key: cord-336144-e7hvp9wy authors: friedman, kevin g.; harrild, david m.; newburger, jane w. title: cardiac dysfunction in multisystem inflammatory syndrome in children: a call to action date: 2020-10-27 journal: j am coll cardiol doi: 10.1016/j.jacc.2020.09.002 sha: doc_id: 336144 cord_uid: e7hvp9wy [figure: see text] infection. indeed, only 2% of confirmed cases have occurred in persons <18 years, and the mortality rate in children is 0.5% (1) . however, the early comfort that healthy children were largely spared from critical covid-19-related illness has been shattered in recent months by descriptions of a severe postinfectious syndrome among children exposed to sars-cov-2, with clinical features resembling both kawasaki disease (kd) and toxic shock syndrome. this emerging syndrome has been defined by health organizations worldwide and named multisystem inflammatory syndrome in children associated with covid-19 (mis-c) by the us centers for disease control and prevention (cdc). mis-c prevalence typically surges 3 to 6 weeks after the peak of covid-19 in a geographic region (2) (3) (4) (5) . this timing, together with findings of positive serology and negative ntpcr in most affected children suggest that pathogenesis is related to host immune response and hyperinflammation (3) (4) (5) (6) . involvement of the cardiovascular system in mis-c is common (80% to 85% of cases) and is a primary to date, the trajectory of recovery of systolic function has been characterized only in small retrospective case series (2) (3) (4) (5) (6) (7) (8) (9) . however, early reports suggest that lvef normalizes in most patients within 1 to 2 weeks after initial presentation (7, 8) . (33% with ef 30% to 54% and 5% with ef <30%). hospitalization rates and characteristics of patients hospitalized with laboratory-confirmed coronavirus disease 2019-covid-net, 14 states clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with sars-cov-2 distinct clinical and immunological features of sars-cov-2-induced multisystem inflammatory syndrome in children multisystem inflammatory syndrome in children in new york state multisystem inflammatory syndrome in u.s. children and adolescents covid-19-associated multisystem inflammatory syndrome in children -united states acute heart failure in multisystem inflammatory syndrome in children in the context of global sars-cov-2 pandemic multimodality cardiac evaluation in children and young adults with multisystem inflammation associated with covid-19 hyperinflammatory shock in children during covid-19 pandemic echocardiographic findings in pediatric multisystem inflammatory syndrome associated with covid-19 in the united states key words coronary artery abnormality, covid-19, deformation, echocardiography, multisystem inflammatory syndrome in children (mis-c) cardiac dysfunction in mis-c key: cord-355636-mq7xb9d4 authors: booth, r.; aliozo, c.; mureb, a.; ahmad, m.; clarke, a.; nash, g; qureshi, t.; siddiqi, n.; parvaiz, a. title: minimally invasive surgery in the covid‐19 pandemic: an early single centre experience date: 2020-08-21 journal: br j surg doi: 10.1002/bjs.11986 sha: doc_id: 355636 cord_uid: mq7xb9d4 nan surgical practice has changed dramatically during last few months owing to the covid-19 pandemic. concern for the safety of patients and staff with concerning outcomes reported by some units worldwide has generated controversy 1 . various surgical societies published guidelines which were not in favour of minimally invasive surgery (mis) due to the perceived risk of virus spread from aerosolisation 2,3 . initial experience from china and italy favours open surgery over laparoscopic 4 . variability in surgical practice was noted globally due to poor understanding of how the virus is transmitted 5 . as of 15 th may 2020, the global death toll from covid-19 had passed 300,000 with nearly 4⋅5 million people infected worldwide. overall, there have been 45 deaths in our hospital. mis has become the standard approach across several disciplines including general surgery, gynaecology and urology, in the elective and emergency setting. mis leads to better short term outcomes including, less post-operative pain, wound infections, chest infections and shorter length of hospital stay. as open surgery is associated with an increased hospital stay, it may increase exposure to nosocomial covid transmission, with added pressure on resources and itu capacity. guidelines have suggested caution with a perceived risk of virus spread through aerosol generating procedures (agps) including laparoscopy and robotic surgery. they have advocated a shift in practice towards open surgery and conservative management where appropriate. the risk of virus spread with agps can be minimised by using ports with balloons, smaller skin incisions and avoiding 5 mm instruments through 10 mm ports. at the end of the laparoscopic procedure and before making an extraction site for specimen retrieval, careful evacuation of co2 using special filters and suction would reduce leakage of co2. we report our single centre experience during this pandemic. mis was only performed in emergency and urgent cancer patients across three specialities (upper gi, colorectal and gynaecology). patient data was collected over eight weeks period retrospectively, from 16 th march to 15 th may 2020. a total of 128 cases were performed of which 86 were minimally invasive, breakdown of data is shown in table 1 . all patients for elective surgery were self-isolated for two weeks and had covid-19 test performed 48 hours before the procedure. emergency surgery patient underwent pcr covid-19 test prior to their procedure where feasible. during the study period, there was no covid-19 positive case reported amongst the patients in the mis group or theatre staff. balloon ports were used for all laparoscopic procedures. all robotic and initial eight laparoscopic cases were performed using airseal ® (conmed, utica, new york, usa) system and standard co 2 system for the others. ultralow particulate filtration system and suction was used in all laparoscopic cases to evacuate the gas at the end of the procedure. theatre staff including surgeons wore full ppe including fitted n95 masks with face shields when working within 2 meters of the patient. surgeons who performed robotic surgery used 3-ply surgical mask when operating from the console. this data would suggest that, with appropriate screening of patients and protection of theatre staff as outlined, mis is safe and feasible. with improved test kits and shorter turn around time the screening of patients provides an additional layer of safety to perform mis surgery. we also recommend the use of closed circuit evacuation of the smoked co2, or an ultralow particulate air filtration system. we believe that the risk of viral spread through mis has been overstated and with appropriate safety measures it can be safely performed, with benefits to both the patient and healthcare providers. patients should not be denied the clear advantages of laparoscopic surgery over open surgery during the current covid-19 pandemic. covid-19 pandemic: perspectives on an unfolding crisis sages and eaes recommendations regarding surgical response to covid-19 crisis the association of coloproctology of great britain and ireland urgent intercollegiate general surgery guidance on covid-19 minimally invasive surgery and the novel coronavirus outbreak: lessons learned in china and italy covid-19: what are the challenges for nhs surgery? we would like to thank upper gi, gynaecology and emergency surgery department to contribute their data in the paper. key: cord-313058-nrrl4kjc authors: rivas, magali noval; porritt, rebecca a.; cheng, mary hongying; bahar, ivet; arditi, moshe title: covid-19 associated multisystem inflammatory syndrome in children (mis-c): a novel disease that mimics toxic shock syndrome. the superantigen hypothesis date: 2020-10-16 journal: j allergy clin immunol doi: 10.1016/j.jaci.2020.10.008 sha: doc_id: 313058 cord_uid: nrrl4kjc nan as of mid-september, the novel severe acute respiratory syndrome coronavirus 2 26 (sars-cov-2) has infected more than 30 million people, resulting in approximately one 27 million deaths worldwide, including over 200,000 deaths in the usa alone. fever, dry 28 cough, breathing difficulties and gastrointestinal (gi) symptoms are typical features of 29 coronavirus disease-2019 . although 80% of infected people develop a mild 30 disease, approximately 20% progress to severe covid-19, which is associated with 31 lung damage and breathing difficulties, and may lead to respiratory failure and death. 32 exacerbation of the covid-19 immune response manifested by extensive cytokines 33 release, called cytokine storm, may lead to multisystem inflammatory syndrome that is 34 fatal in 28% of cases 1 . children can also be infected with sars-cov-2 (<2%), however 35 the majority of confirmed pediatric cases have a less severe outcome and milder 36 in late april, 2020, reports from europe described the emergence of a new febrile 38 pediatric entity that involved persistent fever, systemic hyperinflammation, multiorgan 39 involvement with prominent and severe gi symptoms, and cardiogenic shock and 40 hypotension, requiring pediatric icu care in the majority of cases. some who developed 41 this syndrome, referred to as covid-19-associated multisystem inflammatory which are all very rare in kd 2 . in addition, the overall clinical picture of mis-c is similar 55 in many respects to the late, severe covid-19 phase in adults, which is characterized 56 by a cytokine storm, hyperinflammation, and multiorgan damage, and often includes 57 severe myocarditis and acute kidney injury, and laboratory and clinical features of tss 4 . 58 a causal link between sars-cov-2 infection and mis-c has not yet been clearly 59 established, however, many mis-c patients were reportedly exposed to someone 60 known or suspected to have covid-19. although only around a third of mis-c patients 61 are positive for sars-cov-2 by pcr, a large majority are pcr-negative but positive 62 serologically for sars-cov-2 antibodies and/or have a history of mild covid-19 63 infection or exposure several weeks before presentation. such timing suggests that 64 mis-c is a post-infectious disease or immune or autoimmune disease. moreover, the 65 virus may still be present in the gi tract of these patients, as they demonstrate very 66 severe gi symptoms. 67 through structure-based computational modeling, we discovered that the sars-68 cov-2 s gene encodes a high-affinity sag-like sequence motif near the s1/s2 cleavage adult covid-19 patients 9 . the pathologic mechanisms leading to these symptoms 93 remain unknown. interestingly, sag-induced tss has been associated with long-term 94 neuropsychologic deficits in adults, including cognitive decline 10 , and we identified a 95 homology between the sag motif of sars-cov-2 and neurotoxin-like sequences which 96 are able to bind the tcr 5 . notably, sars-cov-2 spike contain other neurotoxin-like 97 motifs as well, including in particular the segment t299-y351 which has been recently 98 observed to be a highly cross-reactive epitope that triggers cd4 + t cell response 5 . it 99 will be interesting to determine whether these neurotoxin-like sequences in the sars-100 cov-2 s protein contribute to the neurological manifestations observed in children with 101 why only a small fraction of sars-cov-2 infected children develop mis-c 103 remains unclear. it is possible that a poor initial antibody response to the virus in a 104 subset of children fails to produce neutralizing antibodies, leading to immune 105 enhancement following sars-cov-2 re-exposure. alternatively, some human leukocyte 106 antigen (hla) types may be more permissive, and respond more robustly to certain viral 107 antigenic structures 5 . indeed, among the reported cases from london 2 , 50% of mis-c 108 patients were of afro-caribbean descent, which suggests a possible genetic component 109 for mis-c susceptibility. 110 finally, our findings suggest that immunomodulatory therapeutic approaches 111 used for tss, such as ivig and steroids, may also be effective for mis-c. indeed, most 112 mis-c patients respond well to intravenous immunoglobulin (ivig; 2 gm/kg) and aspirin, 113 with or without steroids 3 . given the structural similarities between seb and the sars-114 j o u r n a l p r e -p r o o f cov-2 s protein sag motif 5 , it is possible that antibodies within ivig that neutralize 115 seb cross-react with sars-cov-2 s, which may in part explain the beneficial response 116 of mis-c cases to ivig. in addition, in the mouse model of tss, lethal seb 117 superantigen challenge can be prevented by short peptide mimetics of the sag motif 6 . 118 therefore, it would be important to investigate the therapeutic potential of peptide 119 mimetics of sars-cov-2 spike sag-like region in covid-19-induced 120 hyperinflammatory syndromes in future studies. further elucidation of the parameters 121 affecting the interaction between sars-cov-2 s glycoprotein and immune cells will be 122 necessary to design effective preventive and therapeutic interventions. 123 124 we gratefully acknowledge support from nih awards p41 gm103712 (to ib) and r01 126 ai072726 (to ma). 127 table 1 the trinity of covid-19: immunity, 129 inflammation and intervention clinical 131 characteristics of 58 children with a pediatric inflammatory multisystem syndrome 132 temporally associated with sars-cov-2 multisystem inflammatory syndrome related to covid-19 in previously healthy 135 children and adolescents in new york city novel paediatric 137 presentation of covid-19 with ards and cytokine storm syndrome without respiratory 138 symptoms superantigenic character of an insert unique to sars-cov-2 spike supported by skewed 141 tcr repertoire in patients with hyperinflammation binding of superantigen 143 toxins into the cd28 homodimer interface is essential for induction of cytokine genes 144 that mediate lethal shock the immunology 146 of multisystem inflammatory syndrome in children with covid-19 engagement of mhc class ii molecules by staphylococcal 148 superantigens activates src-type protein tyrosine kinases neurological 150 associations of covid-19 persistent 152 neuropsychological sequelae of toxic shock syndrome key: cord-301868-ehck72z2 authors: jhaveri, simone; ahluwalia, neha; kaushik, shubhi; trachtman, rebecca; kowalsky, shanna; aydin, scott; stern, kenan title: longitudinal echocardiographic assessment of coronary arteries and left ventricular function following multisystem inflammatory syndrome in children (mis-c) date: 2020-08-05 journal: j pediatr doi: 10.1016/j.jpeds.2020.08.002 sha: doc_id: 301868 cord_uid: ehck72z2 nan covid-19, a disease caused by the novel severe acute respiratory syndrome coronavirus 2 (sars-cov-2) has accounted for over 460,000 deaths globally as of june 2020. [1] children of all ages have been affected, although the clinical manifestations are less severe than adults. in early may, reports emerged from europe and north america describing a hyperinflammatory condition in children related to sars-cov-2 and presenting with some features similar to kawasaki disease and toxic shock syndrome [2, 3] . on may 14, 2020, the centers for disease control and prevention (cdc) recognized this clinical complex as multisystem inflammatory syndrome in children (mis-c) associated with covid-19 and released a case definition based on clinical and laboratory criteria. [4] mis-c patients come to medical attention with fever, elevated inflammatory markers, multisystem organ involvement (renal, gastrointestinal, neurologic, dermatologic, cardiac), with evidence of a current or recent sars-cov-2 infection or recent close contact with a known or suspected case of covid-19. in a report describing the experience of mis-c in new york, 80% of diagnosed children were admitted to the intensive care unit. of the hospitalized children, 52% had myocardial dysfunction and 9% had coronary artery aneurysms. [5] management for mis-c has involved intravenous immunoglobulins, vasoactive agents, anticoagulants and immune-modulating drugs with varied response [6] . to date, reports are limited to description of cardiac findings during hospitalization, however there is paucity of data on the longitudinal follow-up and sequelae in this population. we sought to describe the echocardiographic manifestations of mis-c including evolution of abnormalities of coronary artery dilation and ventricular systolic function over short-term follow-up after discharge from the hospital. a single-center retrospective review was conducted on all pediatric patients (<21 years of age) admitted with mis-c to mount sinai kravis children's hospital between april 24 (first admission) and may 16, 2020 who had at least one echocardiogram performed during hospitalization. the determination of diagnosis of mis-c was based on cdc criteria [4] . only patients with confirmed sars-cov-2 infection j o u r n a l p r e -p r o o f by reverse transcriptase polymerase chain reaction (rt-pcr) and/or serology during hospitalization were included. all of the patients in our cohort were described previously in three recent multicenter publications [7] [8] [5] that focused on acute presentation and inpatient outcomes. additionally, 4 patients from this cohort were described in a recent case series [9] . table (available at www.jpeds.com). the average lv ejection fraction (ef) at first echocardiogram was 49.5% (range 29-58%). eight patients (53%) presented with lv dysfunction (ef <55%) ranging from mild to severe (n=2 with ef 50-54%; n=4 with ef 40-49% and n=2 with ef <35%). 10/13 of children (excluding one lost to follow up and one deceased patient) had recovery of cardiac function within one month of the initial study. three patients continue to have low-normal systolic function (ef=50-55%) and are in ongoing follow-up. (figure 1, a) of the four patients (27%) who had rv dysfunction on initial echocardiogram, all but one (deceased) had complete recovery of rv function on follow-up imaging. two patients had pericardial effusions (small) on initial echocardiograms that resolved. approximately half (n=8, 53%) of the cohort had mitral regurgitation (mild), all but two resolved over the study period. all patients received therapeutic anticoagulation. aspirin was started in patients with coronary artery dilation and/or after discontinuation of enoxaparin in patients without dilation. coronary artery evaluation was performed in 12 patients (80%) and 10/12 had more than one echocardiogram performed in the study period. three patients did not have coronary arteries assessing during echocardiography, 2/3 were due to hemodynamically instability, and one patient was the first admission with mis-c, before the importance of coronary artery assessment was recognized. of the patients with coronary artery evaluation, one-third (n=4) had coronary involvement (z score >2.5). lmca aneurysms (1 small, one medium) were seen in two patients; one resolved and one remains persistent at follow-up. (figure 1, b and figure 2, a) . lad aneurysms were seen in three patients (2 small, 1 medium aneurysm). within 30 days, all patients with lad involvement had normal z-scores (figure 1, c) . only one patient had an aneurysm in the rca (small) that has remained aneurysmal, albeit slightly smaller on recent echocardiogram (figure 1, d and figure 2 , b). this longitudinal study provides information on short-term echocardiographic outcomes of 15 patients with mis-c. although lv dysfunction was common at initial evaluation (53%), significant improvement was seen within a 30-day follow-up period. however, some patients had residual low-normal function at 4-6 weeks follow-up. our findings are congruent to two larger multicenter studies from new york that showed 53%-65% of patients had evidence of myocardial dysfunction during hospitalization. follow-up outpatient data on systolic function was not reported. [5] [7] we found that coronary artery abnormalities can be evident in the first two weeks and tend to have a rapid resolution, with only one patient in this study demonstrating persistence of aneurysms. one-third (33%) of our patients (4/12) had coronary aneurysms. this is higher than a recent report by capone et al, in this study provides short-term longitudinal cardiac information for a small number of patients with mis-c that may aid in clinical management and counseling of families. medium and long-term follow-up using echocardiography as well as advanced imaging modalities such as cardiac magnetic resonance and computed tomography will be important to provide comprehensive data. an outbreak of severe kawasaki-like disease at the italian epicentre of the sars-cov-2 epidemic: an observational cohort study covid-19 and kawasaki disease: novel virus and novel case multisystem inflammatory syndrome in children in new york state hyperinflammatory shock in children during covid-19 pandemic multisystem inflammatory syndrome in children (mis-c) associated with sars-cov-2 infection: a multiinstitutional study from new york city multisystem inflammatory syndrome in u.s. children and adolescents features of covid-19 post-infectious cytokine release syndrome in children presenting to the emergency department diagnosis, treatment, and long-term management of kawasaki disease: a scientific statement for health professionals from the normal echocardiographic values for cardiovascular structures a serological assay to detect sars-cov-2 seroconversion in humans characteristics, cardiac involvement, and outcomes of multisystem inflammatory disease of childhood (mis-c) associated with sars-cov-2 infection (7) 80% (12) corticosteroids administered, % (n) 25% (1) 12.5% (1) 20% (3) tocilizumab administered, % (n) 100% (4) 62.5% (5) 60% (9) anakinra administered, % (n) 25% (1) 0% (0) 13.3% (2) therapeutic anticoagulation % (n) 100 (4)% 100% (8) 100% (15) remdesivir administered, % (n) 25% (1) 12.5% (1) 20% (3) plasma therapy administered, % (n) 0% 0% (0) 6.7% (1) asa during admission, % (n) 50% (2) 0% (0) 13.3% (2) site of coronary artery involvement (individual patient)1. mid-lad, lmca, mid-rca 2. lad 3. lad 4. lmca key: cord-271186-82q22u6i authors: picichè, marco title: cardiac involvment in sars-cov-2-associated inflammatory syndromes date: 2020-08-05 journal: trends cardiovasc med doi: 10.1016/j.tcm.2020.07.008 sha: doc_id: 271186 cord_uid: 82q22u6i nan in their review discussing the effects of severe acute respiratory syndrome coronavirus-2 (sarsin children and adolescents, loke, berul and harahsheh highlight the overlapping features between kawasaki disease (kd) and the recently described inflammatory syndrome called multisystem inflammatory syndrome in children (mis-c) [1] . regrettably, dr. kawasaki, who initially described the disease that bears his name, passed away last month. he started studying this unreported sickness in 1961, labelling the relevant folder -g.o.k‖ for -god only knows‖ [2] . since then, numerous novel infectious and inflammatory diseases have appeared, but the world has rarely seen a large-scale infectious disaster like coronavirus disease-19 (covid-19). first reported in china in december 2019, covid-19 initially appeared among workers at a food market in wuhan, presumably secondary to viral transmission from bats [3] . the world health organization (who) declared covid-19 a public health emergency of international concern on january 30 th , 2020 and released interim guidelines for patient management [4]. however, due to the infection's rapid and devasting spread worldwide, that same organization declared covid-19 a pandemic on march 11 th [5] . it initially seemed that this new disease only affected seniors, especially those with pre-existing comorbidities like diabetes and obesity. soon, however, it increasingly became evident that covid-19 also could affect middle-aged and, albeit less frequently, young adults. it also initially seemed that only the lungs were involved, with involvement similar to adult respiratory distress syndrome (ards); but this too was discovered to be inaccurate. pulmonary involvement was only one aspect of covid-19, true nature of which was that of a systemic, inflammatory disease that could involve other organs, including the cardiovascular system, in many ways [6] . finally, even children and adolescents, heretofore believed to be immune to covid-19's effects, were getting sick, albeit in a way different than adults. this was first observed in the united kingdom [7] where critically ill children with overlapping features of atypical kd and toxic shock syndrome were found to test positive for sars-cov-2. this new condition was soon recognized by both the centers for disease control (cdc) in the united states [8] , and who [9] , who characterized the condition differently. the cdc characterization, named multisystem inflammatory syndrome in children (mis-c) with covid-19, has been more uniformly adopted. clinical features of mis-c are fever, multi-organ dysfunction, evidence of inflammation with high neutrophilia and elevated inflammatory markers, and exclusion of any other microbial cause [1] . for their review, loke et al compiled data on 130 children across five countries (italy, france, switzerland, usa, uk) whose ages ranged from 1.8-16 years. all had fever. other common symptoms/signs included abdominal and respiratory symptoms (in 70 and 40%, respectively), skin rash (55%), conjunctivitis (61%), and fissured lips or strawberry tongue (41%) [1] . the review highlights the cardiac and other features that overlap mis-c and kd. one peculiar aspect of kd is coronary aneurysm formation, which is identified in roughly 25% of untreated patients. aneurysm formation may be followed by thrombosis, myocardial ischemia, and even cardiac death. myocarditis also may occur. often, there is left ventricular dysfunction and hypotension, and sometimes, cardiogenic shock. in mis-c, aneurysm formation has been observed in 15% of patients, including two with giant coronary aneurysms, as has circulatory shock requiring fluids or vasoactive drugs in 64% of cases, arrhythmias in 6%, and decreased left ventricular function in 56% [1] . in adults affected by covid-19, the incidence of acute cardiac injury varies from 7-28% among hospitalized patients, but this number is partially dependent upon the definition of -cardiac injury‖ used [10] [11] [12] . in the literature, this varies from cardiac troponin elevation ≥99 percentile alone, to troponin elevation plus a composite of echocardiographic and electrocardiographic abnormalities. ventricular tachycardia and fibrillation have been seen in 6-44% of patients. heart failure, cardiogenic shock and myocarditis have also been described. while myocarditis is quite infrequent, heart failure has been a reported complication of covid-19 in 23% [11] . furthermore, coagulation and fibrinolytic system dysfunctioncharacterized by prolonged prothrombin times, elevated d-dimer levels and activated partial thromboplastine time, disseminated intravascular thrombosis, venous and arterial thrombi, and pulmonary embolihas become a prominent feature in adults [13] . mechanisms of cardiac injury vary from inflammation to toxicity from direct viral injury, oxygen supply-to-demand mismatch, microvascular dysfunction, and plaque rupture. also in adults with covid-19, the systemic inflammatory responsecharacterized by elevated inflammatory biomarkers, cytokines (e.g., interleukin-2r, tumor necrosis factor, interleukin-6), c-reactive protein, and ferritinmay be devastating, even leading to a cytokine storm and multi-organ dysfunction [14] . although in children with mis-c, the inflammatory response may sometimes be associated with transitory respiratory impairment, this feature is more prominent in adults with covid-19, who may even require venous-venous extracorporeal membrane oxygenation (v-v ecmo) support. who guidelines recommended administering v-v ecmo to eligible patients with covid-19-related ards at centers with sufficient case volumes and extensive clinical expertise [4, 5] . however, notwithstanding the existence of considerable observational data on the use of ecmo for influenza a (h1n1) and middle east respiratory syndrome (mers) coronavirus-related ards, the real utility of ecmo in adult covid-19 patients with respiratory failure is uncertain and remains under investigation [15] . to date, data in adults suggest that roughly one out of every 2-3 patients on v-v ecmo survive [16] , while outcomes with a-v ecmo for mis-c-related cardio-circulatory impairment are almost always favorable [1] . while europe carefully reopened its borders to travelers after the incidence of new covid-19 cases dramatically decreased during a lockdown, the virus continues to run rampant in the united states and latin america. there also is the possibility that a new outbreak will arise in europe next autumn, which makes it crucial to further study the role of ecmo in covid-19. in conclusion, sars-cov-2 may generate an inflammatory syndrome in both adults and children, albeit with several different characteristics and consequences. among them is that adults experience more multisystem inflammatory syndrome in children: is there a linkage to kawasaki disease? doctor who identified inflammatory disease in children, dies at 95. the washington post genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding who: rolling updates on coronavirus disease sars-cov-2: characteristics and current advances in research guidance: paediatric multisystem inflammatory syndrome temporally associated with covid-19 us centers for disease control and prevention. multisystem inflammatory syndrome in children (mis-c) associated with coronavirus disease multisystem inflammatory syndrome in children and adolescents temporally related to covid-19 clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in wuhan, china clinical course and risk factors for mortality of adult inpatients with covid-19 in wuhan, china: a retrospective cohort study cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (covid-19) jama cardiol coagulation abnormalities and thrombosis in patients with covid-19 covid-19 for the cardiologist: a current review of the virology, clinical epidemiology, cardiac and other clinical manifestations and potential therapeutic strategies ecmo use in covid-19: lessons from past respiratory virus outbreaks-a narrative review role of extracorporeal membrane oxygenation in covid-19: a systematic review key: cord-035239-5zdjxtm7 authors: makvandi, shayan; alibrahim, omar; abdul-aziz, rabheh; abdul-fattah sallam, mohammad; mcgreevy, megan title: a rare presentation of multi-system inflammatory disease in children associated with severe acute respiratory syndrome coronavirus 2 (sars-cov-2) date: 2020-10-10 journal: nan doi: 10.7759/cureus.10892 sha: doc_id: 35239 cord_uid: 5zdjxtm7 management of multi-system inflammatory disease in children (mis-c) remains a challenge due to the evolving nature of the coronavirus disease 2019 (covid-19) pandemic. this article reports a rare presentation of multi-system inflammatory disease in a previously healthy 16-month-old male who fully recovered with minimal residual cardiac insufficiency upon discharge. our case is unique due to patient's young age, cardiac findings, and his response to our treatment protocol. a multi-disciplinary team in a tertiary center was involved with care. since april 2020, multiple reports emerged from europe and later from new york of multi-system inflammatory disease in children (mis-c) presenting with different clinical patterns that occur from one to six weeks following severe acute respiratory syndrome coronavirus 2 (sars-cov-2) infection in the pediatric age group [1] [2] [3] [4] [5] [6] [7] [8] . different clinical patterns were reported, including kawasaki disease (kd)-like illness, vasoplegic shock, cardiogenic shock/myocarditis, and hyperinflammatory clinical pattern with the absence of shock and mucocutaneous involvement [2] . cardiac involvement was variable among reports with suggested pathophysiology of cardiac edema rather than acute necrotic inflammatory myocardial injury [1] . cardiac magnetic resonance imaging (mri) examination supported this theory by finding little evidence of myocardial cell degeneration and necrosis [9] . the median age of affected children with mis-c is reported to be consistently older than children affected by kd (mean: 8.5 -10) [5, 1] . evidence of sars-cov-2 infection was also variable among the reports, ranging from 69% to 100% [4] [5] [6] . a previously healthy 16-month-old male presented with febrile seizure, rash, and diarrhea. initial workup in the emergency room, including a ct scan of the head, was not conclusive. he was sent home and returned 12 hours later with 40.4 c fever, worsening upper body rash, and diarrhea. vital signs were significant for heart rate 120, hypotensive with blood pressure 72/40, tachypneic with respiratory rate 36, and oxygen saturation of 99% while breathing ambient air. physical exam was prominent for periorbital edema, hepatomegaly 4cm below the right costal margin, bilateral inguinal lymphadenopathy, and slightly raised non-pruritic erythematous rash concentrated on the trunk and proximal arms. shortly after admission, he developed distributive shock with worsening hypotension and tachycardia. the patient was intubated with concern for acute hypoxic respiratory failure and shock state. vasopressors and inotropes were initiated for hypotension. blood and urine cultures were obtained, and broad-spectrum antibiotics with cefepime and vancomycin were started. patient met centers for disease control and prevention (cdc) criteria for mis-c with fever, anemia hemoglobin 8.8 g/dl, hypoalbuminemia 2.7 g/dl, thrombocytopenia 69 x10^9/l, elevated c-reactive protein 134 mg/l, erythrocyte sedimentation rate 10mm/hr, elevated procalcitonin 33.9 ng/ml, elevated ferritin 2763 ng/ml, elevated lactic acid dehydrogenase 987 u/l, il6 318pg/ml, il2 4705pg/ml, il10 38pg/ml, coagulopathy with significantly elevated d-dimer 18 mcg/ml, prolonged prothrombin time (pt) 17.9 sec, prolonged partial thromboplastin time (ptt) 39.3 sec, elevated brain natriuretic peptide (bnp) 498 pg/ml and low anti-thrombin iii 39, positive covid-19 immunoglobulin g (igg) antibody and negative polymerase chain reaction (pcr). the rapid viral panel was negative. serial echocardiograms showed hyperdynamic left ventricle systolic function and mild tricuspid regurgitation with no clinical significance and ultimately resolved (figures 1-2 showed nonspecific t-wave changes. troponin was within a normal range. the patient received methylprednisolone 20mg/kg, anakinra 2mg/kg, intravenous immunoglobulin (ivig) 2g/kg, and prophylactic lovenox® dosing with 0.5mg/kg twice daily. the patient remained intubated on mechanical ventilation and remained on vasopressors/inotropes for three days with a maximum epinephrine dose of 0.08 mcg/kg/min and norepinephrine 0.15 mcg/kg/min. anakinra dosage was gradually increased over time due to persistent fevers. the patient completed 12 days of anakinra with a maximum dosing of 12mg/kg/day, two doses of ivig, and was maintained on a high dose of methylprednisone 30 mg/kg/day on the second and third days and then 8mg/kg/day with tapering for the rest of stay, which switched to oral prednisone once oral tolerance improved. the patient stayed at the hospital for a total of 15 days and was discharged on steroid taper. laboratory data for the initial 10 days of admission are presented in table 1 . management of mis-c remains a challenge due to the evolving nature of this pandemic. a multi-disciplinary team is required to guide care. due to the novelty of this condition, well-established treatment guidelines are not available; therefore, newly proposed institutional guidelines were utilized [8] . clinical improvement and inflammatory markers reduction were adopted as markers for disease improvement. our approach in pharmacological treatment was parallel to most institutions with ivig, glucocorticoids, and interleukins receptor antagonists (treatment guidelines: montgomery v, vidwan j, statler v, et al.: ebc guideline: evaluation for multisystem inflammatory syndrome -children and management of mis-c. norton children's hospital, 2020). other institutions used biologic modifying agents only in patients unresponsive to ivig and corticosteroids [3, 5] . early development of shock with cardiac dysfunction has been the hallmark of mis-c in acutely ill patients [3] . the positive outcome of this case emphasizes the importance of early recognition of shock state, proper and judicious fluid resuscitation, the early establishment of invasive monitoring, intubation, mechanical ventilation, and appropriate initiation of inotropes and vasopressors. almost half of the patients presenting with mis-c show some degree of ventricular dysfunction, pericardial effusion, or coronary aneurism. the rate of cardiac dysfunction without coronary involvement is much higher in mis-c compared to kd [9] . notably, patients with mis-c have a higher prevalence of shock (76%) and cardiac dysfunction compared to kawasaki disease (3%) [3] . our patient showed noticeable bilateral atrioventricular (av) valves regurgitation, which is a new finding compared to documented cases [10] . persistence of cardiac dysfunction has been noticed in many cases on discharge [3] . this requires a close follow up of recovered patients with serial echos. concomitant cytokine storm in some patients with mis-c makes it challenging to treat patients with only one clinical approach. there is not enough data for early prophylactic anticoagulation for the pediatrics population with mis-c. in our patient with multiorgan failure and significant coagulation derangement, anticoagulation was justified. in some institutions, aspirin is used for initial anticoagulation, and low molecular weight heparin (lmwh) is only used in patients with noticeable elevation in d-dimer [3] . further studies are warranted to investigate the pathophysiological mechanism of this post-infectious immune-mediated disease. the unique about our case is the young age of the patient, unique cardiac involvement with valvar regurgitation, patient's initial presentation with seizure, and response to our treatment protocol. up to date, there is no approved treatment protocol for similar critical cases. it is important to share our experience with providers taking care of these newly evolving critical cases human subjects: consent was obtained by all participants in this study. conflicts of interest: in compliance with the icmje uniform disclosure form, all authors declare the following: payment/services info: all authors have declared that no financial support was received from any organization for the submitted work. financial relationships: all authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. other relationships: all authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work. acute heart failure in multisystem inflammatory syndrome in children (mis-c) in the context of global sars-cov-2 pandemic clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with sars-cov-2 characteristics, cardiac involvement, and outcomes of multisystem inflammatory disease of childhood (mis-c) associated with sars-cov-2 infection multisystem inflammatory syndrome related to covid-19 in previously healthy children and adolescents in new york city multisystem inflammatory syndrome in children during the covid-19 pandemic: a case series paediatric multisystem inflammatory syndrome temporally associated with sars-cov-2 mimicking kawasaki disease (kawa-covid-19): a multicentre cohort hyperinflammatory shock in children during covid-19 pandemic covid-19 associated multisystem inflammatory syndrome in children (mis-c) guidelines; a western new york approach cardiac mri of children with multisystem inflammatory syndrome (mis-c) associated with covid-19: case series multisystem inflammatory syndrome in children in new york key: cord-322435-c88tkbnz authors: rekhtman, sergey; tannenbaum, rachel; strunk, andrew; birabaharan, morgan; wright, shari; garg, amit title: mucocutaneous disease and related clinical characteristics in hospitalized children and adolescents with covid-19 and mis-c date: 2020-10-24 journal: j am acad dermatol doi: 10.1016/j.jaad.2020.10.060 sha: doc_id: 322435 cord_uid: c88tkbnz background little is known about mucocutaneous disease in acutely-ill children and adolescents with covid-19 and mis-c. objective to characterize mucocutaneous disease and its relation to clinical course among hospitalized patients with covid-19 and mis-c. methods descriptive cohort study of prospectively and consecutively hospitalized eligible patients between may 11, 2020 and june 5, 2020. results in covid-19 patients, 4/12 (33%) had rash and/or mucositis, including erythema, morbilliform pattern, and lip mucositis. in mis-c patients, 9/19 (47%) had rash and/or mucositis, including erythema, morbilliform, retiform purpura, targetoid and urticarial patterns, along with acral edema, lip mucositis, tongue papillitis, and conjunctivitis. covid-19 patients with rash had less frequent respiratory symptoms, picu admission, and invasive ventilation, as well as shorter stay (vs covid-19 without rash). mis-c patients with rash had less frequent picu admission, shock, ventilation, as well as lower levels of crp, ferritin, d-dimer, and troponin (vs mis-c without rash). neutrophil-to-lymphocyte ratio was similar for patients with and without rash in both groups. none of the mis-c patients met criteria for kawasaki disease. limitations small sample sizes. conclusions mucocutaneous disease is common among children and adolescents with covid-19 and mis-c. laboratory trends observed in patients with rash may prognosticate a less severe course. coronavirus disease 2019 has variability within its constellation of findings among 73 children and adolescents. [1] [2] [3] [4] [5] in addition to fever and respiratory symptoms, pediatric patients infected with 74 severe acute respiratory syndrome coronavirus 2 (sars-cov-2), the pathogen in covid-19, also 75 develop eruptions and mucositis. yet little is understood about the morphologic spectrum of 76 mucocutaneous disease and its relation to outcomes among acutely-ill children and adolescents with 77 covid-19, or its presumed sequela, multisystem inflammatory syndrome in children (mis-c). the new 78 york metropolitan area was an epicenter for the pandemic in the united states, 6 and this provided an 79 opportunity to characterize mucocutaneous disease in pediatric hospitalized patients with covid-19 and 80 mis-c. the purpose of this study was to estimate prevalence of integumentary findings in hospitalized 81 patients with covid-19 and mis-c, to characterize their morphologic patterns, to evaluate whether rash 82 prognosticates clinical course, and to determine how closely features in mis-c align with kawasaki 83 disease (kd). 84 this study was performed at cohen children's hospital (northwell health), a tertiary hospital 86 located in queens, new york. the study sample consisted of all hospitalized patients between may 11, 87 2020 and june 5, 2020 who were aged ≤18 years and who were suspected of having covid-19 or mis-88 c. criteria for confirming the diagnosis of mis-c included age <21 years, fever for ≥24 hours, clinically 89 severe illness requiring hospitalization, multisystem organ involvement, no alternative plausible 90 diagnosis, and exposure to a suspected or confirmed covid-19 case or positive sars-cov-2 infection 91 by pcr/serology testing. 7 the sample was limited to patients who had 1) diagnosis of mis-c based on all 92 six criteria above, and this group comprised the mis-c cohort; or 2) positive covid-19 pcr test among 93 those not meeting the definition of mis-c, and this group comprised the covid-19 cohort. presence of at least one covid-19-related rash. we categorized covid-19 and mis-c patients 104 separately because these diseases have different clinical characteristics and disease courses, and because 105 mis-c is considered to be a later, non-infectious complication of covid-19. 106 given the anticipated sample size, and consequently low statistical power, the intent of our 108 analysis was descriptive and hypothesis generating. medians (iqr) were used to describe continuous 109 variables, and frequencies (percentages) were used to describe categorical variables. this study was 110 approved by the institutional review board at the feinstein institutes of medical research at northwell 111 of 39 hospitalized pediatric patients identified as possible covid-19 or mis-c during the study 114 period, 31 were eligible for inclusion. six patients did not test positive for sars-cov-2 pcr and were 115 also ruled out for mis-c prior to discharge. others excluded were one child whose family deferred skin 116 examination, and one newborn having limb necrosis with negative sars-cov-2 pcr and igm antibody, 117 who was felt to have fetal compartment syndrome. demographic characteristics for 12 patients classified 118 as covid-19 and 19 patients classified as mis-c are listed in table 1 . those with rash were younger. (table i) . only three of 12 (25%) were febrile (≥100.4°f) during 122 type and frequencies of morphologic patterns observed in patients with covid-19 are described 124 in table 1 . none of the hospitalized covid-19 patients with rash had pernio-like lesions of the toes or 125 fingers, and none had conjunctivitis. locations and frequencies of mucocutaneous eruptions in patients 126 with covid-19 are described in figure 1 . 127 compared to covid-19 patients without rash, those with rash were observed to have less 128 frequent respiratory symptoms, admission to the pediatric intensive care unit (picu), and ventilation, as 129 well as shorter length of hospital stay. maximum neutrophil-to-lymphocyte ratio (nlr) observed during 130 hospitalization was similar for patients with and without rash. (table ii) 131 in patients with mis-c, 9/19 (47%) had rash and/or mucositis. (figure 2 ; supplemental figure 133 2) all 19 patients (100%) were febrile during hospitalization. 134 morphologic patterns were heterogeneous. (table i ) lip fissuring or cracking was present in 135 44% (4/9), while papillitis of the tongue was present in 22% (2/9). conjunctivitis was present in 22% 136 (2/9) of patients with rash. locations and frequencies of mucocutaneous eruptions in patients with mis-c 137 are described in figure 1 . 138 compared to mis-c patients without rash, those with rash were observed to have less frequent 139 picu admission, shock, and requirement for invasive mechanical ventilation. patients with rash also had 140 lower levels of inflammatory markers. maximum nlr observed during hospitalization was similar for 141 patients with and without rash. (table ii) we observed that presence of rash appears to prognostic a less severe clinical course. finally, we 157 observed that mis-c and kd may be more dissimilar the presently postulated. and adolescents, and the basis for preferential involvement of skin, warrants further study. 180 the nlrs were similar between covid-19 patients with and without rash, as well as between 181 mis-c patients with and without rash. we did however observe higher nlr in mis-c patients as 182 compared with covid-19 patients, and this may prove to be a useful differentiating marker. in adults, 183 nlr has been observed to distinguish mild from severe cases of covid-19. may and june of 2020 in the new york metropolitan area. as such, we had inadequate power to perform 196 hypothesis tests and we cannot rule out that differences observed between groups were due to chance. 197 however, the finding of less severe course was observed across several indicators among both and mis-c patients with rash. pathology was not obtained as there was no clear indication this could 199 specify diagnoses or change the courses of care. chinese pediatric novel coronavirus study team. sars-cov-2 209 infection in children epidemiology of covid-19 among children in china characteristics of and important lessons from the coronavirus disease 2019 213 (covid-19) outbreak in china: summary of a report of 72 314 cases from the chinese center for disease 214 control and prevention screening and severity of coronavirus disease clinical and epidemiological features of 36 children 219 with coronavirus disease 2019 (covid-19) in zhejiang, china: an observational cohort study department of health. coronavirus disease 2019 (covid-19) multisystem inflammatory syndrome in children disease committee of the council on cardiovascular disease in the young council on cardiovascular and stroke nursing; council on cardiovascular surgery and anesthesia and council on epidemiology and prevention. diagnosis, treatment, and long-term management 229 of kawasaki disease: a scientific statement for health professionals from the an outbreak of severe kawasaki-like disease at the italian 232 epicentre of the sars-cov-2 epidemic: an observational cohort study multisystem inflammatory syndrome related to covid-235 previously healthy children and adolescents in clinical characteristics of 58 children with a pediatric 238 inflammatory multisystem syndrome temporally associated with sars-cov-2 pernio-like skin lesions associated with covid-19: a 241 case series of 318 patients from 8 countries angiogenesis in covid-19 endothelial cell infection and endotheliitis in covid-19 clinical characteristics of 138 hospitalized patients with coronavirus-infected pneumonia in wuhan dysregulation of immune response in patients with coronavirus clinical and immunological features of severe and moderate 253 coronavirus disease 2019 key: cord-308046-y9kui730 authors: naka, fludiona; melnick, laura; gorelik, mark; morel, kimberly d. title: a dermatologic perspective on multisystem inflammatory syndrome in children()() date: 2020-09-23 journal: clin dermatol doi: 10.1016/j.clindermatol.2020.09.003 sha: doc_id: 308046 cord_uid: y9kui730 as of may 2020, an emerging immune-mediated syndrome primarily affecting children has been detected primarily in europe and the united states. the incidence of this syndrome appears to mirror the initial infectious assault, with a delay of several weeks. this syndrome has been termed multisystem inflammatory syndrome in children (mis-c), and is observed in association with the coronavirus disease 2019 (covid-19). the phenotypes of presentation include several characteristic features, including prolonged fever, eruption, neck stiffness and gastrointestinal manifestations with pronounced abdominal pain. shock and organ dysfunction on presentation are frequently but inconsistent, while respiratory distress is typically, and notably, absent. we have reviewed recently published data aiming to better understanding mis-c, with a focus on its mucocutaneous manifestations. • mucocutaneous manifestations of mis-c: conjunctivitis, oral mucosal changes, rash. • the rash of mis-c is typically diffuse and non-specific. • mucocutaneous manifestations of mis-c are more common in younger children. • kd and mis-c differ in mean age of onset, race predilection, and associated symptoms. documented worldwide. 13 as the spotlight shines on this new inflammatory disease, we are beginning to get more clarification of its clinical presentation and pathogenesis. both the cdc and the who have released their own mis-c diagnostic criteria to help clinicians in making such diagnosis. table 1 and table 2 review these criteria in detail. the main clinical manifestations that both groups focus on include fever for over 24 hours, laboratory evidence of inflammation, two or more organ involvement (commonly gi, followed by cardiac and renal), mucocutaneous findings, and either a positive test or exposure within four weeks of clinical manifestations. a negative covid pcr does not rule out this diagnosis. because mis-c is thought to be an immune-mediated secondary response to the virus, covid pcrs are usually negative at the time of the illness, and antibodies are positive in the majority of cases. 11, [14] [15] [16] [17] [18] [19] [20] [21] because diagnostic criteria for this condition are generally very broad, there is a significant challenge in identifying which patients falling under these diagnostic criteria are 'true' mis-c. 22 demographic data of children with mis-c from thirteen recent large case series are summarized in table 3 . the size of these studies ranges from eight to 186 children. we recap patient mean/median age, sex, cutaneous signs/symptoms, sars-cov-2 testing method, treatments, and outcome. fever and gi symptoms were the top two most common systemic signs/symptoms seen in children who met criteria for mis-c. the majority of patients were previously healthy. the two most common comorbidities were asthma and obesity. the median age of children with mis-c was between 8-12 years old. boys were equal or more prevalent in all but two publications. in the us studies, the majority of the children affected were black non-hispanic, hispanic or latino, or ashkenazi jewish. 15, 19, [23] [24] most patients were treated with ivig +/-systemic steroids. the majority of patients had a negative covid pcr at the time of diagnosis, likely because the disease tends to present 4-6 weeks after the viral infection. with the j o u r n a l p r e -p r o o f journal pre-proof exception of one report, 20 all other case series found that patients were more likely to have positive antibodies as compared to pcr. covid pcr positivity ranged from 13% -50%, while antibody positivity ranged from 75%-100%. 