 . Use of intravenous immunoglobulin (IVIG) similar to normal KD therapy and corticosteroids 4,13,15,20,30,44 has been encountered in MIS-C patients 9,11,13,21,26,32, 45, 46 . Patients with a low J o u r n a l P r e -p r o o f index of suspicion present with some but not all of the MIS-C symptoms should be examined for inflammatory screening, including a complete blood count (CBC) and C-reactive protein (CRP), along with SARS-CoV-2 PCR and antibody testing 13 . Empiric antibiotic coverage is prescribed in children, who have been assessed for having MIS-C and have been admitted to the hospital, with initial broad-spectrum antibiotics, since symptoms overlap with severe bacterial infections. Ceftriaxone is generally suggested if they are sick to a moderate extent. In cases of severe illness or shock, vancomycin, clindamycin, and cefepime, or vancomycin, meropenem, and gentamicin are recommended 13,45,47 . If redeliver (an antiviral drug with activity against SARS-CoV-2 approved for compassionate use in young children and restricted clinical trials) is available, it must be evaluated, especially for individuals who have been PCR positive and/or have a characteristic COVID-19 presentation 4, 9, 13, 20, 26, 45 . For children, the current recommended dose is 5 mg/kg IV once (max dose 200 mg) on day 1, then 2.5 mg/kg IV daily for nine days (max dose 100 mg) 13, 45 . In case of all children exhibiting KD-like illness and evidence of significant inflammation (CRP > 30 g/dL, ferritin > 700 ng/mL), cardiac involvement, or multi-fold organ failure, 20-25 mg/kg/dose every 6 hours (80-100 mg/kg/day) of aspirin is advised as a medication. However, individual health centers may use different amounts of aspirin. When a patient has been afebrile for 24 hours or more, the aspirin dose typically reduces to 3-5 mg/kg as a single daily dose, which will be continued after discharge 9,11,13,30 . Anakinra is prescribed at a dose of 2-6 mg/kg/day IV/SQ, with the period of treatment determined with the help of a pediatric rheumatologist or immunologist 4,11-13,20,21,26,32,48-50 . A major percentage of patients got intravenous steroids, Infliximab, and IL-6 inhibitors (Tociluzimab or Siltuximab) as antiinflammatory therapy 4,11-13,20,21,45,51,52 . Owing to the involvement of TNF-α in MIS-C, anti-TNF-α medication is useful for the control of auto-inflammatory disorders in which many cytokines are high, implying that anti-TNF-α therapy may stop a cytokine cascade on its own 51, 53 . A significant percentage of MIS-C patients are referred to the ICU, frequently requiring respiratory and cardiac assistance. Several studies indicated that about 44-100 % of the J o u r n a l P r e -p r o o f children were sent to the ICU 30 . A major proportion of children also required routine ventilation 18 . Mild to medium doses of vasoactive medicines, like vasopressors and inotropes, were regularly administered to MIS-C ICU patients due to shock-induced by myocardial dysfunction (e.g., acute myocarditis) and/or intense vasoplegia 22,30 . Studies have revealed several guidelines that are to be taken care of before patients are discharged off. Some of them include two days without fever, two days out of vasopressors and supplemented oxygen, two to four days of declining inflammatory markers like ferritin, D-dimer, CRP, lowers levels of troponin, standard Electrocardiogram (the German spelling-Elektrokardiogramm) or EKG with stable blood pressure 4,13,20,45,51 . Patients released from the emergency unit must receive particular discharge manuals including a follow-up clinic or telemedicine consultation within 72 hours. A repetition of the laboratory tests must be conducted within one week. The interval between the initial echocardiography and the cardiology follow-up should be at least two weeks 13 . COVID-19 instances (after COVID as well as current COVID) linked to MIS-C have been discovered all over the world. Some of the occurrences from various nations have been summarised in Table 2 and Table 3 simultaneously. Pediatric patients distressed with MIS-C exhibit large amounts of SARS-CoV-2 antibodies in their serum but test negative for the virus through RT-PCR, indicating that certified reports of COVID-19 are relatively few in children or they might have had a prior infection 1,3 . The feedback from antibodies in children was unique from those of the adults stating that the induction of adaptive immune reaction to SARS-CoV-2 virus in the former corresponds with the onset of inflammatory symptoms and is not influenced by viral attack 1 . Angiotensin-Converting Enzyme-2 (ACE2) receptor, which renders its activity along with TMPRSS2 cell surface protein, representing a type II Transmembrane Serine Protease (TTSPs), preferably in the alveolar pneumocytes 3,37,54-58 . Mainly TMPRSS2 sunders the S-J o u r n a l P r e -p r o o f protein of SARS-CoV-2 utilizing its protease activity, into two parts S1 and S2, which facilitate binding of the virus and its unification with the target cell respectively (Figure 2A) 3,37,59,60 . The gene encoding for TMPRSS2 protein has been spotted in chromosome 21 of humans, whose transcription is modulated by allosomal androgen receptor (AR) transcription factor 54, 55, 58, 61, 62 . Sex-steroid hormones such as testosterone reactive promoter sequence existing upstream of the gene, thereby deploy AR's activity through several signaling systems 54, 55 . Though hints of estrogen affecting the task of TMPRSS2 have been obtained, 78 have also studied the role of auto-antibodies found against endothelial and gastrointestinal cells in MIS-C patients, which fails to distinguish between self and non-self cells, ultimately attacking a patient's native tissues 1, 78 . Thus, it can be inferred that localized inflammation and the build-up of pathogenic macrophage congregations in body tissues are two especially common factors that cause MIS-C syndrome and more analysis is needed to illustrate the role of macrophages further 3 . MIS-C is generally curable and rarely happens, but a certain lack of knowledge could make it severe in the long term aspect 4 . As it is a rare condition, most children who have it improve with medical treatment. However, some children swiftly deteriorate to the point where their lives are jeopardized. As the number of MIS-C cases related to COVID-19 is increasing incessantly, it can be clearly stated that COVID-19 is not only just a respiratory disease 6 , further elaborate research is needed to know more about the etiology of MIS-C associated with COVID-19, as it is still unknown how the risk factor for MIS-C varies among child J o u r n a l P r e -p r o o f community 4 . Children develop COVID-19, unlike adults, by ADE due to a lack of androgens 3,54 , which directly regulates the TMPRSS2 receptor 55, 66 . Therefore, to prevent the transmission of COVID-19 in this age group, parents should be more careful of their children in surroundings with a high population density 4 . Precautions and safety measures such as social distancing, use of face masks, frequent washing of hands, use of alcohol-based disinfectants, should be followed in places like schools 4 , parks, crèche, etc. Parents, babysitters, teachers, and school officials should primarily be cognizant of the indications and signs of both COVID-19 and MIS-C so that proper treatment is provided before its late. We do not have any funding support from any organizational or institutional level. The authors acknowledge the immense help received from the scholars whose articles are cited and included in references of this manuscript. 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