10-12, 14-21, 23-24 mucocutaneous manifestations of mis-c while mucocutaneous manifestations are not very common among children with covid-19 at large, they are among the top clinical manifestations in children with mis-c, making them important to identify and recognize these in an attempt to understand the disease. most of the clinical information to date comes from small descriptive studies, such as case series and case reports. documented cutaneous findings reported in children with covid-19 include non-specific maculopapular eruptions, followed by chilblain-like or pernio-like acral lesions, urticarial lesions, livedo reticularis, papulovesicular or varicella-like lesions, petechiae or dengue-like lesions, and erythema multiforme-like lesions. [25] [26] [27] [28] [29] [30] [31] [32] [33] multiple larger case series published in the recent months 10-12, 14-21, 23-24 focus on characterizing and understanding mis-c. each case series has identified children who met criteria for mis-c and described the cutaneous findings with which they presented. the following descriptive terminology was used to describe the skin findings: "conjunctivitis," "eruption," "red/cracked lips," lips/oral cavity changes," "cheilitis," "extremity changes," or "hand/feet edema". most of the studies did not provide photos of the eruption and did not attempt to describe it. others that did, used the following non-descriptive terminology: j o u r n a l p r e -p r o o f journal pre-proof "polymorphous," "general," "variable," "skin desquamation," "diffuse," "non-specific," or simply "eruption." refer to table 3 . the investigators of one of the major series conducted targeted surveillance for mis-c at multiple pediatric health centers across the united states and identified 126 children who met criteria for mis-c. mucocutaneous findings were identified in 74% of children who met criteria for mis-c. of these, 59% had non-specific eruption, 55% bilateral conjunctivitis, 42% oral mucosal changes, and 37% peripheral extremity changes. 24 in a review of over 191 potential mis-c cases of hospitalized children reported to the new york state department of health, 95 met criteria for mis-c. they found that 60% of children who met criteria for mis-c had a diffuse non-specific eruption, while 56% had conjunctivitis and 27% oral mucosal changes. 19 looking at all the thirteen-case series presented in table 3 , the percentage of children diagnosed with mis-c who developed mucocutaneous findings included: conjunctivitis 27% -93%, oral mucosal changes 25% -87%, eruption 47% -81%, and hand/feed erythema and edema 27% -68%. table 4 summarizes the top mucocutaneous manifestations of children with mis-c. 10-12, 14-21, 23-24 the skin findings associated with mis-c tend to be more common in younger children and decrease with age. 87% of children between 0-5 years old had mucocutaneous findings, compared to only 61.5% of those 13-20 years old. 19 as we discuss the various mucocutaneous manifestations associated with mis-c, many sounds similar to other diseases, specifically kawasaki disease (both typical and atypical); however, a wide differential diagnosis consideration is needed, when seeing a child with a 36 the presence of an aneurysm itself is not a defining feature that would necessitate relating the two syndromes. table 5 first case of 2019 novel coronavirus in the united states cdc covid-19 response team. coronavirus disease 2019 in children -united states characteristics of and important lessons from the coronavirus disease 2019 (covid-19) outbreak in china: summary of a report of 72314 cases from the chinese center for disease control and prevention multisystem inflammatory syndrome in children and adolescents with covid-19. scientific brief sarscov-2 infection in children severe acute respiratory syndrome coronavirus 2 (sars-cov-2) infection in children and adolescents: a systematic review epidemiology of covid-19 among children in china information for healthcare providers about multisystem inflammatory syndrome in children (mis-c). case definition for mis-c guidance: pediatric multisystem inflammatory syndrome temporally associated with covid-19 hyperinflammatory shock in children during covid-19 pandemic childhood multisystem inflammatory syndrome -a new challenge in the pandemic pediatric inflammatory multisystem syndrome: temporally associated with sars-cov-2 (pims-ts): cardiac features, management and short-term outcomes at a uk tertiary pediatric hospital multisystem inflammatory syndrome in children associated with severe acute respiratory syndrome coronavirus 2 infection: a multi-institutional study from new york city acute heart failure in multisystem inflammatory syndrome in children (mis-c) in the context of global sars-cov-2 pandemic multisystem inflammatory syndrome in children (mis-c) related to covid-19: a new york city experience kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic in paris, france: prospective observational study multisystem inflammatory syndrome in children in new york state pediatric multisystem inflammatory syndrome temporally associated with sars-cov-2 mimicking kawasaki disease (kawa-covid-19): a multicenter cohort acute myocarditis and multisystem inflammatory emerging disease following sars-cov-2 infection in critically ill children multi-system inflammatory syndrome in children (mis-c) following sars-cov-2 infection: review of clinical presentation, hypothetical pathogenesis, and proposed management multisystem inflammatory syndrome related to covid-19 in previously healthy children and adolescents multisystem inflammatory syndrome in u.s. children and adolescents clinical characteristics of coronavirus disease 2019 in china classification of the cutaneous manifestations of covid -19: a rapid prospective nationwide consensus study in spain with 375 cases varicella-like exanthem associated with covid-19 in an 8-year-old girl: a diagnostic clue? reply to covid-19 can present with a rash and be mistaken for dengue: petechial rash in a patient with covid-19 infection chilblain-like lesions in children following suspected covid-19 infection clustered cases of acral perniosis: clinical features, histopathology, and relationship to covid-19 chilblains in children in the setting of covid-19 pandemic comment on "chilblains-like lesions in children following suspected covid-19 infection erythema multiforme-like lesions in children and covid-19 key: cord-317822-e4uhop4w authors: bahrami, ahmad; vafapour, maryam; moazzami, bobak; rezaei, nima title: hyperinflammatory shock related to covid‐19 in a patient presenting with multisystem inflammatory syndrome in children: first case from iran date: 2020-07-08 journal: j paediatr child health doi: 10.1111/jpc.15048 sha: doc_id: 317822 cord_uid: e4uhop4w nan the novel coronavirus (sars-cov-2) that is responsible for coronavirus disease (covid-19) has emerged as a global crisis. 1 according to the johns hopkins university information site, as of 4 june 2020, over 6.29 million cases have been confirmed, and about 380 000 deaths due to covid-19 have been reported world-wide. the severity of the disease has been reported to range from mild to severe and eventually death. 1 paediatric populations seem to comprise only a small proportion of total affected individuals and are less likely than adults to be severely affected by covid-19. according to a recent epidemiological study, 731 cases of covid-19 were confirmed in children, of whom more than 90% of patients were reported as asymptomatic or with mild to moderate symptoms. 2 the clinical presentation of paediatric patients may differ from those of the adults and can range from asymptomatic to acute upper respiratory tract infection, gastrointestinal symptoms with shock or coagulation dysfunction in severe cases. to date, the exact pathophysiology of covid-19 has not been fully understood. however, emerging evidence suggests that a vascular disease process may be a contributing factor in covid-19 pathogenesis. 3 these findings indicate that direct viralmediated tissue damage and endothelial dysfunction in the setting of an inflammatory state could be responsible for various adverse outcomes. a growing body of evidence from the uk, europe and the usa suggests that a number of paediatric patients could present with fever, rash and shock with concomitant covid-19 infection. recently, the royal college of paediatrics and child health (uk) called this phenomenon paediatric inflammatory multisystem syndrome temporally associated with sars-cov-2. 4 similarly, the centers for disease control and prevention (usa) termed this new presentation multisystem inflammatory syndrome in children (mis-c). the exact underlying mechanisms for this kawasaki disease (kd)-like condition described in these reports are not clear; but may be due to antibody or immunecomplex mediated effects in the setting of a post-infectious delayed inflammatory process. herein, we describe an iranian paediatric case of a concurrent kd-like inflammatory syndrome and covid-19 infection who presented with shock. the patient was a 5-year-old girl who presented to paediatric urgent care with 5 days of high-grade fever, vomiting, diarrhoea and abdominal pain, which had been managed as an outpatient as a viral infection. on the third day, she developed conjunctivitis, blotchy rash and swelling of the hands. in the patient's history, she had experienced upper respiratory symptoms over the past 3 weeks that had improved with supportive care. at the initial clinical examination, the patient was ill and had generalised erythematous skin rash, non-purulent bilateral conjunctivitis, periorbital oedema and erythema, swelling and congestion of the lips, mild swelling of the hands and moderate dehydration due to vomiting and diarrhoea (fig. 1 ). there was no evidence of lymphadenopathy. vital signs showed a temperature of 39.5 c, sinus tachycardia (165 beats/min), tachypnoea with normal key points 1 a growing body of evidence from the united kingdom (uk), europe, and the united states of america (usa) suggests that a number of paediatric patients could present with kawasakilike symptoms such as fever, rash and shock with concomitant covid-19 infection which has been referred to multisystem inflammatory syndrome in children (mis-c). 2 the negative results of polymerase chain reaction (pcr) test for covid-19 in a patient with high levels of serum igg could suggest that the virus had been cleared and the presence of kawasaki-like manifestations may be due to delayed immunemediated phenomenon caused by covid-19. 3 despite the growing number of mis-c cases around the world, many questions remain unanswered about the underlying pathophysiology of hyperinflammatory shock related to covid-19 as well as treatment modalities, epidemiological and clinical characteristics associated with mis-c. breath sounds and an oxygen saturation of 98% and the blood pressure was 75/55. laboratory tests revealed lymphopaenia, thrombocytopaenia, mildly elevated c-reactive protein (crp) of 23 mg/l and erythrocyte sedimentation rate of 40 mm/h. she had hyponatraemia (na: 120 meq/l) and elevated liver function tests (table 1) . about 4 weeks before she was admitted to our hospital, she had a positive history of exposure to her uncle who was diagnosed with covid-19. owing to this history of exposure, reverse transcriptase-polymerase chain reaction (rt-pcr) and serology for sars-cov-2 were requested. the pcr was negative on two occasions; however, igg for sars-cov-2 was positive (igg: 10.3 times higher than reference standard; igm: 0.2 times lower than reference standard; normal range was defined as lower than 1.1 ratio) suggesting previous sars-cov-2 infection. prompt treatment with fluid resuscitation was initiated due to the patient's dehydration and low blood pressure. after vital signs stabilised, the patient was evaluated for the possible diagnosis of kd. after establishing the diagnosis, standard treatment for kd was started according to guidelines. she was treated with a single dose of 2 g/kg intravenous immunoglobulin (ivig) and high-dose acetylsalicylic acid. the patient's fever subsided after the initiation of ivig and she was without fever for about 24 h. however, she developed high-grade fever again as well as hypotension the next day. in serial laboratory tests, a markedly elevated crp level along with high procalcitonin and d-dimer were observed (table 1 ). there was evidence of shock and ivigresistant kd. inotropic management of the shock with epinephrine was started for the patient. according to advice from the infectious diseases team, broad-spectrum antibiotics including meropenem, vancomycin and ciprofloxacin was also administered. after the shock resolved, a second dose of the ivig was initiated. there were no significant findings on chest x-ray and the echocardiogram was normal with no evidence of coronary artery dilation. our patient suffered from severe generalised abdominal pain. on abdominal ultrasound scan, a fluid accumulation measuring 33 × 34 × 14 mm was localised in the right lower quadrant and a volume of 9 ml was reported. after 48 h, the abdominal ultrasound scan was repeated in which a mild free fluid collection was noted in the right paracolic area and pelvis. during this time, the patient had orthostatic hypotension and lower limb mottling while standing which was due to the presence of hyperinflammatory shock (fig. 2) . the symptoms and fever were present for another 48 h. all of our patient's signs and symptoms began to improve on the third day of hospitalisation after starting the second dose of ivig and antibiotics. antibiotic treatment was continued for 1 week. the patient's blood culture and adenovirus-specific pcr tests were negative. at the time of discharge, evidence of desquamation was observed on the patient's fingers. the patient was discharged with instructions to take low dose aspirin (3 mg/kg daily) and plans for repeating her follow-up echocardiogram 1 week after discharge. since the first reported kd-like case of a 6-month-old female infant who was concurrently diagnosed with covid-19 in stanford children's hospital in usa, a growing number of mis-c cases have been reported world-wide. 5 recently, an italian cohort of kd-like cases in bergamo province, which experienced the highest rate of covid-19 infection and death in italy, reported a sudden surge of new cases of kd with an increased incidence of nearly 30-fold over the past 5 years in that region. 6 although it has been hypothesised that a delayed immune response to the virus might be contributing to the clinical feature of mis-c, the exact link between covid-19 and mis-c remains unclear. the role of respiratory viruses in the pathogenesis of kd is not fully understood. according to previous studies, the most common viruses detected in kd patients were rhinovirus and enterovirus. 7 although most of the reported covid-19 cases among children experienced mild symptoms, the potential to progress to a more severe course such as with shock still exist and could lead to permanent organ damage and mortality. the observed negative results of pcr in our patient along with high levels of serum igg could suggest that the virus had been cleared and the manifestations displayed in this patient may be due to delayed immune-mediated phenomenon caused by covid-19. 8 however, limited data exist regarding the exact immunological mechanism of covid-19 in predisposing individuals to hyperinflammatory shock. the patient presented in this study had severe symptoms consistent with mis-c and developed hyperinflammatory shock during the admission but had a good response to standard treatments. the high procalcitonin and crp levels along with symptoms of shock in this patient suggest a serious and lifethreatening medical condition. with respect to her history of contact with covid-19, preceding upper respiratory tract symptoms, positive igg for sars-cov-2 and negative blood culture; our patient's symptoms appear to be related to covid-19. as more cases of concurrent covid-19 and mis-c have been increasingly reported world-wide, whether this relationship is causation or association is not yet fully elucidated. on the epidemiological aspect of the current pandemic, the timing between positive cases of covid-19 and identification of new cases of mis-c in various locations, suggest that this phenomenon may be partly contributed to by a delayed immunemediated process that is triggered by the sars-cov-2 infection. this observation is supported by the fact that the majority of reported cases were pcr negative for sars-cov-2, while serology testing has been found to be positive in many cases. 6 nevertheless, it is worth noting that although vasculitis is known to be caused by coronavirus, it is too early to conclude that kd is due to coronavirus. despite the growing number of reported cases, many questions remain unanswered about the new coronavirus such as the treatment modalities, epidemiological, and clinical features associated with covid-19, especially in the paediatric population. early recognition and management of this novel phenomenon is crucial in order to minimise potential complications of this disease in the paediatric population. further studies are needed to increase our knowledge regarding mis-c related to covid-19 pathogenesis. written informed consent for publication of this patient's clinical details and clinical images was obtained from the parents. a new coronavirus associated with human respiratory disease in china epidemiological characteristics of 2143 pediatric patients with 2019 coronavirus disease in china facing covid-19 in the icu: vascular dysfunction, thrombosis, and dysregulated inflammation guidance-paediatric multisystem inflammatory syndrome temporally associated with covid-19. uk: royal college of paediatrics and child health covid-19 and kawasaki disease: novel virus and novel case an outbreak of severe kawasaki-like disease at the italian epicentre of the sars-cov-2 epidemic: an observational cohort study concurrent respiratory viruses and kawasaki disease complex immune dysregulation in covid-19 patients with severe respiratory failure we would like to thank both our patient and her family for letting us share their experience. also, we thank all doctors and nurses who fought bravely during this pandemic. key: cord-354093-zdhfyotl authors: kohli, utkarsh; lodha, rakesh title: cardiac involvement in children with covid-19 date: 2020-08-07 journal: indian pediatr doi: 10.1007/s13312-020-1998-0 sha: doc_id: 354093 cord_uid: zdhfyotl in contrast to adults, severe acute respiratory syndrome coronavirus 2 (sars-cov-2) usually leads to a mild illness in children. however, a few children have been reported to have severe manifestations including pneumonia, acute kidney injury, multi-organ failure and cardiac injury. this review focuses on cardiac involvement during sars-cov-2 infection and the recently described likely immune mediated post-covid-19 syndrome. therapeutic strategies for cardiac dysfunction in both these settings are briefly discussed. w e are currently in the midst of a sars-cov-2 mediated novel coronavirus disease 2019 (covid19) pandemic. in contrast to adults, sars-cov-2 mostly leads to a mild illness in children typically manifested as fever, cough or gastrointestinal symptoms [1, 2] . however, a few children have been reported to manifest severe disease which has been characterized by pneumonia, acute kidney injury, liver injury, metabolic acidosis, neurological injury, rhabdomyolysis, multi-organ system failure, and cardiac injury [1, [3] [4] [5] . this review focuses on cardiac involvement during covid-19 infection and the multisystem inflammatory syndrome in children (mis-c) [6, 7] . therapeutic strategies for cardiac dysfunction in both these settings are briefly discussed. cardiac involvement, which can manifest as acute myocardial injury with elevated plasma troponin concentration, acute coronary events, heart failure and arrhythmias is both common and associated with a higher morbidity and mortality in adults with covid-19 [8] [9] [10] . hypothesized mechanisms of cardiac injury include direct viral invasion leading to cardiomyocyte death and inflammation and indirect mechanisms of injury -cardiac stress due to respiratory failure and hypoxemia and cardiac inflammation secondary to severe systemic hyper-inflammation, which is thought to be mediated by cytokines such as interleukin (il)-6, il-2, il-7, tnf (tumor necrosis factor)-α and ifn (interferon)-γ [11] . cardiac involvement during covid-19 is not common in children who require pediatric intensive care unit (picu) admission; use of inotropes was reported in 12 (25%) patients admitted to a north american picu in a recent study [4] . the plasma concentration of cardiac bio-markers and echocardiographic findings in these patients were not reported, therefore it is unclear if inotropic requirement was due to primary cardiac dysfunction [4] . cardiac involvement in patients with covid-19 has included elevation in cardiac biomarkers such as troponin, cpk-mb, and pro-brain type natriuretic peptide (pro-bnp), echocardiographic abnormalities such as diminished left ventricular function with segmental or global wall motion abnormality and coronary artery dilation, and electrical abnormalities such as sinus tachycardia, atrial arrhythmias, non sustained ventricular tachycardia, first-degree atrioventricular block, premature atrial and ventricular contractions, and incomplete right bundle branch block [3, [12] [13] [14] [15] [16] [17] (table 1 ). in one of the largest pediatric series (n=2135) from china, 0.6% of children had symptomatic myocardial injury and heart failure [18, 19] . it is difficult to draw any firm conclusions, given the small numbers and lack of any systematic prospective studies. however, currently available data indicates that cardiac involvement in children with covid-19 is not common. in addition to clinical evaluation, electrocardiography and cardiac imaging, cardiac biomarkers such as plasma troponin, ck-mb and pro-bnp may be helpful in diagnosis. ivig may have a role in treatment of children with cardiac involvement. the role of other drugs such as remdesivir and hydroxychloroquine is unclear at this time. volume 57 __ october 15, 2020 kohli & lodha cardiac involvement and covid-19 a few weeks following the peak of covid-19 epidemic in the us and the european union, a novel systemic illness which clinically overlaps with kawasaki disease with or without shock syndrome, macrophage activation syndrome (mas) and toxic shock syndrome (tss) was reported in children. this entity was labeled as multisystem inflammatory syndrome in children (mis-c) by the centers for disease control and prevention (cdc), usa and by the world health organization (who) [6, 7] . a few cases have also been reported from india [20] . cardiac involvement as evidenced by perturbation of cardiac chamber size and/or function, coronary artery abnormalities (ectasia, aneurysm) or elevated cardiac biomarkers such as troponin or pro-bnp is not only common in children with mis-c but can also be severe (web table i) . a vast majority of children with mis-c had been previously healthy; a few have had minor comorbidities such as asthma and obesity. in addition to fever and weakness/malaise, gastrointestinal symptoms have been common at presentation. many of these children have had marked hemodynamic instability requiring inotropic support and intensive care at admission. in addition, a small proportion has required extracorporeal membrane oxygenation support; though, mortality has been low [20] [21] [22] [23] [24] [25] [26] [27] . in contrast to patients volume 57 __ october 15, 2020 cardiac involvement and covid-19 with typical kawasaki disease, atypical features including a higher incidence of cardiac involvement (60%), shock syndrome like features (50%), mas (50%) and need for steroids following ivig administration (80%) were noted in a previous study [22] . the precise mechanisms that underlie genesis of mis-c and its cardiac manifestations are yet unknown. however, given the fact that a vast majority of children have presented 4-6 weeks after the peak of the local covid-19 epidemic, many have been sars-cov-2 pcr negative but antibody positive, have had markedly elevated inflammatory markers such as c-reactive protein, erythrocyte sedimentation rate, fibrinogen, procalcitonin, ferritin, or interleukin 6, and have responded well to ivig and immunomodulators; an immune origin is likely. genetic factors may underlie the overall rarity of mis-c and relative preponderance in african americans. given the multiorgan dysfunction and potential for sudden and severe decompensation in patients with mis-c, our practice has been to admit these patients to picu where they are cared for by a team which involves specialists from pediatric rheumatology/immunology, pediatric critical care, pediatric cardiology, pediatric infectious diseases, and pediatric hematology. inotropes should be initiated in children with mis-c if clinically indicated and ecmo should be reserved for children with inotrope-refractory shock. in addition to clinical markers, mixed venous oxygen saturation and plasma lactate can be used to guide therapy. a vast majority of children with mis-c have responded well to ivig (1-2 g/ kg), which as per the recently proposed american college of rheumatology guidelines [28] should be the initial therapeutic agent. though the data are scarce, patients with suboptimal clinical response (hemodynamic instability) or biochemical response (persistent elevation in inflammatory markers) to ivig have benefitted from steroids (intravenous methylprednisolone 2 mg/kg/day) or immunomodulators such as anakinra (interleukin-1 antagonist) (2-8 mg/kg/day subcutaneous injection once or twice a day, maximum dose: 100 mg twice a day) and tocilizumab (interleukin-6 antagonist). the dosing of tocilizumab for systemic onset juvenile idiopathic arthritis is 12 mg/kg intravenous or 162 mg subcutaneous every other week for those weighing less than 30 kg and 8 mg/kg intravenous every other week or 162 mg subcutaneous every week for those weighing >30 kg. the optimal dose and dosing frequency for mis-c is not known; intravenous doses of 400-800 mg and a subcutaneous dose of 162 mg has been used in adults with covid-19 associated cytokine release syndrome [29] , and 8 mg/kg in children [30] . though adjunctive immune modifying therapies such as anakinra, tocilizumab and convalescent plasma have been used in patients with both acute covid-19 and mis-c, their role has not been systematically evaluated. given the potential risk of thrombotic complications, we also initiate aspirin and low molecular weight heparin at admission, both of which we discontinue upon normalization of inflammatory markers. in addition to aspirin and low molecular weight heparin, we have typically discharged these patients on oral steroids which are gradually tapered as guided by their clinical status and cardiac and inflammatory biomarkers. cardiac imaging with a focus on coronary arteries is obtained at regular intervals after discharge [28] . cardiac involvement in children with covid-19 is uncommon; however, a handful of patients have had severe involvement with markedly diminished ventricular function and hemodynamic instability. these patients have benefited from ivig. the role of antivirals such as remdesivir, hydroxychloroquine, and adjunctive immunomodulatory therapies in patients with covid-19 and cardiac involvement is unclear at this time. cardiac involvement as evidenced by perturbation of cardiac chamber size and/or function, coronary artery abnormalities (ectasia, aneurysm) or elevated cardiac biomarkers such as troponin or pro-bnp is not only common in children with mis-c but can also be severe. these children have responded to ivig and or corticosteroids. a few have required additional immunomodulators such as anakinra and tocilizumab. [20] [21] [22] [23] [24] [25] [26] patients severe acute respiratory syndrome coronavirus 2 (sars-cov-2) infection in children and adolescents: a systematic review systematic review of covid-19 in children shows milder cases and a better prognosis than adults a 55-day-old female infant infected with 2019 novel coronavirus disease: presenting with pneumonia, liver injury, and heart damage characteristics and outcomes of children with coronavirus disease 2019 (covid-19) infection admitted to us and canadian pediatric intensive care units pediatric covid-19-associated rhabdomyolysis: a case report centers for disease control and prevention. multisystem inflammatory syndrome in children (mis-c) associated with coronavirus disease 2019 (covid-19 multisystem inflammatory syndrome in children and adolescents temporally related to covid-19 available from cardiovascular disease and covid-19 cardiac involvement in a patient with coronavirus disease 2019 (covid-19) association of cardiac injury 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hyperinflammation in covid-19 utilizing tocilizumab for the treatment of cytokine release syndrome in covid-19 hyper-inflammatory syndrome in a child with covid-19 treated successfully with intravenous immunoglobulin and tocilizumab key: cord-351126-d6lfktf9 authors: kofman, aaron d.; sizemore, emma k.; detelich, joshua f.; albrecht, benjamin; piantadosi, anne l. title: a young adult with covid-19 and multisystem inflammatory syndrome in children (mis-c)-like illness: a case report date: 2020-09-29 journal: bmc infect dis doi: 10.1186/s12879-020-05439-z sha: doc_id: 351126 cord_uid: d6lfktf9 background: a healthy 25-year-old woman developed covid-19 disease with clinical characteristics resembling multisystem inflammatory syndrome in children (mis-c), a rare form of covid-19 described primarily in children under 21 years of age. case presentation: the patient presented with 1 week of weakness, dyspnea, and low-grade fevers, followed by mild cough, sore throat, vomiting, diarrhea, and lymph node swelling. she was otherwise healthy, with no prior medical history. her hospital course was notable for profound acute kidney injury, leukocytosis, hypotension, and cardiac dysfunction requiring icu admission and vasopressor support. mis-c-like illness secondary to covid-19 was suspected due to physical exam findings of conjunctivitis, mucositis, and shock. she improved following ivig, aspirin, and supportive care, and was discharged on hospital day 5. conclusion: mis-c-like illness should be considered in adults presenting with atypical clinical findings and concern for covid-19. further research is needed to support the role of ivig and aspirin in this patient population. background covid-19 is increasingly recognized to have a protean range of clinical manifestations in adults, from respiratory illness to hyper-inflammatory and coagulopathic complications, as well as a broad spectrum of disease severity. when the epidemic began in china in late december 2019, case reports of pediatric illness were relatively rare, and almost all children had mild clinical courses. however, a growing number of reports from the united kingdom, italy, the united states, and elsewhere has now described a severe inflammatory syndrome in children similar to kawasaki's disease, a vasculitic illness of unclear etiology originally described in japan in 1967 [1] [2] [3] . this syndrome has been named multisystem inflammatory syndrome in children (mis-c). to date, case series of mis-c have described multisystem organ involvement including the mucocutaneous, cardiac, gastrointestinal, and respiratory systems [4] . the mortality rate of mis-c appears to be low, though severe illness is common, and a number of fatalities in children have been reported. anecdotal reports of mis-c-like illness have been reported in young adults in their early twenties, raising concern that this rare presentation of covid-19 may also have some penetrance into younger adult age groups [5] . herein we describe a unique case report of mis-c-like illness in a young adult with covid-19. a 25-year-old previously healthy woman presented to an emergency department (ed) in atlanta, georgia in june 2020 with a chief complaint of fatigue. she reported 1 week of weakness, dyspnea, and low-grade fevers, followed by mild cough, sore throat, vomiting, diarrhea, and lymph node swelling. she lived at home with family and had no recent travel or known sick contacts. she was a nonsmoker, drank alcohol socially, and did not use recreational drugs. she was not on any chronic medications and had no known allergies. she endorsed taking ibuprofen and acetaminophen over the prior week for symptomatic relief. on presentation, she was afebrile, with mild hypotension (blood pressure 98/56 mmhg) and normal oxygen saturation on room air. she appeared ill, with tender cervical lymphadenopathy; significant conjunctival injection without perilimbal sparing; injected, erythematous, and cracked lips; and tenderness to palpation in the left lower abdominal quadrant. she had no rash, splenomegaly, or swelling of the extremities. laboratory work-up was notable for profound acute kidney injury and leukocytosis (table 1) . sars-cov-2 pcr from nasopharyngeal swab and sars-cov-2 igg from serum were both positive. blood cultures and legionella urine antigen was negative. the patient's urine culture grew escherichia coli, which was treated with ceftriaxone switched to piperacillin-tazobactam due to ampc-type resistance of the isolate. chest x-ray and ct without contrast were unremarkable. point of care echocardiogram revealed a dilated inferior vena cava. ct abdomen/pelvis demonstrated mild peripancreatic fat stranding, felt to possibly represent acute uncomplicated pancreatitis, as well as nonspecific bilateral perinephric fat stranding. the patient was admitted to the intensive care unit (icu) for hypotension, with diagnosis of covid-19 and concern for possible mis-c due to mucocutaneous, renal, gi and cardiac system involvement. the patient's blood pressure initially normalized and her creatinine improved to 2.5 mg/dl with aggressive fluid resuscitation. she was transferred to the floor on hospital day 2, however, within 7 h she experienced recurrent hypotension requiring transfer to the icu for the initiation of vasopressors. workup for the new shock revealed evidence of worsening cardiac dysfunction. an electrocardiogram demonstration right axis deviation, troponin-i was newly detectable at 0.06 ng/ml and bnatriuretic peptide (bnp) increased to 1617 pg/ml. she due to concern for inflammatory multi-system organ involvement similar to that seen in mis-c, and risk of progression to more florid cardiac involvement, a riskbenefit discussion was held with the patient regarding treatment with intravenous immunoglobulin (ivig), including potential risk of hypercoagulability [6] . she was treated with ivig 2 g/kg split equally between hospital days 2 and 3 to reduce risk for thromboembolic and renal toxicities, along with aspirin 325 mg daily for 7 days, based on treatment courses suggested for pediatric patients with mis-c or kawasaki disease [7] [8] [9] . additionally, the patient was offered remdesivir under an emergency use authorization (eua) basis, but declined. her leukocytosis began to downtrend on hospital day 4, and clinical symptoms improved including conjunctivitis. she was discharged on hospital day 5 with pulmonary clinic follow-up for pulmonary hypertension, and she was treated with a 7-day course of apixaban for covid-19-associated coagulopathy per emory university hospital covid-19 treatment guidelines. the centers for disease control and prevention (cdc)'s case definition for mis-c is (1) an individual less than 21 years of age presenting with fever, (2) laboratory evidence of inflammation by one or more markers (such as crp, esr, fibrinogen), (3) evidence of clinically severe illness requiring hospitalization, with greater than 2 organ systems involved (cardiac, renal, respiratory, hematologic, gi, mucocutaneous, or neurological), (4) no other plausible alternative diagnosis, and (5) sars-cov-2 infection confirmed by rt-pcr, serology, or antigen testing (or, absent a positive sars-cov-2 test, exposure to a suspected or confirmed covid-19 case within 4 weeks prior to symptom onset). our patient, a previously healthy young adult woman in her mid-20's, met these criteria with the exception of age. several features of our patient's presentation raised concern for mis-c-like illness. first, she was noted to have conjunctivitis and mucositis upon evaluation in the ed, and the cracked lips in particular were suggestive of the mucositis seen in kawasaki's disease. conjunctivitis has very rarely been reported in adults with covid-19 [10] , but multiple case series of mis-c in the pediatric population have noted this clinical feature [2, 3, 11] . additionally, our patient had profound gi symptoms leading to hypovolemia and aki to a creatinine of 7.7, which was fluid-responsive. while gi symptoms do occur in adults with covid-19, they are typically less severe; by contrast, prominent gi symptoms are seen in many patients with mis-c [4, 12] . finally, our patient's stable respiratory status was itself a feature shared by patients with mis-c, who often lack intrinsic respiratory disease [2] . other features were potentially compatible with mis-c-like illness, including shock and cardiac dysfunction. like many patients with mis-c, our patient required treatment with vasopressors in the icu; her shock was thought to be multifactorial including hypovolemic and cardiogenic. she had elevated troponin and bnp, but unlike many patients with mis-c, her cardiac dysfunction was primarily right-sided. echocardiogram showed severe right ventricular dysfunction and ct showed evidence of pulmonary vascular disease by enlarged pa without evidence of thrombus. it is interesting to speculate whether she had a covid-19 related vasculitic process or diffuse microthrombi leading to elevated pulmonary vascular resistance and subsequent right ventricular strain. she did not have lv dysfunction, coronary aneurysms, or valvular dysfunction, as have been described in pediatric patients with mis-c [2, 13] . several other features of our patient's clinical presentation were less consistent with mis-c as it has been described in the pediatric population. her profound acute kidney injury and leukocytosis were not features described in the majority of mis-c cases described to date [4] . additionally, her neutrophilia and lymphopenia were more consistent with typical covid-19 findings in adults, though they have been described in cases of mis-c as well. in conclusion, we describe an unusual case of misclike illness in a young adult with covid-19. mis-c is an emerging and poorly understood clinical entity associated that has been described in children with covid-19 and has features similar to kawasaki's disease. children with mis-c are increasingly treated with ivig, aspirin, and steroids; it is not clear what if any clinical features in adults may warrant similar treatment approaches. our patient was treated with ivig and aspirin and improved without further cardiac involvement, but this is obviously anecdotal. further research into covid-19 in the young adult population is needed to better characterize the full range of clinical manifestations, and to identify potential opportunities for targeted treatment of inflammatory processes. authors' contributions ak and ap analyzed and interpreted the patient data regarding clinical infectious diseases presentation. jd analyzed and interpreted the patient data regarding critical care portion of hospitalization. ba provided interpretation regarding pharmacological treatment for the patient. es provided interpretation regarding the patient's initial clinical presentation to the emergency department. all authors read and approved the final manuscript. there was no funding source for this report. data sharing is not applicable to this article as no datasets were generated or analysed as a part of this case report. ethics approval and consent to participate ethics approval and consent to participate was not applicable for this case report. written informed consent was obtained from the patient for publication of this case report and any accompanying images. a copy of the written consent is available for review by the editor of this journal. acute febrile mucocutaneous syndrome with lymphoid involvement with specific desquamation of the fingers and toes in children hyperinflammatory shock in children during covid-19 pandemic an outbreak of severe kawasaki-like disease at the italian epicentre of the sars-cov-2 epidemic: an observational cohort study multisystem inflammatory syndrome in u.s. children and adolescents young adults are also affected by kawasakilike disease linked coronavirus, doctors say association of immune globulin intravenous and thromboembolic adverse events covid-19 associated multisystem inflammatory syndrome in children (mis-c) guidelines; a western new york approach aspirin dose and prevention of coronary abnormalities in kawasaki disease comparison of risk of recrudescent fever in children with kawasaki disease treated with intravenous immunoglobulin and low-dose vs high-dose aspirin evaluation of coronavirus in tears and conjunctival secretions of patients with sars-cov-2 infection multisystem inflammatory syndrome in children in new york state gastrointestinal symptoms as a major presentation component of a novel multisystem inflammatory syndrome in children (mis-c) that is related to covid-19: a single center experience of 44 cases acute heart failure in multisystem inflammatory syndrome in children (mis-c) in the context of global sars-cov-2 pandemic springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations the authors declare that they have no competing interests.received: 5 august 2020 accepted: 21 september 2020 key: cord-344683-lr1xr2um authors: cabler, stephanie; french, anthony; orvedahl, anthony title: a cytokine circus with a viral ringleader: sars-cov-2-associated cytokine storm syndromes date: 2020-09-30 journal: trends mol med doi: 10.1016/j.molmed.2020.09.012 sha: doc_id: 344683 cord_uid: lr1xr2um an unbridled host immune response to sars-cov-2 infection likely underlies severe cases of the disease and has been labeled a “cytokine storm syndrome”. we emphasize that categorization of syndromes triggered by a completely novel pathogen based on other seemingly similar, but potentially distinct, known entities is an inherently risky endeavor. infection with sars-cov-2, the etiologic agent of coronavirus disease 2019 (covid19) , can lead to severe pneumonia, multi-organ failure, and death. an over-exuberant immune response may contribute to severe covid19 which is temporally associated with the sars-cov-2 pandemic. whether the sars-cov-2associated css (termed s-css for purposes of this review) and mis-c fall within a spectrum of disorders familiar to us, or represent groups of novel clinical entities-a herd of zebras, in essence-remains undetermined. however, new evidence in this rapidly moving area indicates that sars-cov-2-associated inflammatory disorders may be unique entities triggered by this completely novel pathogen. here we review the proposed pathogenesis of mis-c within the context of s-css, and highlight the need to gain further understanding of these disorders to define optimal therapeutic targets. css involve life-threatening immune activation triggered by genetic, infectious, or iatrogenic causes, with associated hypercytokinemia, hemodynamic compromise, and multiorgan dysfunction. while different forms of css share these features, varying underlying host risk factors and inciting triggers have important implications for the pathogenesis of the disease. css in general, with reference to covid-19, has recently been reviewed [1] . briefly, viral but also other infections may trigger primary (inherited) and secondary (acquired) [4], while cure of some patients with hlh may require bone marrow transplantation [5] . while targeted therapies based on understanding of the pathogenesis of unique css are emerging (e.g. neutralization of il-6 for crs, or interferon-gamma neutralizing antibodies for pediatric hlh [6] ), and there may be overlap in the pathogenesis and therapy, it is clear that a "one-size fits all" approach does not work. initial reports of adult patients with covid-19 described hemodynamic compromise, endovascular lesions, multi-organ dysfunction, and elevated markers of inflammation that could not be ascribed entirely to respiratory failure from viral pneumonia [7] . biphasic onset of fever and clinical worsening after an initial period of stability invoke the "cytokine storm" (figure 1 ). commonly involved systems in s-css include severe pulmonary disease with acute respiratory distress syndrome (ards), cardiac impairment, liver dysfunction, acute kidney injury, and coagulopathy. markers of more severe disease include lymphopenia [8] , and elevated c-reactive protein (crp), lactate dehydrogenase (ldh), and ferritin which are nonspecific indicators of inflammation and cellular injury [9] [10] [11] . elevated d-dimer levels and thrombocytopenia portend worse outcomes and reflect an associated coagulopathy [11, 12] . large cohorts of pediatric patients with severe covid-19 and associated laboratory findings are uncommon. though detailed descriptions of pediatric s-css are few, the available data suggests elevated ferritin and crp and endovascular damage with elevated d-dimers are common in these patients as well [13] . a dysregulated immune response with suppression of ifn responses and concurrent hyper-production of other cytokines (e.g., il-6 and tnf) has been proposed to give rise to s-css [14, 15] . cytokines correlating to disease severity and poor survival include il-6, il-8, and il-10, among others [8] [9] [10] 12, 16] . one recent study found elevated markers of apoptosis on lymphocytes profiled from severe covid-19 patients, indicating a potential route to their depletion [15] . nevertheless, it remains undetermined if hyperproduction of cytokines in s-css is a cause or a consequence of the observed organ injury and immune cell abnormalities. trials j o u r n a l p r e -p r o o f journal pre-proof with therapies that inhibit specific cytokines (e.g., il-6 and il-1) and more indiscriminate immunosuppressants (e.g., steroids) are underway and may provide further insights. cohorts of pediatric patients with mis-c reveal overlapping but distinct pictures from s-css with respect to their clinical and laboratory profile ( table 1) . the syndrome is defined by fever, multi-organ dysfunction, and laboratory evidence of inflammation ( table 2) . abdominal pain, vomiting and diarrhea, mucocutaneous findings (conjunctivitis and rash) and shock with cardiac involvement are more common in mis-c than in s-css [17, 18] . respiratory symptoms, while often present, are mild, and musculoskeletal and neurological findings are rare. the patients) [17] , which is a lower mortality rate than severe covid-19. given the clinical and laboratory features, it is reasonable to consider mis-c as a separate but related entity to the severe multi-organ dysfunction observed in patients with s-css (figure 1 ). for example, mis-c patients less commonly have severe respiratory, renal, and hepatic involvement and more often have cardiac dysfunction. lymphopenia and thrombocytopenia are observed in a minority of mis-c patients (40% and 41%, respectively, in group 1 patients reported in [17] ), and while lower levels are associated with more severe covid-19 [21, 22] , an association for these factors in outcomes in mis-c remains to be additionally, cardiac involvement with mis-c most typically presents as ventricular dysfunction, with only a small percentage having coronary artery dilation [17] . it is important to note that the pathogenesis of kd itself remains enigmatic. kd is a medium vessel vasculitis that may involve antibodies to a persistent, as of yet unidentified, viral pathogen. in contrast, tss results from superantigens elaborated by bacteria that lead to indiscriminate cytokine release from lymphocytes. thus, mis-c exhibits features of two entities with patently distinct disease mechanisms. it is also important to note that typical kd, tss, and other similar disorders could occur in patients testing positive for acute or recent sars-cov-2 infection, and diagnostic inertia should be avoided so as not to detract from their appropriate diagnosis and management. one critical unresolved question is the mechanism by which sars-cov-2 infection higher sars-cov-2 qpcr ct values in mis-c patients suggests a lower viral load and also points towards a para-infectious etiology [19] . interestingly, even within mis-c patients, there are suggestions of different subtypes, with younger non-white patients presenting with conjunctivitis and abdominal pain having positive antibodies (sub-acute infection). this contrasts with a group of mis-c patients that presents with respiratory symptoms and positive pcr testing (acute infection) [23] . it is also important to consider that initial criteria for mis-c case identification were relatively broad in order to capture many cases, and it remains possible that patients meeting current criteria with primarily respiratory disease could represent an entity that is distinct from mis-c. two recent studies provide immunological data suggesting that mis-c and severe covid-19 are distinct entities. systematic profiling of serum cytokines showed distinct inflammatory profiles in adults with s-css versus children with mis-c and kd, with elevated il-8 and il-7 defining the s-css group, and mis-c appearing more similar to kd in this comparison [20] . comparing groups of healthy children, those with sars-cov-2, mis-c, or kd, revealed that il-6 and il-17a were significantly higher only in the kd group [20] . a second study showed pediatric patients with mis-c exhibit distinct cytokine profiles from those with severe sars-cov-2 respiratory disease, exhibiting higher il-10 and tnf [19] . it is not clear if differences observed in cytokines that define these groups are a result of different patient populations, testing strategies, or in the groups used for comparisons. as with s-css, additional study and identification of effective (and ineffective) therapies will help in the "taxonomic" classification of mis-c and potential subgroups. one lesson that will surely emerge from the covid-19 pandemic is that the necessity to intervene in the setting of immense devastation must be tempered by a core principle of medical ethics: first, do no harm. empiric treatments of inflammatory entities related to a novel disease with an incomplete molecular understanding of the virulence factors and host j o u r n a l p r e -p r o o f journal pre-proof response, increases the risk of violating this maxim. the risk increases further when demand for individual therapies exceeds supply and additional alternatives are sought. in this setting we face even higher chances of getting "burned" and are forced to walk a narrower tightrope. as we gain a deeper understanding of the pathogenesis of s-css and mis-c, and the results of randomized trials are published, a clearer picture will emerge and targeted therapies may be identified (see outstanding questions). knowledge in this area is keeping pace with the spread of the virus with new insights arising on a continual basis. we may ultimately find that manifestations of s-css represent a circus of unique zebras in which the virus is orchestrating the chaos at center ring. as the tent over this complex host-pathogen interaction comes down, rigorous studies will surely tip the scales in our favor and lessons learned may improve our readiness for when the next circus inevitably comes to town. cns does not include headache, does include meningeal signs; mucous membrane ("muc. memb.") includes conjunctivitis; cardiac includes echocardiographic findings, need for resuscitative medications, and elevated cardiac markers (troponin, bnp); gastrointestinal does not include isolated abdominal pain which was uncommonly reported as an isolated symptom among studies, but is present in up to 62% of reported patients [17] ; renal includes acute kidney injury. patients from initial cohort recognizing the what is the mechanism by which sars-cov-2 infection contributes to multisystem inflammation? is the hyperproduction of cytokines in sars-cov-2 cytokine storm syndrome (s-css) a cause or a consequence of the observed organ injury and immune cell abnormalities? trials with therapies that inhibit specific cytokines (e.g., il-6 and il-1) and more indiscriminate immunosuppressants (e.g., steroids) should provide further insights. is multisystem inflammatory syndrome in children (mis-c) a distinct syndrome or does it exist along the spectrum of disease seen in s-css? in the absence of data on the community prevalence of sars-cov-2 infection (i.e. the denominator), it is not yet possible to determine the relative risk of developing mis-c in children exposed to sars-cov-2, or the baseline probability of testing positive for the virus in the general population. what are the optimal clinical characteristics and biomarkers to identify and classify cases of mis-c, s-css, and other diseases associated with cytokine storm syndrome? precise disease classification may help to guide cohort selection for trials to identify optimal therapies. do we need to re-consider the initial criteria for mis-c case identification that were set relatively broad in order to capture many cases? this could help to better evaluate and treat patients. j o u r n a l p r e -p r o o f cytokine storms: understanding covid-19 genetic and mechanistic diversity in pediatric hemophagocytic hlh-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis emapalumab in children with primary hemophagocytic lymphohistiocytosis clinical progression of patients with covid-19 in shanghai clinical and immunological features of severe and moderate coronavirus disease 2019 hematologic, biochemical and immune biomarker abnormalities associated with severe illness and mortality in coronavirus disease 2019 (covid-19): a meta-analysis prognostic value of interleukin-6, c-reactive protein, and procalcitonin in patients with covid-19 factors associated with death outcome in patients with severe coronavirus disease-19 (covid-19): a case-control study epidemiology, clinical course, and outcomes of critically ill adults with covid-19 in new york city: a prospective cohort study pediatric critical care and covid19 imbalanced host response to sars-cov-2 drives development of covid-19 impaired type i interferon activity and inflammatory responses in severe covid-19 patients profiling serum cytokines in covid-19 patients reveals il-6 and il-10 are disease severity predictors covid-19-associated multisystem inflammatory syndrome in children -united states pediatric sars-cov-2: clinical presentation, infectivity, and immune responses multisystem inflammatory syndrome in children and covid-19 are distinct presentations of sars-cov-2 the immunology of multisystem inflammatory syndrome in children with covid-19 lymphopenia in severe coronavirus disease-2019 (covid-19): systematic review and meta-analysis thrombocytopenia is associated with severe dehydrogenase; pmn, polymorphonuclear cell/ neutrophil; alt, alanine aminotransferase; wbc, white blood cell count; csf, cerebrospinal fluid we thank melanie yarbrough, phd, for helpful comments on the manuscript. j o u r n a l p r e -p r o o f key: cord-294729-c9f0iokr authors: orr, william b.; elward, alexis m.; lin, john c.; reich, patrick j.; scheel, janet n.; hayes, ericka v.; remy, kenneth e. title: delayed development of coronary artery dilitation in suspected severe acute respiratory syndrome coronavirus 2 multisystem inflammatory syndrome: more research needed date: 2020-10-01 journal: crit care explor doi: 10.1097/cce.0000000000000236 sha: doc_id: 294729 cord_uid: c9f0iokr although significant disease burden in the severe acute respiratory syndrome coronavirus 2 pandemic has been relatively uncommon in children, worldwide cases of a postinfectious multisystem inflammatory syndrome in children and possible atypical kawasaki-like disease attributing to severe acute respiratory syndrome coronavirus 2 infection have arisen. original thinking for coronavirus disease-19 disease was that an overwhelming proinflammatory response drove disease pathogenesis. emerging reports suggest that a robust immune suppression may be more relevant and predominant. recently reported data on children with multisystem inflammatory syndrome in children have demonstrated a heterogeneity of immune phenotypes among these patients, with concern for a strong initial proinflammatory state; however, data are lacking to support this. likewise, understanding development of certain clinical findings to changes in the immune system is lacking. case summary: we report a 12-year-old multiracial male with negative coronavirus disease-19 nasopharyngeal rna polymerase chain reaction testing but positive severe acute respiratory syndrome coronavirus 2 serology, subsequent development of vasodilatory shock with myocardial depression, and subsequent delayed development of coronary artery dilatation after resolution of myocardial depression. unlike previous reported cases of multisystem inflammatory syndrome in children, he exhibited profound lymphopenia without specific inflammatory cytokines elevations, whereas nonspecific markers (ferritin and c-reactive protein) were increased. he subsequently was discharged on day 12 of hospitalization with complete recovery. conclusion: our representative case of a patient with coronavirus disease-19-associated multisystem inflammatory syndrome in children without robust hyperinflammation and a delayed finding of coronary artery dilatation compared with reported case series highlights the need for further mechanistic understanding of coronavirus disease-19 disease and subsequent multisystem inflammatory syndrome in children or kawasaki disease development. this report offers a number of disease mechanisms and clinical evolution considerations for further elucidation to guide development of potential therapies. background: although significant disease burden in the severe acute respiratory syndrome coronavirus 2 pandemic has been relatively uncommon in children, worldwide cases of a postinfectious multisystem inflammatory syndrome in children and possible atypical kawasaki-like disease attributing to severe acute respiratory syndrome coronavirus 2 infection have arisen. original thinking for coronavirus disease-19 disease was that an overwhelming proinflammatory response drove disease pathogenesis. emerging reports suggest that a robust immune suppression may be more relevant and predominant. recently reported data on children with multisystem inflammatory syndrome in children have demonstrated a heterogeneity of immune phenotypes among these patients, with concern for a strong initial proinflammatory state; however, data are lacking to support this. likewise, understanding development of certain clinical findings to changes in the immune system is lacking. case summary: we report a 12-year-old multiracial male with negative coronavirus disease-19 nasopharyngeal rna polymerase chain reaction testing but positive severe acute respiratory syndrome coronavirus 2 serology, subsequent development of vasodilatory shock with myocardial depression, and subsequent delayed development of coronary artery dilatation after resolution of myocardial depression. unlike previous reported cases of multisystem inflammatory syndrome in children, he exhibited profound lymphopenia without specific inflammatory cytokines elevations, whereas nonspecific markers (ferritin and c-reactive protein) were increased. he subsequently was discharged on day 12 of hospitalization with complete recovery. conclusion: our representative case of a patient with coronavirus disease-19-associated multisystem inflammatory syndrome in children without robust hyperinflammation and a delayed finding of coronary artery dilatation compared with reported case series highlights the need for further mechanistic understanding of coronavirus disease-19 disease and subsequent multisystem inflammatory syndrome in children or kawasaki disease development. this report offers a number of disease mechanisms and clinical evolution considerations for further elucidation to guide development of potential therapies. key words: coronavirus disease-19; immune suppression; kawasaki disease; multisystem inflammatory syndrome in children; research s ignificant disease burden in the severe acute respiratory syndrome coronavirus 2 (sars-cov-2) pandemic has been relatively uncommon in children with less than 5% of cases in the united states and globally under 18 years old (1) (2) (3) (4) (5) (6) . although severe disease is rare, many children become infected with the sars-cov-2 virus and some may serve as asymptomatic reservoirs for coronavirus disease-19 (covid-19) disease transmission (7) . however, although children appear to have a less severe acute disease course, worldwide cases of a postinfectious multisystem inflammatory syndrome in children (mis-c) and possible atypical kawasaki-like disease attributed to sars-cov-2 infection have arisen (8) (9) (10) . preliminary evidence and hypotheses suggested that covid-19 disease pathogenesis was driven by an overwhelming hyperinflammatory response. more recent emerging reports suggest that a robust immune suppression may be more relevant and predominant (11) (12) (13) . recently reported data on children with mis-c have demonstrated a heterogeneity of immune phenotypes among these patients, with concern for a strong initial hyperinflammatory state; however, data are lacking to support this. in these reported cases and in our own experiences with a case of mis-c with delayed development of an atypical kawasaki-like disease, a number of questions have been developed. a 12-year-old, previously healthy, fully immunized, multiracial male presented to our quaternary-care hospital after 1 week of fever and diarrhea. a nasopharyngeal covid-19 rna polymerase chain reaction was negative three times, and the serology of both parents was positive for sars-cov-2 immunoglobulin-g (igg) (abbott laboratories, chicago, il). at admission, he had vasodilatory septic shock with multiple laboratory and cardiac abnormalities including profound lymphopenia (absolute lymphocyte count [alc] 392), thrombocytopenia (nadir 57), hyponatremia, hypophosphatemia, and fever ( table 1) . during his 11 day icu course, he received empiric broad-spectrum antibiotics, hemodynamic support for catecholamine-resistant septic shock, stress dose hydrocortisone for critical illnessrelated corticosteroid insufficiency (two doses), and high-flow nasal cannula with subsequent noninvasive bilevel positive sirway pressure support without the need for intubation. cardiac specific evaluation showed initial electrocardiogram findings with prolonged corrected qt interval, transthoracic echocardiogram (tte) showed borderline left ventricle ejection fraction with dyskinetic septum, and probrain natriuretic peptide (bnp) and troponin-i were both significantly elevated (table 1) . by days 4-6, an sars-cov-2 igg test was positive, he became hypertensive requiring a nitroprusside infusion and subsequent transition to lisinopril, and his left ventricular ejection fraction increased to 50%. an initial cytokine panel demonstrated tumor necrosis factor (tnf)-α, interferon (ifn)-γ, and interleukin (il)-6 levels below the limit of detection and elevated il-2r and il-10 ( table 2) . all other cytokines were within normal limits. his nonspecific inflammatory markers all normalized including d-dimer, ferritin, c-reactive protein (crp), and fibrinogen, and he defervesced. at day 11, a predischarge tte revealed normal systolic function, but his left main coronary artery, left anterior descending artery, circumflex artery, and right coronary artery (rca) were all diffusely dilated with the rca demonstrating the greatest amount of dilation with a fusiform appearing aneurysm and proximal rca stenosis. he was discharged on low-dose aspirin and clopidogrel with a presumed diagnosis of covid-19 mis-c and atypical kawasaki-like disease. a 4-week postdischarge tte continued to have normal systolic function with unchanged coronary artery dilation and a slightly elevated troponin-i of 0.18 ng/ml. anticoagulation therapy was continued and antihypertensive medications stopped after normalization of blood pressure. recent u.s. and u.k. reports of over 500 mis-c patients have shown findings of lymphopenia, elevated crp, ferritin, bnp, d-dimer, il-6, and fibrinogen (8, 10, 14, 15) . however, unlike these case series, our patient had much higher nonspecific inflammatory markers (crp, ferritin, d-dimer, and fibrinogen) without elevation in il-6 or tnf-α cytokine levels. previous reports have demonstrated lymphopenia between 1,000 and 2,000 cells/mm 2 . in contrast, our patient had an alc less than 400, a finding similar to that seen in aids. our patient's divergent findings of elevation of some hyperinflammatory markers and depression of others highlight the presence of differing innate and adaptive immune phenotypes. in turn, this questions whether reported descriptive immune findings in adults can be accurately ascribed to children when children are presenting with different clinical manifestations over an altered time course. likewise, prior to uniform pediatric use of therapies that have been attempted in adults, we must gain better understanding of key mechanistic pathways of sars-cov-2 infection and extrapolate and apply known pathologic mechanisms in other similar and previously elucidated diseases (e.g., known kawasaki disease [kd] findings and other viruses). current covid-19-induced kawasaki-like disease may have overlapping mechanisms with canonical kd or may represent a completely different disease with overlapping clinical findings. comparing the clinical and laboratory characteristics of these two entities has very distinct properties. from a clinical standpoint, patients with mis-c have a broader age range with a median of 9 years, whereas kd patients have a narrower age range with a median of 2 years (8, 16) . patients with mis-c also have a lower prevalence of developing the classic kd findings of conjunctivitis, rash, mucositis, extremity swelling, and cervical lymphadenopathy (16) . interestingly, it has been reported that patients with mis-c compared with covid-19-associated kd have lower wbc counts, worsened thrombocytopenia and lymphopenia, and decreased erythrocyte sedimentation rates with less anemia (higher hemoglobin values) (16) . our patient demonstrated more severe lymphopenia than previously reported and yet had hematologic findings that bridged both previously reported findings in mis-c and kd (i.e., higher wbc counts with thrombocytopenia and anemia). additionally, our patient developed coronary artery dilatation 11 days after acute presentation and after recovery of myocardial function. this novel finding has not been reported in case series that have focused on cardiac manifestations of mis-c (17) . this further delineates mis-c and kd as heterogeneous syndromes with potentially differing subphenotypes. furthermore, canonical kd has previously demonstrated coronary vascular infiltration of neutrophils, cluster of differentiation 8 t lymphocytes, immunoglobulin-a-producing plasma cells, macrophages, and eosinophils (18) (19) (20) . numerous reports in adult covid-19 disease have demonstrated isolated proinflammatory marker elevations but likely predominant immune suppression with t cell exhaustion and significant peripheral lymphopenia (11) (12) (13) . based on preliminary concerns of a hyperinflammatory state driving disease progression, many patients with mis-c are treated with anti-inflammatory agents (corticosteroids, anakinra, and nonsteroidal anti-inflammatory drugs) (14, 15, 21, 22) . however, if children demonstrate similar findings as in adults with immune suppression, these agents may have negative effects including the potential for development of secondary infections and/or unmitigated viral tissue replication. it is unclear how this may affect development from acute disease to mis-c or kd. thus, a number of considerations remain regarding the broad definition of this syndrome, mechanisms involved, and the need for targeted rather than nonspecific therapies. this underscores a need for future studies in children to better characterize alterations in innate and adaptive immune functions not solely in acute infectious disease presentation but also in disease evolution to postinflammatory syndrome. our case describes a patient that meets centers for disease control and prevention criteria for mis-c with evolution of delayed kd findings of coronary artery dilations. a number of questions thus arise as follows: • what mechanistically could describe findings of mis-c at presentation and yet delayed findings of kd with coronary artery dilatation after four echocardiograms that have not been previously reported in large case series? • when and how often should echocardiogram surveillance occur with children that meet mis-c criteria at admission but may not have evidence of kd? • why in this illustrative case do we see a clinical presentation of vasodilatory shock with increased nonspecific inflammatory biomarkers and an absence of a "cytokine storm" of il-6, tnf-α, or related proinflammatory cytokines but with profound lymphopenia and reduction in ifn-γ demonstrating immune exhaustion? could changes in il-2r be more relevant than il-6 and provide further insight into jak1, jak3, or other tyrosine kinase/map kinase signaling pathways? • with oversampling of diagnostic testing including serial echocardiograms, are we unearthing a phenomenon restricted only to sars-cov-2 virus or would other common childhood viruses with the same testing reveal similar findings? • recent data suggest that children less than 10 years old have diminished nasal gene expression of angiotensin-converting enzyme 2 (ace-2) compared with greater than 10 year olds (23) . does this age-related increase in ace-2 expression play a role in the observation that kd-like disease in sars-cov-2 infection occurs more frequently in an older population compared with kd and what other potential signaling pathways may be involved? • would the well-established ability of other coronaviruses to block type 1 and type iii ifn responses provide further insights in additional therapies that may influence janus kinases-stat pathways? could further elucidation of these pathways demonstrate more refined targeted therapies with improved outcomes for this syndrome or previously described canonical kd? presently, our understanding of mis-c is limited to associations temporal to the covid-19 disease. better elucidation of relevant signaling pathways that define transition from acute disease to mis-c is not only important for covid-19 disease but may provide insights into understanding kd associated with other pathogens. further evaluation of these considerations and questions could present many avenues for further investigation. invariably, many children will present with sars-cov-2 positive antibody serology testing in the fall with signs and symptoms consistent with sepsis, hemophagocytic lymphohistiocytosis, or mis-c; differentiating between these entities diagnostically and with subsequent therapies will be important in patient management and potential outcomes. coronavirus disease (covid-19) and pediatric patients: a review of epidemiology, symptomatology, laboratory and imaging results to guide the development of a management algorithm clinical characteristics of novel coronavirus disease 2019 (covid-19) in newborns, infants and children covid-19 infection in children screening and severity of coronavirus disease 2019 (covid-19) in children in coronavirus disease 2019 in children -united states characteristics and outcomes of children with coronavirus disease 2019 (covid-19) infection admitted to us and canadian pediatric intensive care units lessons unfolding from pediatric cases of covid-19 disease caused by sars-cov-2 infection multisystem inflammatory syndrome related to covid-19 in previously healthy children and adolescents in gastrointestinal symptoms as a major presentation component of a novel multisystem inflammatory syndrome in children (mis-c) that is related to covid-19: a single center experience of 44 cases clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with sars-cov-2 immunotherapies for covid-19: lessons learned from sepsis targeted immunosuppression distinguishes covid-19 from influenza in moderate and severe disease severe immune suppression and not a "cytokine storm" characterize covid-19 infections multisystem inflammatory syndrome in children in new york state multisystem inflammatory syndrome in u.s. children and adolescents distinct clinical and immunological features of sars-cov-2-induced multisystem inflammatory syndrome in children characteristics, cardiac involvement, and outcomes of multisystem inflammatory disease of childhood (mis-c) associated with sars-cov-2 infection immunogenetics of kawasaki disease american heart association rheumatic fever, endocarditis, and kawasaki disease committee of the council on cardiovascular disease in the young; council on cardiovascular and stroke nursing; council on cardiovascular surgery and anesthesia; and council on epidemiology and prevention: diagnosis, treatment, and long-term management of kawasaki disease: a scientific statement for health professionals from the american heart association kawasaki disease: pathophysiology and insights from mouse models multisystem inflammatory syndrome in us children and adolescents safety and efficacy of early highdose iv anakinra in severe covid-19 lung disease nasal gene expression of angiotensinconverting enzyme 2 in children and adults we thank our patient and his family who provided consent for this report and to the washington university in st. louis institutional review board that who waived review with exempted approval.for information regarding this article, e-mail: kremy@wustl.edu key: cord-351634-x1aw6gv2 authors: brumfiel, caitlin m.; dilorenzo, ashley m.; petronic-rosic, vesna m. title: dermatologic manifestations of covid-19-associated multisystem inflammatory syndrome in children date: 2020-11-01 journal: clin dermatol doi: 10.1016/j.clindermatol.2020.10.021 sha: doc_id: 351634 cord_uid: x1aw6gv2 multisystem inflammatory syndrome in children (mis-c) affects a small percentage of pediatric patients infected with covid-19 and is characterized by fever, laboratory evidence of inflammation, multisystem involvement, and severe illness necessitating hospitalization. skin findings are often present in these patients and while initially compared to kawasaki disease, likely represent distinct phenomena and overall remain poorly characterized. in this retrospective review of 34 case reports and series, we identified cutaneous manifestations documented in 417 of 736 patients (57%) with mis-c associated with covid-19. “rash” was the sole descriptor of skin findings in nearly half of patients. case reports and smaller case series provided more detail, outlining a broad range of lesion morphologies (polymorphic, maculopapular, morbilliform, erythrodermic, urticarial, reticular, petechial, purpuric) in variable anatomic distribution. more thorough descriptions of dermatologic manifestations in patients with mis-c are warranted to better characterize this syndrome, as they may lend important insight into pathogenic mechanisms of disease. at the outset of the novel coronavirus disease 2019 (covid-19) pandemic, it was thought that children were generally unaffected by the deadly viral infection rapidly sweeping across the globe. this was likely due to the disproportionately lower rates at which children are affected by covid-19 compared to adults, both in terms of infection rates and symptom severity. 1,2 despite a relatively benign clinical course for most, pediatric patients may rarely exhibit exaggerated immune responses that fall on a spectrum ranging from a mild febrile inflammatory state without multisystem involvement, to a moderate kawasaki disease (kd)-like illness, to a severe multisystem inflammatory syndrome with shock. 3 beginning in late april 2020, multisystem inflammatory syndrome in children (mis-c) became an increasingly recognized hyperinflammatory phenotype in pediatric patients with evidence of covid-19 infection. on may 14, 2020 the centers for disease control (cdc) issued a national advisory to report all cases meeting criteria for mis-c. cases were defined as individuals aged <21 years with severe illness requiring hospitalization, minimum 24-hour history of fever (>38 degrees celsius), laboratory evidence of inflammation, multisystem (≥2) organ involvement, and laboratory confirmed positive sars-cov-2 infection (via realtime reverse transcriptase polymerase chain reaction [rt-pcr] or antibody test) or epidemiologic connection to a person with covid-19 infection (table 1 ). 4 following this call for reporting, 570 cases of mis-c have been reported to the cdc as of july 29, 2020. 5 with overlapping features of kd and toxic shock syndrome, patients with mis-c exhibit a constellation of variable mucocutaneous as well as gastrointestinal, cardiac, hematologic, and respiratory findings. [5] [6] [7] [8] cutaneous features are present in the majority of patients with mis-c and are currently not well characterized. detailed descriptions of eruption morphology in these patients are limited to small case series and case reports, while larger studies typically document the presence of a "rash", but they do not elaborate further and lack precise dermatologic description. dermatologists are instrumental in classifying this hyperinflammatory syndrome, particularly in delineating differences between the novel mis-c associated with covid-19 and other well-known entities such as kd, should they exist. individuals below the age of 18 years account for less than 8% of all covid-19 infections in the us; 9 however, case numbers have been rising in recent months. 10 mis-c appears to be a rare complication of covd-19 in children with one study reporting 2 per 100,000 covid-19 cases. 7 according to cdc data from the 570 reported mis-c cases, median age at presentation was 8 years (range 2 weeks-20 years). 5 6, 7 notably, however, there is likely significant patient overlap between these studies and the cdc-reported data. in the united kingdom, davies et al. detailed 78 cases of pediatric inflammatory multisystem syndrome temporally associated with sars-cov-2 (pims-ts), which is very similar to mis-c but with a slightly less restrictive case definition, particularly patients may exhibit single organ system dysfunction and may or may not require hospitalization. 11 their cohort had a somewhat higher male predominance (67%) and age of presentation (median 11 years, interquartile range 8-14). 8 regarding ethnicity, 47% of their patients were afrocaribbean, 28% were asian, 22% were white, and 3% were documented as other. underlying comorbidities were present in 22% of patients. of note, cases of mis-c are less prevalent, even absent, in asia with some nations with high covid-19 rates reporting zero cases since the start of the pandemic. [12] [13] [14] skin lesions are present in anywhere from 0. 2-20% of adults with covid-19 infection 15, 16 and are typically transient with highly variable morphology. 17 morbilliform, urticarial, pseudochilblain, vesicular, papulosquamous, pernio-like, livedoid, and necrotic lesions have all been described in large case series and systematic reviews. 16 of these articles state "rash" as the sole descriptor of skin findings. some smaller case series and case reports provide more detailed characterizations: polymorphic, maculopapular, morbilliform, and diffuse erythroderma were the most common morphologies noted. 3, 25, 34, [38] [39] [40] 45, 46, 48, 51 skin lesions in single case reports were described as urticarial 34 , reticular 47 , petechial 32 , and purpuric. 46 with regard to distribution, some rashes were generalized while others were localized to the face, trunk, extremities, or acral regions. palm and sole involvement including edema or erythema were present in some patients 30, 32, 41, 46, 47 while others had desquamation of the extremities and/or digits. 24, 30, 42, 51 conjunctivitis and cheilitis were described in many patients. erythema, edema, and/or induration of the extremities and/or hands and feet were also frequently reported. the time to rash appearance in relation to fever and other symptom onset was not commonly included but ranged from day 2 to day 6 of illness [40] [41] [42] 48 , and in one case the rash appeared 12 days following positive covid-19 test result. 40 symptomatology was infrequently documented, but varied with skin lesions described as nonpruritic in several cases 40, 43, 48 pruritic in one 47 , and painful in another. 50 specific dermatologic diagnoses other than kd were made in three cases of mis-c associated with covid-19. target lesions consistent with erythema multiforme were described in two cases. 30 the pathogenic mechanisms and etiology of mis-c as it relates to covid-19 infection are unknown. some propose it is due to a delayed, postviral immune dysregulation as opposed to a true viral response. 52 this is supported by the fact that many children do not display typical preceding symptoms of covid-19 infection prior to developing mis-c. 53 further, many patients test positive for anti-sars-cov-2 antibodies at the time of mis-c diagnosis, but lack polymerase chain reaction (pcr) positivity for the virus. 32,53 others speculate mis-c is a result of the known ability of sars-cov-2 to block type i and type iii interferon responses, resulting in unrestrained viral proliferation and high viral load. 54 additionally, appropriate questions have been raised surrounding the lack of cases in asia; is this a result of mutational differences of sars-cov-2 in different geographic regions or are there genetic susceptibilities which predispose individuals to develop mis-c? further research is necessary to address these questions. commonalities exist between the clinical spectrum of mis-c and the better-known kd. kd is a medium-vessel vasculitis which occurs in young children ≤ 5 years. clinical features of kd include prolonged fever, rash, cervical lymphadenopathy, and mucosal changes (table 1) ; however, other organ systems (cardiovascular, hepatic, respiratory, gastrointestinal, neurologic) may be involved. 52 like in kd, patients with mis-c variably demonstrate a range of clinical features, including polymorphous exanthema, conjunctivitis, mucositis, and extremity changes. [6] [7] [8] many patients with mis-c meet criteria for complete or incomplete kd. however, gastrointestinal symptoms (abdominal pain, vomiting, diarrhea) are more predominant and cardiovascular abnormalities (myocarditis, ventricular dysfunction, coronary artery aneurysms, hypotension) are reportedly more severe in mis-c, even in patients who lack overlapping features of kd. 6, 31, 52 mucosal involvement is also less consistently present in mis-c than kd. 8 regarding laboratory evaluation, mis-c patients demonstrate higher elevations in inflammatory markers (procalcitonin, esr, crp, ferritin) and relative cytopenias (leukocytopenia, thrombocytopenia), as well as elevated ventricular natriuretic peptide compared to those with kd. 31, 54 further, patients with mis-c are significantly older with a broader age range than the patients who traditionally develop kd. 31 an apparent predilection for hispanic and black populations exists in mis-c, 6, 7, 31 whereas asians typically have the highest rates of kd. 54 this may be a reflection of the generally higher covid-19 infection rates in these populations in the united states 55 ; however, reports of mis-c are nearly absent in asia. 12, 14 while significant overlap exists among these syndromes, many of their shared features are nonspecific findings observed in numerous infectious disease processes in children. 54 their differing epidemiologic trends and laboratory features, as well as the inconsistent overlap of their clinical signs altogether suggest these are perhaps related but distinct phenomena. notably, however, a small subset (≤5%) of patients with kd may progress to develop "kd shock syndrome," which more closely resembles mis-c in terms of laboratory findings and disease severity. 52 while rare, mis-c is a novel syndrome in pediatric patients that is increasingly recognized. skin manifestations are present in the majority of those affected but are not well documented in the literature. more detailed descriptions of cutaneous findings by dermatologists is warranted to further characterize this syndrome, as they may yield important morphologic clues. skin biopsies are generally not performed in children with mis-c but could serve to better guide future understanding of pathophysiologic mechanisms of disease. severe acute respiratory syndrome coronavirus 2 (sars-cov-2) infection in children and adolescents: a systematic review hospitalization rates and characteristics of children aged <18 years hospitalized with laboratory-confirmed covid-19 -covid-net, 14 states clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with sars-cov-2 centers for disease control and prevention health alert network (han) covid-19-associated multisystem inflammatory syndrome in children -united states multisystem inflammatory syndrome in u.s. children and adolescents multisystem inflammatory syndrome in children in new york state intensive care admissions of children with paediatric inflammatory multisystem syndrome temporally associated with sars-cov-2 (pims-ts) in the uk: a multicentre observational study demographic trends of covid-19 cases and deaths in the us reported to cdc guidance: paediatric multisystem inflammatory syndrome temporally associated with covid-19 defining association between covid-19 and the multisystem inflammatory syndrome in children through the pandemic pediatric coronavirus disease-2019-associated multisystem inflammatory syndrome covid-19 and kawasaki disease in children clinical characteristics of coronavirus disease 2019 in china cutaneous manifestations in covid-19: a first perspective clinical and histopathological features and potential pathological mechanisms of skin lesions in covid-19: review of the literature classification of the cutaneous manifestations of covid-19: a rapid prospective nationwide consensus study in spain with 375 cases the spectrum of covid-19-associated dermatologic manifestations: an international registry of 716 patients from 31 countries sars-cov-2 endothelial infection causes covid-19 chilblains: histopathological, immunohistochemical and ultrastructural study of seven paediatric cases a clinical, histopathological and laboratory study of 19 consecutive italian paediatric patients with chilblain-like lesions: lights and shadows on the relationship with covid-19 infection acute heart failure in multisystem inflammatory syndrome in children (mis-c) in the context of global sars-cov-2 pandemic cardiac mri of children with multisystem inflammatory syndrome (mis-c) associated with covid-19: case series multisystem inflammatory syndrome related to covid-19 in previously healthy children and adolescents multisystem inflammatory syndrome in children during the coronavirus 2019 pandemic: a case series severe coronavirus disease-2019 in children and young adults in the washington, dc, metropolitan region acute myocarditis and multisystem inflammatory emerging disease following sars-cov-2 infection in critically ill children spectrum of imaging findings on chest radiographs, us, ct, and mri images in multisystem inflammatory syndrome in children (mis-c) associated with covid-19 multisystem inflammatory syndrome in children associated with severe acute respiratory syndrome coronavirus 2 infection (mis-c): a multi-institutional study from new york city erythema multiforme and kawasaki disease associated with covid-19 infection in children distinct clinical and immunological features of sars-cov-2-induced multisystem inflammatory syndrome in children sars-cov-2-induced kawasaki-like hyperinflammatory syndrome: a novel covid phenotype in children gastrointestinal symptoms as a major presentation component of a novel multisystem inflammatory syndrome in children (mis-c) that is related to covid-19: a single center experience of 44 cases covid-19 multisystem inflammatory syndrome in three teenagers with confirmed sars-cov-2 infection paediatric multisystem inflammatory syndrome temporally associated with sars-cov-2 mimicking kawasaki disease (kawa-covid-19): a multicentre cohort multisystem inflammatory syndrome in children (mis-c) related to covid-19: a new york city experience hyperinflammatory shock in children during covid-19 pandemic kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic in paris, france: prospective observational study an outbreak of severe kawasaki-like disease at the italian epicentre of the sars-cov-2 epidemic: an observational cohort study features of covid-19 post-infectious cytokine release syndrome in children presenting to the emergency department novel coronavirus mimicking kawasaki disease in an infant hyperinflammatory shock related to covid-19 in a patient presenting with multisystem inflammatory syndrome in children: first case from iran hyperinflammatory syndrome in a child with covid-19 treated successfully with intravenous immunoglobulin and tocilizumab special dermatological presentation of paediatric multisystem inflammatory syndrome related to covid-19: erythema multiforme covid-19-associated pediatric multisystem inflammatory syndrome pediatric crohn disease and multisystem inflammatory syndrome in children (mis-c) and covid-19 treated with infliximab toxic shock-like syndrome and covid-19: a case report of multisystem inflammatory syndrome in children (mis-c) covid-19 and kawasaki disease: novel virus and novel case incomplete kawasaki disease in a child with covid-19 introductory histopathological findings may shed light on covid-19 paediatric hyperinflammatory shock syndrome dermatological manifestation of pediatrics multisystem inflammatory syndrome associated with covid-19 in a 3-year-old girl multi-system inflammatory syndrome in children (mis-c) following sars-cov-2 infection: review of clinical presentation, hypothetical pathogenesis, and proposed management sars-cov-2-related inflammatory multisystem syndrome in children: different or shared etiology and pathophysiology as kawasaki disease? jama understanding sars-cov-2-related multisystem inflammatory syndrome in children the disproportionate impact of covid-19 on racial and ethnic minorities in the united states diagnostic criteria for multisystem inflammatory syndrome in children (mis-c) 4 fever (documented ≥ 38.0º c ≥ 24 hours or subjective fever ≥ 24 hours) laboratory evidence of inflammation (elevated erythrocyte sedimentation rate (esr), c-reactive protein (crp), fibrinogen, procalcitonin, d-dimer, ferritin, lactic acid dehydrogenase (ldh) multisystem involvement (≥2 organ systems) recent or current sars-cov-2 infection (as confirmed by rt-pcr, serology, or antigen test) or fever ≥ 5 days plus 4 of the 5 following: 1. bilateral bulbar conjunctival injection 2. oral mucositis (erythematous or fissured lips, injected pharynx, or strawberry tongue) 3. extremity changes (erythema of palms or soles, edema of hands or feet, periungual desquamation) 4. polymorphous rash 5. cervical lymphadenopathy table 1 : diagnostic criteria for mis-c and kd key: cord-271662-h281jgcb authors: dove, m.; jaggi, p.; kelleman, m.; abuali, m.; ang, j.; ballan, w.; basu, s.; campbell, j.; chikkabyrappa, s.; choueiter, n.; clouser, k.; corwin, d.; edwards, a.; gertz, s.; ghassemzadeh, r.; jarrah, r.; katz, s.; knutson, s.; kuebler, j.; lighter, j.; mikesell, c.; mongkolrattanothai, k.; morton, t.; nakra, n.; olivero, r.; osborne, c.; parsons, s.; panesar, l.; patel, r.; schuette, j.; thacker, d.; tremoulet, a.; vidwan, n.; oster, m. title: multisystem inflammatory syndrome in children: survey of early hospital evaluation and management date: 2020-08-01 journal: nan doi: 10.1101/2020.07.29.20164459 sha: doc_id: 271662 cord_uid: h281jgcb background: in the absence of evidence-based therapies for multisystem inflammatory syndrome in children (mis-c), we aimed to describe the similarities and differences in the evaluation and treatment of mis-c at hospitals in the united states. methods: we conducted a cross-sectional survey from june 16 to july 16, 2020 of u.s. pediatric hospitals regarding protocols for patients with mis-c. elements included hospital characteristics, clinical definition of mis-c, evaluation, treatment, and follow-up. we summarized key findings and compared results from centers that had treated >5 patients vs. those that had treated <5 patients. results: forty centers of varying size and experience with mis-c participated. about half (21/40) of centers required only 1 day of fever for mis-c to be considered. in the evaluation of patients, there was often a tiered approach. intravenous immunoglobulin was the most widely used medication to treat mis-c (98% of centers). corticosteroids were listed in 93% of protocols for primarily the moderate or severe cases. aspirin was commonly used including for mild cases, whereas heparin or low molecular weight heparin were used primarily in severe cases. in severe cases, anakinra and vasopressors were frequently recommended. nearly all centers (39/40) recommended follow up with cardiology. there were similar findings between centers that had treated >5 patients vs. those that had treated <5 patients. a supplement containing hospital protocols is provided. conclusion: there are many similarities yet some key differences between hospital protocols for mis-c. these findings can help healthcare providers learn from others regarding options for managing mis-c patients. and features of toxic shock syndrome. 5 this rare but life-threatening condition has been reported with increasing frequency in the united states, and growing evidence establishes mis-c as an immune-mediated condition following sars-cov-2 infection. [6] [7] [8] [9] given the novelty of this new syndrome, evidence-based guidelines for management of children with mis-c are lacking. early reports of mis-c highlight the variability in the evaluation and management of these patients. 2, [5] [6] [7] [9] [10] [11] the american college of rheumatology and the american academy of pediatrics have released guidelines, but these are based primarily on expert opinion . 12, 13 in the absence of evidence-based therapies for mis-c, many centers have created protocols to guide hospital evaluation and management. the purpose of this study is to describe the similarities and differences in the evaluation and treatment of mis-c at hospitals in the united states. we conducted a cross-sectional survey of u.s. children's hospitals regarding their protocols for patients with mis-c. participants were recruited via e-mails to pediatric cardiology and infectious disease list serves and via direct contact to physicians known to be coordinating the mis-c response at their hospital. the survey was administered from june 16 to july 16, 2020 through the electronic database research electronic data capture (redcap) at children's healthcare of atlanta (choa). 14, 15 redcap is a secure, web-based software platform designed to support data capture for research studies, providing 1) an intuitive interface for validated data capture; 2) audit trails for tracking data manipulation and export procedures; 3) automated export procedures for seamless data downloads to common statistical packages; and 4) procedures for data integration and interoperability with external sources. no patient data were collected as part of this inquiry, and this study was considered non-human subjects research by the choa institutional review board. we developed an online questionnaire to learn about the protocol at each center (supplement 1). elements of the questionnaire included hospital characteristics (location, number of pediatric beds, number of mis-c patients treated), clinical definition of mis-c (duration of fever, organ system involvement, evidence of sars-cov-2 infection), evaluation (laboratory studies, imaging), treatment (medications and dosages), and follow-up. finally, participants were invited to share their protocol for inclusion in this publication. participants at centers without a protocol were able to complete the survey but their responses were excluded from the analyses. we performed descriptive statistics to summarize quantitative elements via sas 9.4 and microsoft excel. we reviewed the qualitative elements for key themes and summarized the responses as appropriate. we excluded survey responses which did not have sufficient data for analysis. we then performed a subanalysis to compare the quantitative elements comparing the responses of those centers who had treated >5 patients with mis-c as compared to those centers with <5 patients. in the subanalysis we conducted chi-square analyses, or fisher's exact test where appropriate. finally, for the subanalysis we performed a sensitivity analysis comparing results for centers that had treated >10 mis-c patients vs. those that had treated <10 patients. there were 48 surveys completed from participants at 48 unique centers across the united states. one record was excluded due to insufficient data submitted, 6 records were excluded because the center did not have a protocol, and 1 record was removed after submission at the request of the contributing center. thus, survey responses from 40 centers were available for analysis ( figure 1 ). protocols from 32 centers were submitted with the survey and are included in supplement 2. participating centers varied in size: 15 small pediatric centers (<200 pediatric beds), 15 medium centers (200-<350 pediatric beds), and 10 large centers (>350 pediatric beds). experience with treating mis-c differed between centers: 2 centers with 0 mis-c patients, 18 centers with 1-5 patients, 9 centers with 6-10 patients, 5 centers with 11-25 patients, and 6 centers with >25 patients. of the 40 protocols, 21 had been revised since inception. all respondents indicated that fever is required as part of the definition of mis-c, however the duration and degree of fever varied. about half (21/40) of the centers required only 1 day of fever, 2 centers required at least 2 days, 15 centers required at least 3 days, and 2 centers required at least 4 days of fever. of the 22 centers that specified a minimum temperature for fever, 20 set 38.0 o c as the minimum. almost all (38/40) centers specified the presence of certain organ system involvement; of these, 3 required only 1 organ system, 31 required at least 2 organ systems, and 4 required at least 3 organ systems involved. in 36 of the 40 protocols, abnormal laboratory markers of inflammation were required to meet mis-c inclusion criteria. most centers (31/40) did not require laboratory evidence of current or prior sars-cov-2 infection. instead, prior exposure to someone with covid-19 in the 4 weeks preceding the onset of symptoms sufficed to meet inclusion criteria. three centers commented that, given the high prevalence of covid-19 in their community, the requirement of a known exposure is waived as all children are assumed to have had prior exposure to someone with covid-19 in the preceding 4 weeks. one center commented that the working definition for mis-c was too broad, resulting in often unnecessary testing and, in at least one case, delayed diagnosis of perforated appendicitis. in the evaluation of patients with possible mis-c, there was often a tiered approach, with some centers performing initial laboratory tests on all patients and then further tests only on those patients with high suspicion of mis-c or with relevant symptoms ( figure 2 ). for the identification of sars-cov-2, all centers performed pcr testing from a nasopharyngeal or oropharyngeal sample. most centers also tested for sars-cov-2 antibody in all of their possible mis-c patients. routine bloodwork included complete blood count, basic metabolic panel, liver function tests, c-reactive protein, and erythrocyte sedimentation rate. further bloodwork including investigation for inflammation, cardiac involvement, and abnormal anticoagulation were often performed. further testing including electrocardiogram, echocardiogram, urinalysis, and chest radiograph were common. evidence of potential alternative causes or co-infection was routinely pursued via blood culture or respiratory viral panel. for admitted patients, the infectious disease service was almost universally consulted, followed by cardiology, rheumatology, and hematology. some centers had a similar treatment approach for all patients, while others varied the approach by severity of illness ( figure 3 ). severity of illness was defined specifically at each center, with no uniform definition. submitted criteria for severity of illness included vasoactiveinotropic score, location in the hospital (intensive care unit vs. general floor), degree of hyperinflammation, and presence of shock or cardiac involvement. intravenous immunoglobulin (ivig) was the most widely used medication to treat mis-c, with 98% of centers including ivig in their recommendations and 60% recommending the use of ivig regardless of severity. of the 39 protocols that mentioned any use of ivig, 21 recommended a second dose of ivig for cases that were refractory to the first dose. corticosteroids were listed in 93% of protocols, although these tended to be reserved primarily for moderate or severe cases. aspirin was commonly used including the mild cases, whereas heparin or low molecular weight heparin were used primarily in severe cases. in severe cases, anakinra and vasopressors were frequently recommended. other medications that were recommended in fewer than 25 of the 40 protocols included clopidogrel (3 centers), warfarin (3 centers), remdesivir (10 centers), and tocilizumab or infliximab (13 centers); these medications were primarily reserved for severe or refractory cases. hydroxychloroquine was not recommended in any of the protocols included in the study. while there was no standardized follow-up plan for patients with mis-c, 26 participants responded that their protocol recommends follow-up similar to that of the american heart associations for kd. nearly all centers (39/40) recommended follow up with cardiology, but they differed as to the timing of follow-up and echocardiogram. seven centers arranged followup in 1 week, 22 centers planned for 2 weeks, and 9 centers in 1 month (with one participant not providing a time of follow-up). almost all centers (36/40) included aspirin as a discharge medication, with 26 centers including this medicine regardless of degree of coronary involvement. there was no consensus regarding the utility of cardiac magnetic resonance imaging (mri), with 22 centers mentioning the use of cardiac mri in mis-c patients, primarily for evaluation and follow-up of cardiac dysfunction. protocols at 2 centers included mri during the initial inpatient hospitalization, 9 centers recommended it during outpatient follow-up (6 at 1-3 months, 3 at 3-6 months), and 10 centers deferred to cardiology regarding when to obtain mri. other common specialty follow-up visits included rheumatology by 24 centers, infectious disease by 20, and hematology by 8. in the subanalysis there were similar findings among almost all components of the evaluation and management of mis-c for centers that had treated >5 patients as compared to those that had treated <5 patients (table 1 ). the only significant difference was that centers that had treated >5 patients were more likely to arrange follow-up in infectious disease clinic (70% vs. 30%). in the sensitivity analysis comparing findings for those centers that had treated >10 mis-c patients vs. those that had treated <10 patients, there were likewise similar results (data not shown); the only significant difference between centers was that centers that had treated >10 patients were less likely to include anakinra in their protocols (36% vs. 83%, p=0.008). states highlights the major similarities and differences among centers; these findings can inform centers creating or modifying mis-c protocols. most centers adhered to the mis-c definition that was put forth by cdc in may 2020. however, some centers require 3 days of fever instead of 1, and centers in areas with high prevalence of covid-19 do not require positive sars-cov-2 test results or a known exposure to someone with the disease. in the evaluation of patients for mis-c, most centers begin with a tiered approach that is standard for the workup of a febrile illness, with further testing often dictated by symptoms or initial laboratory results. the findings form this survey underscore the collaborative effort to combat mis-c, as most centers consult multiple subspecialists in the management of these patients. ivig is a mainstay of treatment at most centers, with corticosteroids, aspirin, and heparin often used as well. anakinra and vasopressors are frequently used in children with severe illness. almost all children are discharged on aspirin with planned follow up in cardiology. many of the elements of the protocols for mis-c are similar to those for kd. 2,5-7 as cases of mis-c were emerging, the patients were noted to have clinical signs and symptoms of incomplete kd, left ventricular systolic dysfunction as seen in kd shock syndrome, and occasional coronary dilation. the current aha kd guidelines recommend 2 g/kg ivig after diagnosis and consideration of a 2-3 week course of tapering corticosteroids for high risk patients. administration of a second dose of ivig, high dose iv methylprednisolone, and other immunomodulatory agents are considered if the patient continues to be febrile 36 hours after initial ivig dose. low dose aspirin is recommended until 4-6 weeks post onset of illness, and systemic anticoagulation with lmwh or warfarin is recommended for rapidly progressing coronary aneurysms or those with z-score >10. 16 our survey revealed that treatment for mis-c among u.s. children's hospitals roughly correlated with these recommendations. a large diversion from the kd guidelines was the inclusion of systemic anti-coagulation in some mis-c protocols. this choice was potentially made due to the elevated d-dimers, frequent deep venous thromboses and pulmonary emboli seen in acutely ill adults with covid-19, and a small number of reported mis-c cases with thrombosis. 6, 17 the current choice of therapeutic agents appear reasonable as many patients have recovery of left ventricular systolic function at the time of discharge. 3,5 until long-term data are obtained, it is likely reasonable to continue low dose aspirin in the acute 4-6 week period as in kd. however, this approach is not without risk given the concern for reye syndrome, and the benefit in mis-c may be less than that in kd as patients with mis-c are less likely to have elevated platelet counts or coronary involvement 6,7,10,18 . the evaluation and management of mis-c is clearly an evolving process, as more than half of the centers modified their protocols since inception. this iterative process has similarly been seen in the management of adults with covid-19. for instance, recent data from the recovery trial indicates that dexamethasone may improve mortality in hospitalized adults with severe covid-19 with severe illness. 19 it remains to be seen whether such treatment would be useful in children. we anticipate frequent revisions to hospital protocols as new information is learned regarding sars-cov-2 and mis-c. these findings have important implications during the current pandemic. in the united states, cases of covid-19 continue to rise, especially among the younger age group. 20 as a result, we anticipate that cases of mis-c will rise as well. the findings of this survey can help hospitals with little or no experience yet with these patients to prepare for how to evaluate and manage them. around the world, the covid-19 pandemic continues in many countries. in some developing nations, certain treatment options such as ivig are not readily available. these survey results can help identify other potential options in resource-limited settings. this study is not without its limitations. first, we did not provide a definition for severity of illness, as severity can differ between institutions. therefore, what may be considered a moderate case at one center may be severe at another; this difference should be acknowledged when interpreting the treatment options. second, there was a wide variation in experience in managing mis-c; there were 6 centers with experience treating >25 patients, and 2 centers with no experience treating mis-c patients. thus, some protocols may be based on experience whereas others may be based on personal opinion. we attempted to overcome this limitation by comparing the protocols at those centers with more experience vs. those without. finally, it is important to recognize that this study captures what centers have recommended for the evaluation and management of mis-c at their institution, not what has actually been done for those patients. indeed, protocols may serve as a framework for managing patients with mis-c, but care may be individualized as dictated by patient signs, symptoms, and response to treatment. mis-c is a new syndrome with rapidly evolving strategies for evaluating and managing the condition. there are many similarities yet key differences between hospital protocols. in the absence of evidence-based guidelines, these findings can help healthcare providers learn from others regarding options for evaluating and managing patients with mis-c. it is expected that the understanding of this condition will continue to evolve as more is learned regarding mis-c and as evidence mounts as to what treatment strategies may be best. m e d i c a l m a n a g e m e n t o f p a t i e n t s w i t h m i s -c ( f o r a t l e a s t o n e t y p e o f s e v e r i t y ) i n t r a v e n o u s i m m u n o g l o b u l i n 2 0 ( 1 0 0 between centers for sars-cov-2 testing, basic bloodwork, infectious workup, ancillary testing, and consultant services. some protocols included certain aspects for all patients with potential mis-c, whereas others performed portions for only some patients. medical management of multisystem inflammatory syndrome in children often varied by severity, with severity being defined differently by each center. for centers that gave ivig, 54% recommended a second dose for patients who were refractory to the first dose. medications used by <20 of the 40 centers are not shown. hyperinflammatory shock in children during covid-19 pandemic clinical characteristics of 58 children with a version 1. arthritis rheumatol the redcap consortium: building an international community of software platform partners research electronic data capture (redcap)--a metadata-driven methodology and workflow process for providing translational research informatics support diagnosis, treatment, and long-term management of kawasaki disease: a scientific statement for health professionals from the american heart association venous thrombosis among critically ill patients with coronavirus disease 2019 (covid-19) kawasaki syndrome, reye syndrome, and aspirin dexamethasone in hospitalized patients with covid-19 -preliminary report . we would also like to thank the multidisciplinary teams that helped to create mis-c protocols at the children's hospitals in this study, without whose collaborative efforts this study would not have been possible. key: cord-293715-lipme817 authors: hutchison, lisa; plichta, anna m.; lerea, yehuda; madora, marlee; ushay, h. michael title: neuropsychiatric symptoms in an adolescent boy with multisystem inflammatory syndrome in children (mis-c) date: 2020-06-30 journal: psychosomatics doi: 10.1016/j.psym.2020.06.015 sha: doc_id: 293715 cord_uid: lipme817 background: multisystem inflammatory syndrome in children (mis-c) related to coronavirus disease-2019 (covid-19) is an emergent syndrome affecting children globally in the wake of the sars-cov-2 pandemic. the clinical presentation has similarities to kawasaki disease and toxic shock syndrome. as knowledge of the cardiac and gastrointestinal manifestations has been emerging, little is known about the impact on the brain. method: this case describes a 14-year-old boy who developed prominent neuropsychiatric symptoms including delirium followed by impairments in executive functioning in the context of mis-c with positive sars-cov-2 antibodies. these symptoms improved in correlation with improvements in inflammatory markers. results: neuropsychiatric manifestations including confusion, irritability, and headaches have been reported in pediatric patients with mis-c. potential mechanisms include direct neurotropic effect of sars-cov-2, secondary effects of systemic inflammation, and/or adverse side effects of treatment. conclusions: mis-c is a novel and poorly understood syndrome related to sars-cov-2 with effects on multiple organ systems including the central nervous system. as additional cases are reported and research expands, so too will our understanding of the neuropsychiatric manifestations. better understanding of the underlying pathophysiology would aid in determining targeted interventions. the recent sars-cov-2 pandemic has been associated with emergence of a new syndrome referred to as multisystem inflammatory syndrome in children (mis-c) related to coronavirus disease-2019 (covid19) . as this is an emerging syndrome, knowledge of its presentation and pathophysiology is evolving. mis-c is currently defined by the presence of fever, inflammation, and multi-organ dysfunction in the context of present or recent sars-cov-2 infection or known covid-19 exposure (1). the syndrome has similarities to kawasaki disease and toxic shock syndrome. case series out of europe and the united states have described presenting symptoms variably including fever, gastrointestinal symptoms, rash, mucosal changes, adenopathy, edema, and respiratory symptoms (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) . headache, irritability, and confusion have also been described, but details regarding these neuropsychiatric symptoms have not been provided. given the paucity of knowledge concerning this syndrome's effect on the nervous system, the intent of this case report is to describe the neuropsychiatric symptoms in one 14-year-old boy presenting with multisystem inflammatory syndrome and positive sars-cov-2 antibodies. case a 14-year-old african american boy, with no past medical or psychiatric history, presented to an emergency department in new york city with abdominal pain, fever, and truncal rash in mid-may, 2020. the patient had no known sick contacts and no members of his family had been diagnosed with covid-19. in the emergency department, the patient was found to have a painful, distended abdomen and was febrile to 102.8 o f with tachycardia and hypotension concerning for shock. laboratory studies were notable for low white blood cell count (3.8 k/μl) and elevations in c-reactive protein (crp) (30.2 mg/dl), creatinine (1.4 mg/dl), erythrocyte sedimentation rate (53 mm/h), ferritin (1,305 ng/ml), d-dimer (> 20 μg/ml), bilirubin (2.2 mg/dl), and liver enzymes (alt 31 u/l, ast 53 u/l). sars-cov-2 polymerase chain reaction (pcr) testing was negative. chest and abdominal computed topography (ct) showed diffuse enterocolitis and bilateral ground glass opacities in the lungs. the patient received fluid resuscitation, empiric antibiotics, and a surgical evaluation. he was admitted to the pediatric intensive care unit (picu) where he required initiation of norepinephrine to support falling blood pressure. arterial and central venous catheters were inserted using brief sedation with ketamine and midazolam. on the day of admission, the patient was started on a five-day course of methylprednisolone 0.5mg/kg every six hours, as well as anticoagulation with low molecular weight heparin. he was placed on high flow nasal cannula for worsening respiratory distress and was noted to have peripheral and facial edema, likely secondary to fluid resuscitation. serum interleukin-6 (il-6) was significantly elevated at 5,651 pg/ml (normal < 17.4 pg/ml) while interleukin-1 (il-1) was mildly elevated at 3.4 pg/ml (normal < 3.0 pg/ml). echocardiogram showed a left ventricular ejection fraction of 58% and mild coronary artery dilation (z-score < 2.5). during the first night of hospitalization, the patient was noted to be restless, agitated, and confused. soft wrist restraints were temporarily applied after he pulled out his femoral central line and nasogastric tube. ketamine was administered for replacement of the central line and a dexmedetomidine drip was started to reduce agitation. on the second hospital day, the patient's parents felt that he was back to his usual self, though sleepy. due to concerns for worsening cytokine storm the patient received a single dose of anakinra to target the multisystem inflammation. a repeat echocardiogram showed worsening left ventricular function (ejection fraction 42%) and milrinone was started. repeat sars-cov-2 pcr testing was again negative. as the day progressed, the patient again became disoriented and confused, intermittently sleeping for 10-15 minutes at a time, then awakening and attempting to leave the bed. this culminated in an episode of agitation in the early afternoon during which the patient was disoriented, appeared to respond to internal stimuli, and became aggressive. several staff members were required to physically restrain the patient to prevent injury and haloperidol 5mg was given intravenously (iv) to target psychosis. haloperidol was perceived to worsen the agitation, so twenty minutes later, lorazepam 2mg iv was administered, after which the patient calmed and fell asleep. the child and adolescent psychiatry team was consulted but were unable to perform a full evaluation due to medication effects. the psychiatry team suspected hyperactive delirium due to the fluctuation changes in awareness and attention, though the reported worsening of agitation with haloperidol and improvement with lorazepam raised concern for possible agitated catatonia. with this differential in mind, the team recommended olanzapine 5mg by mouth at bedtime. the dexmedetomidine drip was also increased. by that afternoon, the patient had met diagnostic criteria for atypical kawasaki disease, so a course of 2 gram/kg of intravenous immunoglobulin (ivig) was initiated, divided over 4 days due to concerns for excess fluid volume in a patient with diminished ventricular heart function and persistent tachypnea. on hospital day three, the patient remained sedated on dexmedetomidine with intermittent restlessness and verbal aggression inconsistent with the patient's baseline character, which was described as quiet and shy. on hospital day four, the dexmedetomidine drip was discontinued and immediately the patient demonstrated confusion, disorientation, delusions, and aggression. he again received lorazepam 2mg iv, which had a calming effect, and dexmedetomidine was restarted. the patient was given an additional dose of olanzapine 5mg by mouth for refractory delirium and the standing dose was increased to 5mg twice a day. a noncontrast magnetic resonance imaging (mri) study of the brain was obtained and was unremarkable. a lumbar puncture (lp) was considered but not performed due to the patient's anticoagulation status. laboratory studies showed ferritin at its peak (1753 ng/ml) while ddimer declined for the first time to 13.37 μg/ml, and crp (which peaked on day of admission) had come down to 7.8 mg/dl. on hospital day five, the dexmedetomidine drip was once again discontinued, this time without emergent agitation. the pediatric neurology team evaluated the patient and found him to be sleepy, inattentive, and unable to follow multi-step commands. tone, strength, and sensation were all intact. over hospital days six to eight, the patient showed gradual improvements. he was able to wean off norepinephrine and milrinone, markers of kidney and liver injury improved, and inflammatory markers continued to come down. coronavirus antibody testing showed presence of sars-cov-2 immunoglobulin g antibodies. the olanzapine was decreased from twice a day to once a day and then discontinued. ongoing abnormalities in mental status documented by picu staff included increased speech latency, flat affect, and minimal spontaneous activity. by hospital day nine, the patient was stable on room air. he had been off antipsychotics for over 24 hours and had not had recurrence of agitation. this was the first occasion when the psychiatry team was able to perform a formal, in-person mental status exam while the patient was awake. the exam was significant for flat affect, poor eye contact, and minimal spontaneous movement or speech. his thought process was concrete but linear. on cognitive assessment, the patient was oriented to self, date, and location (hospital), but not circumstances. he believed that he was still in the emergency department and was unaware of how long he had been in the hospital. he had significant impairment in attention, concentration, and short-term memory demonstrated by inability to perform serial 7s (became stuck after first subtraction) or serial 3s (adding instead of subtracting, despite several prompts), inability to say days of the week backwards (reversed directions after two days), and difficulty recalling events from earlier in the day. strength and tone were normal, but he showed slowing on rapid alternating movements. the patient was able to follow simple commands ("touch my finger") but not multi-step commands ("touch my finger then touch your ear"). he had no difficulty repeating sentences ("no ifs, ands, or buts"), but he demonstrated impairments in executive functioning on the clockdrawing task, needing to have instructions reiterated repeatedly and initially writing all the numbers on one side. he positioned the clock hands to show 6:00 rather than the time instructed (2:50). there was no evidence on exam of hallucinations, delusions, or waxing and waning of his mental status. as of hospital day eleven, the patient appeared to be back to his baseline neurocognitive status per his parents' assessment: that of a typically developing 8 th grader. on mental status exam, spontaneous movement and speech had returned, and affect was reactive and appropriate. he exhibited good eye contact, full cooperation, and ability to follow complex multi-step commands ("touch my finger, then touch your ear and close your eyes"). attention, concentration, and short-term memory were all improved as demonstrated by ability to complete serial 7s without hesitation, successfully spelling world backwards, and detailed recall of recent events and conversations. repeat inflammatory markers showed il-6 49 pg/ml, ferritin 584 ng/ml, d-dimer 2 μg/ml, crp 5 mg/dl. he was discharged home the following day. identically, to kawasaki disease (kd), an inflammatory syndrome associated with systemic vasculitis (12) . classic kd presents with fever in combination with rash, cervical lymphadenopathy, conjunctivitis, mucosal changes, and swelling/redness of the extremities (13) . most cases of mis-c reported thus far have not met full criteria for kd, but overlapping symptoms have been present to varying degrees (11) . based on review of ten case series published so far, fever is the most prevalent presenting symptom (part of the case definition), followed by gastrointestinal complaints (present in 60-100% of cases) . rates of neurological and/or neuropsychiatric symptoms have ranged from 25-56% with the most common symptom being meningism, followed by headache and irritability. confusion has been reported less frequently but the exact incidence is unclear due to lumping with other neurological symptoms (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) . five of the ten case series reviewed specifically mentioned confusion as a presenting symptom in at least one of the included patients (4-6, 9, 11) . overt delirium and/or neurocognitive changes have not been specifically reported. the relationship between mis-c and sars-cov-2 remains undetermined. an epidemiological study of mis-c in france demonstrated that cases of mis-c peaked approximately 4-6 weeks following the peak of covid-19 cases in that country (14) . this finding suggests a post-infectious inflammatory process, though the temporal relationship with the virus is still under investigation. across case series, the number of patients with mis-c who had a positive sars-cov-2 pcr ranged from 13-69% while the number of patients with positive serology ranged from 53-97% (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) . some of the discrepancy across and within studies is due to changes in the availability of these tests over time. our patient's positive antibodies with negative pcr supports the post-infectious theory, though the finding of ground glass opacities on chest ct raised concern for active infection. four cases with facial nerve palsy, one with hemiplegia, and a final patient had both facial palsy and hemiplegia (16) . cases with more diffuse central nervous system (cns) involvement include one describing a four-year-old with hypotonia, coma, hemiparesis, and seizures during the acute phase of kd illness followed by prolonged neurocognitive impairment resembling autism with intractable seizures (17) . another case series described four patients with the syndrome of mild encephalopathy with a reversible splenial lesion (mers) in the context of kd. the clinical symptoms in these patients included delirium and drowsiness lasting 3-8 days with normal csf studies and characteristic findings on mri (18) . finally, a team in serbia described a 7-year-old boy who presented with generalized convulsive status epilepticus and depressed mental status which was attributed to cerebral vasculitis secondary to kd. his symptoms improved significantly with ivig and steroid treatment (19) . there are several potential mechanisms for our patient's neuropsychiatric symptoms and the etiology was almost certainly multifactorial. first, delirium and other neuropsychiatric symptoms ranging from encephalitis to focal neuropathies, changes in taste and smell, and acute brainstem dysfunction have been described in patients with covid-19 (20) (21) . the relationship between the sars-cov-2 virus and these neurological manifestations may be primary, secondary, or both. a portion of the neuropsychiatric manifestations are likely due to secondary mechanisms such as hypoxia, systemic inflammation, and coagulopathy, but csf studies and pathological analysis of brain tissue in some patients have shown evidence for direct neurotropic activity by the virus (22) . while our patient's sars-cov-2 pcr testing was negative, we cannot rule out active infection. cytokine neurotoxicity is also high on the differential as elevated interleukin-6 has been independently linked to delirium in adults (23) (24) . cytokine storm has been documented in covid-19 infections and cytokines are similarly thought to play an important pathologic role kd (13, 25) . knowledge of the neurotoxicity of cytokines is primarily derived from experience with t-cell therapies which are known to trigger cytokine release syndrome. this cytokine release has been associated with confusion, delirium, and language disturbances (26) . neurotoxicity from cytokines would explain why the patient manifested the most severe symptoms during the period when his inflammatory markers were most elevated. another potential explanation is direct involvement of the cns by autoantibodies. autoantibodies targeting the cns in the post-infectious period has been documented in syndromes including acute disseminated encephalomyelitis (adem) and autoimmune encephalitis (27) . since no lumbar puncture was performed, it was not possible to directly evaluate the csf for evidence of a humoral immune process, which could include presence of white blood cells, elevated proteins, or oligoclonal bands. our patient's unremarkable mri is inconclusive given that mris are often normal in autoimmune encephalitides, especially in the early phases of illness (28) . the effectiveness of ivig in the treatment of mis-c suggests that antibodies likely play a role in the pathophysiology, though as in kd, the exact role of antibodies is yet unknown (29) . finally, the neuropsychiatric symptoms could have been secondary to treatment with high-dose corticosteroids. corticosteroids carry significant risk of neuropsychiatric side effects including mood changes, psychosis, delirium, and changes in executive functioning (30) . the patient's symptoms began approximately 18 hours after methylprednisolone was initiated and significantly improved after its discontinuation. since steroid exposure and the peak of the inflammatory process were temporally correlated, it remains difficult to tease apart their individual effects. iatrogenic administration of other deliriogenic medications including ketamine, midazolam, and lorazepam may also have contributed to symptoms, though the patient's exposure to these medications was sporadic and failed to temporally associate with symptoms. as the sars-cov-2 pandemic progresses, cases of mis-c associated with covid-19 are expected to increase and with it, our understanding of the underlying pathophysiology and potential manifestations. there are not, as of yet, any evidence-based treatment guidelines and due to the potentially serious outcomes of the presenting syndrome (shock, cytokine storm, vasculitis), early treatment with potent pharmacologic agents is empirically initiated. this case represents one example of neuropsychiatric symptoms associated with mis-c, but it is not the only one in which similar symptoms were reported. as additional cases are described, a pattern of neuropsychiatric manifestations may emerge, or evidence of an iatrogenic mechanism may become apparent. hopefully, additional experience and research will provide a better understanding of this syndrome and more targeted interventions. the authors declare that they have no conflicts of interest to report. acute heart failure in multisystem inflammatory syndrome in children (mis-c) in the context of global sars-cov-2 pandemic multisystem inflammatory syndrome related to covid-19 in previously healthy children and adolescents in new york city multisystem inflammatory syndrome in children during the covid-19 pandemic: a case series gastrointestinal symptoms as a major presentation of a novel multisystem inflammatory syndrome in children 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inflammation, coagulation, and brain injury as predictors of delirium duration in older hospitalized patients change in serum level of interleukin 6 and delirium after coronary artery bypass graft the role of cytokines including interleukin-6 in covid-19 induced pneumonia and macrophage activation syndromelike disease neurotoxicity associated with cd19-targeted car-t cell therapies post infectious encephalitis in adults: diagnosis and management autoimmune encephalitis: pathophysiology and imaging review of an overlooked diagnosis b cells and antibodies in kawasaki disease corticosteroid-induced neuropsychiatric disorders: review and contrast with neuropsychiatric lupus key: cord-350401-suefuurq authors: lima-setta, fernanda; magalhães-barbosa, maria clara de; rodrigues-santos, gustavo; figueiredo, elaine augusta das neves; jacques, melissa de lorena; zeitel, raquel de seixas; sapolnik, roberto; borges, cibelle teixeira da siva; lanziotti, vanessa soares; castro, roberta esteves vieira de; bellinat, ana paula novaes; silva, thiago peres da; oliveira, felipe rezende caino de; reis, bárbara carvalho santos dos; castro, natália almeida de arnaldo silva rodriguez; macedo, joão henrique garcia cobas; scarlato, ana carolina cabral pinheiro; riveiro, paula marins; mota, isabele coelho fonseca da; lorenzo, vivian botelho; lucena, natalia martins lima de; azevedo, zina maria almeida de; cunha, antonio josé l.a.; prata-barbosa, arnaldo title: multisystem inflammatory syndrome in children (mis-c) during sars-cov-2 pandemic in brazil: a multicenter, prospective cohort study()()() date: 2020-11-09 journal: j pediatr (rio j) doi: 10.1016/j.jped.2020.10.008 sha: doc_id: 350401 cord_uid: suefuurq objective: to describe the clinical, laboratory, and radiological characteristics, as well as the outcomes of children with mis-c. method: multicenter, prospective cohort study, conducted in 17 pediatric intensive care units in five states in brazil, from march to july 2020. patients from 1 month to 19 years who met the mis-c diagnostic criteria were included consecutively. results: fifty-six patients were included, with the following conditions: kawasaki-like disease (n = 26), incomplete kawasaki disease (n = 16), acute cardiac dysfunction (n = 10), toxic shock syndrome (n = 3), and macrophage activation syndrome (n = 1). median age was 6.2 years (iqr 2.4-10.3), 70% were boys, 59% were non-whites, 20% had comorbidities, 48% reported a contact with covid-19 cases, and 55% had a recent sars-cov-2 infection confirmed by rt-pcr and/or serology. gastrointestinal symptoms were present in 71%, shock symptoms in 59%, and severe respiratory symptoms in less than 20%. d-dimer was increased in 80% and cardiac dysfunction markers in more than 75%. treatment included immunoglobulin (89%); corticosteroids, antibiotics, and enoxaparin in about 50%; and oseltamivir and antifungal therapy in less than 10%. only 11% needed invasive mechanical ventilation, with a median duration of five days (iqr 5-6.5). the median length of picu stay was six days (iqr 5-11), and one death occurred (1.8%). conclusions: most characteristics of the present mis-c patients were similar to that of other cohorts. the present results may contribute to a broader understanding of sars-cov-2 infection in children and its short-term consequences. long-term multidisciplinary follow-up is needed, since it is not known whether these patients will have chronic cardiac impairment or other sequelae. in april 2020, a few months after the beginning of the sars-cov-2 virus pandemic, some reports called attention to the increase in hospitalizations of children and adolescents with clinical features similar to toxic shock syndrome or kawasaki disease (kd) . [1, 2] this condition, initially called pediatric multisystem inflammatory syndrome temporally associated with covid-19, was later named multisystemic inflammatory syndrome in children (mis-c). several studies have described this new syndrome, [3] [4] [5] [6] [7] and both the centers for disease control and prevention (cdc) and the world health organization (who) have released a case definition. [8, 9] currently, it is already known that mis-c and kd are different clinical entities, [10, 11] and that mis-c may present with different phenotypes. [11, 12] to date, few studies have been published on covid-19 or mis-c in latin america. a multicenter study from chile, colombia, and other countries reported 17 children with covid-19, but no case of mis-c; [13] another multicenter study in brazil reported 79 confirmed cases of sars-cov-2 infection, of which ten were classified as mis-c; [14] and the other two were case series from southeastern brazil (66 cases, six of mis-c), [15] and from northern brazil (11 cases of mis-c). [16] the present study aimed to describe the epidemiological, clinical, laboratory, and radiological characteristics, as well as outcomes of a broader cohort of children with mis-c in brazil, the epicenter of the covid-19 epidemic in south america. this was an observational, multicenter study, partly retrospective, partly prospective, conducted in 17 picus from five states in brazil: 11 in the southeast, five in the northeast, and one in the north; 12 private, four public, and one mixed; all associated with the brazilian research network in pediatric intensive care (brnet-pic). from march 25 to august 23, 2020, pediatric patients (age range: 1 month -19 years) were consecutively included if they met the cdc case definition[8] for mis-c: 1) fever > 38.0°c for ≥ 24 hours (objective or subjective); 2) laboratory evidence of inflammation, including, but not limited to, one or more of the following: high values of c-reactive protein (crp), erythrocyte sedimentation rate (esr), fibrinogen, procalcitonin, d-dimer, ferritin, lactic acid dehydrogenase (ldh), or interleukin 6 (il-6); elevated neutrophils, reduced lymphocytes, and low albumin; 3) no alternative plausible diagnosis; 4) current or recent sars-cov-2 infection diagnosed by a positive reverse transcription polymerase chain reaction (rt-pcr) or positive serological tests (igm, igg or iga), or exposure to a suspected or confirmed covid-19 case within the four weeks prior to the onset of symptoms. the study was approved by the research ethics committees of all institutions. the families agreed to participate by signing an informed consent form. demographic, clinical, epidemiological, radiological, laboratory, and outcome data were prospectively collected, using standardized case report forms (redcap; vanderbilt university -tn, united states). laboratory tests were ordered at the discretion of the health team in each pediatric intensive care unit (picu) and according to local availability. tests to detect sars-cov-2 infection were performed by rt-pcr using oro/nasopharyngeal swabs or tracheal aspirates and/or serology. the serological tests to detect the presence of specific covid-19 antibodies in the blood/serum of the patients were of two types: 1) rapid immunodiagnostic tests (commercially available immunochromatographic lateral flow immunoassays) for detection of igm and/or igg; 2) enzyme-linked immunosorbent assays (elisa) for detection of igm, igg, and iga, according to the local availability of these diagnostic tests. j o u r n a l p r e -p r o o f data processing and statistical analysis continuous variables were described as medians and interquartile ranges (iqrs) and categorical variables as frequencies and percentages. demographic, clinical, laboratory, and outcome data were categorized in the following groups: kawasaki-like disease, incomplete kd, acute cardiac dysfunction, toxic shock syndrome, and macrophage activation syndrome. the analyses were performed using the software r (v. 3.6.1, r foundation -vienna, austria). fifty-six patients were included. the median age was 6.2 years; 70% were boys; 57% were of mixed-race or black; about 20% had comorbidities, of which almost half were chronic neurological diseases; and of the patients who reported contact with a suspected case (approximately half), almost 100% were household contacts. sars-cov-2 infection could be confirmed in 55% of patients, since rt-pcr and serology immunoassays were not available in all picu: 14 out of 30 tested positive by rt-pcr, of whom five also presented serology (two positive); 19 out of 22 tested positive by serology, of whom 18 also underwent rt-pcr (16 negative; table 1 ). all cases described as confirmed sars-cov-2 infection in this study had either a positive rt-pcr or a positive serology result. the main multisystem inflammatory phenotype at presentation was kawasakilike disease (46%) and incomplete kd (29%), followed by acute cardiac dysfunction (18%), toxic shock syndrome (5%), and macrophage activation syndrome (2%). the median duration of symptoms before hospitalization was five days, and the median duration of fever was six days. gastrointestinal symptoms were present in 71% of patients, mainly abdominal pain (54%), diarrhea (54%), and vomiting (38%). skin rash (68%), prostration (54%), and headache or irritability (48%) were also very common. shock symptoms were present in 59% of patients, mainly tachycardia (43%), hypotension (30%), and prolonged capillary refill (29%). respiratory symptoms occurred in 46% of patients, but severe symptoms, such as low spo2 (18%) and dyspnea (16%) were not very frequent. all patients had elevated inflammatory markers, and over 75% had elevated cardiac dysfunction markers. more than half (53%) also had laboratory signs of coagulopathy (table 2) . altered chest radiographs were found in 25 of 48 patients (52%), mainly bilateral diffuse interstitial infiltrate (23%), while ground glass opacities were observed j o u r n a l p r e -p r o o f in 11 of 35 patients (31%) who underwent chest computerized tomography. the echocardiogram was altered in 34 patients (61%), mainly showing mild pericardial effusion (50%), although 27% of the patients had left ventricular dysfunction and also 27% had signs of coronary dilatation (table 2) . of the 56 patients included, 18 had c-reactive protein (crp) below 10.0 mg/dl, two patients had borderline results between 1.0 and 3.0 mg/dl and only three had crp below 1.0 mg/dl. from these five patients with crp below 3.0 mg/dl, three of them had altered esr (> 20 mm) and the two remaining had altered fibrinogen (> 300 mg/dl). thus, all patients had altered inflammatory markers, in accordance with the cdc criteria. cardiac dysfunction markers were increased in more than 75% of the patients tested. troponin i was higher than 0.1 ng/ml in 53% of patients; pro-b type natriuretic peptide (probnp) was elevated in more than 75% of patients, and above 1,000 pg/ml in 42% of those; and 38% had creatinine kinase myocardial band (ck-mb) values higher than 25 u/l. d-dimer was high (> 500 ng/ml) in 80% of 41 patients tested; fibrinogen and activated prothrombin time (aptt) were also elevated in more than half of the patients. blood count was performed in all patients: anemia, leukocytosis, lymphopenia, and thrombocytopenia were observed in more than 30% of the patients, but thrombocytosis in only 14%. lactate dehydrogenase (ldh) was high (> 295 u/l) in 78% of 50 patients; the results of liver function tests were slightly abnormal in some patients, but hypoalbuminemia (< 3 g/dl) was present in 62%. renal function was normal in all patients (table 3) . a total of 89% of patients received intravenous immunoglobulin (ivig), and more than 50% received corticosteroids and enoxaparin (prophylactic or therapeutic). acetylsalicylic acid (aas) was administered in 45%, antibiotics in 59%, but oseltamivir and antifungal therapy were used in less than 10% of patients. of the 20 patients (36%) who needed respiratory support, only 11% required invasive mechanical ventilation (imv), of whom only two patients had a more severe course, with acute respiratory distress syndrome (ards), but no with pulmonary arterial hypertension. the median duration of imv was five days and the highest median positive end j o u r n a l p r e -p r o o f expiratory pressure (peep) was 8.5. no special ventilatory strategies, such as intermittent prone position or alveolar recruitment maneuver, were necessary. there was only one death in this cohort (1.8%; table 4 ). most patients (75%) had the complete kd or incomplete kawasaki phenotype, of which boys (76%) were most frequent. in the group with acute cardiac dysfunction, the median age was higher than in the other groups and non-whites represented 88% of patients. comorbidities were not frequent in any phenotype. more than 70% of patients of all groups were treated with igiv. the median picu length of stay was six days, except for the only macrophagic activation syndrome patient (22 days; table s1 this is the first brazilian multicenter study that described a cohort of patients with mis-c only. the clinical features of the present patients are very similar to those previously reported in literature: most patients did not meet the complete criteria for kd; the median age was higher than that described for patients with covid-19 only, but slightly lower than that described for mis-c, [3] [4] [5] [6] [7] 10 ] and greater than that observed in classic kd. [17] in this study, males were much more frequent than females (2:1), and this predominance was even higher in the kawasaki-like phenotype (3:1). this high proportion of males was also observed in other multicenter studies of mis-c in the united kingdom and the united states, [5, 6] and in critically ill children with covid-19 alone. [14] biological differences (genetic and epigenetic) between males and females may affect the immune response to sars-cov-2 infection, as has already been described in kd. [18, 19] most of the present patients were non-white, similar to what has been described in europe and america, although this may reflect the general ethnical distribution of brazil. [5, 6, 11] as to the frequency of comorbidities, the present results were also similar to other studies of mis-c, [5, 6] but the predominance of chronic neurological diseases has not been previously reported. almost half of the present patients had a history of a contact with someone with covid-19 and 55% had sars-cov-2 infection either detected by rt-pcr, serological test or both, corroborating a causal association with the new coronavirus. fourteen patients tested j o u r n a l p r e -p r o o f positive for sars-cov-2 by rt-pcr, which generally reflects an acute phase of the infection, although the virus or its fragments may be detected for longer periods in some patients and could be responsible for these results, outside the classical period of positivity of the acute phase of covid-19. however, it is still unclear how long after the acute phase of sars-cov-2 infection it takes for the first signs and symptoms of mis-c to appear, or even whether this condition may still occur during the acute phase of covid-19. the high frequency of gastrointestinal symptoms, the low prevalence of severe respiratory failure, and the lower degree of mucosal involvement have already been described, which characterizes mis-c as a distinct entity, unrelated to classic kd. [5, 6] as expected in proinflammatory states and as part of the criteria for defining mis-c, all children in the present cohort had increased inflammatory markers, such as crp, esr, and ferritin, which is also reported in other mis-c cohorts in england, united states, france, switzerland, and italy. [3] [4] [5] 7, 10] the proinflammatory effect of sars-cov-2 infection has been reported in adults with severe covid-19, with whom mis-c shares some characteristics, such as dysregulated innate immune response and cytokine storm. [6, 10, [20] [21] [22] in this study, il-6 was measured in only three patients, due to its low availability and high cost. il-6 is a pro-inflammatory cytokine that has been studied for many years as a sepsis biomarker, and its concentrations appear to correlate positively with sepsis severity. [23] il-6 appears to play an important role in severe adult patients with covid-19, in whom the compassionate use of tocilizumab for pharmacologic inhibition of il-6 has been described. [24] the levels of d-dimer, fibrinogen, and aptt were also elevated in most patients, reflecting a state of coagulopathy associated with hyperinflammation, which has been described in severe covid-19 and mis-c. [10, 20, 24, 25] lymphopenia and thrombocytopeniawhich have been described as distinct hematological features of mis-c and are not present in classic kdwas observed in 30% to 45% of patients in the present cohort. anemia and hypoalbuminemia were also common in our patients, but these findings are characteristics of kd. [2] although mis-c is already recognized as a distinct clinical entity, the overlap of many features of other multisystem inflammatory syndrome phenotypes is frequently reported. a striking difference between mis-c and severe covid-19 in adults is the absence of renal impairment,[10] this is described in other cohorts of mis-c and we also found normal renal function in our patients. cardiac dysfunction markers were altered in most of our j o u r n a l p r e -p r o o f patients. normal troponin levels of < 0.1 ng/ml have been described in healthy children under 1year of age. [26] pro-bnp cut-off points of 502 ng/l, 456 ng/l, 445 ng/l, and.355 ng/l have been suggested for detecting cardiac failure in children aged 1-3 years, 4-7 years, and 8-14 years, respectively. [27] in the present cohort, troponin levels were highly increased in at least half of the patients who were tested, while pro-bnp was highly increased in more than three quarters of the tested patients. echocardiographic findings similar to those of kd were also common in this cohort. these findings are compatible with myocardial dysfunction and inflammation consistently described in mis-c reports. [3] [4] [5] [6] its mechanism is not fully understood, but it may be related to microvascular damage, stress cardiomyopathy (takotsubo syndrome) and systemic inflammatory response syndrome. [28] although there is no current evidence for the best management of mis-c, guidelines from different organizations recommend treatment based on the clinical phenotype. [6, 29] in the present cohort, the clinical syndromes at admission were mostly complete or incomplete kd, followed by acute cardiac dysfunction, and in a lesser extent toxic shock syndrome and macrophage activation syndrome. accordingly, igiv was used in the vast majority of patients, and corticosteroids and aas in approximately half. the role of aas in the treatment of kd is well established and has been used in all patients with a phenotype similar to complete kd. although there is no evidence of the benefit of corticosteroid for pediatric patients with severe covid-19 and/or mis-c, the use of corticosteroid in mis-c patients has been described in many studies in an attempt to reduce the hyperinflammatory response. [5, 6, 10] in addition, the recent multicenter codex trial showed that, in severe adult patients with covid-19, the use of dexamethasone increased the ventilator-free-days in the first 28 days by two-thirds. [30] enoxaparin was also used in more than half of the present patients, since d-dimer was highly elevated in most of them. actually, coagulopathy and thrombosis are important features in severe covid-19 in adults. [28] children with mis-c are at risk for thrombotic complications of multiple causes, including hypercoagulable state, possible endothelial injury, immobilization stasis, ventricular dysfunction, and coronary artery aneurysm. for these reasons, antiplatelet and/or anticoagulation treatment is recommended, based on coagulation tests and clinical presentation. [28] although no information on associated bacterial or fungal infection and/or codetection of other viruses is available, the described use of antibiotics, antifungal therapy and oseltamivir in this study can be justified by these possibilities. empirical j o u r n a l p r e -p r o o f antibiotic therapy in hospitalized patients with mis-c is recommended, as symptoms overlap with severe bacterial sepsis. [28] the protocol of the brazilian ministry of heath for severe respiratory acute syndrome recommends the use of oseltamivir until an influenza infection can be excluded. although children diagnosed with mis-c often require intensive care treatment, studies have shown good outcomes and a low mortality rate. [5, 10] this study found similar outcomes, with only one death, but with a longer length of picu stay than that reported in other cohorts. [3, 7, 10, 11] the comparison of demographic and clinical features among the different phenotypes showed that they were relatively equivalent. the present study has some limitations. brazil is a country with great racial miscegenation, which may limit the generalization of the present results, especially considering that individual genetic variations has been reported to affect the severity and phenotypes of sars-cov-2 infection. in addition, although this is a multicenter study, the number of patients is small, making comparison among phenotypes difficult. however, the present number is similar to other cohorts of mis-c patients previously described. [3] [4] [5] [6] [7] 10] additionally, only 55% of the patients had confirmed laboratorial sars-cov-2 infection and not all patients had inflammatory and cardiac dysfunction markers checked. also, information about the history of previous symptoms that suggest another previous viral disease or when it has occurred was not available. nevertheless, this article provides relevant information on the clinical features and outcomes of the novel described mis-c in hospitalized children and adolescents in brazil, which the authors believe to be an important contribution to the understanding of sars-cov-2 infection in children and its short-term consequences. it is important to reinforce the need for long-term multidisciplinary follow-up, since it is still not known whether these patients will have chronic cardiac impairment or other sequelae. this study was supported by grants from the following brazilian research promotion agencies: conselho nacional de desenvolvimento científico e tecnológico -cnpq b some patients presented more than one comorbidity. c non-progressive encephalopathy (n = 3), autism (n = 2). d some patients presented positive rt-pcr and serology. j o u r n a l p r e -p r o o f iqr, interquartile range; mis-c, multisystem inflammatory syndrome in children; spo2, pulse oximeter oxygen saturation; ekg, electrocardiogram a some patients presented more than one comorbidity j o u r n a l p r e -p r o o f guidance: paediatric multisystem inflammatory syndrome temporally associated with covid-19 and kawasaki disease: novel virus and novel case hyperinflammatory shock in children during covid-19 pandemic an outbreak of severe kawasaki-like disease at the italian epicentre of the sars-cov-2 epidemic: an observational cohort study multisystem inflammatory syndrome in u.s. children and adolescents intensive care admissions of children with paediatric inflammatory multisystem syndrome temporally associated with sars-cov-2 (pims-ts) in the uk: a multicentre observational study kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic in paris, france: prospective observational study world health organization. multisystem inflammatory syndrome in children and adolescents temporally related to covid-19 -scientific brief covid-19-associated multisystem inflammatory syndrome in children-united states mapping systemic inflammation and antibody responses in multisystem inflammatory syndrome in children (mis-c) peripheral immunophenotypes in children with multisystem inflammatory syndrome associated with sars-cov-2 infection pediatric critical care and covid-19 pediatric patients with covid-19 admitted to intensive care units in brazil: a prospective multicenter study severe clinical spectrum with high mortality in pediatric patients with covid-19 and multisystem inflammatory syndrome multisystem inflammatory syndrome associated with coronavirus disease in children: a multi-centered study in belém emergence of kawasaki disease related to sars-cov-2 infection in an epicentre of the french covid-19 epidemic: a time-series analysis epidemiological and clinical features of kawasaki disease in spain over 5 years and risk factors for aneurysm development considering how biological sex impacts immune responses and covid-19 outcomes covid-19: consider cytokine storm syndromes and immunosuppression human leukocyte antigen susceptibility map for severe acute respiratory syndrome coronavirus 2 genomic diversity of severe acute respiratory syndrome-coronavirus 2 in patients with coronavirus disease 2019 use of biomarkers in pediatric sepsis: literature review covid-19, cytokines and immunosuppression: what can we learn from severe acute respiratory syndrome? coagulopathy of coronavirus disease 2019 value of troponin testing for detection of heart disease in previously healthy children determining the optimal cutoff values of plasma n-terminal pro-b-type natriuretic peptide levels for the diagnosis of heart failure in children of age up to 14 years cardiac manifestations in sars-cov-2-associated multisystem inflammatory syndrome in children: a comprehensive review and proposed clinical approach picu guidelines: for high-and limited-resource settings alanine aminotransferase 000/µl), 23 (41.1%) platelet count (x1,000/µl pro-b type natriuretic peptide, na, non-available the authors declare no conflict of interests.j o u r n a l p r e -p r o o f key: cord-030192-ebsh62ll authors: winant, abbey j.; blumfield, einat; liszewski, mark c.; kurian, jessica; foust, alexandra; lee, edward y. title: thoracic imaging findings of multisystem inflammatory syndrome in children (mis-c) associated with covid-19: what radiologists need to know now date: 2020-07-30 journal: radiol cardiothorac imaging doi: 10.1148/ryct.2020200346 sha: doc_id: 30192 cord_uid: ebsh62ll the covid-19 global pandemic is an ongoing public health emergency, with over 4 million confirmed cases worldwide. due to the novel nature of this coronavirus and our evolving understanding of its pathophysiology, there is continued uncertainty surrounding diagnosis and management of covid-19, especially in pediatric patients. in addition, a new febrile hyperinflammatory kawasaki-like syndrome (also known as multisystem inflammatory syndrome in children, or mis-c) has emerged in pediatric patients with temporal association to covid-19 infection. this review article aims to provide an up-to-date review of the clinical and imaging findings of pediatric mis-c associated with covid-19, compared with typical acute pediatric covid-19 infection, with an emphasis on thoracic imaging findings. originating in wuhan, china in december 2019, the covid-19 global pandemic is an ongoing public health emergency, with more than 4 million confirmed cases and over 285,000 reported deaths, as of may 15, 2020. 1 as of april 20, 2020 , in the united states, there were an estimated 2572 pediatric covid-19 cases (1.7% of total us covid-19 cases). 2 although no published estimates currently exist on the worldwide prevalence of pediatric covid-19 infection, based on prior us and chinese cdc data, an extrapolated estimate may be approximately 2% of overall worldwide cases. 2, 3 still, knowledge of the thoracic manifestations of pediatric covid-19 infection is limited. in adults, covid-19 is typically characterized by severe pneumonia and hyperactivation of the inflammatory cascade. [4] [5] [6] [7] several early studies suggested that covid-19 infection in children was relatively mild compared with adults, with very few pediatric fatalities reported and the majority of critically ill children possessing underlying medical comorbidities. 2, [8] [9] [10] [11] however, chao et al recently found a higher than previously recognized rate of severe illness in pediatric patients with covid19. 12 furthermore, emerging new evidence suggests that covid-19 infection in children and adolescents is associated with a multisystem inflammatory syndrome (mis-c), with features similar to kawasaki disease and toxic shock syndrome, frequently requiring intensive care unit (icu) admissions. 1 in light of these new findings, it is clear that our understanding of the manifestations of pediatric covid-19 infection is dynamic and evolving. for example, increasing evidence suggests that the respiratory tract is not the only organ system susceptible to infection. 13 furthermore, innate host immunity, possibly due to inflammatory hyperactivation and cytokine storm, may mediate much of the tissue damage in acute covid-19 infection and drive the multisystem hyperinflammation in mis-c. 4, 5, 14, 15 therefore, it is becoming clear that covid-19 is much more than simply a viral pneumonia, but rather a multiorgan systemic disease. 4, 5, 13, 16 given the current lack of available information related to the thoracic imaging findings of pediatric mis-c associated with covid-19 infection, the purpose of this article is to provide an up-to-i n p r e s s date review of the clinical and imaging features of pediatric mis-c associated with covid-19 infection, compared with acute pediatric covid-19 infection, with an emphasis on thoracic imaging findings. in april 2020, after the peak of covid-19 in many european countries, new reports from western europe warned of a new pediatric febrile hyperinflammatory syndrome, affecting children with temporal association to covid-19 infection. 15, 17, 18 for example, clinicians in the united kingdom reported increased incidence of a severe inflammatory syndrome with kawasaki disease-like features in mostly previously healthy children. 17 similarly, verdoni et al reported a 30-fold increase in incidence of a kawasaki-like disease in children in bergamo, italy in the months following the peak of the covid-19 pandemic. 18 children manifesting similar illness have also been recognized in the united states, especially in new york city area. [19] [20] [21] as of may 12, 2020, the new york state department of health has identified 102 pediatric patients with similar hyperinflammatory illness. 21 referred to as pediatric covid-associated multisystem inflammatory syndrome (pmis) or multisystem inflammatory syndrome in children (mis-c) associated with covid-19, this hyperinflammatory syndrome occurs in children testing positive for current or recent infection with sars-cov-2 (rt-pcr or serologic assay) or had an epidemiologic link to a known or suspected covid-19 positive patient. 1, 21 temporally, mis-c cases have been clinically manifesting approximately one month or more after the peak of covid-19 cases in a geographic region. 15 although the etiology is unknown, mis-c is presumed to reflect a postinfectious cytokine-mediated hyperinflammatory process, triggered by covid-19 infection. 15, 22 although a causal link between covid-19 infection and the presumed post-viral hyperinflammation of mis-c has not yet been definitively established, it is strongly suggested by the temporal association and history of covid-19 exposure in mis-c patients. 23 proposed mechanisms i n p r e s s include direct triggering of autoinflammatory response, possibly by molecular mimicry or unknown mechanism, and/or dysregulation of immune responses after covid-19 infection, which could result in other environmental insults triggering a hyperinflammatory pathology in predisposed patients. 23 although the clinical features of mis-c resemble kawasaki disease, there are important demographic differences between mis-c patients and kawasaki disease patients, including older age of onset and differences in ethnicity predisposition. first, although mis-c associated with covid-19 affects pediatric patients of all ages (reported cases range from 6 months to 16 years), the majority of mis-c patients are school age children, with mean age of 7.5-10 years. [17] [18] [19] [20] 22 in contrast, the vast majority of kawasaki disease patients present before five years of age, most under 2 years of age. 24 in addition, while the incidence of kawasaki disease is highest in asia, strikingly, there have been no reported cases of mis-c in asia, despite being an early hotspot of covid-19 infection, with some of the earliest published series on acute pediatric covid-19 infection emerging from china. 15, 24, 25 two series have found a predilection of mis-c to affect children of afro-caribbean descent. 17, 26 although the cause for difference in distribution of mis-c worldwide is not definitively known, genetic predisposition has been suggestive as a factor in this predisposition for development of mis-c. 23 different strains of the virus, due to mutation, could also possibly account for the increased incidence of mis-c in western europe and north america compared with asia. similar to kawasaki disease, two series of pediatric cases of mis-c associated with covid-19 have reported a male predilection (62.5-70%), although a larger series found males and females to be equally affected. 17,18, 22 the most commonly reported comorbidities in children with mis-c associated with covid-19 were overweight status (bmi 25, 17-38%) and asthma (8.5%). 17, 22 clinical presentation i n p r e s s children affected by mis-c associated with covid-19 typically present with persistent high fever (> 3 days) and systemic hyperinflammation, reflected in a constellation of symptoms involving multiple organ systems, frequently manifesting abdominal pain and gastrointestinal symptoms, kawasaki disease-like features, and cardiogenic shock. in published series, the most common presenting signs and symptoms include prolonged high fever (94-100%), weakness/malaise (100%); prominent gastrointestinal symptoms (60-100%), typically abdominal pain, vomiting, and diarrhea; and less commonly, variable maculopapular rash (37-57%) and respiratory distress (0-65%). 17,18,22,26-29 a small number of reported mis-c patients have presented with such severe abdominal pain that laparoscopy was performed for suspected appendicitis (n=3), two of which were found to have mesenteric adenitis and one was found to have aseptic peritonitis. 22, 26 clinical features of kawasaki disease, including non-vesicular skin rash, extremity changes, adenopathy, conjunctivitis, cheilitis, and meningeal signs, are frequently reported, however only six reported patients have met criteria for the classical form of kawasaki disease. 18, 19, 22, 30 the vast majority of mis-c patients present with cardiogenic shock requiring icu admission. all the united states cdc has presented the following case definition for a diagnosis of mis-c associated with covid-19, with pediatric patients required to meet all three of the following criteria: (1.) individual under 21 years of age presenting with fever, laboratory evidence of inflammation, and evidence of clinically severe illness requiring hospitalization, with multisystem (≥2) organ involvement (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic, or neurologic); (2.) no alternative plausible diagnosis; (3.) positive current or recent sars-cov-2 infection by rt-pcr, serology, or i n p r e s s antigen test; or covid-19 exposure within four weeks prior to symptom onset. fever is defined as temperature greater than 38.0 o c for greater than 24 hours or a subjective fever greater than 24 hours. laboratory evidence of inflammation is defined as including, but not limited to: elevated c-reactive protein (crp), erythrocyte sedimentation rate (esr), fibrinogen, procalcitonin, d-dimer, ferritin, lactate dehydrogenase (ldh), and interleukin-6 (il-6). 21 the vast majority of children affected with mis-c associated with covid-19 present in cardiogenic shock requiring inotropes (80-100%) and mechanical ventilation (66-88%) for cardiovascular stabilization. 17, 19, 20, 22 over a quarter of children with mis-c with acute heart failure at presentation require mechanical circulatory assistance with venoarterial extracorporeal membrane oxygenation (ecmo). 22 although the cdc and who have not provided treatment guidelines, common treatment 22 this recovery of systolic function after treatment may suggest that the mechanism of heart failure is not myocardial damage as seen in adults i n p r e s s with covid-19 infection, however additional studies will be needed to assess whether long-term cardiac complications arise. 22 mainly due to its recent emergence, knowledge of the thoracic manifestations of mis-c associated with covid-19 is limited. however, the following imaging findings were observed in our 20 pediatric patients with confirmed mis-c. three main thoracic imaging findings have been observed in pediatric patients with mis-c associated with covid-19: heart failure, ards pattern, and pulmonary embolus. we observed that the majority of pediatric patients with mis-c associated with covid-19 present with cardiogenic shock, many with imaging findings of acute heart failure. this is in keeping with several reported series that found the majority of mis-c patients (43-67%) present with myocarditis and heart failure. 18, 26, 28, 29 characterized by impaired left ventricular systolic dysfunction, elevated bnp, and significantly elevated proinflammatory cytokines ("cytokine storm," including il-6, c-reactive protein, and procalcitonin), the acute heart failure that is common in mis-c is hypothesized to be the result of a postviral immune-mediated myocarditis. 22, 26, 27 most mis-c patients have positive sars-cov-2 antibodies (80-100%), rather than positive rt-pcr, supporting a post-viral etiology. 17-20,22 infectious diseases have long been considered a trigger for autoimmune diseases, possibly via molecular mimicry or dysregulated immune response. 23 il-6, specifically, has been implicated in the pathogenesis of myocarditis. 23 chest radiographs typically show cardiomegaly, pulmonary edema, and pleural effusions, in keeping with acute left heart failure (fig. 1) . echocardiography typically reveals left ventricular systolic dysfunction with depressed ejection fraction (movie 1). 22 in mis-c with heart failure, cardiac mri typically demonstrates diffuse left ventricular myocardial t2 hyperintensity, suggesting myocardial edema and hyperemia. 27 late gadolinium enhancement is not typically visualized, arguing against the presence of myocardial necrosis or fibrosis. 27 contrary to adult covid-19-related myocarditis, which is typically characterized by extensive transmural late gadolinium enhancement, suggesting extensive necrosis and/or fibrosis, the absence of myocardial necrosis in mis-c may reflect the difference between post-viral immune-mediated cytokine storm and direct viral myocardial toxicity in adult covid-19-myocarditis. 27, 32 of note, the cardiac imaging abnormalities in pediatric mis-c may be transient. for example, relatively rapid recovery of systolic function and normalization of cardiac mri signal abnormalities has been found in mis-c after appropriate supportive care. 22, 27 recovery of systolic function and the absence of late gadolinium enhancement has led investigators to hypothesize that the left ventricular systolic dysfunction in mis-c is most likely due to transient myocardial stunning or edema, rather than myocardial damage. 22, 27 in adults, respiratory failure from acute respiratory distress syndrome (ards) is the leading cause of mortality due to covid-19 infection. 33 it has been postulated that hyperinflammation and i n p r e s s cytokine storm may contribute to the development of severe manifestations of covid-19 infection, including ards and multiorgan failure. 4, 14 we observed that children with mis-c associated with covid-19 can present with hypoxic respiratory failure and imaging findings of ards. 19 chest radiographs demonstrate bilateral multifocal ground-glass and consolidative airspace opacities (fig. 2) . in some pediatric patients with mis-c associated with covid-19 presenting with an ards pattern, airspace opacities were noted to be asymmetric. a prothrombotic coagulopathy is a hallmark of severe covid-19 in adults. 34 while severe covid-19 infection in adults has been associated with high incidence of thrombotic complications, including dvt, pe, ischemic stroke, and myocardial infarction, this association has not yet been demonstrated in typical pediatric covid-19 infection. 35 although the mechanism for adult thromboembolic complications of covid-19 is not known, it has been suggested that overproduction of proinflammatory cytokines contribute to a prothrombotic coagulopathy. 5 interestingly, some authors have suggested that pediatric mis-c and late-stage severe adult covid-19 are characterized by a similar proinflammatory milieu, both characterized by elevated inflammatory markers, including fibrinogen, ddimer, ferritin and il-6. 15, 18, 20 poyiadi et al found that adult covid-19 patients with elevated d-dimer and crp are significantly more likely to develop pulmonary emboli than patients without elevated inflammatory markers. 36 given that elevations in these inflammatory markers are a hallmark of pediatric mis-c associated with covid-19, it is conceivable that the hyperinflammatory state of mis-c may predispose to a similar prothrombotic coagulopathy and thromboembolic complications, including pulmonary emboli. we observed small segmental pulmonary emboli (pe) in some pediatric patients affected by mis-c associated with covid-19. on ct pulmonary arterial angiography, pulmonary embolus appears as an expansile filling defect in a pulmonary artery in pediatric patients with mis-c associated with covid-19 i n p r e s s (fig. 3) . currently, the clinical significance of these small segmental pulmonary emboli in pediatric mis-c patients is unclear. 37, 38 for example, poyiadi et al found no significant difference in icu admission, requirement for intubation, or duration of intubation between adult covid-19 patients who developed pe and those who did not. 36 further studies on the significance of pe in children with mis-c associated with covid-19 will be important. in addition to the characteristic thoracic imaging findings of mis-c associated with coivd-19, characteristic extrathoracic imaging findings are also emerging in pediatric patients with mis-c associated with covid-19 infection. abdominopelvic mesenteric lymphadenopathy, often most prominent in the right lower quadrant, sometimes with surrounding inflammatory fat stranding, with an overall appearance similar to mesenteric adenitis, is a common finding in mis-c associated with covid-19 (fig. 4) . in fact, belhadjer et al found 2 children with mis-c associated with covid-19 underwent appendectomy for suspected appendicitis, with an ultimate diagnosis of mesenteric adenitis. 22 indeed, mesenteric lymphadenopathy is in keeping with the impressive frequency of gastrointestinal symptoms in children with mis-c as well as the likely propensity of the virus to infect the gastrointestinal tract. 13 additional abdominal findings observed in pediatric patients affected by mis-c associated with covid-19 include echogenic kidneys (fig. 5) , ascites (fig. 5) , hepatomegaly, and gallbladder wall thickening, in keeping with multiorgan involvement. 17 children: what are the differences? the typical chest radiographic findings in typical acute pediatric covid-19 infection include bilateral peripheral and subpleural ground-glass opacities and/or consolidations 39, 40 (fig. 6a ). on ct, the i n p r e s s most common appearance of typical acute pediatric covid-19 infection is bilateral multifocal peripheral ground-glass opacities, with or without consolidations, often with a posterior and lower lobe predominant distribution 25, 39, 40 (fig. 6b ). it has been suggested that there are three imaging phases of typical acute pediatric covid-19 infection: early, progressive, and developed phases. 40 as there is significant clinical and imaging variation between patients, there is, at present, no known timeline for demarcating these phases. typically, the "halo" sign ( fig. 6b) , which denotes a rim of ground-glass opacity surrounding a nodule or consolidation, if often observed in the early phase (reported in up to half of cases), often progressing to ground-glass (progressive phase), and ultimately developing into a confluent consolidation (developed phase). 25, 40 additional ct findings reported in typical acute pediatric covid-19 infection include adjacent bronchial wall thickening and inflammation along the bronchovascular bundle are more frequently reported in pediatric patients compared to adults. 25 fine mesh reticulations and "crazy paving" have also been reported, but with less frequency. 25 pleural effusions and thoracic adenopathy are rare and considered atypical. 39, 40 differences between thoracic imaging findings of typical pediatric covid-19 and mis-c associated with there are some differences between the thoracic imaging findings of typical pediatric covid-19 infection and mis-c associated with covid-19 (table 1 ). such differences may be partially explained by the hypothesis that typical covid-19 reflects an acute infection, whereas mis-c associated with covid-19, which is typically occurs approximately 1 month after covid-19 peak in a geographic region and is most often associated with positive antibodies (suggesting prior infection), most likely reflects post-viral hyperinflammatory process. 15, 18, 22 the main radiologic difference between typical pediatric covid-19 and mis-c associated with covid-19 is the location of imaging abnormalities. typical pediatric covid-19 infection predominantly affects the pulmonary parenchyma, manifesting primarily with bilateral peripheral and subpleural airspace opacities. 25, 39, 40 extrapulmonary abnormalities are rare and unexpected in typical acute i n p r e s s pediatric covid-19 infection. 25, 39, 40 in contrast, pediatric mis-c associated with covid-19 is a systemic hyperinflammatory state characterized by multiorgan system involvement, often with prominent cardiovascular abnormalities, such as heart failure, manifesting with cardiomegaly, pulmonary edema, and pleural effusions. 22 as previously described, the hyperinflammatory state of mis-c associated with covid-19 may contribute to a prothrombotic coagulopathy predisposing to thromboembolic complications, including pulmonary emboli. 14,34-36 furthermore, the hyperinflammatory state of mis-c associated with covid-19 is often associated with adenopathy, which is rare and unusual in typical pediatric covid-19 infection. 22, 26, 28, 40 lastly, ards, a common thoracic imaging pattern in late-stage adult covid-19 infection, is also observed in some pediatric mis-c cases, although much less common in typical pediatric covid-19 infection. [39] [40] [41] [42] as previously described, it has been suggested that mis-c associated with covid-19 and latestage adult covid-19 may be characterized by a similar hyperinflammatory milieu, which may account for some overlap in imaging findings and pathophysiology, although more scientific evidence is needed for validation. 15, 18, 20 the growing number of pediatric cases of mis-c associated with covid-19 suggests that covid-19 is likely far more than just a respiratory illness in the pediatric population. in addition to the previously described pulmonary parenchymal abnormalities seen in typical, presumed acute covid-19 infection, mis-c associated with covid-19, which is likely a post-viral hyperinflammatory process, is now known to cause multiorgan damage, including heart disease, liver injury, kidney failure, gastrointestinal and dermatologic manifestations, among others. this signals an important paradigm shift in our understanding of pediatric covid-19 infection: from a primarily respiratory illness to multi-organ system disease. interestingly, many of the clinical and imaging features of mis-c associated with covid-19 resemble late-stage severe adult covid-19 infection, possibly due to a similar hyperinflammatory i n p r e s s cytokine storm, predisposing to some similar thoracic imaging manifestations, including heart failure, ards, and thromboembolic complications. currently, more scientific evidence is needed to guide clinical and imaging study decisions for mis-c associated with covid-19. however, based on our preliminary observation of mis-c associated with covid-19 in our practice, a judicious approach to imaging pediatric patients, who meet the cdc criteria for a diagnosis of mis-c associated with covid-19 infection or exposure, may need to be broadened to include echocardiography, abdominal imaging, and ctpa in pediatric patients with high clinical suspicion for pe, in addition to typical chest radiographs and/or ct. as knowledge and scientific evidence about the imaging findings of mis-c associated with covid-19 grow, better understanding of the characteristic imaging findings and the need for specific imaging evaluations is expected in the future. in addition, because there is currently a lack of pathologic data explaining the underlying causes and imaging findings of mis-c, future studies focusing on the radiology-pathology correlation will shed light on this new and challenging disorder, unique to the pediatric population. i n p r e s s table table 1 . differences in imaging findings between mis-c associated with covid-19 and typical covid-19 in children typical covid-19 findings multisystem inflammatory syndrome in children and adolescents temporally related to covid-19: scientific brief. world health organization website cdc covid-19 response team. coronavirus disease 2019 in children -united states characteristics of and important lessons from the coronavirus disease 2019 (covid-19) outbreak in china: 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syndrome? pediatric covid-associated multi-system inflammatory syndrome (pmis) on the alert for cytokine storm: immunopathology in covid hyperinflammatory shock in children during covid-19 pandemic an outbreak of severe kawasaki-like disease at the italian epicentre of the sars-cov-2 epidemic: an observational cohort study covid-19 associated pediatric multi-system inflammatory syndrome cardiac dysfunction and thrombocytopenia-associated multiple organ failure inflammation phenotype in a severe paediatric case of covid-19 multisystem inflammatory syndrome in children (mis-c) associated with coronavirus disease acute heart failure in multisystem inflammatory syndrome in children (mis-c) in the context of global sars-cov-2 pandemic autoimmune and inflammatory diseases following covid-19 epidemiology of kawasaki disease in asia, europe, and the united states clinical and ct features in pediatric patients with covid-19 infection: different points from adults kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic in paris, france: prospective observational study cardiac mri of children with multisystem inflammatory syndrome (mis-c) associated with covid-19: case series spectrum of imaging findings on chest radiographs, us, ct, and mri images in multisystem inflammatory syndrome in children (mis-c) associated with covid-19 paediatric multisystem inflammatory syndrome temporally associated with sars-cov-2 mimicking kawasaki disease (kawa-covid-19): a multicentre cohort covid-19 and kawasaki disease: novel virus and novel case cardiac involvement in a patient with coronavirus disease 2019 (covid-19) clinical predictors of mortality due to covid-19 based on an analysis of data of 150 patients from wuhan, china abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia incidence of thrombotic complications in critically ill icu patients with covid-19 acute pulmonary embolism and covid-19 children suspected of having pulmonary embolism: multidetector ct pulmonary angiography--thromboembolic risk factors and implications for appropriate use mdct pulmonary angiography evaluation of pulmonary embolism in children covid-19) pneumonia: what radiologists need to know international expert consensus statement on chest imaging in pediatric covid-19 patient management: imaging findings, imaging study reporting and imaging study recommendations tissue plasminogen activator (tpa) treatment for covid-19 associated acute respiratory distress syndrome (ards): a case series acute respiratory failure in covid-19: is it 'typical' ards? i n p r e s s figure 5 9-year-old male with mis-c with acute kidney injury. grayscale sagittal ultrasound image of the right kidney demonstrates increased echogenicity of the right renal parenchyma, in keeping with acute kidney injury, and adjacent small abdominal ascites. figure 6a 13-year-old girl, with a history of sickle cell disease, with rt-pct positive for covid-19, who presented with hypoxia, respiratory distress and chest pain. a. frontal chest radiograph shows bilateral peripheral lung zone-predominant diffuse and patchy ground-glass opacities as well as more focal confluent opacity in the retrocardiac i n p r e s s region, which are typical chest radiographic findings of pediatric covid-19 pneumonia.cardiomegaly, which was stable compared to prior radiographs, due to the patient's underlying sickle cell disease, is also shown. figure 6b 13-year-old girl, with a history of sickle cell disease, with rt-pct positive for covid-19, who presented with hypoxia, respiratory distress and chest pain.i n p r e s s b. axial lung window ct image shows several right lower lobe and right middle lobe peripheral rounded nodular consolidative opacities, with surrounding ground-glass halo ("halo" sign) (arrows), which is often seen in the early phase of pediatric covid-19pneumonia. in addition, more confluent opacity (asterisk) is seen in the left lung, which is typical finding of developed phase of pediatric covid-19 pneumonia. key: cord-281948-xv7vuypd authors: hoang, ansel; chorath, kevin; moreira, axel; evans, mary; burmeister-morton, finn; burmeister, fiona; naqvi, rija; petershack, matthew; moreira, alvaro title: covid-19 in 7780 pediatric patients: a systematic review date: 2020-06-26 journal: eclinicalmedicine doi: 10.1016/j.eclinm.2020.100433 sha: doc_id: 281948 cord_uid: xv7vuypd background: studies summarizing the clinical picture of covid-19 in children are lacking. this review characterizes clinical symptoms, laboratory, and imaging findings, as well as therapies provided to confirmed pediatric cases of covid-19. methods: adhering to prisma guidelines, we searched four medical databases (pubmed, litcovid, scopus, who covid-19 database) between december 1, 2019 to may 14, 2020 using the keywords “novel coronavirus”, “covid-19” or “sars-cov-2”. we included published or in press peer-reviewed cross-sectional, case series, and case reports providing clinical signs, imaging findings, and/or laboratory results of pediatric patients who were positive for covid-19. risk of bias was appraised through the quality assessment tool published by the national institutes of health. prospero registration # crd42020182261. findings: we identified 131 studies across 26 countries comprising 7780 pediatric patients. although fever (59·1%) and cough (55·9%) were the most frequent symptoms 19·3% of children were asymptomatic. patchy lesions (21·0%) and ground-glass opacities (32·9%) depicted lung radiograph and computed tomography findings, respectively. immunocompromised children or those with respiratory/cardiac disease comprised the largest subset of covid-19 children with underlying medical conditions (152 of 233 individuals). coinfections were observed in 5.6% of children and abnormal laboratory markers included serum d-dimer, procalcitonin, creatine kinase, and interleukin-6. seven deaths were reported (0·09%) and 11 children (0·14%) met inclusion for multisystem inflammatory syndrome in children. interpretation: this review provides evidence that children diagnosed with covid-19 have an overall excellent prognosis. future longitudinal studies are needed to confirm our findings and better understand which patients are at increased risk for developing severe inflammation and multiorgan failure. funding: parker b. francis and pilot grant from 2r25-hl126140. funding agencies had no involvement in the study. in december 2019, an unprecedented number of pneumonia cases presented in adult individuals from wuhan, china [1] . despite rapid action by the chinese government and health officials, the number of similar presenting cases continued to rise at an alarming rate [2] . by january 2020 an emerging zoonotic agent, known as severe acute respiratory syndrome coronavirus 2 (sars-cov-2), was identified in respiratory samples in patients diagnosed with pneumonia who subsequently developed respiratory failure [1] . the spread of sars-cov-2 from human to human, through respiratory droplets, has now resulted in a worldwide outbreak, now classified as a pandemic by the world health organization [3] . as of june 3rd, 2020, there has been more than 6¢4 million confirmed cases worldwide and >380,000 fatalities [4] most symptomatic cases have occurred in the adult population, characterized by fever, cough, malaise, and frequent hospitalization [1] . accordingly, most of the published data is derived from adults with coronavirus disease 2019 (covid19) who were hospitalized in china [5] . as the pandemic continues, we are now observing numerous reports describing the clinical presentation and hospital course of children with confirmed covid-19 [5] . what is currently known is that children have milder symptoms and are less likely to be hospitalized when compared to adults [6] . however, on may 14th, 2020 the united states centers for disease control and prevention (cdc) released a health advisory reporting a multisystem inflammatory syndrome in children (mis-c) associated with covid-19 [7] . this statement stemmed from a subset of pediatric patients manifesting with severe inflammation, multi-organ failure, and testing positive for sars-cov-2 [8, 9] . data extraction was performed by all investigators and compared by at least two investigators for consistency. data collected included the type of article (e.g., case series), country of origin, number of pediatric patients, demographic information, and all clinical symptoms (e. g., fever, cough), laboratory values (e.g., cbc, lfts, bmp), imaging studies (e.g., chest x-ray, ct, mri), clinical outcomes (e.g., icu admission), and treatments provided (e.g. antivirals). the risk of bias for observational studies was appraised through the quality assessment tool published by the national institutes of health [10] . we opted to use this guide as the development of the assessment tool was conducted rigorously by researchers in the agency for healthcare research and quality evidence-based practice centers, the cochrane collaboration, the united states preventive services task force, the scottish intercollegiate guidelines network, the national health service centre for reviews and disseminations, and consulting epidemiologists. moreover, it was a preferred tool in a systematic review on risk of bias assessments used in prospero-registered protocols [11] . risk of bias was assessed independently by at least two investigators and disagreements were resolved by a third researcher (am). furthermore, the level of evidence was assessed according to sackett [12] . all laboratory data were converted to similar units and presented as mean with standard deviation (sd). laboratory information presented as median (iqr) were converted to mean (sd), and denoted when unable to convert [13] . publications that provided multiple timepoints (e.g., hospital course of individuals) for laboratory results were gathered and averaged. if the symptom was present anytime during the hospitalization, it was considered positive and characterized as a count with percent. a similar approach was taken for imaging information. means, standard deviations, and proportion ratios were calculated using microsoft excel. statistical analyses between covid-19 pediatric patients with/ without mis-c was conducted on stata v¢13. all statistical tests were two-sided, and significance was defined as a p value <0¢05. continuous data was summarized as mean (standard deviation) or median (interquartile range) and assessed by student's t-test or wilcoxon rank sum. categorical data was summarized as counts (percent) and analyzed by fisher's exact test. the funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. the search yielded 1,142 studies. after removing 237 duplicates, 905 articles were reviewed by abstract and title. after initial screening, only 319 articles met inclusion criteria and underwent full text evaluation. publications that were retracted, or consisted of editorials, reviews, or commentaries that did not meet our criteria were removed, generating a final list of 131 articles (see fig. 1 ). studies included in this review were published between january 24th to may 11th, 2020. eight studies were cross sectional, 75 were case series, and 48 were case reports (refer to table 1 ). twenty-six countries were represented with the largest data derived from 2572 children from the united states. china comprised 64¢1% of the studies included in this review. appendix 1 displays publications by the country of origin. twenty of the publications pertained to the neonatal population and the ages extended from an extremely premature neonate at 26 weeks gestation to 20 years of age. the level of evidence for all of the studies was 5 (1 is highest, 5 is lowest) and the risk of bias scores were between 2 to 7 (1 is lowest, 9 is highest, refer to appendix 2). a total of 7780 covid-19 positive children were included. fifty six percent of the individuals were male ( table 2 ). the mean age was 8¢9 years (sd 0¢5) and 75¢6% of patients were exposed to a family member who was diagnosed with covid-19. the most common method for detection of the virus was through nasopharyngeal or throat swab (86¢5%). need for intensive care unit observation or treatment was low (3¢3%). twenty studies (n=655 individuals) reported an underlying medical condition; covid-19 positive children who were immunosuppressed or had a history of a respiratory or cardiac condition comprised the majority (65¢%). moreover, influenza and mycoplasma were the most common co-infections (see table 3 ). table 4 summarizes clinical symptoms and imaging findings in covid-19 confirmed pediatric patients. no symptoms were described in 456 of 2367 patients (19¢3%), while the two most common symptoms were fever (59¢1%), and cough (55¢9%). while upper respiratory symptoms were characteristic of covid-19, some patients presented with mild or often overlooked symptoms such as fatigue, abdominal pain, or decreased appetite [14à16] . table 4 also summates imaging findings. according to chest x-ray and computed tomography (ct), 23¢6% and 18¢9% had normal results, respectively. patchy lesions were observed in 105 of 501 patients on chest radiography and bilateral ground glass opacities were the most frequent ct abnormality. complete blood counts were the most common laboratory results described (see table 5 ). overall, leukocytes were within normal values (7¢1 £ 10 3 /ml), whereas neutrophils were mildly decreased (44¢4%) while lymphocytes were marginally elevated (39¢9%). markers of liver and renal function were normal. four serum inflammatory markers were above the mean: d-dimer, procalcitonin, creatine kinase, and interleukin-6. sixty-six studies (n=614 individuals) provided information regarding treatments. interferon was the most commonly administered drug (41¢0%), followed by empiric antibiotics (20¢2%). of note, glucocorticoids, and intravenous immunoglobulin was used in 4¢1% and 3¢1% of patients, respectively. complications we evaluated were rare and only described in 21 studies. there were 7 cases of kidney failure (0¢09%), 19 cases of shock (0¢24%), and 42 children were intubated (0¢54%). more details on treatments provided and complications can be found in table 6 . asymptomatic ( abbreviations: abg-arterial blood gas; asa-aminosalicylate; alt-alanine aminotransferase; ast-aspartate aminotransferase; bun-blood urea nitrogen; bnp-brain natriuretic peptide; cbc-complete blood count; ck-creatine kinase; cpap-continuous positive airway pressure; cr-creatinine; crp-c-reactive protein; ct-computed tomography; cxr-chest radiograph; esr-erythrocyte sedimentation rate; hgb-hemoglobin; ig-immunoglobulin; il-interleukin; ivig-intravenous immunoglobulin; ldh-lactate dehydrogenase; lfts-liver function tests; lus-lung ultrasound; nk-natural killer cell; nr-not reported; pct-procalcitonin; plts-platelets; pt-prothrombin time; ptt-partial thromboplastin time; rsv-respiratory syncytial virus; tnf-tumor necrosis factor. *one patient met our inclusion, but the publication was a case series. eleven patients (0¢14%) met the cdc's criteria for mis-c [7] . compared to control (n=14), children with severe inflammation were more likely to present with dyspnea (72¢7% vs 28¢6%), vomiting (45¢5% vs. 7¢1%), and diarrhea (45¢5% vs. 21¢4%). white blood cell counts were comparable between the groups; however, patients with mis-c have significant lymphopenia (11¢1% vs. 41¢8%). no difference was noted in platelets or liver function markers. serum lactate dehydrogenase and d-dimer were higher in children with mis-c (p<0¢05, details provided in table 7) . also, patients with mis-c had lower expression of circulating cd16 + cd56 + natural killer cells. imaging findings and treatments were comparable in mis-c and non-mis-c patients. over the last 6 months, there have been over 6¢4 million worldwide cases of sars-cov-2 infection and our knowledge of the disease and its epidemiologic and clinical characteristics continue to evolve [4]. however, since it was first reported in wuhan city in december 2019, most studies have focused on symptomatic adults. in the presence of this rapidly emerging, novel infection, identification of clinical and laboratory characteristics in the pediatric population is essential to guide clinical care, predict disease severity, and determine prognosis. in this context, we performed the largest and most comprehensive systematic review of published studies involving pediatric patients with known covid-19. our systematic review summarized the clinical, laboratory and radiologic features of covid-19 in neonates, children, and adolescents. our review also supports the findings by a recent systematic review by castagnoli et al. [17] their study included a total of 1,065 covid-19 infected children and concluded that, by and large, the prognosis for children was excellent, demonstrated by only one death. compared to that review and other covid-19 pediatric systematic reviews, [18à21] this manuscript has several key advantages: (1) we summarize 131 studies that includes 7780 children from 26 different countries, (2) this report synthesizes underlying pediatric medical conditions and delineates bacterial and viral coinfections, (3) we quantitatively describe clinical symptoms and imaging findings, (4) herein, we conglomerate the mean and standard deviation of frequently used laboratory analytes in covid-19 positive children, (5) our report presents antiviral therapies by specific agents, and (6) our systematic review offers a preliminary comparison of patients with/without mis-c. although sars-cov-2 infection was first identified in china, the united states has now amassed the highest number of confirmed cases [18] . calculations made on june 4th, 2020 from the covid-19 dashboard by the center for systems science and engineering at johns hopkins university indicate that china has 4¢5% of total confirmed covid-19 cases compared to the united states [4] . as expected, the most common vector for childhood infection is close contact to an affected family member or residing in an area with a high population of cases. our findings align with the results of an april 2020 report by dong et al, in which there was a clear trend that the disease spread rapidly from a chinese province to surrounding provinces and cities in children from december to february [22] . furthermore, qiu and colleagues studied 36 pediatric covid-19 positive patients in which ten patients (28%) were asymptomatic latent cases identified secondary to an adult family member who was infected, symptomatic, or traveled to an endemic area [23] . this lends concern that children, who may be asymptomatic, may play a role in community transmission of the virus. continuous data presented as mean § sd. np-nasopharyngeal. results from this systematic review echo findings describing milder symptoms in pediatric cases of sars-cov-2 infection [17, 21] . for instance, the most common clinical manifestations we found were fever (59¢1%), cough (55¢9%), rhinorrhea (20¢0%) and myalgia/fatigue (18¢7%). unlike adults, children rarely progressed to severe upper respiratory symptoms requiring intensive care unit admission [24, 25] . although transmission rates for sars-cov-2 are high, symptoms are less severe than sars/middle east respiratory syndrome (mers) infection [26] . serum inflammatory markers, specifically d-dimer, procalcitonin, creatine kinase, and interleukin-6, were consistently abnormal in the studies included in this review. alterations to acute-phase infectionrelated biomarkers are corroborated in adult case series and metaanalyses [27, 28] . however, we must take caution when interpreting these outcomes and await more robust, longitudinal laboratory analyses. again, these blood analyses are non-specific and may merely represent a pro-inflammatory state induced by the virus [26] . in terms of imaging findings, we found that most patients had normal chest x-rays, a finding that is not surprising as most pediatric patients did not present with respiratory symptoms. paralleling this review, a meta-analysis of ct features for covid-19, showed that diffuse bilateral ground-glass opacities were the most common finding at all stages of disease [29, 30] . despite these promising associations, it is important to consider that radiologic manifestations from various pathogens may have a similar impression and should be ruled out. co-infections with other respiratory illnesses including influenza and mycoplasma were described in 72 patients. as elegantly described by cox and colleagues, most fatalities from the 1918 influenza outbreak were secondary to bacterial infection [31] . thus, future reports should not only describe coinfections but also detail pertinent negatives. at present, our study had a low rate of reporting the infectious workup (26¢7) of patients. illustrating the importance, one of two patients that died in the study by shekerdemian et al was due to gram negative sepsis in a child with comorbidities who developed end organ failure [32] . although most children have an uneventful course, a present concern is an inflammatory cascade in pediatric patients with covid-19 [8, 9] . clinical presentation includes an unremitting high fever, and includes systemic signs such as rash, conjunctivitis, and/or gastrointestinal symptoms. the case series of eight children from london required respiratory assistance, whether it was oxygen support (n=1), noninvasive ventilation (n=2) or intubation and mechanical ventilation (n=4) [8] . one patient was so ill that he required mechanical ventilation and extracorporeal membrane oxygenation. in addition, all required vasopressor support and demonstrated elevated levels of ferritin, d-dimers, troponin, procalcitonin, and c-reactive protein (crp). additionally, cardiac imaging showed ventricular dysfunction in five children. in another article, italian investigators describe ten patients with mis-c. correspondingly, they describe patients manifesting with fever, diarrhea (n=6), and abnormal echocardiograms (n=6). laboratory specifics showed elevated crp, lymphopenia, thrombocytopenia, and elevated ferritin levels [9] . we found evidence of mis-c features in 11 children who also presented with fever (n=11), dyspnea (n=8), and diarrhea (n=6). according to riphagen and verdoni, lymphopenia was marked in our cohort of patients, as well as increased levels of lactate dehydrogenase, crp and d-dimer [8, 9] . despite low numbers we did observe an interesting lower level of cd16 + cd56 + natural killer (nk) cells in patients with mis-c. both lymphopenia and a reduced number/activity of nk cells in adults has correlated with a more severe covid-19 disease progression [33à36] . little is known about the perinatal aspects of covid-19, and there have been several reported cases of neonatal infection, suggesting a possible perinatal or vertical transmission during pregnancy [37] . however, in a report by chen et al., all nine neonates born to covidgiven that the mean (sd) in our pediatric population was 8.9 § 0.5 years we provide the lowest to highest numbers presented in children with a similar age range when possible (data from nelson textbook of pediatrics 2019). *gregory's pediatric anesthesia 2012 5 th edition. y mayo clinic laboratories. 19 positive mothers tested negative for the virus after cesarean delivery [38] . in another study by zhang et al., 10 neonates from covid-19 positive mother all tested negative for the infection [39] . moreover, this is further supported by analysis of breast milk and placental pathologic specimens from covid-19 positive mothers, which have returned negative for the virus [40, 41] . lastly, vertical transmission was not observed with either sars-cov-1 or in mers-cov; [41] therefore, it is unlikely that maternal vertical transmission during third trimester occurs, or is likely very rare. however, from the limited data published, we cannot determine the consequences of sars-cov-2 infection in early pregnancy and if it can be transmitted to the fetus and hinder organ development, malformations, growth abnormalities, or even lead to premature labor or spontaneous abortions [42, 43] . also, dong et al communicated an alarming finding in which the proportion of severe and critical cases were higher in neonates when compared to the >16-year-old age group (10¢6% vs. 3¢0%) [44] . as a community, we must stay vigilant, practice social distancing, hand wash frequently, and be especially careful with our children who are at potentially higher risk for critical disease (e.g. multiple comorbidities, weakened immune systems, etc.). there are several limitations to this review. first, many of the included studies were case reports or cases with low patient numbers. second, the level of evidence for all the studies was low. next, we unified the laboratory data to mean and standard deviation. there are inherent issues when using averages including the impact of outliers. we did not include suspected cases, which would allow for a direct comparison of symptoms, labs, imaging, and outcome data. of concern, many of the studies were incomplete and did not include a comprehensive picture of the patients. future studies should not generalize data ("cbc was normal"), or categorize laboratory values (i.e., number of patients with elevated crp), or group therapies (i.e., patient received "antiviral therapy"), or display aggregate data between adults and children. if feasible, divide the symptoms, laboratory markers, and imaging characteristics by children vs. adults. a better understanding of covid-19 requires access to data, even if it is provided in the appendix or supplementary section of the article. in this way, we will be able to identify the best biomarkers that can stratify disease severity and potential short-and long-term outcomes. another limitation, is that we had a small number of patients that fit the criteria for mis-c. reasons for the small number of patients includes a lack of reporting all of the signs, symptoms, and laboratory markers necessary to make the diagnosis (especially duration of fever). missing information for laboratory markers (d-dimer, interleukins, and cd%) hinders our preliminary findings. lastly, the table 7 comparison between covid-19 children with and without multisystem inflammatory syndrome in children (mis-c). mis-c data are presented as mean (sd) or median (iqr). student's t test, wilcoxon rank sum, or fisher's exact was conducted as appropriate. * denotes limited data was in at least one group (d-dimer in mis-c=3; interleukins and cds had 4 in non-mis-c group vs. 4-5 in mis-c). literature focusing on covid-19 is very dynamic and growing rapidly and we expect the rates, especially for mis-c, of our outcomes to change. ansel hoang-literature search, study design, data collection, data analysis, data interpretation, manuscript writing, risk of bias, tables. kevin chorath-literature search, study design, data collection, data interpretation, manuscript writing, risk of bias. axel moreira-literature search, study design, data collection, manuscript writing, data interpretation, risk of bias. mary evans-data collection, verifying data integrity, risk of bias. finn burmeister-morton-data collection, verifying data integrity. fiona burmeister-data collection, verifying data integrity, risk of bias. rija naqvi-data collection, verifying data integrity, risk of bias. matthew petershack-data collection, risk of bias. alvaro moreira-literature search, study design, data collection, data analysis, data interpretation, manuscript writing, figure, tables, oversight. none. creatine kinase (u/l) 77 risk for transportation of coronavirus disease from wuhan to other cities in china the epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (covid-19 who declares covid-19 a pandemic who. coronavirus disease 2019 (covid-19): situation report-28 covid-19 in children: an epidemiology study from china resources for emergency health professionals hyperinflammatory shock in children during covid-19 pandemic lancet2020 an outbreak of severe kawasaki-like disease at the italian epicentre of the sars-cov-2 epidemic: an observational cohort study quality assessment tool for observational cohort and cross-sectional studies. nhlbi. nih.gov/health-topics/study-quality-assessment-tools risk of bias tools in systematic reviews of health interventions: an analysis of prospero-registered protocols rules of evidence and clinical recommendations on the use of antithrombotic agents estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range coronavirus disease 2019 in children -united states, 2020. mmwr morb mortal wkly rep 2020february 12àapril 2 sars-cov-2 infection with gastrointestinal symptoms as the first manifestation in a neonate neonatal early-onset infection with sars-cov-2 in 33 neonates born to mothers with covid-19 in wuhan, china severe acute respiratory syndrome coronavirus 2 (sars-cov-2) infection in children and adolescents: a systematic review clinical manifestations of children with covid-19: a systematic review clinical characteristics of covid-19 infection in newborns and pediatrics: a systematic review characterisation of covid-19 pandemic in paediatric age group: a systematic review and meta-analysis systematic review of covid-19 in children shows milder cases and a better prognosis than adults epidemiological characteristics of 2143 pediatric patients with 2019 coronavirus disease in china clinical and epidemiological features of 36 children with coronavirus disease 2019 (covid-19) in zhejiang. china observat cohort study lancet infect dis clinical, laboratory and imaging features of covid-19: a systematic review and meta-analysis clinical features of patients infected with 2019 novel coronavirus in wuhan middle east respiratory syndrome coronavirus in children elevated interleukin-6 and severe covid-19: a metaanalysis clinical characteristics of 3,062 covid-19 patients: a metaanalysis clinical and ct features in pediatric patients with covid-19 infection: different points from adults a systematic meta-analysis of ct features of covid-19: lessons from radiology co-infections: potentially lethal and unexplored in covid19 characteristics and outcomes of children with coronavirus disease 2019 (covid-19) infection admitted to us and canadian pediatric intensive care units nkg2a and covid-19: another brick in the wall immunology of covid-19: current state of the science lymphopenia predicts disease severity of covid-19: a descriptive and predictive study prognostic value of leukocytosis and lymphopenia for coronavirus disease severity. emerg infect dis possible vertical transmission of sars-cov-2 from an infected mother to her newborn clinical characteristics, and intrauterine vertical transmission potential of covid-19 infection in nine pregnant women: a retrospective review of medical records clinical characteristics of children with coronavirus disease 2019 in hubei coronavirus disease 2019 (covid-19) and pregnancy: what obstetricians need to know perinatal aspects on the covid-19 pandemic: a practical resource for perinatal-neonatal specialists epidemiology of covid-19 among children in china funding sources: parker b. francis; pilot grant 2r25-hl126140. funding agencies had no role in the writing of the manuscript or the decision to submit. supplementary material associated with this article can be found in the online version at doi:10.1016/j.eclinm.2020.100433. key: cord-315508-8bcpxo02 authors: sperotto, francesca; friedman, kevin g.; son, mary beth f.; vanderpluym, christina j.; newburger, jane w.; dionne, audrey title: cardiac manifestations in sars-cov-2-associated multisystem inflammatory syndrome in children: a comprehensive review and proposed clinical approach date: 2020-08-15 journal: eur j pediatr doi: 10.1007/s00431-020-03766-6 sha: doc_id: 315508 cord_uid: 8bcpxo02 initial reports on covid-19 described children as largely spared from severe manifestations, with only 2–6% of children requiring intensive care treatment. however, since mid-april 2020, clusters of pediatric cases of severe systemic hyperinflammation and shock epidemiologically linked with covid-19 have been reported. this condition was named as sars-cov-2-associated multisystem inflammatory syndrome in children and showed similarities to kawasaki disease. here, we present a narrative review of cases reported in literature and we discuss the clinical acute and follow-up management of these patients. patients with sars-cov-2-associated multisystem inflammatory syndrome frequently presented with persistent fever, gastrointestinal symptoms, polymorphic rash, conjunctivitis, and mucosal changes. elevated inflammatory markers and evidence of cytokine storm were frequently observed. a subset of these patients also presented with hypotension and shock (20–100%) from either acute myocardial dysfunction or systemic hyperinflammation/vasodilation. coronary artery dilation or aneurysms have been described in 6–24%, and arrhythmias in 7–60%. cardiac support, immunomodulation, and anticoagulation are the key aspects for the management of the acute phase. long-term structured follow-up of these patients is required due to the unclear prognosis and risk of progression of cardiac manifestations. conclusion: multisystem inflammatory syndrome is a novel syndrome related to sars-cov-2 infection. evidence is still scarce but rapidly emerging in the literature. cardiac manifestations are frequent, including myocardial and coronary involvement, and need to be carefully identified and monitored over time. electronic supplementary material: the online version of this article (10.1007/s00431-020-03766-6) contains supplementary material, which is available to authorized users. initial reports during the early phase of the covid-19 pandemic indicated that children were relatively spared from severe manifestations, with 2-6% of children presenting with severe illness [1] [2] [3] . however, since mid-april 2020, clusters of pediatric cases of severe systemic hyperinflammation and shock epidemiologically linked with covid-19 were reported. riphagen et al. first described a case series of 8 previously asymptomatic children presenting with hyperinflammatory shock, ventricular dysfunction, and multiorgan involvement [4] . this was followed by other reports of patients with kawasaki disease (kd) and kd-like syndrome, frequently complicated by significant cardiac involvement [5] [6] [7] [8] [9] . the increasing number of reported cases led to a health advisory from the royal college of pediatrics and child health (rcpch), the centers for disease control and prevention (cdc), and the world health organization (who), which identified these cases as a novel condition named multisystem inflammatory syndrome in children (mis-c), also called pediatric multisystem inflammatory syndrome (pmis) [10] [11] [12] . for the purpose of this review, the term mis-c will be used. here, we aim to review the published case reports and case series of patients with mis-c, summarize the existing evidence on its cardiac manifestations in a form of narrative review, and propose a consensusbased approach for the management of mis-c. methods of the review process are reported as supplemental material. the rcpch's, cdc's, and the who's definitions of the novel syndrome are shown in table 1 [10] [11] [12] . all three definitions include presence of fever, laboratory evidence of inflammation, and multisystem organ involvement without alternative plausible diagnoses, as well as evidence of covid-19 infection or recent exposure to a covid-19 case. the duration of fever, criteria for organ involvement, and need for documentation of sars-cov-2 infection vary between definitions. children with mis-c commonly present with persistent fever, asthenia, diffuse erythematous polymorphic rash, non-purulent conjunctivitis, and prominent gastrointestinal symptoms (table 2) [4] [5] [6] [7] [8] [9] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] . other commonly reported symptoms are mucosal changes and peripheral edema, which, along with the rash and conjunctivitis, resemble the clinical characteristics of kd [5] [6] [7] [8] [9] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] . in contrast with adults, odynophagia and respiratory symptoms were rarely seen [4, 9, 14, 15, [22] [23] [24] [25] [26] [27] . notably, a subset of patients presents with hypotension and shock from either acute myocardial involvement or systemic hyperinflammation/vasodilation, frequently requiring intensive care admission, circulatory, and respiratory support (tables 2 and 3 ) [4, 5, 8, 9, 13-20, 22-25, 27] . although comorbidities have been associated with more severe disease in both adults and children with severe covid-19 [2] , their role in mis-c remains unclear. while belhadjer, dufort and feldstein et al. hypothesize that overweight patients may have a higher risk to present mis-c [24, 25, 27] , patients overall were reported to be previously healthy, and only occasionally had a baseline chronic condition such as asthma or autoimmune disorders (table 2) [4, 8, 15, 19, 20, 25, 27, 28] . interestingly, none of the reported patients had known congenital heart disease or preexisting cardiovascular disease. finally, several case series have described a high proportion of african ethnicity or ancestry [4, 18, 20, 24, 25] , as well as hispanic subjects [23] [24] [25] . future studies may help better understand the role of genetic and socioeconomic status in the pathophysiology of mis-c. [17, 18, 25, 27] . overall, a variable percentages of subjects, from 0 [15, 30] to 100% [16] had positive rt-pcr; however, in most of the reports, sars-cov-2 positivity varies between 20 and 53% (table 2 ) [4, 5, 14, 17, 18, 20, [22] [23] [24] [25] 27] . generally, a higher percentage (75-100%) had evidence of igg antibodies (table 2 ) [5, 15, 17, 18, 20-25, 27, 30] and suggest that a postinfectious immune response may be responsible for this condition [32] . elevated inflammatory markers and evidence of hyperinflammation were widely reported and consistently found in patients with mis-c [4-9, 13-33]. supplemental table 1 summarizes the main laboratory characteristics of the existing cases in the literature. overall, c-reactive protein (crp), procalcitonin (pct), and erythrocyte sedimentation rate (esr) are highly elevated, as well as ferritin and il-6. a significant increase in d-dimer and fibrinogen are key features of the coagulation profile, while the hematologic aspect of the disease is characterized by leukocytosis, neutrophilia with immature forms, lymphopenia, normal or decreased red blood cell count and normal or decreased platelet count. left ventricular (lv) systolic dysfunction has been described in a large proportion of children diagnosed with mis-c in both the initial reports and subsequent case series. cardiac findings in children with mis-c are summarized in table 2 and table 3 . in the first mis-c case-series reported from the uk, cardiac dysfunction was present in 6/8 patients (75%) [4] . in subsequent case series, ventricular dysfunction has been reported in 35-100% of children with mis-c, depending on definition and inclusion criteria (table 2 ) [4, 5, 8, 9, 13-25, 27, 30, 31] . two of the published case series described selected cohorts of patients with myocardial dysfunction as inclusion criteria [17, 27] . belhadjer et al. reported a selected cohort of 35 mis-c patients who developed acute lv failure (lv ejection fraction (lvef) < 50%) or shock, fever, and elevated inflammatory markers [27] . management of these patients included mechanical ventilation and inotropic support in 80% of patients, and extracorporeal membrane oxygenation (ecmo) support in 28%. all patients successfully weaned off ecmo and none had died at the time of publication. [27] . grimaud at el. reported 20 patients admitted with cardiogenic/vasoplegic shock and a median lvef of 35% (iqr 25-55%). nineteen out of 20 patients required inotropes/vasopressors but no ecmo support was needed. all patients had a full recovery of the lv function prior to discharge [17] . a high proportion of patients also had elevated troponin level or b-type natriuretic peptide (bnp)/pro-bnp values ( table 2) , which may be a useful marker for myocardial involvement. most patients had recovery of ventricular function, but 6-14% of patients had persistent dysfunction at discharge ( table 3) . the mechanism underlying myocardial dysfunction in mis-c has not been yet fully elucidated. possible causes of myocardial injury in adults with covid-19 include acute myocarditis, hypoxic injury, ischemic injury caused by cardiac microvascular damage or coronary artery disease, right heart strain (acute cor pulmonale), stress cardiomyopathy (takotsubo), and systemic inflammatory response syndrome [3, [34] [35] [36] [37] . the variable timing and modality of presentation with ventricular dysfunction suggests that different pathophysiological mechanisms may be responsible: while the acute infection may explain the occurrence of acute myocardial damage, a second phase characterized by a post-viral immunological reaction and systemic hyperinflammation may explain the occurrence of myocardial inflammation and dysfunction in predisposed subjects. in this second phase, a combination of cardiogenic and distributive shock may be observed. advanced cardiac imaging in patients with mis-c and ventricular dysfunction may help us better understand the underlying mechanism of injury, and presence of long-term scar or myocardial damage. coronary artery dilation or aneurysms have been described in 6-24% of patients (table 2) [4, 5, 14, 15, [18] [19] [20] [21] [22] [23] [24] [25] 27] . most cases described mild coronary artery dilation with z-scores 2-2.5. as coronary artery z-scores are based on healthy, nonfebrile children, some of the findings in the acute phase may be related to coronary vasodilation in the setting of fever and inflammation. however, there have also been reports of large and giant coronary artery aneurysms [4, 20] , and progression of coronary aneurysm following discharge raising concerns for coronary artery intimal disruption [4, 5, 19, 20] . the late development of coronary artery aneurysm highlights the need for ongoing follow-up of those patients. studies focusing on arrhythmic manifestations have described 7-60% of patients having rhythm abnormalities of variable severity ( table 2 ). the most frequently reported electrocardiogram (ecg) anomalies were non-specific and included st segment changes, qtc prolongation, and premature atrial or ventricular beats. first-and second-degree atrioventricular blocks were reported in one series, while atrial fibrillation was described in two reports [9, 20] . however, there have also been reported cases of sustained arrhythmias leading to hemodynamic collapse and need for ecmo support [4, 20] . hyperinflammatory state and resemblance to kawasaki disease mis-c overlaps with many features of kd [5, 20, 32] . kd is an acute pediatric vasculitis involving mediumsized vessels typically affecting children < 5 years of age [38, 39] . the etiology of kd is still unknown, but it has been considered an inflammatory syndrome likely resulting from an infectious or other environmental trigger in a genetically susceptible host. while no specific infectious trigger has been confirmed, several viruses have been implicated, including coronaviruses [40, 41] . clinical diagnostic criteria include a persistent fever (> 5 days) and at least 4 of 5 clinical symptoms including mucocutaneous involvement, non-purulent conjunctivitis, polymorphous rash, unilateral lymphadenopathy, and palmar/plantar erythema and desquamation. an incomplete form of kd is defined by persistent fever and presence of < 4 of classical symptoms with suggestive laboratory data and/or echo findings [38, 39] . in the acute phase of the disease, about 7% of patients manifest hemodynamic instability, a condition known as kd shock syndrome (kdss) [39, 42] . compared with kd patients without any signs of shock, kdss patients were more frequently female, had a larger proportion of bands, higher crp, and lower hemoglobin and platelet counts [42] . the small case series from bergamo, italy, reported a 30-fold increase in the incidence of kd or kd-like illness during the height of covid-19 outbreak in the region (uncorrected for seasonal incidence), with many patients testing positive for igg antibody and negative rt-pcr [5] . when these cases were compared with 19 classical kd, covid-19-associated cases were found to be older (7.5 ± 3.5 vs 3.0 ± 2.5 years), more likely to present in shock (50% vs 0%), to have more cardiac involvement (abnormal echocardiogram in 60% vs 10%), and more likely to have elevation in troponin or bnp. similarly, whittaker et al. compared patients meeting the mis-c definition with classical kd or kdss patients [20] , reporting that patients with mis-c were generally older, had higher white blood cell count, neutrophil count, crp, fibrinogen levels and higher troponin, as well as more profound lymphopenia, anemia, and lower platelet counts. while generally self-limited, kd can have a number of long-term sequelae, the most important of which are cardiovascular. in addition to ventricular and valvular dysfunction, patients with kd can develop persistent coronary aneurysms, occurring in 20-25% of untreated children [38, 43, 44] . coronary dilation or aneurysms have been reported in up to 25% of mis-c patients, suggesting a pathophysiologic similarity with kd. even if mis-c patients have different clinical characteristics and laboratory findings compared with classical kd, the similarity in clinical features and the development of coronary artery aneurysms in both disorders may represent a key point for the future understanding of underlying pathophysiologic mechanisms [32] . further studies will be needed to deeply understand the pathophysiology of this disorder. table 3 . overall, admission to the intensive care unit (icu) for management of shock was described in 20-100% of the patients, most often for inotropic support (table 3) [4, 5, 8, 9, 13-25, 27, 30, 31] . more rarely, patients required v-a ecmo support (0-28%) [4, 9, 20, [23] [24] [25] 27] . most patients received immunomodulatory treatment with intravenous immunoglobulin. the use of corticosteroids was less consistent and ranged from low-dose treatment to high-dose methylprednisolone pulses [4, 5, 8, 13, 14, 16-25, 27, 30, 31] . the use of antiinflammatory dosages of aspirin has been also occasionally reported [5, 6, 21, 22] . not infrequently, cytokine blockers have been added as a supplemental therapy, with a preference for il-6 inhibitors (tocilizumab), but also il-1 or tumornecrosis-factor (tnf)-αinhibitors (anakinra, infliximab) [4, 14-17, 19, 20, 22, 23, 25, 27, 28, 31, 33] . antiplatelet treatment with aspirin was frequently adopted, especially in patients with kd-like clinical presentations, or in those with evidence of coronary involvement. a therapeutic or prophylactic anticoagulation approach was less frequently used, except for a few case series [16, 19, 23, 25, 27, 31] . due to the scarce knowledge and the small number of reported cases so far, the management of patients with mis-c has been largely based on expert opinion and extrapolated from kd treatment, adult experience with covid-19, and other systemic inflammatory disorders in children. here, we describe a consensus-based approach for the acute and medium-term management of children with mis-c, as well as a follow-up algorithm, developed within our institution. however, it is necessary to emphasize that there are currently no approved therapies for mis-c patients, and data from higher-evidence studies may quickly lead to changes in clinical practice. a multidisciplinary team should be involved in the management of patients with mis-c, including cardiology, rheumatology, intensive care, and infectious disease specialists. given the lack of established treatment, possibility of harm, and limited drug supply, treatment is currently not recommended for (a) prevention or postexposure prophylaxis or (b) non-hospitalized patients. as described above, a high proportion of patients will present with shock and require acute resuscitation. pediatric resuscitation guidelines should be followed [45] . in patients with suspicion or evidence of ventricular dysfunction, smaller fluid boluses (10 mg/kg) should be administered with careful reassessment for signs of fluid overload between each. extracorporeal membrane oxygenation should be considered if medical support fails. there may be a benefit of immunomodulatory therapy in patients with mis-c, severe disease, and evidence of cytokine storm syndrome and/or those with cardiac involvement. due to recent emergence of mis-c, no randomized trials or comparative effectiveness studies have evaluated treatment strategies, but the benefits of immunomodulatory therapy are well established in kd [39] , and they are often used for the treatment of infective myocarditis [46] [47] [48] and other systemic inflammatory diseases [49, 50] . therefore, based on the experience in similar conditions, it appears reasonable to suggest an immunomodulation approach based on intravenous immunoglobulins (ivigs). slower ivig administration should be considered in patients with myocardial dysfunction to decrease the risk of fluid overload. low-dose corticosteroids should be considered in sicker patients, in patients with known baseline conditions which can benefit from steroid treatment, or based on clinical judgment. the use of biologic drugs (tocilizumab, anakinra, infliximab) could be considered in patients with severe or critical illness, especially if they did not respond to first-line treatments. children with mis-c are at risk of thrombotic complications from multiple causes, including hypercoagulable state, possible endothelial injury, stasis from immobilization, ventricular dysfunction, and coronary artery aneurysm. for these reasons, antiplatelet and/or anticoagulation treatment is recommended. decisions about anticoagulation should be based on coagulation tests, viscoelastic testing [51, 52] , and clinical presentation. patients with evidence of myocardial involvement or coronary artery dilation may benefit from antiplatelet therapy and prophylactic anticoagulation. in addition, therapeutic anticoagulation may be considered in patients with very abnormal coagulation profile (i.e., d-dimer ≥ 3 mg/ml), documented thrombosis, arrhythmia, ventricular dysfunction greater than moderate, or giant coronary artery aneurysm. however, it should be emphasized that this is based on experts' opinion, with no evidence to support recommendations. the role of antiviral therapies (e.g., remdesivir) in the management of children with mis-c is uncertain [53, 54] . evidence suggests that mis-c represents a postinfectious complication rather than an active infection. although we did not include antiviral therapies as an established step in our algorithm, antiviral therapy may be considered in patients with severe manifestations and concerns for ongoing infection with positive rt-pcr. a consultation with specialists in infectious disease is highly recommended in this case. cardiac manifestations often improve and/or normalize prior to hospital discharge, but some patients have shown residual cardiac lesions. additionally, some series reported progression of coronary artery aneurysm following discharge, highlighting our limited knowledge of this disease and the potential for long-term complications. therefore, it is essential to guarantee an adequate medium and long term follow-up to these patients. at this point of knowledge, we recommend follow-up for at least a year after initial diagnosis ( fig. 1) . at initial visits, laboratory testing should be obtained to document normalization of inflammatory markers and resolution of hematologic anomalies. laboratory testing may also guide weaning of corticosteroids if used in the acute phase. echocardiograms should be obtained at regular intervals for evaluation of ventricular function and coronary artery dimensions. ecgs should also be obtained due to reports of arrhythmias including atrioventricular block, which may progress after initial diagnosis. if anomalies are identified on ecg, holter monitors may be useful as further investigation. in patients with a history of ventricular dysfunction, cardiac magnetic resonance imaging (mri) may be considered 2-6 months after initial diagnosis for evaluation of ventricular function, edema, diffuse fibrosis, and scar. while the prothrombotic risk is greatest in the acute phase, the optimal duration of antiplatelet and anticoagulation and/or coronary artery aneurysm may also benefit from long-term antiplatelet and/or anticoagulation depending on the severity of cardiac involvement. due to the high prevalence of myocardial involvement with mis-c, the safety to return to physical activity and exercise after discharge is unanswered. while the etiology of the myocardial involvement remains unknown, it is clear that there are similarities to acute myocarditis. thus, one can argue that guidelines for return to sport participation after myocarditis should be followed in those patients [48, 55] . after acute myocarditis, restriction from physical activity for at least 6 months following diagnosis is recommended. preparticipation evaluation with echocardiograms and exercise testing may be beneficial to document the safety of exercise participation. mis-c is a novel syndrome related to sars-cov-2 infection characterized by fever, signs of inflammation, and organ dysfunction. evidence is still scarce but rapidly emerging from literature. myocardial involvement, due to either acute myocarditis or secondary hyperinflammation, is frequent in children with mis-c. coronary dilation or aneurysm and arrhythmias may develop and evolve over time. cardiac support, immunomodulation, and antiplatelet/anticoagulation treatments are part of the management of acute mis-c. finally, follow-up of mis-c patients is essential to better understand the evolution and prognosis of this disease. future studies are needed to define evidence-based management of this novel condition. authors' contributions f.s. and a.d conceptualized the review, systematically reviewed the literature, evaluated articles for eligibility, extracted relevant data, interpreted the results, and drafted the manuscript. k.f., j.n., m.b.s., and c.j.v. critically revised the first draft of the manuscript and contributed with important intellectual content. all the authors approved the final version of the manuscript to be published and agree to be accountable for all aspects of the work. funding information open access funding provided by università degli studi di padova within the crui-care agreement. conflict of interest the authors declare that they have no conflict of interest. ethical statement this is a review article. no ethical approval is required. fig. 1 suggested outpatient follow-up of patients with mis-c. avb atrioventricular block, ecg electrocardiogram, cbc complete blood count, crp c-reactive protein, esr erythrocyte sedimentation rate, mri magnetic resonance imaging, pct procalcitonin, ldh lactic dehydrogenase open access this article is licensed under a creative commons attribution 4.0 international license, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the creative commons licence, and indicate if changes were made. the 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therapy in rheumatic diseases the clinical picture of severe systemic capillary-leak syndrome episodes requiring icu admission fibrinolysis shutdown correlates to thromboembolic events in severe covid-19 infection viscoelastic testing in covid-19: a possible screening tool for severe disease? transfusion 4-5 remdesivir for the treatment of covid-19 -preliminary report remdesivir for 5 or 10 days in patients with severe covid-19 european society of cardiology working group on myocardial and pericardial diseases (2013) current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the european society of cardiology working group on myocardial and pericardial diseases key: cord-278672-pxzsntfg authors: milenkovic, aleksandar; jankovic, dragan; rajkovic, petar title: extensions and adaptations of existing medical information system in order to reduce social contacts during covid-19 pandemic date: 2020-06-16 journal: int j med inform doi: 10.1016/j.ijmedinf.2020.104224 sha: doc_id: 278672 cord_uid: pxzsntfg objective: the main objective of this paper is the reduction of the covid-19 pandemic spread by increasing the degree of social distancing by using and upgrading the existing medical information system (mis). material and methods: the existing mis medis.net, currently used in the largest health center in the balkans, has been adapted and further developed. results: during the adaptation of existing mis medis.net 4 new and 9 existing modules were developed. a quick questionnaire for the smart triage of patients was also implemented. discussion: the adapted mis successfully influenced the reduction of social contacts within the health center nis. the need for the arrival of children and their parents to receive appropriate health certificates for the school enrolment is reduced. the therapy of chronic patients has been prolonged for 6 months via an electronic prescription. an online service for the communication between patients and the chosen physicians is provided. possible social contacts and exposure to the viral environment of patients are reduced by making appointments in extended slots and at determined physical locations. patients are notified per sms or email about the availability of chosen and physician on duty. the social distancing of patients and physicians is also established by sending laboratory analyses per email or sms. keeping the central registry for covid-19 is enabled throughout the country. conclusion: the smart adaptation of mis, and its collaboration with other state systems can significantly influence the reduction of social contacts and thus mitigate the consequences of covid-19 pandemic. the emergence and rapid expansion of major epidemics, besides the influence on the daily lives of people through changing health, economic, working style, social and political routines, also has a significant impact on existing information technology (it) products, with a great emphasis on large-scale information systems (is) which are exploited on a daily basis. during outbreaks, especially those with a pandemic character, the following key activities [1] which are updated with covid-19 strategy [2] have been identified whose strict implementation has an impact on the reduction of number of infected people and suppression of the spread of epidemic: 6 . isolation of persons who are suspected to be infected with the virus [6] (the persons not yet diagnosed with the disease), 7 . monitoring persons during home isolation in order to check whether they follow the rules of self-isolation, 8 . make as many digital (government, administration, health such as telehealth [7] ) online services as possible available to people to reduce their need to exit and be exposed to the infectious environment. the main problem that naturally arises is the efficient suppression of the rapid spread of epidemic i.e. reducing the number of persons who could be exposed to the infection through the proposed key activities. the reduction of disease transmission is most efficiently conducted by socially distancing people from each other and reducing their contacts [8] . additionally, educational campaigns which strengthen the understanding of the outbreak and adhere to mitigation strategies need to be conducted in order to raise awareness about the covid-19 disease and its consequences. some epidemics have the characteristic of rapid pathogen spread, which causes them with the high incidence of hospitalized and severely ill patients. emerging of an enormous number of patients, suffering from the disease which causes the epidemic, within a short period of time, can become a major problem for the whole healthcare system of a country especially with an emphasis on the secondary or tertiary protection level. even well-developed countries with the most sophisticated healthcare systems can easily experience the healthcare collapse during epidemics [9] (e.g. italy [10] , usa [11] , spain [12] , uk [13] ). the primary healthcare system in such circumstances needs to undertake significant steps in early diagnosing of ill patients and reducing the degree of contact in order to avoid the collapse of secondary and tertiary level. besides engaging healthcare resources to combat the epidemic, the need emerges for an intensive use of it solutions. this paper presents the adaptation and extension of existing medical information system (mis) as an efficient response to the rapid covid-19 epidemic spread, mostly through influencing the reduction of social contacts and earliest possible identification of potentially infected persons. the objective of this paper is increasing the degree of social distancing (decreasing unnecessary physical contacts in a healthcare institution and city in general) which is accomplished by adapting the existing mis medis.net [14] . the implementation of social distancing is based on the following relationships: patient to patient and patient to healthcare worker. the adjusted mis gave an efficient response to the rapid spread of pandemic caused by covid19 . by adapting mis medis.net a software support is granted to the healthcare centre nis (hcn) to combat the j o u r n a l p r e -p r o o f fast-spreading disease covid-19. the software support is provided to the following key proposed activities: 1, 4, 5, 6, 8. the novel coronavirus appeared by the end of 2019 and is named sars-cov-2 [15] . it was discovered in china by the end of 2019 in the city of wuhan, the province of hubei [16] . the disease caused by the virus sars-cov-2 is named covid-19. for covid-19 the world health organization (who) assigned the urgent icd-10 diagnosis u07.1 [17] . since its emergence, covid-19 is the center of attention of many researchers. one recent study [18] reviewed the virology, origin, epidemiology, clinical manifestations, pathology and treatment of covid19 showed bilateral patchy shadows or ground glass opacity in the lungs [19] . the covid-19 disease in most of the cases affects older men with comorbidities and can lead to severe as well as life-threatening respiratory diseases. the average age of these patients infected by new coronavirus in wuhan was 55.5 years (sd 13.1) and 51% of them had some chronic disease [20] . the most vulnerable patients have chronic diseases such as diabetes, hypertension and cardiovascular disease with possible complications, which include acute respiratory distress syndrome (ards), rnaaemia, acute cardiac injury and secondary infection [21] . the fig. 1 shows the exponential growth of the affected and deceased people worldwide infected by covid-19 [22]. due to prolonged lockdown and fear of infection, covid-19 adversely affect the mental health of the general the first case of the affected by the virus in the republic of serbia (rs) was recorded on march 6, 2020. the exponential growth of patients affected by covid-19 is recorded in rs [25] . the government of rs formed on april 3 the covid-19 is [26] . the aim of this is is to carry out epidemiological surveillance related to covid-19. due to the exponential and easy spread of the highly contagious covid-19 disease, it was necessary to rapidly adapt the existing mis during the beginning of the covd-19 pandemic. due to the exponential growth of the covid-19 disease it is crucial to develop triage protocols in order to identify and isolate patients suspected of having the covid-19 infection in covid-19 temporarily hospitals or special departments in existing health institutions for the isolation of patients. in this way the disruption of normal medical care would be mitigated. a successful protocol for triage during a pandemic requires a more detailed planning, which involves a constant data collection: about the patient (demographic and medical data), data about availability of healthcare resources [27] . a patient portal-based covid-19 self-triage and self-scheduling tool was created and it was made available to all primary care patients at the large academic health system at the university of california, san francisco (ucsf) health [28] . based on the results, during first 16 days of use symptomatic patient triage dispositions were as follows: 193 emergent (24%), 193 urgent (24%), 99 nonurgent (12%), 329 self-care (40%) and sensitivity for detecting emergency-level care was 87.5%. according to the research findings the integration of patient self-triage tools into electronic health record (ehr) systems has a great potential in improving the triage efficiency and preventing unnecessary visits during the covid-19 pandemic. the estimate of effects of physical distancing measures on the progression of the covid-19 epidemic was conducted [29] . synthetic location-specific contact patterns in wuhan were used and adapted in presence of school and workplace closures as well as the general reduction in mixing in the community. using an age-structured susceptible-exposed-infected-removed (seir) model the authors simulated the ongoing trajectory of the epidemic. they fitted the latest estimates of epidemic parameters and investigated the age distribution of cases. lifting of the control measures, such as allowing people to return to work in a phased-in way was also simulated. the effects of returning to work at the beginning of march or april were investigated. based on the results, physical distancing measures showed to be most effective if staggered return to work happened at the beginning of april, which reduced the average number of cases by more than 92%. the authors summed up that if restrictions maintained until april, they would delay the peak of epidemic. sudden lifting of measures could provoke an earlier secondary peak. such a scenario can be avoided by relaxing the measures gradually. the tools and methods developed for the identification of possible patients who suffer from some chronic disease show that the automatic summarization would help identify all patients with at least one record related to the diagnosis usually marked as chronic, with the final approval of medical professionals [30] . the results show that depending on the data filter definition, the total percentage of newly discovered patients with a chronic disease is between 35% and 53%, as expected. it is important to mark chronic patients during the regular physician's visit during the covid-19 pandemic in mis medis.net since they belong to the vulnerable and high-risk groups. the use of smart technologies has been the focal point of many researches worldwide. especially in recent times the researchers are focusing on developing phone applications which track infected and potentially infected people in order to suppress the spread of covid-19. the pan-european privacy preserving proximity tracing (pepp-pt) [31] is a platform on whose development works a team of 130 researchers from 8 european countries. on the basis of this software national authorities remain free to decide how to inform persons that they were in contact with someone who was tested positive. world-renowned companies such as apple and google [32] are developing a smartphone platform that tracks the spread of covid-19 by using proximity capabilities built into bluetooth low energy transmissions, which enables the actual tracking of physical contacts of phone users who agreed to participate. the user who is tested positive for covid-19 can enter the result into a health department-approved application. all other participating phone users who recently had a contact at the distance of approximately six feet with the infected user will be contacted by the application. during the largest ebola epidemic in west africa (2014 -2016) researches developed an ebola j o u r n a l p r e -p r o o f contact tracing (ect) application for tracing contacts [33] . the authors compared results of the application developed with the existing paper-based system. based on their research, the app-based contact tracing recorded 63% of contacts of laboratory-confirmed cases, whereas paper-based contact tracing achieved the result of 39% with often incomplete data. the developed smartphone application is linked to an alert central system to notify the district ebola response centre of symptomatic contacts. the authors agreed that despite many challenges the use of application had benefits, such as improved data completeness, storage and accuracy. the development of smart healthcare system is a highly important factor from the perspective of patients (e.g. better health self-management, timely and appropriate medical services can be accessed when needed), healthcare employees (e.g. reduce costs, relieve personnel pressure, achieve unified management of materials and information, and improve the patient's medical experience) and research institutions (e.g. reduce the cost of research, reduce research time, and improve the overall efficiency of research) [34] . the researchers emphasized the importance of new generation of information technologies, such as internet of things (iot), mobile internet, cloud computing, big data, 5g, microelectronics, and artificial intelligence in order to build smart healthcare. furthermore, big data computational epidemiology is a new and exciting multidisciplinary area that uses computational models and big data for identifying and controlling the spatiotemporal spread of disease through populations (e.g. the h1n1 influenza) [35] . in today's era of informatization many health care institutions are facing the need to rapidly improve their it infrastructure to meet the challenges of modern times, such as the outbreak of covid-19. the health facilities need to be prepared for the exponential growth of patients [36]. on the territory of rs as mis several solutions are used among which are, during the last 10 years, the most (table 1 , table 2 ), as well as the development of additional software modules, which help healthcare workers to proactively act in the suppression of pandemic. before the beginning of covid-19 pandemic mis medis.net did not have specifically developed software functionalities (modules, subsystems) which would help healthcare workers and patients to combat seasonal and exceptional pandemics. in the fig. 2 due to the covid-19 pandemic the state service of covid-19 republic is [26] was urgently developed and put smart ehr module enhances mis medis.net making it a more advanced version. one of the functionalities of the module is the clustering of patients based on the demographic and medical data by using the dnn [41] . logistic regression [42] , random forest [43] and dnn are used for the implementation of subsystem for the smart identification and assessment of patients who will not come to the appointment with the chosen physician or/and to expensive diagnostic examinations for which a patient needs to wait, sometimes even for several months. this system has enabled patients to make appointments in overlapping slots [44] during the covid-19 pandemic. for chronic patients [30] during a pandemic, a special submodule is used which suggests to general practitioners a possible therapy with the amounts of a medicine and the periodicity of taking a medicine, as well as possible referrals for specialist examinations [45] . due to the use of new medicines during the treatment of infected patients with the covid-19 infection, a subsystem is used as an assistance, which warns the physician whether the prescribed therapy corresponds to the established diagnosis. the subsystem also informs about the possible contraindications with other medicines the patient is using. a smart mobile reminder for taking the prescribed therapy [46] helps elderly and chronic patients during the pandemic not to forget to take the therapy at the predefined time. the developed subsystem for the use of existing data from mis medis.net in the education of students at the faculty of medicine and newly employed workers, as well as for medical research [47] , enables tracking and studying the covid-19 disease at this stage. open data service is used for obtaining the demographic data from available open data sets in serbia [48] . scheduling module is responsible for recording scheduled/cancelled appointments of patients for an examination with chosen physicians/diagnostic devices. the centralized management of arranged checkup appointments and j o u r n a l p r e -p r o o f diagnostic procedures of patients was accomplished by integrating scheduling module with the service/application "moj doktor" is [49] . mail notification modul is responsible for providing service information to patients and health center employees via email. sms notification module enables providing service information via sms [50] . during the pandemic these modules were used for sending information to health care employees and patients. in order to receive updated demographic data for each patient during the pandemic reporting modul was connected to opendata available services of the rs [48] . in the fig. 5 and fig. 6 a significant decrease of the arrival of patients during pandemic weeks at hcn is presented after the implementation of additional modules developed during the covid-19 pandemic. from the 12 th pandemic week, the number of patients who received referrals for specialist examinations decreased notably (fig. 6 ). out of all the patients who came to the hcn, the patients who were referred to specialist examinations were predominantly chronic patients. in most of the cases those were the patients with diagnosed i10 -essential (primary) hypertension and e11 -type 2 diabetes mellitus. the reduced number of patients at the hcn also influenced the decrease in the laboratory referrals. the fig. 6 . presents also the most frequent diseases for which prescriptions, referrals and laboratory orders were used. all the patients who visited the health center showing some symptoms of covid-19 went through the triage algorithm. despite the lower arrival of patients ( table 3 ) the number of patients who were forwarded to the clinics of infectious diseases and pulmonology was higher in comparison with last years. taking into consideration that the number of arrivals of patients at hcn was in general reduced (fig. 5, fig. 6 ), the increase of such referrals was significant. covid-19 as a significant manifestation had a rapid change of health condition on the lungs of a patient, j o u r n a l p r e -p r o o f so patients were after completing triage urgently referred to already mentioned external clinics for urgent further diagnostics. were patients who could be in home isolation, patients who were tested and not diagnosed with covid-19, although they showed some infection symptoms or were in contact with infected or potentially infected persons. patients with a yellow priority had a clear picture of disease and were hospitalized in temporary covid-19 hospitals. patients with a red priority were confirmed covid-19 cases who also had some chronic disease and belonged to highly vulnerable groups (table 1) . these patients were hospitalized and required constant monitoring. patients with a blue priority needed to be hospitalized and were directly transported from home to covid-19 hospitals. one the most significant decrease of arrivals of patients at the hcn was recorded during the 13 th , 14 th and 15 th pandemic week. it was influenced by the developed modules which were distributed to the hcn as they were developed and adapted. the greatest decrease so far was recorded in the 14 th week of 2020 (fig. 5, fig. 6 ). during the 13 th pandemic week the integration with covid-19 is was completed so patients started to significantly communicate online with chosen physicians. at the same time, the number of their arrivals at the hcn decreased, which means that contacts and the stay in the environment with high virus presence incidence were reduced. the age structure of patients who were coming the most during pandemic weeks was from 35 to 65 years of age were the data about the persons who were coming to physicians for examinations, during the period when the physicians were infected, and who were later diagnosed with the presence of covid-19 (14-28 days before registering the disease). these data were provided by covid19 analyses, which can be accepted or denied by the physician. the authors argue that the ehr is a necessary tool in supporting the clinical needs of a health system during the covid-19 pandemic management. one of the limitations of this study is that the top 10 chronic icd-10 diagnoses did not include psychiatric illnesses such as depression. psychiatric patients were deprived of psychiatric care and resulted in more severe levels of depression and anxiety during covid-19 pandemic [52] . workers are reluctant to taking time off work to attend hospital/clinic during covid-19 pandemic [53] and the mis medis.net may help them to book appointment. future research is required to extend the application of mis medis.net to psychiatric patients and workers. furthermore, mis medis.net can work with smartphone applications to deliver counselling [54] , rehabilitation [55] , support caregivers [56] and monitor symptoms [57] . since the coronavirus has potential for long lasting global pandemic with huge mortality rates and overloaded health systems, currently the only possible prevention is case isolation, contact tracing and quarantine, physical distancing, and hygiene measures [58] . a key approach to avoid the exceeding of health care capacities is by successfully implementing social distancing as a measure to control the spread of covid-19. in order to achieve this, prolonged social distancing might be required until 2022 [59] . the the following contributions are made by the authors: -aleksandar milenkovic, dragan jankovic and petar rajkovic made initial design of system functionalities; -aleksandar milenkovic and dragan jankovic lead the system development and later deployment to the production environment; -aleksandar milenkovic and petar rajkovic extracted the data and performed analysis and data interpretation; -aleksandar milenkovic and petar rajkovic made a literature review; -all the authors made initial article draft; -all the authors revised and made a final approval of the submitted version. medical information system medis.net, whose usage overview is presented in the submitted work, is a result of a joint project of the laboratory of medical informatics and health center nis. as a commercial product, it is sold to other public health centers in the republic of serbia. aleksandar milenkovic and dragan jankovic received personal fees as full members of laboratory of medical informatics. during the conduct of this research, petar rajkovic received no financial compensation, but was allowed to use statistically processed data for other researches. this work has been supported by the ministry of education, science and technological development of the republic of serbia (project number: on174026). j o u r n a l p r e -p r o o f use the real medical data for the research that is presented in this paper. the assistance provided by slavica cvetkovic for language editing and proofreading is greatly appreciated. what was previously known on the topic: -social distancing is one of the most significant measures in suppressing the spread of a virus during epidemics and pandemics (such as the current covid-19 pandemic). -initially, medical information systems were not created for the purposes of social distancing. -the adequate adaptation and upgrading of medical information systems can significantly increase social distancing by reducing patient to patient and patient to healthcare worker contacts. -by customizing the medical information system social contacts can be significantly reduced and the spread of the virus slowed down without severely disrupting people's lives. 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immunopsychiatry characterize health and economic vulnerabilities of workers to control the emergence of covid-19 in an industrial zone in vietnam online and smartphone based cognitive behavioral therapy for bariatric surgery patients: initial pilot study, technology and health care the untapped potential of smartphone sensors for stroke rehabilitation and after-care conceptualization of an evidence-based smartphone innovation for caregivers and persons living with dementia digital platforms in the assessment and monitoring of patients with bipolar disorder quantifying sars-cov-2 transmission suggests epidemic control with digital contact tracing projecting the transmission dynamics of sars-cov-2 through the postpandemic period the authors would like to offer their special thanks to all the staff at the laboratory of medical informatics at the faculty of electronic engineering in nis. the special thanks are extended to the health center nis for enabling the key: cord-339709-49q2xxkw authors: sermet, i.; temmam, s.; huon, c.; behillil, s.; gadjos, v.; bigot, t.; lurier, t.; chretien, d.; backovick, m.; moisan-delaunay, a.; donati, f.; albert, m.; foucaud, e.; mesplees, b.; benoist, g.; fayes, a.; duval-arnould, m.; cretolle, c.; charbit, m.; aubart, m.; auriau, j.; lorrot, m.; kariyawasam, d.; fertita, l.; orliaguet, g.; pigneur, b.; bader-meunier, b.; briand, c.; toubiana, j.; guilleminot, t.; van der werf, s.; leruez-ville, m.; eloit, m. title: prior infection by seasonal coronaviruses does not prevent sars-cov-2 infection and associated multisystem inflammatory syndrome in children date: 2020-06-30 journal: nan doi: 10.1101/2020.06.29.20142596 sha: doc_id: 339709 cord_uid: 49q2xxkw background: children have a lower rate of covid-19, potentially related to cross-protective immunity conferred by seasonal coronaviruses (hcovs). we tested if prior infections with seasonal coronaviruses impacted sars-cov-2 infections and related multisystem inflammatory syndrome (mis). methods: this cross-sectional observational study in paris hospitals enrolled 739 pauci or asymptomatic children (hos group) plus 36 children with suspected mis (mis group). prevalence, antigen specificity and neutralizing capability of sars-cov-2 antibodies were tested. antibody frequency and titres against nucleocapsid (n) and spike (s) of the four seasonal coronaviruses (nl63, hku1, 229e, oc43) were measured in a subset of seropositive patients (54 sars-cov-2 (hos-p subgroup) and 15 mis (mis-p subgroup)), and in 118 matched sars-cov-2 seronegative patients (ctl subgroup). findings: sars-cov-2 mean prevalence rate in hosp children was 11.7% from april 1 to june 1. neutralizing antibodies were found in 55.6% of seropositive children, and their relative frequency increased with time (up to 100 % by mid-may). a majority of mis children (25/36) were sars-cov-2 seropositive, of which all tested (n=15) had neutralizing antibodies. on average, seropositive mis children had higher n and s1 sars-cov-2 titres as compared to hos children. patients from hos-p, mis-p, and ctl subgroups had a similar prevalence of antibodies against the four seasonal hcovs (66.9 -100%). the level of anti-sars-cov-2 antibodies was not significantly different in children who had prior seasonal coronavirus infection. interpretation: prior infection with hcovs does not prevent sars-cov-2 infection and related mis in children. children develop neutralizing antibodies after sars-cov-2 infection. covid-19 is due to sars-cov-2, a betacoronavirus subgenus sarbecovirus 1 , which has expanded 94 worldwide since its emergence in china at the end of 2019. observations indicate that children are 95 less likely to develop the disease and that the clinical course of covid-19 in children is less severe than 96 in adults 2-4 . accordingly, children represent only 0.6-2.3% of confirmed cases in china and 0.8-5.2% 97 outside china outside context of household 2,5,6 . as asymptomatic or mildly symptomatic children are 98 underdiagnosed, and their viral loads are comparable to those of adults, children may act as an 99 asymptomatic reservoir for the spread of the virus to their adult and elderly relatives 7,8 , albeit with 100 low efficacy 9 . children's susceptibility to infection might also be low 5 and the paediatric cohort may 101 represent a pool of "immune naïve" population. differences in susceptibility profiles for children and 102 adults might be driven by infections with seasonal human coronaviruses (hcovs), which are very 103 frequent at a very young age 10 , and could lead to cross-protective immunity in children. this may be 104 mediated either by cross-binding or cross-neutralizing antibodies 11 , or by t cell responses that target 105 epitopes shared by sars-cov-2 and hcovs 12,13 . indeed, it was recently shown that cd4+ t cells of 106 unexposed subjects (sampled before the pandemic) recognized sars-cov-2. 107 despite a low frequency of respiratory symptoms, cases of multisystem inflammatory 108 syndrome (mis) have been reported in children that were infected by sars-cov-2 or were in contact 109 with covid-19 patients 14, 15 . mis shares similarities with classic kawasaki disease but displays different 110 prominent clinical signs including cardiogenic shock or myocarditis 15 . as for other post infectious 111 diseases 16 , it is possible that a low antibody response to sars-cov-2, or cross-reactive antibodies 112 without any neutralizing capability, facilitate immune-dependent enhancement following re-113 exposure, potentiated by a specific genetic background 17,18 . interestingly, a domain of the sars-cov-114 2 spike protein which binds with high affinity to t cells may act as a super antigen, and trigger 115 excessive adaptive immune responses 19 . 116 the aim of this study was to analyse the impact of endemic seasonal coronaviruses on sars-117 cov-2 infection in children. this was performed in a large cohort of children aged 0 -18 years, 118 6 hospitalized in paris. to measure if prior infections with hcovs (detected by antibody responses 119 against two major antigens, s and n) conferred protection towards sars-cov-2 infection, we analysed 120 their frequency in sars-cov-2 positive children as compared to sars-cov-2 negative matched 121 controls. we also analysed sars-cov-2 and seasonal hcovs humoral responses of patients with mis 122 regarding antibody targets and functional neutralizing activity. our study is the first to analyse in depth 123 the typology of humoral responses to sars-cov-2 in children, and provides evidence that prior 124 infections by seasonal coronaviruses has no significant impact on sars-cov-2 infection or related mis 125 disease in children. 126 127 128 all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. we recorded the history of suspected covid-19 cases based on a standardized study-specific form. 140 we collected data on clinical symptoms consistent with covid-19 occurring from december 2019 until 141 up to 7 days before enrolment. demographic information, relevant epidemiological history (e.g. 142 international travel or contact with an infected person or a suspected case), comorbidities, reasons 143 for hospitalization were collected. 144 the local ethics (ceraphp paris v) approved this study (irb registration: #00011928). patients and/or 146 their parents/guardians were informed about the study 147 for sars-cov-2 prevalence, we used a lips (luciferase immunoprecipitation system) test as 149 previously reported 22 , which identifies antibodies (ab) targeted to the s1 and s2 domains of the spike 150 (s) and to the nucleoprotein (n). for the neutralization assay we used a viral pseudotype-based assay 151 and a neutralization test using live sars-cov-2. in a fraction of samples, we assessed by lips tests, 152 antibodies to the nucleoprotein and to the full spike ectodomain in a pre-fusion conformation for 153 sars-cov-2, and the four human coronaviruses (hku1, nl63, oc43, and 229e). detailed technical 154 8 information together with sensitivity and specificity evaluations are given respectively in 155 supplementary material s1 and s2. 156 we did not detect any difference in terms of age, sex ratio, and main comorbidities between patients 158 recruited in march (n=133; single centre study) and afterwards (n=642; multicentric seroprevalence 159 study) (supplemental table 1 ). we therefore present the demographic and clinical data of the whole 160 cohort of children enrolled. cases were grouped based on the results of serology testing and clinical 161 presentation. data were assessed for normal distribution using the kolmogorov-smirnov test. 162 continuous variables were presented as mean (sd) and compared using the student t test. categorical 163 variables were compared using chi2 or fisher's exact tests, as appropriate. statistical analyses were 164 conducted with excel or graphpad prism 8 (graphpad software, llc). principal component analysis 165 was performed to identify the serological profile according to sars-cov-2 abs and seasonal hcov abs. 166 data were processed with r 3.6.3 using ggplot2 with ggally for matrices of plots, and ggfortify for 167 pca plots packages. two-sided p value of <0.05 was considered significant. 168 169 all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june 30, 2020. . https://doi.org/10.1101/2020.06.29.20142596 doi: medrxiv preprint results 170 in total, 775 children, mean (sd) age 8 (5·6) years were enrolled in the study (figure 1 ). one hundred 172 six (13·6%) were below 15 years of age. the reason for consultation or hospitalization was regular 173 follow-up for 58%, surgery for 11·7% and medical emergency for 15% (hos population). among those, 174 17 patients (2·1%) were hospitalized for neurological disorders including encephalitis (n=4), 175 cerebellitis (n=5), polyradiculoneuritis (n=7), and labyrinthitis (n=1). thirty-six other patients (4·6%) 176 presented with a mis and among those, 25 were hospitalized in intensive care unit because of signs 177 of shock, and 28 developed myocarditis. 178 the apparent prevalence of seropositive children was in the range 10% -15% between 6 th april and 179 1 st june, except on the week starting 11 th may where it reached 27%. the patients with mis were 180 mainly detected from the last week of april to mid-may (figure 2) . the seropositive patients with 181 neurological disorders were hospitalized over the whole study period. 182 table 1 the seropositive children (hos-p and mis-p) did not show an age-dependent specific distribution 194 (supplemental figure s3 ). more than 70% of them (121 out of the 172) did not report any history 195 consistent with covid-19 during the preceding weeks. the only symptoms that were marginally but 196 significantly reported in the previous months in seropositive children were headache, shortness of 197 breath and rhino-pharyngitis. neurological disorders were significantly more frequent in the 198 seropositive group (13 children out of 17). 199 hos-p patients ab profile was characterized by a dominant s2 response compared to responses to s1, 201 n and to the full s ectodomain (figure 3) . the hos-p children with neurological symptoms showed n, 202 s1 and s2 responses similar to those of the hos-p group without neurological symptoms 203 (supplemental figure s4 ) and were analysed together. 204 mis-p patients showed a distinct ab profile directed against n, s1 and s2 altogether (figure 4 ). levels 205 of n and s1 abs to sars-cov-2 were significantly higher in the mis-p than in the hos-p group ( figure 206 3c-d). 207 to investigate the neutralization activity, we first performed a pseudo-neutralization assay in the 209 subset of 54 hos-p and 15 mis-p patients (figure 1) . overall, 55·6% of hos-p and 100% of mis-p 210 children showed a neutralizing activity. interestingly, the fraction of hos-p children whose abs 211 displayed a pseudo-neutralizing activity (pnt+) increased with time ( figure 2b) , from 18% to 38% 212 during march and april to 100% at the beginning of may. for a fraction of these children, we 213 investigated the correspondence between pnt and live sars-cov-2 neutralizing activity determined 214 in a plaque reduction test (prnt) ( table s6) . all tested sera positive in pnt (n=28) were prnt+ and 2 215 out of the 11 pnt-negative sera were also prnt+. in total, 73·7% of hos-p tested sera showed a 216 neutralizing activity. neutralizing titres of pnt+ and prnt+ sera of mis-p patients were similar to those 217 of hos-p patients (figure 3) . 218 all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june 30, 2020. . we compared the prevalence of anti-n and -s antibodies against the four seasonal hcovs in a 220 subpopulation of children among the hos-p (n=54), mis-p (n=15) and ctl (n=118) groups (figure 1) . 221 prevalence rates for the two betacoronaviruses (hku1 and oc43) and the two alphacoronaviruses 222 (229e and nl63) were similar for all viruses between the ctl and hos-p groups. they were also similar 223 for hku-1, 229e and nl63 in the mis-p group, whereas abs to oc43 n were more frequent in the mis-224 p group (73%) than in the ctl group (39.4%), which was not paralleled by the anti-s response that was 225 near 100% in the two groups ( table 2) . patients. there was no significant difference between hos-p and ctl patients regarding antibody 233 levels to the four seasonal hcovs (figure 3) . this demonstrates that humoral responses between 234 seasonal coronaviruses and sars-cov-2 were not related. this is confirmed by the pca analysis which 235 showed that the patient groups (hos-p, mis-p and ctl) were only clustered by sars-cov-2 abs and 236 not by seasonal hcov abs. (figure 4 ). this suggests that the risk of sars-cov-2 infection and of related 237 mis disease were not influenced by prior seasonal hcov infection. in support to this observation, there 238 was an association, for each virus, between all s and n antibody titres within each of the three groups 239 of patients (ctl, hos-p and mis-p). this correlation was stronger for sars-cov-2 than for seasonal 240 hcovs. (supplemental figures s5 and s6 ) importantly, there was no significant association between 241 sars-cov-2 and seasonal hcov quantitative ab responses (supplemental figures s5 and s6) . mis-p 242 and hos-p groups did not differ for abs titers against seasonal hcovs, except for oc43-n abs that 243 were increased in mis-p children, but this tendency was not confirmed by the oc43-s ab response 244 ( figure 3a-b) . this was coherent with the abs prevalence study (table 2) . . 245 all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june 30, 2020. . this cross-sectional prospective multicentric study provides to the best of our knowledge the largest 248 report on covid-19 in the paediatric population outside of china. we enrolled nearly 800 children 249 during the first three months of the covid-19 epidemic in paris. from april to may, the prevalence 250 rate of abs against sars-cov-2 was in the range of 10-15%. we noticed an outlier peak of incidence 251 during the week of 11 may, which was likely associated with an increase of vigilance of physicians 252 following the information of severe clinical presentations in children. this prevalence rate is in 253 contrast with previous epidemiological cohort studies, based on rt-pcr, where children represent 254 less than 2% of diagnosed cases 24-23 . these numbers are compatible with the prevalence estimated in 255 paris 24 despite the specificity of the population of children recruited in university hospitals. here, in a 256 large cohort of children less than 15 years old, we demonstrate that (i) a substantial proportion of 257 children can become infected and (ii) the risk is not related to age. in nearly 15% of the cases, a contact 258 with a parent suspected of covid-19 was identified, which increased by 2·5 fold the risk to be infected. 259 very importantly, more than 50% of the seropositive children did not report any symptoms, a 260 proportion similar to that recently reported in adults 25 . the reminders reported mild and non-specific 261 symptoms such as headache, rhino-pharyngitis and shortness of breath. this confirms previously 262 published data showing that covid-19 is less severe in children than in adults 26 . the largest study in 263 children published so far that described sars-cov-2 infection in 2,143 chinese children also reported 264 asymptomatic infection or mild symptoms such as fever, cough, a sore throat, sneezing, myalgia and 265 fatigue 27 . altogether, these results and ours underline that most children remain undiagnosed 266 because of asymptomatic infections, which makes them potential drivers of virus spread 28 . 267 this is to our knowledge the first study profiling the humoral immune response in children 268 experiencing pauci-symptomatic infection by sars-cov-2. we showed that around half of sars-cov-269 2 positive sera present a significant neutralizing activity based on two independent assays (based on 270 lentivirus pseudo-typed with the sars-cov-2 spike or based on live virus). interestingly, this rate 271 all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june 30, 2020. . https://doi.org/10.1101/2020.06.29.20142596 doi: medrxiv preprint 13 increased up to 100% at the end of the observation period on mid-may, almost 2 months after the 272 peak of the epidemic. as reported by others 29 , this suggests that appearance of neutralizing antibodies 273 is delayed relative to initial seroconversion. this is in contrast to severe covid-19 forms 22,30 , where 274 neutralizing antibody responses against the immunodominant s viral protein are elicited as soon as 275 after two weeks of infection at higher frequency and titres. importantly, considering these data, it 276 must be underlined that quantitative correlates of protection are currently unknown, which makes it 277 difficult to relate the neutralizing titres to a clinically relevant effect. have an impact on sars-cov-2 replication. indeed, antibodies are unlikely to act as primary effectors 290 of protection, as there is no or very low 11 cross neutralization between these coronaviruses, but 291 antibodies serve as an indicator of underlying cellular responses. we found no evidence of cross-292 protective immunity linked to previous infection by seasonal hcovs. first, similar seasonal hcov 293 prevalence was found in sars-cov-2 positive versus negative patients. second, on a quantitative side, 294 there was no significant correlation between sars-cov-2 and any hcov antibody titres, whatever the 295 antigen considered (s or n). on the contrary, the level of sars-cov-2 antibodies to n and s were 296 correlated, which corresponds to a good internal control. this was also the case for the n and s 297 responses for each hcov, but to a lesser extent. we hypothesized that multiple infections by seasonal 298 all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june 30, 2020. . 14 hcovs would boost ab responses against shared epitopes that are more frequent in the nucleoprotein 299 than in the spike, and that this would lead to a decrease of correlation between n and s responses 300 over time. when analysing the s and n responses to hcovs, we found no obvious difference in n to s 301 correlations in ctl patients as compared to the hos-p group, suggesting that infection with sars-cov-302 2 did not significantly boost pre-existing antibody responses to hcovs n and s. 303 this lack of hcov/sars-cov-2 cross-protection contrasts with the recent demonstration of pre-304 existing immune effectors recognizing sars-cov-2 in subjects sampled before the sars-cov-2 305 pandemic. moreover, a very sensitive cytometric assay reported frequent low levels of cross-reacting 306 anti-s iggs, mainly targeting the sars-cov-2 s2 domain of the spike 11 . although those abs neutralized 307 entry of sars-cov-2 s-pseudo-typed lentiviruses in hek-293t cells mediated by the spike protein, the 308 clinical relevance of the sars-cov-2 pseudo-neutralisation test is questionable, because the 309 mechanism of entry did not involve the ace2 receptor of the virus. moreover, t-helper cells detected 310 in healthy subjects also recognized the c-terminal part of s (that contains the s2 subunit) but not the 311 receptor-binding domain (rbd) which belongs to s1 13 . in contrast, our results clearly show that cross-312 reactive antibodies directed against endemic seasonal hcovs and underlying cross-reacting cd4+ t-313 cells do not seem to confer any significant protection against sars-cov-2 infection. this could be 314 explained by low identity between coronaviruses of important targets such as the rbd. importantly, 315 this also suggests that potentially cross-reactive cd8+ t cells, which should be elicited upon seasonal 316 hcov infections as is the case following sars-cov-2 infection 39 , are not able to significantly contribute 317 to protection against sars-cov-2 infection. 318 we analysed the sars-cov-2 ab profile in 25 mis cases associated with a positive sars-cov-2 ab 319 response. we found higher s1 and n responses, but not an increased neutralizing capacity as 320 compared to hos-p patients who experienced an asymptomatic or pauci-symptomatic infection 321 (figure 2a) . this was not the case for the beta-(oc43) or alpha-(229e and nl63) coronaviruses ab 322 responses, suggesting that the increased sars-cov-2 response is not a non-specific feature triggered 323 by inflammation. furthermore, the lack of cross-reactivity between anti-s1 abs of the different 324 all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june 30, 2020. . viruses 40 does not favour the hypothesis of sars-cov-2 infection boosting pre-existing hcov immunity 325 in mis patients. as a whole, our data do not support that previous hcov infection facilitates cov-2 infection and mis-related disease. 327 neutralizing tests for the four seasonal hcovs were not available but some extrapolation can be done 328 based on sars-cov-2 neutralization and lips results, because equivalent lips tests were used for all 329 viruses. as the sars-cov-2 results show that up to 100% of lips positive sera sampled one to two 330 months post-infection had neutralizing activity, it can be anticipated that most hcov positive sera 331 would also neutralize corresponding hcovs. this means that, in a perspective of herd immunity, most 332 of the general population would have antibodies neutralizing seasonal hcovs, among other immune 333 effectors. as common colds due to seasonal hcovs are experienced repeatedly, this leads to 334 questioning whether coronavirus immune responses induce a long-term clinically protective response. 335 our results therefore pose a doubt regarding the humoral protective response against sars-cov-2 in 336 a perspective of herd immunity, even when the prevalence of antibodies will be high in the population. 337 the strengths of the study are the high number of well documented paediatric cases including mis 338 cases and the extensive exploration of ab responses to sars-cov-2, their neutralizing activity, and the 339 correlation with seasonal hcov immune responses. we acknowledge that infection rates are probably 340 biased in this cohort of hospitalized children, despite the fact that we focused as much as possible on 341 regular follow-up or covid-19 unrelated emergencies. in this cohort, we observed no correlation 342 between the ab responses against sars-cov-2 and seasonal hcovs. although cellular and local 343 immune defenses were not directly tested, our results do not provide evidence for cross-protective 344 immunity or facilitation linked to previous infections by seasonal hcovs on the risk of developing a 345 sars-cov-2 infection or a mis disease once infected. 346 in conclusion, our results show that 11.7 % of children admitted in parisian hospitals have abs against 347 sars-cov-2 and that these abs are able to neutralize sars-cov-2 in vitro. as seasonal hcovs circulate 348 efficiently in the human population despite very high antibody prevalence, our results point to the 349 limits of herd immunity applied to seasonal coronaviruses and maybe sars-cov-2. 350 all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june 30, 2020. . (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june 30, 2020. . and dr emeline roy who helped for data collection. we thank simon cauchemez for critical lecture of 375 the manuscript. 376 377 all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june 30, 2020. . (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june 30, 2020. coronaviridae study group of the international committee on taxonomy of viruses. the species 380 severe acute respiratory syndrome-related coronavirus: classifying 2019-ncov and naming it 381 sars-cov-2 2 cdc covid-19 response team. coronavirus disease 2019 in children -united states sars-cov-2 infection in children epidemiology of covid-19 among children in china characteristics of and important lessons from the coronavirus disease 389 2019 (covid-19) outbreak in china: summary of a report of 72 314 cases from the chinese 390 center for disease control and prevention epidemiology and clinical features of coronavirus 393 disease 2019 in children an analysis of sars-cov-2 viral load by patient age clinical characteristics of coronavirus disease 2019 in china cluster of coronavirus disease 2019 (covid-19) in the french 399 first infection by all four non-severe acute respiratory 401 syndrome human coronaviruses takes place during childhood pre-existing and <em>de novo</em> humoral immunity to 403 sars-cov-2 in humans targets of t cell responses to sars-cov-2 coronavirus in 405 humans with covid-19 disease and unexposed individuals presence of sars-cov-2 reactive t cells in covid-19 patients 408 and healthy donors an outbreak of severe kawasaki-like disease at the italian 410 epicentre of the sars-cov-2 epidemic: an observational cohort study acute heart failure in multisystem inflammatory syndrome in 413 children (mis-c) in the context of global sars-cov-2 pandemic antibody-dependent enhancement of viral infection: molecular 416 mechanisms and in vivo implications hyperinflammatory shock 418 in children during covid-19 pandemic kawasaki-like multisystem inflammatory syndrome in 421 children during the covid-19 pandemic in paris, france: prospective observational study an insertion unique to sars-cov-2 exhibits 424 superantigenic character strengthened by recent mutations 20 case definition for coronavirus disease 2019 (covid-19), as of 29 diagnosis, treatment, and long-term 429 management of kawasaki disease: a scientific statement for health professionals from the 430 sars-cov-2 serological analysis of covid-19 hospitalized 432 patients, pauci-symptomatic individuals and blood donors spread of sars-cov-2 in the icelandic population estimating the burden of sars-cov-2 in france prevalence of asymptomatic sars-cov-2 infection systematic review of covid-19 in children shows milder cases and a better 440 prognosis than adults an interactive web-based dashboard to track covid-19 in real time a well infant with coronavirus disease 2019 (covid-19) with high 444 viral load serologic responses to sars-cov-2 infection among 446 hospital staff with mild disease in eastern france cross-sectional evaluation of humoral responses 448 against sars-cov-2 spike intrafamilial exposure to sars-cov-2 induces cellular 450 immune response without seroconversion human coronavirus nl63 and 229e seroconversion in 452 children a prospective hospital-based study of the clinical impact of 454 non-severe acute respiratory syndrome (non-sars)-related human coronavirus infection update on rhinovirus and coronavirus infections genetic recombination, and pathogenesis of 459 coronaviruses a systematic review of antibody mediated 461 immunity to coronaviruses: antibody kinetics, correlates of protection, and association of 462 antibody responses with severity of disease development of a nucleocapsid-based human 464 coronavirus immunoassay and estimates of individuals exposed to coronavirus in a human coronavirus nl63, a new respiratory virus broad and strong memory cd4 + and cd8 + t cells induced by sars-469 cov-2 in uk convalescent covid-19 patients analysis of serologic cross-reactivity between common human 471 coronaviruses and sars-cov-2 using coronavirus antigen microarray no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity.the copyright holder for this preprint this version posted june 30, 2020. . https://doi.org/10.1101/2020.06.29.20142596 doi: medrxiv preprint key: cord-314662-nem6dw34 authors: nakra, natasha a.; blumberg, dean a.; herrera-guerra, angel; lakshminrusimha, satyan title: multi-system inflammatory syndrome in children (mis-c) following sars-cov-2 infection: review of clinical presentation, hypothetical pathogenesis, and proposed management date: 2020-07-01 journal: children (basel) doi: 10.3390/children7070069 sha: doc_id: 314662 cord_uid: nem6dw34 severe acute respiratory syndrome coronavirus 2 (sars-cov-2) infection may result in the multisystem inflammatory syndrome in children (mis-c). the clinical presentation of mis-c includes fever, severe illness, and the involvement of two or more organ systems, in combination with laboratory evidence of inflammation and laboratory or epidemiologic evidence of sars-cov-2 infection. some features of mis-c resemble kawasaki disease, toxic shock syndrome, and secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome. the relationship of mis-c to sars-cov-2 infection suggests that the pathogenesis involves post-infectious immune dysregulation. patients with mis-c should ideally be managed in a pediatric intensive care environment since rapid clinical deterioration may occur. specific immunomodulatory therapy depends on the clinical presentation. the relationship between the immune response to sars-cov-2 vaccines in development and mis-c requires further study. severe acute respiratory syndrome coronavirus 2 (sars-cov-2) infection has rapidly spread worldwide since it was first identified in china in late 2019, with subsequent epicenters being recognized in europe and the u.s. previous reports of sars-cov-2 infection indicated that young children were disproportionately spared from infection [1, 2] , although it remains unclear if this is due to a lack of detection because of predominantly asymptomatic or mild disease in this age group. in the latter half of april 2020, a novel syndrome in children and adolescents termed "multisystem inflammatory syndrome in children" (mis-c) with likely relation to sars-cov-2 infection was first described. initial reports surfaced in the uk [3] and italy [4] , followed by new york and other parts of the u.s. preliminary accounts of the features of this syndrome resemble those of known entities such as kawasaki disease (kd), toxic shock syndrome (tss), and secondary hemophagocytic lymphohistiocytosis (shlh)/macrophage activation syndrome (mas). here we review the preliminary (1) an individual aged < 21 years with: (2) clinical criteria: • a minimum 24-h history of subjective or objective fever ≥ 38.0°c and • severe illness necessitating hospitalization and • two or more organ systems affected (i.e., cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic, neurological) data regarding the clinical presentation and epidemiologic characteristics of children with mis-c are still limited and evolving daily. in a case series from the uk [3] , italy [4] , france, and data regarding the clinical presentation and epidemiologic characteristics of children with mis-c are still limited and evolving daily. in a case series from the uk [3] , italy [4] , france, and switzerland [6, 7] , the ages of affected children (n = 70) ranged from 2-16 years, and the majority did not have underlying comorbidities. most had fever present for ≥4 days, and common presenting symptoms included gastrointestinal symptoms (59/70 = 84%), including vomiting, abdominal pain, and/or diarrhea; mucocutaneous symptoms reminiscent of kd, including conjunctivitis and rash; and neurologic findings including headache, irritability, and encephalopathy. a few children presented with an acute surgical abdomen and underwent exploratory laparotomy, with intra-operative findings of mesenteric lymphadenitis and peritonitis. several children developed hypotension (52/70 = 74%) requiring admission to pediatric intensive care unit (picu) and inotropic support, and some required non-invasive or invasive mechanical ventilation due to respiratory distress from cardiac dysfunction. a minority of children (11/70 = 16%) were placed on extra-corporeal membrane oxygen (ecmo) support. echocardiography demonstrated depressed cardiac ventricular function in the majority of patients, but they were less commonly reported to have valvular regurgitation, dilated coronary arteries (11/70 = 16%). or frank coronary artery aneurysms (caas) (3/70 = 4%). universally, laboratory testing revealed the significant elevation of inflammatory markers, such as c-reactive protein (crp), erythrocyte sedimentation rate (esr), procalcitonin, and/or ferritin. other common findings included hyponatremia, acute kidney injury, and hypoalbuminemia, and several patients had serous effusions (pleural, pericardial, and peritoneal), suggestive of generalized inflammation. troponin levels were elevated in many patients (57/70, 81%), and pro-b-type natriuretic peptide (probnp) levels were markedly elevated in most (59/65 = 70%), suggesting myocardial damage and heart failure, respectively. hematologic abnormalities reported included neutrophilia, lymphopenia, low to normal platelet levels, elevated d-dimer, and low fibrinogen. thrombotic events were not reported. the majority of affected children were treated with intravenous immune globulin (ivig), and several also received adjunctive high-dose steroids. most responded favorably to therapy with an improvement in vital signs and cardiac dysfunction, and only a few children required additional therapies, such as anakinra (recombinant il-1β antagonist) or a second dose of ivig. one child in the uk cohort was reported to develop a giant caa after discharge from the initial hospitalization. overall mortality has been low, with a single death in the uk cohort (due to a cerebrovascular accident while on ecmo), and three reported deaths in new york city (ny times) [8] . of note, a case report from the u.s. described a six-month infant with positive sars-cov-2 reverse transcriptase polymerase chain reaction (rt-pcr) testing from a nasopharyngeal swab who met the classical criteria for kd without evidence of multisystem involvement [9] . she was treated with ivig and high dose aspirin, as per kd guidelines, and quickly defervesced with the resolution of stigmata of kd. at this time, it is unclear if mis-c with kd features is different from kd. a positive sars-cov-2 test does not necessarily indicate causality and could represent coincident infection [10] . epidemiologic evidence implicates sars-cov-2 as the likely cause of the newly recognized mis-c, although causality has not yet been established ( figure 2 ). the emergence of clusters of cases in locations that have been heavily impacted by covid-19, such as italy, the uk, and new york city, is highly suggestive of a link to infection with sars-cov-2. the case series from bergamo, italy, a region with a high incidence of covid-19 disease, described a 30-fold increase in the monthly incidence of kd cases between 18 february 2020 and 20 april 2020 in comparison to the previous 5 years [4] . on 13 may 2020, the new york state department of health (nysdoh) reported 102 probable cases of mis-c in new york hospitals, following the peak of covid-19 infection in early april [11] . interestingly, the cluster of mis-c cases in these communities lags behind the peak covid-19 incidence among adults by approximately one month. the fact that mis-c was not identified in china and other asian countries affected by covid-19 has led to speculation regarding variations in the virus affecting areas with mis-c cases or an increased susceptibility or genomic variation of these populations, although this is currently conjectural. the majority of published cases have had positive serologic testing for sars-cov-2 (60/69, 87%) and less commonly positive rt-pcr testing from nasopharyngeal testing (23/70, 32%), suggesting that this syndrome may be post-infectious rather than related to acute early infection (stage ifigure 2 ). it is uncertain if broncho-alveolar lavage (bal) sampling would increase the yield of detection in mis-c. in adults with severe respiratory failure from sars-cov-2 infection, who typically experience clinical deterioration about 1 week following illness onset, a dysregulated immune system is thought to drive disease manifestations, as opposed to direct cellular injury from viral infection (stage ii-pulmonary phase). children appear to have less severe pulmonary manifestations compared to adults, possibly due to lower gene expression of the angiotensin converting enzyme (ace)-2 receptor (the target of sars-cov-2) [12, 13] . immune dysregulation in adults with respiratory disease is characterized by lymphopenia (specifically nk cells, cd4 t lymphocytes and b lymphocytes) and sustained production of pro-inflammatory cytokines, such as tumor necrosis factor (tnf)-α and interleukin (il)-6 [14] . this immune dysregulation has been the basis of immunomodulatory therapies for adults with severe sars-cov-2 infection, such as tocilizumab, a humanized monoclonal antibody against the il-6 receptor. in kd, a systemic hyper-inflammatory state is characterized by elevated levels of tnf, il-6, il-1β, il-17, and granulocyte colony stimulating factor (g-csf) [15] . we speculate that mis-c is a delayed immunological phenomenon associated with inflammation (stage iii-hyperinflammation phase) following either symptomatic or asymptomatic covid-19 infection. children 2020, 7, x for peer review 4 of 14 that this syndrome may be post-infectious rather than related to acute early infection (stage ifigure 2 ). it is uncertain if broncho-alveolar lavage (bal) sampling would increase the yield of detection in mis-c. in adults with severe respiratory failure from sars-cov-2 infection, who typically experience clinical deterioration about 1 week following illness onset, a dysregulated immune system is thought to drive disease manifestations, as opposed to direct cellular injury from viral infection (stage iipulmonary phase). children appear to have less severe pulmonary manifestations compared to adults, possibly due to lower gene expression of the angiotensin converting enzyme (ace)-2 receptor (the target of sars-cov-2) [12, 13] . immune dysregulation in adults with respiratory disease is characterized by lymphopenia (specifically nk cells, cd4 t lymphocytes and b lymphocytes) and sustained production of pro-inflammatory cytokines, such as tumor necrosis factor (tnf)-α and interleukin (il)-6 [14] . this immune dysregulation has been the basis of immunomodulatory therapies for adults with severe sars-cov-2 infection, such as tocilizumab, a humanized monoclonal antibody against the il-6 receptor. in kd, a systemic hyper-inflammatory state is characterized by elevated levels of tnf, il-6, il-1β, il-17, and granulocyte colony stimulating factor (g-csf) [15] . we speculate that mis-c is a delayed immunological phenomenon associated with inflammation (stage iii-hyperinflammation phase) following either symptomatic or asymptomatic covid-19 infection. early infection (phase i) with sars-cov-2 is likely to be asymptomatic or mildly symptomatic in children. the pulmonary phase (phase ii) is severe in adults but is mild or absent in many children. the early infection appears to trigger macrophage activation followed by the stimulation of t-helper cells. this in turn leads to cytokine release, the stimulation of macrophages, neutrophils, and monocytes, along with b-cell and plasma cell activation with the production of antibodies leading to a hyperimmune response (stage iii). this immune dysregulation is associated with the inflammatory syndrome in affected children. direct infection with sars-cov-2 is less likely to play a role in mis-c. ace2-angiotensin converting enzyme 2 receptors; tnf-βtumor necrosis factor β; il-interleukins. similarities between patients with mis-c and other well-defined syndromes, including kd, tss, and shlh/mas, allow for hypotheses to be made regarding pathogenesis and may help guide treatment. table 1 compares common clinical and laboratory findings between mis-c, kd, and tss. early infection (phase i) with sars-cov-2 is likely to be asymptomatic or mildly symptomatic in children. the pulmonary phase (phase ii) is severe in adults but is mild or absent in many children. the early infection appears to trigger macrophage activation followed by the stimulation of t-helper cells. this in turn leads to cytokine release, the stimulation of macrophages, neutrophils, and monocytes, along with b-cell and plasma cell activation with the production of antibodies leading to a hyperimmune response (stage iii). this immune dysregulation is associated with the inflammatory syndrome in affected children. direct infection with sars-cov-2 is less likely to play a role in mis-c. ace2-angiotensin converting enzyme 2 receptors; tnf-β-tumor necrosis factor β; il-interleukins. similarities between patients with mis-c and other well-defined syndromes, including kd, tss, and shlh/mas, allow for hypotheses to be made regarding pathogenesis and may help guide treatment. table 1 compares common clinical and laboratory findings between mis-c, kd, and tss. abbreviations: +, generally present; ++, almost always present; −, generally absent; ±, may be present or absent; ↑ increased; ↑↑, highly increased; ↓ decreased; alt, alanine transaminase; pro-bnp, pro-b-type natriuretic peptide; crp, c-reactive protein; id, insufficient data; kd, kawasaki disease; kdss, kawasaki disease shock syndrome; m, months; mis-c, multisystem inflammatory syndrome in children; pt/ptt, prothrombin time and partial thromboplastin time; tss, toxic shock syndrome; wbc, white blood cell count; y, years. kd is an acute medium-vessel vasculitis with a predilection for coronary arteries that occurs more commonly in young children; it is the most common cause of acquired heart disease in childhood in developed countries [16] . the kd defining features include rash, cervical lymph node enlargement, and ocular and oral mucosal changes, although the involvement of other organs, such as the liver, lungs, gastrointestinal tract, the central nervous system, and joints is widely recognized. similar to mis-c, laboratory markers of inflammation, such as crp, are increased. hematologic abnormalities are slightly different, as patients with kd tend to have leukocytosis with neutrophil predominance and thrombocytosis. thrombocytopenia has been described in kd but is rare. the cardiac findings in mis-c also are divergent from kd, as mis-c patients are much more likely to exhibit cardiac dysfunction and hypotension, as opposed to coronary artery abnormalities [17] . despite extensive efforts to identify the triggers for the inflammatory cascade in kd, the etiologic agent remains elusive. however, there is evidence that viral infections may elicit an inflammatory response in genetically predisposed children [18] . a viral trigger seems likely based on the typical occurrence of cases during winter and spring when respiratory viruses are circulating, as well as the young age of affected children, who are susceptible due to a lack of pre-existing immunity. previous studies have attempted to implicate other human coronaviruses as the etiology of kd [19] , but further studies did not confirm this association. the management of children with kd includes the administration of intravenous immune globulin (ivig), treatment with high-dose aspirin, and occasionally the use of other immune-modulating drugs. the mechanism of ivig is unclear, and may include immunomodulatory effects on t regulatory cells [20] . the treatment of children with kd has decreased the risk of caas from 25% to 4% [16] . a subset of children (<5%) with kd will present with shock/hypotension resembling bacterial sepsis. as compared to other children with kd, patients with "kawasaki disease shock syndrome" (kdss) have higher band counts, lower platelet counts, lower hemoglobin levels, and higher c-reactive protein levels [21] . they are also more likely to have coronary artery dilation and abnormalities of cardiac ventricular function [22] . the treatment approach to patients with kd and kdss is similar, although patients with kdss have higher rates of treatment failure with first-line therapies [23] . this subset of kd patients has several similarities to the newly described mis-c. tss is a unique syndrome secondary to the uncontrolled activation of the immune system by "superantigens", proteins that non-selectively stimulate t cells, resulting in massive cytokine release. bacterial species, such as staphylococcus aureus and streptococcus pyogenes, are known to produce exotoxins that can function as superantigens, although viruses can also act as superantigens. interestingly, prior research done on sars-cov-1 indicated that the viral structure included motifs consistent with superantigens [24] . the clinical presentation of toxic shock syndrome includes hypotension, diffuse erythrodermic rash, mucous membrane involvement, and multisystem organ dysfunction (renal, hepatic, hematologic, respiratory, muscular, and neurologic) [25] . typical treatment for tss includes volume resuscitation, treatment with anti-microbial agents directed against the inciting infection, and occasionally the use of ivig for patients with refractory hypotension [26] . the proposed mechanisms of ivig in patients with tss include the neutralization of bacterial superantigens and the downregulation of the overactive immune response. tss can resemble kdss, but patients with tss tend to be older than those with kdss (9 ± 4.6 years vs. 3 ± 3.4 years, respectively) [27] and are more likely to have normal hemoglobin, a lower platelet count, and elevated creatinine compared with kdss patients. patients with kdss are more likely to exhibit coronary artery changes, valvulitis, and impaired cardiac ventricular function on echocardiogram as compared with tss [27] . hemophagocytic lymphohistiocytosis (hlh) is characterized by a robust immune response that is unabated and self-perpetuated. primary hlh is secondary to anomalies in genes that regulate the degranulation of natural killer cells and cytotoxic cd8+ lymphocytes. this results in the inability to eliminate the antigenic stimuli that led to cellular activation, leading to a "cytokine storm" [28, 29] . elevated levels of pro-inflammatory cytokines, such as interferon (ifn)-gamma, il-18, and il-1, subsequently activate other cells of the immune system (i.e., macrophages) leading to organ damage and the characteristic hemophagocytosis of affected organs [29] . hlh is considered secondary when it is triggered by an autoimmune or autoinflammatory condition (referred to as mas in this context), medications, malignancy, or infections. regarding the latter, viral infections are well-known triggers of shlh [30, 31] . kd has also been associated with the development of mas [32] . notably, some patients that are thought to have shlh are found to have mutations seen in primary hlh, so the distinction between primary and secondary hlh may be blurred [33] . although not pathognomonic, the presence of hyperferritinemia (>500 ng/ml) should alert a physician to the possible presence of shlh/mas, especially in the presence of fever [34, 35] . patients with shlh typically have evidence of systemic inflammation with elevated levels of crp, triglycerides, and d-dimer, as well as organ dysfunction, such as coagulopathy, liver failure, cns dysfunction, and cardiac dysfunction. notably, the peripheral white blood cell count, platelet count, and esr tend to be depressed in shlh [29, 34] . mortality is high in untreated shlh. although not designed for infection-related shlh, the criteria for primary hlh (table 2) [36] or mas in systemic juvenile idiopathic arthritis [37] may aid in the diagnosis of shlh. it is important to note that the primary hlh criteria have low sensitivity for mas [38] and this may be true for infection-associated shlh as well. additionally, the absence of hemophagocytosis in a bone marrow aspirate does not rule out the diagnosis. [36] . molecular diagnosis consistent with hlh 2. diagnostic criteria fulfilled by meeting five out of the eight criteria below a. fever b. splenomegaly c. cytopenias affecting two out of three blood lineages in peripheral blood hemoglobin < 90 g/l (in infants < 4 weeks: hemoglobin < 100 g/l) platelets < 100 × 10 9 /l neutrophils < 1.0 × 10 9 /l d. hypertriglyceridemia and/or hypofibrinogenemia: fasting triglycerides ≥ 3.0 mmol/l (i.e., ≥265 mg/dl) fibrinogen ≤ 1.5 g/l e. hemophagocytosis in bone marrow or spleen or lymph nodes and no malignancy f. low or absent nk cell activity (according to local laboratory reference) g. ferritin ≥ 500 mg/l h. soluble cd25 (i.e., soluble il-2 receptor) > 2400 u/ml abbreviations: dl, deciliter; g, grams; il, interleukin; l, liter; mg, milligrams; ml, milliliter; mmol, millimoles; u, units. patients with mis-c may quickly progress to critical illness and hypotension. therefore, they should be managed in a center with pediatric intensive care capabilities. laboratory evaluation for generalized inflammation, multisystem involvement, and possible infection is appropriate (box 2). particular attention should be paid to the monitoring of cardiac function, respiratory status, neurologic status, and renal function. depending on organ system involvement, the early consultation of specialists from pediatric intensive care, cardiology, rheumatology, infectious disease, immunology, and neurology should be considered. box 2. proposed approach to children presenting with signs concerning for mis-c. consider observation in unit with cardio-respiratory monitoring capabilities 2. laboratory evaluation a. complete blood count with differential b. blood chemistry, including bun and creatinine c. liver function tests (alt, ast, albumin, bilirubin) d. cardiac markers: troponin and pro-bnp e. urinalysis with culture if indicated f. blood gas with lactate g. markers of inflammation: esr, crp, procalcitonin, ferritin, triglycerides, il-6 if available h. coagulation panel: pt, ptt, fibrinogen, d-dimer i. creatinine kinase, lactate dehydrogenase j. blood culture k. serology for sars-cov-2 l. np swab or lower respiratory tract sample for sars-cov-2 by rt-pcr; consider sending from stool if presenting with gi symptoms m. additional studies as indicated: respiratory pathogen panel from np swab or lower respiratory tract, stool studies/cultures, viral blood pcrs or serologies to rule out other causes of myocarditis, genetic testing for hlh, soluble il-2 receptor, nk cell function 3. imaging: a. chest x-ray b. abdominal ultrasound or ct scan if concerning symptoms/physical findings 4. twelve-lead electrocardiogram (ekg) 5. echocardiogram (transthoracic) 6. early consultation of specialists to assist in management, such as intensive care, cardiology, rheumatology, infectious diseases, allergy/immunology, neurology abbreviations: alt, alanine transaminase; ast, aspartate transaminase; pro-bnp, pro-b-type natriuretic peptide; bun, blood urea nitrogen; crp, c-reactive protein; ct, computed tomography; esr, erythrocyte sedimentation rate; gi, gastrointestinal; hlh, hemophagocytic lymphohistiocytosis; il, interleukin; mis-c, multisystem inflammatory syndrome in children; nk, natural killer; np, nasopharyngeal; pt, prothrombin time; ptt, partial thromboplastin time; rt-pcr, reverse transcriptase polymerase chain reaction; sars-cov-2, severe acute respiratory syndrome coronavirus 2. of note, in the absence of a positive test for sars-cov-2 or a positive epidemiological exposure, we suggest the consideration of alternative diagnoses. serology can be repeated 2-4 weeks later, and if results are negative but suspicion remains high, serology can be repeated using a different assay. the testing of household contacts can also reveal evidence of exposure. the goals of treatment for mis-c are to decrease systemic inflammation and restore organ function, in order to decrease mortality and reduce the risk of long-term sequelae, such as the development of caas or persistent cardiac dysfunction. treatment should be dictated by phenotype until new research provides clear guidelines. given the novelty of this syndrome, the following recommendations are based on extrapolation from other syndromes and constitute the opinion of the authors (see table 3 for detailed dosing of medications). all patients meeting the criteria for kd should be treated as per published guidelines. first-line therapy for kd includes treatment with high-dose ivig and aspirin. given the highly favorable results in early case series of children with mis-c who received ivig, we would also recommend the consideration of ivig for patients with mis-c who do not meet kd criteria for possible beneficial immunomodulatory effects, analogous to its use in tss. corticosteroid treatment is a commonly used adjunctive therapy to ivig for treatment of kd. in japan, scoring systems such as the kobayashi score predict a high risk of ivig resistance and have been used to inform decisions about who should receive steroids concomitantly with ivig [41] . this approach has been shown to decrease the risk of coronary abnormalities in high-risk children, and could be helpful in to inform treatment decisions in mis-c [42, 43] . per kd guidelines from the european initiative single hub and access point for paediatric rheumatology in europe (share) [39] , corticosteroids should be considered for children with features of severe kd, defined by fever or persistent inflammation ≥ 48 h after ivig, kobayashi score ≥ 5, features of shlh (i.e., ferritin > 500 ng/ml), shock, age < 1 year, or coronary or peripheral aneurysms at the time of diagnosis. therapy with anakinra may be considered for patients with kd-like disease who are refractory to first-line therapy with ivig (with or without the addition of corticosteroids) [44] . tocilizumab is an il-6 inhibitor that has been used in the setting of refractory kd, although one report demonstrated the rapid development of caas in two out of four patients following therapy, suggesting caution be used with this agent in patients with kd [45] . it is important to note that the evidence for this association is weak and contradicts the favorable results obtained with tocilizumab in the treatment of large cell vasculitis in adults [46] . for the management of mis-c with features of shlh involvement, the consultation of pediatric rheumatology, immunology, or hematology/oncology is highly recommended. for initial treatment, we suggest following the cytokine storm treatment pathway described by halyabar et al. [28, 34] with anakinra and ivig. tocilizumab (il-6 inhibitor) has been studied for the treatment of covid-19 infection in adults in an uncontrolled study [47] . although no conclusions can be made from this study regarding the efficacy of tocilizumab in covid-19 pneumonia, the survival rates reported are encouraging and suggest that tocilizumab is at least safe in severe covid-19 infection. we consider that tocilizumab may also be substituted for anakinra in mis-c with shlh features, especially in the setting of active sars-cov-2 infection. for severe disease, the addition of pulsed corticosteroids and other immunosuppressive agents, such as cyclosporine and tacrolimus, may be considered. if mis-c is truly a post-infectious process, the immunosuppressive effects of therapy would not risk the flare of infection, as the infection is resolved. however, in the case of active sars-cov-2 infection, there is the theoretical possibility that immunomodulatory treatment could worsen the infection. anakinra has been proven to be effective and safe for the treatment of sepsis with features of shlh [48] . regarding the safety of steroids in the setting of active covid-19 infection (sars-cov-2 rt-pcr positive), no conclusions can be made with the currently available evidence; steroids or other immunosuppressive agents may be warranted for particular cases. pulsing with a lower dose of methylprednisolone (10 mg/kg/dose) may be an alternative for severe shlh. for some children with short duration of fever (<4 days) who are not critically ill and do not exhibit multi-system involvement, initial evaluation in the ambulatory setting may be considered. a preliminary laboratory workup, including complete blood count with differential, liver function tests, electrolytes, crp, esr, urinalysis, and sars-cov-2 nasopharyngeal pcr and serology can be helpful to decide whether further evaluation or hospitalization is necessary. evaluation for other causes of fever as appropriate based on symptomatology (i.e., respiratory viruses, streptococcal pharyngitis) should be undertaken. for children with persistent fever or new symptoms, repeat clinical evaluation and laboratory testing should be performed in the ambulatory or emergency department (ed) setting every 24 h. referral to a hospital providing specialty pediatric care should be strongly considered for abnormal laboratory values or changes in clinical status. antiviral therapy with remdesivir, a nucleotide analogue with in vitro activity against sars-cov-2 [49] , may be considered for sars-cov-2 rt-pcr positive patients. it is not likely to be of benefit for patients who are pcr negative, as studies have shown its benefit is greatest when administered early in disease [50] . initial treatment with broad antimicrobials is appropriate, given that many of these patients present with clinical features and laboratory findings consistent with bacterial sepsis. however, we recommend that antimicrobial treatment be discontinued once a patient is recognized to have mis-c and bacterial cultures are negative. elucidating the pathogenesis of mis-c will be critical to inform rational management strategies and possible preemptive measures. more robust clinical data will be useful in determining risk factors for the development of mis-c, as well as prognosis. the follow up of mis-c patients is imperative for determining possible sequelae. immunologic studies involving serial measurements of both cell-mediated and cytokine immune responses will provide insight into pathogenesis. the creation of a registry of mis-c patients may be the most expedient manner to compile this information. genetic studies will be vital to our understanding of why some children with sars-cov-2 infection ultimately develop mis-c. of note, a widespread sars-cov-2 vaccine use could theoretically predispose to mis-c, given that this is likely an immune-mediated phenomenon. the risk of mis-c will depend on the qualities of the immune response achieved, for example, whether the th1 or th2 response is predominant [51] . as an example, initial attempts at a respiratory syncytial virus vaccine found that a formalin-inactivated vaccine candidate resulted in enhanced pulmonary disease after subsequent infection [52] . some deaths were attributed to an intense th2 vaccine response which resulted in profuse pulmonary inflammation and subsequent parenchymal tissue damage. this has implications for vaccine development, especially in the selection of adjuvants to generate the intended immune response [53] . an additional concern related to mis-c and immunization is the effect of mutations in circulating sars-cov-2 strains [54] and whether heterotypic immunologic responses may result in severe immunologic manifestations after subsequent infection, similar to concerns regarding dengue vaccines [55] . the close monitoring of mis-c incidence will be required, as immunization trials are carried out in children. the hope is that a fully effective vaccine will preempt mis-c. based on initial reports from china, it was thought that children have a low incidence of symptomatic infection. however, the increased prevalence of mis-c suggests a delayed hyperimmune response to sars-cov-2 infection. the exact incidence of mis-c following an asymptomatic or mildly symptomatic infection with sars-cov-2 is not known. further studies evaluating the predisposing factors and pathogenesis of mis-c are warranted to appropriately prevent and optimally manage this condition. the authors declare no conflict of interest. cdc covid-19 response team. coronavirus disease 2019 in children-united states children with covid-19 in pediatric emergency departments in italy hyperinflammatory shock in children during covid-19 pandemic an outbreak of severe kawasaki-like disease at the italian epicentre of the sars-cov-2 epidemic: an observational cohort study cdc health alert network. mulitsystem inflammatory syndrome in children 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authors: lima, rosiane; gootkind, elizabeth f.; de la flor, denis; yockey, laura j.; bordt, evan a.; d’avino, paolo; ning, shen; heath, katerina; harding, katherine; zois, jaclyn; park, grace; hardcastle, margot; grinke, kathleen a.; grimmel, sheila; davidson, susan p.; forde, pamela j.; hall, kathryn e.; neilan, anne m.; matute, juan d.; lerou, paul h.; fasano, alessio; shui, jessica e.; edlow, andrea g.; yonker, lael m. title: establishment of a pediatric covid-19 biorepository: unique considerations and opportunities for studying the impact of the covid-19 pandemic on children date: 2020-09-11 journal: bmc med res methodol doi: 10.1186/s12874-020-01110-y sha: doc_id: 274834 cord_uid: 24v2b509 background: covid-19, the disease caused by the highly infectious and transmissible coronavirus sars-cov-2, has quickly become a morbid global pandemic. although the impact of sars-cov-2 infection in children is less clinically apparent, collecting high-quality biospecimens from infants, children, and adolescents in a standardized manner during the covid-19 pandemic is essential to establish a biologic understanding of the disease in the pediatric population. this biorepository enables pediatric centers world-wide to collect samples uniformly to drive forward our understanding of covid-19 by addressing specific pediatric and neonatal covid-19-related questions. methods: a covid-19 biospecimen collection study was implemented with strategic enrollment guidelines to include patients seen in urgent care clinics and hospital settings, neonates born to sars-cov-2 infected mothers, and asymptomatic children. the methodology described here, details the importance of establishing collaborations between the clinical and research teams to harmonize protocols for patient recruitment and sample collection, processing and storage. it also details modifications required for biobanking during a surge of the covid-19 pandemic. results: considerations and challenges facing enrollment of neonatal and pediatric cohorts are described. a roadmap is laid out for successful collection, processing, storage and database management of multiple pediatric samples such as blood, nasopharyngeal and oropharyngeal swabs, sputum, saliva, tracheal aspirates, stool, and urine. using this methodology, we enrolled 327 participants, who provided a total of 972 biospecimens. conclusions: pediatric biospecimens will be key in answering questions relating to viral transmission by children, differences between pediatric and adult viral susceptibility and immune responses, the impact of maternal sars-cov-2 infection on fetal development, and factors driving the multisystem inflammatory syndrome in children. the specimens in this biorepository will allow necessary comparative studies between children and adults, help determine the accuracy of current pediatric viral testing techniques, in addition to, understanding neonatal exposure to sars-cov-2 infection and disease abnormalities. the successful establishment of a pediatric biorepository is critical to provide insight into disease pathogenesis, and subsequently, develop future treatment and vaccination strategies. conclusions: pediatric biospecimens will be key in answering questions relating to viral transmission by children, differences between pediatric and adult viral susceptibility and immune responses, the impact of maternal sars-cov-2 infection on fetal development, and factors driving the multisystem inflammatory syndrome in children. the specimens in this biorepository will allow necessary comparative studies between children and adults, help determine the accuracy of current pediatric viral testing techniques, in addition to, understanding neonatal exposure to sars-cov-2 infection and disease abnormalities. the successful establishment of a pediatric biorepository is critical to provide insight into disease pathogenesis, and subsequently, develop future treatment and vaccination strategies. keywords: covid-19, sars-cov-2, multisystem inflammatory syndrome in children (mis-c), viral transmission, viral susceptibility, biorepository, biobank, pediatric the global pandemic of covid-19, caused by the highly infectious and transmissible coronavirus, sars-cov-2, has become a leading cause of death in older adults [1] . while adults can develop life-threatening complications such as pneumonia, acute respiratory distress syndrome (ards), and sepsis from sars-cov-2 infection, its impact on children is less clinically apparent and needs to be studied. collecting high-quality biospecimens from infants, children and adolescents in a standardized manner during the covid-19 pandemic is essential for understanding the biologic consequences of sars-cov-2 infection in children. specific questions that must be addressed revolve around the role children play in viral transmission, differences in pediatric viral susceptibility and immune responses, which could guide potential therapies for adults, the impact of maternal sars-cov-2 infection on fetal development, and factors driving the development of severe hyperinflammatory shock and cardiac damage seen in multisystem inflammatory syndrome in children (mis-c). outlined here is a roadmap for establishing a biorepository of specimens obtained from infants, children and adolescents during the covid-19 pandemic. special attention is provided to pediatric-specific considerations in the establishment of a biorepository during the covid-19 pandemic. the goal is to enable pediatric centers world-wide to collect samples in a standardized manner to drive forward our understanding of covid-19. the impact of sars-cov-2 infection on infants and children is not well-defined. children are typically asymptomatic or mildly symptomatic during the acute infection, although some can develop significant complications requiring intensive care. in order to capture the full range of sars-cov-2 infection in the pediatric population, a covid-19 biospecimen collection study was designed and implemented, including patients seen in urgent care clinics and hospital settings, neonates born to sars-cov-2-infected mothers, and asymptomatic children. each study population required specific tailoring of study conduct to effectively and efficiently collect critical samples. cornerstones of the biorepository included open dialogue between research and clinical team members, a sensitivity to procedures required for specimen collection in children, and clear documentation of study participation and sample collection. close communication and collaborations with the adult covid-19 biorepository enable paralleled recruitment efforts and processing procedures and ensured consistency and harmonization across patient cohorts, facilitating high-quality comparisons between patient groups and with adult cohorts. central to the operation, physician-scientists in pediatrics, neonatology, medicine-pediatrics, and obstetrics-gynecology harmonized sample collection protocols, established clinical connections and provided clinical and scientific context to covid-19-related research in the neonatal and pediatric population. to establish a pediatric covid-19 biorepository during the surge of covid-19 cases locally, protocols were rapidly submitted to our institutional biosafety committee (ibc, mgh ibc#2020b000061) and the institutional review board (irb, mgh irb#2020p000955) for approval. during this initial wave of the covid-19 pandemic in late march 2020, covid-19 research proposals were prioritized by the ibc and irb. a biosafety protocol was submitted to the ibc to transition from a biosafety level 2 (bsl2) to an enhanced bsl2+ laboratory environment, allowing collection, processing, and storage of sars-cov-2-infected samples. ibc approval was obtained within 2 weeks. an expedited irb review facilitated irb approval 2 days following submission. figure 1 displays a timeline of study activity relative to the community surge of covid-19 cases in massachusetts. eligible participants in all cohorts were identified by screening outpatient clinic schedules or hospital admission lists, then discussing potential patients with care team members. if appropriate, parents/guardians or patients (if > 18 years of age) were called by phone to introduce the study and, if interested in participation, an informed consent was completed by phone. participants or their parent/guardian also selected which biospecimens they would provide to the biorepository. assent was completed by phone, when possible, with parents/ guardian present for children 7-17 years of age. inperson consent/assent was waived by the irb to avoid close contact between patients and research staff and to abide by the social distancing measures implemented by the state. witness requirements were also waived as a result of the restricted visitor hospital policy due to the pandemic. one copy of the signed consent form, and assent form if appropriate, was emailed to enrolled patients or parents/guardians, and another was uploaded into the electronic medical record flagging the patient as a research participant, clearly documenting research participation for the clinical care teams facilitating sample collection. paper copies were not provided to participants due to the covid-19 restrictions. upon enrollment, participants were assigned a unique study id number using redcap, a secure, centralized online database platform that allows simultaneous recruitment at multiple sites without risking assigning the same number to multiple patients. in order to include pediatric and neonatal patients from a range of clinical presentations for covid-19, we established 4 cohorts of patients from ages 0-25 years, reflecting the ages of patients cared for by the pediatric teams during the surge of covid-19 cases locally: 1) pediatric patients with mild-moderate covid-19, presenting to the mgh covid-19 urgent care clinics, 2) pediatric patients with severe covid-19 or mis-c requiring hospitalization, 3) newborns born to mothers infected with sars-cov-2 at any point during their pregnancy and infants born to non-infected mothers, and 4) asymptomatic children presenting to their wellvisits during the pandemic. each cohort presented unique challenges and required tailored strategies for a successful recruitment. in the pediatric urgent care units, challenges in enrollment included variability in patient volume and frequent rotation of nurses, medical assistants, and physicians. research coordinators had to be flexible to adapt to the frequently changing workflow within the clinic. for enrollment in the hospitalized cohort, the research team remained attentive to new admission lists and promptly completed enrollment protocols in order to obtain specimens prior to the initiation of treatment, as interventions such as intravenous immunoglobulin or steroids would interfere with the natural immune responses to sars-cov-2 infection. specimen collection from the hospitalized cohort was coordinated with clinical laboratory collections to minimize blood draws and collection procedures. for enrollment of newborns, the research coordinators coordinated with maternal arm of the adult covid-19 biorepository to allow simultaneous enrollment of mother and newborns prior to birth facilitating the recruitment process and limiting non-clinical interactions with the mother during the perinatal period. additionally, blood volumes collected for newborns were minimized to < 1 ml obtained by heal stick and coordinated with blood collection for newborn screening. enrolling well-visits was challenging as blood draws are not routinely obtained in all ages and children are often unwilling to undergo voluntary venipuncture. in each cohort, the research staff was mindful of the physical and [2] emotional stress the care teams were enduring while caring for patients with covid-19 and therefore sought to minimize disruptions in clinical care. figure 2 provides a schematic of the recruitment strategy. pediatric patients with mild-moderate covid-19 as most children did not require hospital-level care, significant efforts were made to enroll patients in the outpatient setting. covid-19 screening clinics, called respiratory infection control clinics, were established at massachusetts general hospital. as covid-19 symptoms are non-specific and current diagnostic reporting is time-delayed, all patients presenting to the pediatric covid-19 screening clinics were eligible to participate in the biorepository. during the surge of covid-19 cases locally, young adults up through 25 years of age were seen in the pediatric covid-19 clinics. for patients seen in the respiratory infection control clinics, the crc called eligible participants via telephone after acquiring approval from the lead physicians in the clinics. after acquiring verbal consent over the telephone, the crc alerted the clinical team of patient enrollment and the clinical teams obtained specimens for research. participants who provided informed consent could give nasopharyngeal, oropharyngeal swabs, and/or blood. stool and urine were not collected given time limitations of clinic visits and patient flow patterns established to minimize potential covid-19 exposures to clinical staff. blood was collected into one tube with an edta anticoagulant (edta tube) (bd), one serum separator tube (sst) (bd), and a paxgene rna tube (bd). blood volumes varied, depending on the age and weight of the patient, in accordance with limits established by the irb. the aerosolizing procedure of collecting nasopharyngeal and oropharyngeal swabs into 15 ml falcon tubes, containing 3 ml phosphate buffered saline (pbs) (gibco), was performed by clinical team members wearing n95 mask, face shield, protective outer gown, and disposable gloves. patients with severe covid-19 or multisystem inflammatory syndrome in children requiring hospitalization pediatric patients who were hospitalized with suspicion of sars-cov-2 exposure and/or symptoms concerning for sars-cov-2 infection or mis-c were identified by members of the research team, who subsequently requested approval from the clinical team to approach the patient. a member of the research team contacted the patient and family via phone to obtain informed consent, as described above, and coordinated with both the clinical and tcrc teams for specimen collection. sample collection was pre-planned with the clinical teams via emails and occurred every 2-3 days for this cohort of patients. hospitalized patients could opt to provide urine, stool, sputum, or if intubated, tracheal aspirates, in addition to blood, nasopharyngeal and oropharyngeal swabs. phlebotomy was aligned with clinical blood draws, when feasible, although participants had an option to undergo a separate venipuncture for research purposes. blood was collected into an edta tube, an sst tube, and a paxgene rna tube. repeat samples were collected on alternating days, as feasible. based on daily coordination between the research and clinical teams, discarded blood from clinical labs were also obtained from hospitalized patients. pregnant women with confirmed sars-cov-2 infection followed in the mgh obstetrics practice, presenting to the labor and delivery (l&d) unit, or hospitalized for sars-cov-2 illness, were approached to enroll their infant in the pediatric covid-19 biorepository following birth in collaboration with the maternal arm of the adult covid-19 biorepository. when universal screening for sars-cov-2 infection was initiated on all pregnant women admitted to l&d, asymptomatic sars-cov-2 positive patients were identified and offered enrollment. women who tested negative for sars-cov-2 were also approached as a control group. the pregnant mothers were simultaneously offered enrollment in the companion obstetric covid-19 biorepository, which included collection of placental biopsies, umbilical cord blood, and other maternal samples. the clinical team assessed the patient's interest in the biorepository, then a member of the research staff contacted the patient via telephone to obtain informed consent. parents could opt to have newborn blood, nasopharyngeal and oropharyngeal swabs, urine, stool, and (if intubated) tracheal aspirates collected. all samples were collected in the clinical setting by the clinical team members to accommodate covid-19 infection control guidelines, minimizing the risk of sars-cov-2 transmission and limit personal protective equipment (ppe) use. blood was collected via heel stick between 24 and 36 h of life, simultaneously with the heel stick for clinical newborn screening, into two edta microtainer tubes (bd). research nasopharyngeal and/or oropharyngeal swabs were obtained after 24 h of life, batched at the time of the nasopharyngeal swab for sars-cov-2 testing, if performed clinically. stool and urine were collected on day of life 0 and 2. stool was collected directly from the diaper. urine was collected by placing cotton balls in the diaper, then transferring the urine-soaked cotton balls into a specimen cup for transport. if the recruited newborn was intubated for clinical indications, tracheal aspirates were collected at the time of clinical suctioning. asymptomatic children presenting to their well-visit during the covid-19 pandemic children presenting for their 2-, 3-, or 4-year annual well-child visit with their pediatrician for planned phlebotomy were eligible to participate in this cohort. eligible patients were identified by study staff and clinicians. if appropriate, researchers contacted the parents via telephone prior to their visit to explain the research and obtain informed consent. blood and saliva were collected during their clinical phlebotomy. saliva collection is not considered an aerosolizing procedure; thus, these specimens could be collected in clinic without the need for n95 mask use. the specimens were immediately transported to the laboratory for processing. redcap databases were used to record all study data, including: 1) an enrollment log serving as the decoding log -study id numbers were assigned consecutively across all four patient groups; 2) a laboratory processing database with pertinent processing and freezer storage location information; 3) a chart review database, with demographic and clinical data, including covid-19 exposures, sars-cov-2 polymerase chain reaction (pcr) results, symptoms, and outcomes; 4) a questionresponse database about covid-19 exposures and risk factors, specifically for the well-visit cohort. in accordance with specimen transport guidelines, specimens were sealed in a leak-proof container labeled with subject's study id, then placed in a tight-sealed, biohazard-labeled, secondary container with a rigid outer container and lockable lid (e.g. igloo cooler) for transport to the laboratory. the entire research team was properly trained on bsl2+ procedures, as required for handling sars-cov-2 specimens. a coordinated effort by research personnel enabled successful and efficient troubleshooting, and processing of high influx of samples to the lab during the acute rise of covid-19 cases in the months of april-june 2020 (fig. 1) . scheduled shifts were implemented throughout the week to ensure the safety of all research staff and sample processing efficiency. three laboratory roles were created: 1) blood processing technician with extensive technical skill required for blood cell isolation, 2) biospecimen processing technician fully trained in bl2+ enhancement protocols, and 3) specimen labeling, quality control, and sample storage staff. these roles optimized processing workflow, safety precautions, and resources (including staff resource). paramount to the success of this biorepository included open communication via emails and the use of mobile group messaging outlets, frequent quality checks between staff regarding data and sample collection and processing, accessible leadership, and coordination with patients' clinical care teams. blood samples were processed following bsl2 safety guidelines, with a lab coat, nitrile/latex gloves, and a face shield or safety goggles. all other samples, including nasopharyngeal and oropharyngeal swabs, sputum, saliva, tracheal aspirates, stool, and urine were processed following bsl2+ safety guidelines. bsl2+ safety precautions require all samples to be processed in a certified biosafety cabinet (bsc), class ii a2, with intake airflow. well-trained laboratory personnel handling infectious specimens were required to wear closed-front water impermeable gowns, double nitrile/latex gloves, sleeve covers, and a face shield. outer gloves were removed when moving away from the bsc and replaced with a new glove when returning to work in the bsc. blood samples collected in tubes with an edta anticoagulant were stored at room temperature until processed, within 24 h of collection. tubes were spun at 1000 g for 10 min with brake activated. plasma was then collected, aliquoted, stored at − 80°c, and logged in the redcap database (fig. 3b) . immediately following the removal of plasma, samples with greater than 2 ml initial volume were processed for pbmc isolation using a ficoll density gradient [3] . briefly, blood was transferred into a 50 ml conical tube, then diluted 1:1 with hanks' balanced salt solution without calcium or magnesium (hbss minus) (gibco). this diluted blood was then gently layered on top of ficoll-paque plus (ge healthcare) at 2:1 ratio (2 volumes of blood diluted with hbss minus to 1 volume ficoll). careful attention was made to avoid any mixing of blood with the ficoll layer. the conical tube was then centrifuged at 1000 g for 30 min at room temperature with brake inactivated to allow adequate layering of cellular components. the cloudy ring below the plasma and above the ficoll (i.e. the pbmc layer) was collected and transferred to a new 15 ml conical tube, with hbss minus added to bring the volume to 15 ml (fig. 3a) . this tube was then centrifuged at 330 g for 10 min, with high brake activated. the supernatant was removed, the pbmc pellet was again washed with hbss minus, and then resuspended in 10 ml hbss minus for counting. cell count was obtained by diluting 10 μl of sample with 90 μl of trypan blue, mixed, and sampled on a hemocytometer. cells were then frozen in freshly-prepared freezing medium (rpmi 1640 medium with 1% penicillin-streptomycin, l-glutamine, 1% sodium pyruvate, 1% non-essential amino-acids, and 20% fetal bovine serum (fbs) (sigma)) with 10% dmso (sigma) for a goal concentration range of 5-10 million cells/vial, placed in a chilled mr. frosty filled with isopropanol, then immediately placed at − 80°c. final concentration (5-10 million cells per 1 ml of freezing medium) and number of aliquot vials were logged. the following day, pbmc cryovials were moved to a liquid nitrogen freezer for long term storage, and location was recorded in specimen log. pbmcs were isolated within 24 h of phlebotomy, although higher cell counts were obtained if isolated within 3-4 h of collection. if less than 5 ml blood was collected, a 15 ml conical tube, rather than a 50 ml conical tube could be used for ficoll layering. fresh freezing media were made throughout the day for each sample batch. neutrophils were extracted from the red blood cell layer that remained following the collection of pbmcs (fig. 3a) . neutrophils were isolated using easysep direct human neutrophil isolation kit (stemcell technologies). the remaining blood layer was incubated with easysep direct rapidspheres and easysep direct human neutrophil isolation cocktail, fig. 3 overview of laboratory blood processing procedures following bsl2 containment guidelines depicting steps for a) collection of plasma, isolation of pbmc and pmn, from blood collected into an edta tube and b) collection of serum from an sst blood tube (created with biorender.com) then diluted in easysep buffer. neutrophils were isolated by successive negative magnet selection using easysep magnets, then counted using a hemocytometer and aliquoted into eppendorf tubes for rna extraction (1 × 10 5 cells/tube) or dna analysis (5 × 10 6 cells/tube). neutrophils designated for rna extraction were resuspended in 100 μl of rna lysis buffer (tcl) (qiagen) with 1% β-mercaptoethanol (sigma), immediately stored at − 80°c and logged. neutrophils planned for dna analysis were pelleted then directly stored at − 80°c and logged. for rna extraction steps, a cleaning agent, such as rna-sezap should be used to remove rnase from the working surface. rna lysis buffer should be newly made for each sample using a 10:1 tcl to β-mercaptoethanol ratio. serum samples were collected from blood drawn into serum separator tubes without any anticoagulant (bd). blood was kept at room temperature, standing upright for 30-60 min, then spun at 1200 g for 10 min with brake activated. serum was then collected, aliquoted, stored, and logged (fig. 3b) . swab samples were delivered in phosphate buffered saline (pbs) [4] . samples were directly aliquoted into 1 ml aliquots, then immediately stored at − 80°c and logged (fig. 4a) . samples collected into a collection cup were mixed well at 1:1 ratio with 500 mm dl-dithiothreitol (dtt) (sigma)/pbs solution according to cdc recommendations. diluted samples were then divided into 1 ml aliquots, volume permitting, immediately stored at − 80°c and logged (fig. 4b) . aspirates collected into a sterile collection cup were divided into 1 ml aliquots (1 ml/vial), immediately stored at − 80°c and logged (fig. 4c) . stool samples collected from a diaper or specimen cup were divided using a micro spatula, volume permitting, into cryovials with 1 ml rnalater (invitrogen), empty cryovials without any additive/reagent, up to the 1.5 ml tube mark, and cryovials with 1 ml buffered glycerol saline (fisher). stool samples were fully submerged in rnalater or glycerol solution prior to immediate storage at − 80°c. samples were logged onto database (fig. 4d) . urine samples collected with cotton balls placed inside baby diapers were transferred using forceps, to a 10 ml syringe to dispense at most 1 ml of fluid into cryovials and immediately stored at − 80°c. samples collected into a tube or a sterile collection cup were aliquoted into cryovials (at 1 ml at most/vial) and immediately stored at − 80°c (fig. 4e) . supplies required for specimen collection and processing are listed in supplemental table 1 . sample labels, logging, storage, and quality control were performed by assigned lab #3 personnel. the pediatric covid-19 biorepository enrolled 327 pediatric and neonatal patients from a range of clinical presentations, including 178 patients from the urgent care/respiratory infection control clinic, 48 hospitalized children, 85 newborns born to mothers with or without sars-cov-2 infection, and 16 asymptomatic children presenting for their well-visits. the average age was 11 (± 8) years for enrolled children and adolescents and 1.3 (±1.3) days for newborns. equal gender distribution was seen, except more males were enrolled in the hospitalized cohort (60%, n = 29). sixty-four participants were positive for sars-cov-2 by clinical testing, most of whom were seen in the respiratory infection control clinic, while 21 patients were diagnosed with mis-c, all of whom were hospitalized. the one patient presenting to the respiratory infection control clinic with mis-c was ultimately hospitalized. table 1 characterizes total enrollment number, age, gender, sars-cov-2 infection status, and mis-c diagnosis within each enrollment site. a total of 972 biospecimens were collected. these biospecimens included 295 blood samples, 181 nasopharyngeal swabs, 145 nasopharyngeal swabs, 172 stool samples, 154 urine samples, 4 tracheal aspirate samples, and 21 sputum/saliva samples. hospitalized patients and newborns had the option of providing subsequent sampling. table 2 depicts the sample collection from each enrollment site. the goal of the biorepository is to provide high quality biospecimens for studies understanding how infants and children are impacted by and contribute to covid-19 pandemic. establishing a standardized biorepository collection protocol facilitates comparison of samples across institutions and with adult biorepositories. key neonatal and childhood factors of interest that will be studied using this biorepository focus on: 1) informing pediatric contribution to viral transmission, 2) teasing apart the dichotomy between pediatric and adult immune responses to covid-19, 3) ascertaining the impact of maternal sars-cov-2 infection on child fetal development, and 4) elucidating factors driving the mis-c. in this study, nasopharyngeal and oropharyngeal swabs were collected from pediatric patients presenting with symptoms concerning for sars-cov-2 infection in both the outpatient and hospitalized setting, from newborns born to mothers infected with sars-cov-2, and from healthy controls. additionally, saliva was collected from young children presenting for their annual well-visit. blood, tracheal aspirates, stool, and urine were also collected from the hospitalized patients and newborns for assessment of viral load. questions relating to the role of viral carriage in the pediatric population can be addressed using these samples. case reports and recent research studies suggests that asymptomatic children carry high viral loads despite lack of symptoms [5] [6] [7] . in adults, severe infection is not necessarily associated with a significant increase in viral loads by nasopharyngeal swab [8] , and asymptomatic individuals appear to have equal viral loads as symptomatic individuals [9] . the potential correlations between viral load, symptoms, and exposures have yet to be clarified in the pediatric population. age-stratification within adults show no differences in viral load across age-groups, although younger patients were less likely to develop severe disease [8] , thus a similar comparison among children would be informative. additional questions remain as to whether there are risk factors affecting viral load density in children, including household contacts or other environmental factors. viral studies are also needed to determine accuracy of viral testing techniques within the pediatric population. including infants born to covid-19 infected mothers will allow assessment of viral exposure in the airway, and through the meconium, giving important insight into neonatal exposure to sars-cov-2 infection. understanding how children are infected with sars-cov-2 will provide critical insight into how viral loads may impact disease severity in children, and how children may contribute to viral transmissibility driving this pandemic. these data will be critical to making decisions about risk factors for re-opening of schools and childcare as the pandemic progresses. covid-19 results in a major apparent dichotomy of immune response between children and adults [10] . children often develop mild infections whereas adults more commonly develop severe disease associated with high levels of mortality [11] . neonates appear to be unaffected, even when born to covid-19 positive mothers [12] . it has been postulated that children are less impacted by viral infection because they have fewer angiotensin-converting enzyme 2 (ace2) viral binding sites [7, 13] , although the research thus far remains conflicted. in this study, rna obtained from nasopharyngeal and oropharyngeal swabs, and/or saliva collected from neonates, children, and young adults, can be used to characterize ace2 expression, and potentially shed light on the availability of viral binding sites across the age span. further, prior research has shown immunosenescence in aged individuals, which affects t cell and b cell function, and cytokine production by innate immune cells [14] . it is yet to be evaluated as to whether this plays a central role in the age differences in the morbidity and mortality from covid-19. additionally, mis-c is shown to be driven by a cytokine storm and macrophage activation [15] . peripheral blood monocytes, plasma, serum, and neutrophil rna collected as part of this biorepository can be used to answer these questions. understanding the disease abnormalities may provide key insight into therapeutic targets. this study collects plasma, serum, pbmcs, and neutrophil rna from sars-cov-2 infected and uninfected children with a range of symptoms for comparison. neonatal development intimately depends on maternal health. prior infections and disease states causing maternal inflammatory activation and cytokine storm have resulted in increased risk of autism spectrum disorder, schizophrenia, cerebral palsy, cognitive delay, depression, and bipolar disorder in exposed children [16] [17] [18] . the effect of the sars-cov-2 hyperinflammatory milieu on the developing fetus is yet to be seen. this biorepository, partnered with the obstetric covid-19 biorepository will obtain placental tissue, cord blood, maternal and neonatal biospecimens to address these critical questions. following a mild or symptomatic infection of covid-19, children can develop a severe, post-infectious inflammatory response syndrome, termed multisystem inflammatory syndrome in children (mis-c), which is characterized by hyperinflammatory shock [19] , "kawasaki-like" cardiac damage, and possible death [20] . risk all enrolled participants provided clinical and demographic data. enrolled subjects had the option of selecting which biospecimens they would like to provide. stool and urine were not collected from participants enrolled in the urgent care and well-visit cohorts for logistic reasons, unless these individuals were later hospitalized for covid-19-related illness. enrolled subjects could also consent to provide specimens, then later decline any or all specimen collection. repeat biospecimen collection could occur if participants re-presented to care, or if hospitalized for multiple consecutive days factors for developing mis-c and biomarkers predicting severe complications need to be identified. these specimens collected through this pediatric covid-19 biorepository will be used to characterize the immune responses driving mis-c in hopes of mitigating this lifethreatening complication. although children were initially felt to be spared from covid-19, it has become clear that much needs to be learned as to how children and newborns are impacted by the pandemic. research is needed to address viral transmission by children, differences in pediatric viral susceptibility and immune responses, the impact of maternal sars-cov-2 infection on fetal development, and factors driving the mis-c. this pediatric covid-19 biorepository will serve as an important resource providing critical insight into disease pathogenesis, covid-19susceptibility, and future treatment and vaccination strategies. supplementary information accompanies this paper at https://doi.org/10. 1186/s12874-020-01110-y. additional file 1 supplemental table 1 . list of supplies required for specimen collection, processing, and storage in the pediatric covid-19 biorepository commonwealth of massachusetts covid-19 reporting isolation of lymphocytes, granulocytes and macrophages evaluation of swabs, transport media, and specimen transport conditions for optimal detection of viruses by pcr a well infant with coronavirus disease 2019 (covid-19) with high viral load viral rna load in mildly symptomatic and asymptomatic children with covid-19 pediatric sars-cov-2: clinical presentation, infectivity, and immune responses association of viral load with serum biomakers among covid-19 cases sars-cov-2 viral load in upper respiratory specimens of infected patients insight into the pediatric and adult dichotomy of covid-19: age-related differences in the immune response to sars-cov-2 infection coronavirus disease 2019 in children -united states vertical transmission risk of sars-cov-2 infection in the third trimester: a systematic scoping review nasal gene expression of angiotensinconverting enzyme 2 in children and adults immunosenescence: emerging challenges for an ageing population multisystem inflammatory syndrome related to covid-19 in previously healthy children and adolescents long-term risk of neuropsychiatric disease after exposure to infection in utero the fetal origins of mental illness schizophrenia and influenza at the centenary of the 1918-1919 spanish influenza pandemic: mechanisms of psychosis risk hyperinflammatory shock in children during covid-19 pandemic multisystem inflammatory syndrome in u.s. children and adolescents publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we are incredibly grateful for the selfless contributions by the entire pediatric and obstetrics covid19 received: 13 july 2020 accepted: 30 august 2020 we also acknowledge funding from the national heart lung and blood institute (5k08hl143183 to ly), the cystic fibrosis foundation (yonker18q0 to ly), and the eunice kennedy shriver national institute of child health and human development (1r01hd100022-01 to age). the funder/sponsor did not participate in the work.availability of data and materials a variety of pediatric samples collected during the covid-19 pandemic may become available to other researchers upon reasonable request to the correspondent author and compliance with the partners innovations office. the study received ethics approval from the partners/massachusetts general hospital institutional review board (irb#2020p000955) and the partners/ massachusetts general hospital institutional biosafety committee (ibc#2020b000061). verbal consent to participate was obtained from the participants or from parents/guardians (for children under 18 years of age). verbal assent was obtained, when possible, from children ages 7-18 years of age. all participants signed an irb-approved informed consent prior to participating. not applicable. the authors declare no competing interest. key: cord-336049-n3swuykg authors: ahmed, mubbasheer; advani, shailesh; moreira, axel; zoretic, sarah; martinez, john; chorath, kevin; acosta, sebastian; naqvi, rija; burmeister-morton, finn; burmeister, fiona; tarriela, aina; petershack, matthew; evans, mary; hoang, ansel; rajasekaran, karthik; ahuja, sunil; moreira, alvaro title: multisystem inflammatory syndrome in children: a systematic review date: 2020-09-04 journal: eclinicalmedicine doi: 10.1016/j.eclinm.2020.100527 sha: doc_id: 336049 cord_uid: n3swuykg background: multisystem inflammatory syndrome in children (mis-c), also known as pediatric inflammatory multisystem syndrome, is a new dangerous childhood disease that is temporally associated with coronavirus disease 2019 (covid-19). we aimed to describe the typical presentation and outcomes of children diagnosed with this hyperinflammatory condition. methods: we conducted a systematic review to communicate the clinical signs and symptoms, laboratory findings, imaging results, and outcomes of individuals with mis-c. we searched four medical databases to encompass studies characterizing mis-c from january 1st, 2020 to july 25th, 2020. two independent authors screened articles, extracted data, and assessed risk of bias. this review was registered with prospero crd42020191515. findings: our search yielded 39 observational studies (n = 662 patients). while 71·0% of children (n = 470) were admitted to the intensive care unit, only 11 deaths (1·7%) were reported. average length of hospital stay was 7·9 ± 0·6 days. fever (100%, n = 662), abdominal pain or diarrhea (73·7%, n = 488), and vomiting (68·3%, n = 452) were the most common clinical presentation. serum inflammatory, coagulative, and cardiac markers were considerably abnormal. mechanical ventilation and extracorporeal membrane oxygenation were necessary in 22·2% (n = 147) and 4·4% (n = 29) of patients, respectively. an abnormal echocardiograph was observed in 314 of 581 individuals (54·0%) with depressed ejection fraction (45·1%, n = 262 of 581) comprising the most common aberrancy. interpretation: multisystem inflammatory syndrome is a new pediatric disease associated with severe acute respiratory syndrome coronavirus 2 (sars-cov-2) that is dangerous and potentially lethal. with prompt recognition and medical attention, most children will survive but the long-term outcomes from this condition are presently unknown. funding: parker b. francis and pilot grant from 2r25-hl126140. funding agencies had no involvement in the study the rapidly evolving pandemic associated with severe acute respiratory syndrome coronavirus 2 (sars-cov-2) has led to more than 19.8 m confirmed cases and over 730,000 global deaths [1] . previous reports suggest that children infected with coronavirus disease 2019 (covid-19) are highly resilient and present with a mild upper respiratory illness [2à4] . for instance, a study of 171 children with confirmed covid-19 reported that only three cases required intensive care unit admission and only one death was observed [5] . however, in early may 2020, investigators from south thames retrieval service in london, uk published a report describing eight severely ill pediatric patients presenting in hyperinflammatory shock with multiorgan involvement [6] specifically, the children manifested with high fever, rash, conjunctivitis, peripheral edema, and gastrointestinal symptoms. the royal college of paediatrics and child health (rcpch) referred to this acute condition as pediatric multisystem inflammatory syndrome temporally associated with covid-19 (pims-ts) [7] . as more cases arose globally, the illness was labelled multisystem inflammatory syndrome in children (mis-c) by the centers for disease control and prevention (cdc) and the world health organization (who) [8à10] . the definition across the organizations is based on 6 principle elements: pediatric age, persistence of fever, presence of laboratory markers of inflammation, manifestation of signs or symptoms of organ dysfunction, lacking an alternative diagnosis, and a temporal relation to covid-19 infection or exposure. while the rcpch definition of pims-ts recognizes the temporal association with covid-19, it does not require proof of infection or exposure to meet the case definition like the cdc and who criteria. one of the initial challenges clinicians were facing was differentiating patients with mis-c versus kawasaki disease (kd) or toxic shock syndrome (tss) [9,11à13] . kd is a vasculitis that typically presents with high fever and acute mucocutaneous inflammation in children <5 years of age [14] . although typically a self-limiting condition, some children may have severe complications including coronary artery aneurysms, myocardial dysfunction, and thrombotic events [15] . kd can be stratified into classic or incomplete, depending on the number of clinical findings characteristic to the disease. fever for 5 days with 4 of the following 5 principle features distinguishes classic kd: (i) conjunctival injection, (ii) rash, (iii) erythema and edema of the hands and feet, (iv) cervical lymphadenopathy, and (v) oral mucosal changes. the diagnosis of incomplete kd includes fever with 2à3 of the principal features [14] . on the other hand, tss is a potentially lethal disease derived from the release of bacterial toxins. it is depicted by fever, rash, shock, vomiting and diarrhea, and treated by hemodynamic stabilization and antibiotics [16] . a recent publication by whittaker et al., elegantly compared the age and laboratory findings in patients with mis-c, kd, and tss [17] . we sought to conduct a systematic review to provide an overview of the current evidence regarding pediatric patients diagnosed with mis-c. in addition, we compared features of mis-c with children with covid-19. we included patients with covid-19 to reinforce to the healthcare community and public the differences in the clinical presentation, to highlight the degree of systemic inflammation in mis-c, and to iterate the differences in treatment and outcome between the two diseases. our methods adhere to the guidelines established by preferred reporting items for systematic reviews and meta-analyses (prisma) [18] . our study protocol was registered with prospero (international prospective register of systematic reviews) with the following registration number crd42020191515 [19] . we performed a systematic search in the following databases: pubmed, litcovid, scopus, and science direct. additionally, we searched references of included articles and any reviews focusing on mis-c. our search terms included "multisystem inflammatory syndrome in children" or "pediatric multisystem inflammatory syndrome". search dates were from january 1st, 2020 to july 25th, 2020. our detailed search with dates can be viewed in appendix 1. we included published or in press peer-reviewed articles reporting cases of mis-c. we accepted the following types of studies: case reports, case-control, case series, cross-sectional studies, and letters to the editors that incorporated clinical, laboratory, imaging, as well as the hospital course of mis-c patients. articles were included if the studies met the criteria for hyperinflammatory syndrome (mis-c or pims-ts) as set by the cdc, rcpch, or the who [7, 9, 10] . duplicate studies were manually removed from the search results prior to the screening process (axm, am). screening by title and abstract was conducted independently by two investigators (axm, am). a third investigator (ma, sa) was consulted to resolve differences of opinion in either phase. subsequent full-text review and data extraction was conducted by investigators (ma, sa, axm, sz, jm, kc, rn, fbm, fb, at, mp, me, ah) using google sheets (google, mountain view, ca, usa). data retrieved from each article was cross-checked by another independent investigator (ma, sa, am). our goals were twofold: (i) to describe the clinical signs, laboratory findings, imaging characteristics, treatments, and outcomes of patients with mis-c, and (ii) compare the clinical variables between children with mis-c to those with covid-19. data collected from the studies included demographics, number of patients, signs and symptoms, laboratory markers, imaging results, medications, and outcomes. only initial laboratory values were recorded (e.g., at time of admission or first reported lab). if only peak laboratory values were provided, they were not included in the analysis. signs and symptoms were considered positive if they occurred any time during the patient's hospitalization. all echocardiograms were taken into consideration. more precisely, if any of the echocardiograms reported a depressed ejection fraction, pericarditis, mitral valvular dysfunction, coronary dilation, or coronary aneurysm we recorded this finding as positive. cardiac dysfunction/depression was evidence before this study severe acute respiratory syndrome coronavirus 2 (sars-cov-2) has spread throughout the world at an alarming rate. previous reports suggested that children infected with coronavirus disease 2019 (covid-19), the condition caused by sars-cov-2, were highly resilient and had mild symptoms. as of late april 2020, reports from the united kingdom surfaced describing a new hyperinflammatory disease that is temporally associated with sars-cov-2 infection. since then, several other countries have also reported patients exhibiting similar features, and this phenomenon has subsequently been coined multisystem inflammatory syndrome in children (mis-c) or pediatric inflammatory multisystem syndrome temporally associated with sars-cov-2 (pims-ts). in this context, our goal was to provide a review of published articles focusing on mis-c. this systematic review summarizes the clinical presentation of mis-c from 662 patients (n = 39 studies). we report the most common signs and symptoms, quantify laboratory findings, and describe imaging characteristics of children with mis-c. furthermore, we summate outcomes, treatments, and compare mis-c to covid-19. results from this systematic review represent a comprehensive evaluation of children meeting mis-c criteria. our findings will inform clinicians of the signs, markers, and outcomes of children who develop this dangerous and potentially life-threatening hyperinflammatory syndrome. future research should focus on identifying variables that can prognosticate which pediatric covid-19 patients will develop mis-c and which, if any, markers correlate with systemic outcomes. defined as an ejection fraction <55% or as a shortening fraction <45% [20, 21] . acute kidney injury was documented according to the definition by the authors. examples of how acute kidney injury was defined included a serum creatinine 1.5 times the upper limit of normal or a serum creatinine above the reference value for age [17, 20, 21] . patients were deemed sars-cov-2 positive if they had a positive rt-pcr or antibody test. shock was defined according to the author's criteria, patient requiring inotropic support, or hypotension necessitating volume resuscitation (>20 ml/kg of colloids). respiratory outcomes were categorized according to level of support (e.g., nasal cannula, noninvasive, mechanical ventilation, ecmo). if the number of intensive care unit (icu) admissions were not explicitly described, we assumed that respiratory support (>nasal cannula) or need for inotropes was a logical surrogate and entered the higher number of the two into the data collection form. co-morbidities, signs and symptoms were grouped according to organ system. reference values for laboratory values were based on the mean age of the whole study population. risk of bias for observational studies was appraised through the quality assessment tool published by the national institutes of health [22] . risk of bias was assessed independently by at least two investigators (sz, jm) and disagreements were resolved by a third researcher (am). furthermore, the level of evidence was assessed according to sackett [23] . for our second aim, we compared mis-c to confirmed pediatric cases of covid-19 [24] . justification and rationale for the chosen article included the following: (i) to maintain consistency the selected study was also a systematic review, that was published by our team, and more importantly (ii) the comparative study also provided detailed information regarding clinical signs/symptoms, laboratory markers, outcomes, and treatments. we understand that this approach has inherent bias and therefore our comparison is strictly descriptive and did not conduct statistical analyses between the two diseases. continuous data were summarized as mean § standard deviation. if results were presented as median with interquartile range, we transformed the data to mean § standard deviation according to wan et al. [25] . categorical data were summarized as counts with percent. means, standard deviations, counts, and percent were calculated using excel (microsoft, redmond, wa, usa). getdata graph digitizer 2.26 (s. fedorov) was used to extrapolate data from figures when information was not in the text. figures were created in excel. the funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. our search identified 371 articles published from january 1st, 2020 to july 25th, 2020. after removing duplicates and screening the titles and abstracts, 314 studies were evaluated for eligibility. ultimately, 39 articles were included in this review with a total sample size of 662 children with mis-c (refer to fig. 1 ). all studies were observational and therefore the level of evidence was 5 (1 is highest, 5 is lowest). appendix 2 depicts that the risk of bias for the studies was moderate to high. twenty-three (59¢0%) of the studies were case series. the two largest studies were from the united states and contributed to 43¢0% of the data (n = 285 individuals) [21, 26] . the mean age of patients was 9¢3 § 0.5 years and 52¢3% of children were male. the total number of deaths was 11 (1¢7%). please see table 1 . data on race/ethnicity was provided for 471 (71¢1%) individuals. children from african american, afro-caribbean, or african race/ethnicity represented 34¢8% (n = 164) of the population. five hundred thirty-two (84¢7%) children were confirmed sars-cov-2 positive. average length of hospital stay was 7¢9 § 0¢6 days. table 2 offers more details. fever (n = 662, 100%), abdominal pain/diarrhea (n = 488, 73¢7%), and vomiting (n = 452, 68¢3%) were the most common symptoms reported (summarized in table 3 ). like kd and tss, conjunctivitis (n = 343, 51¢8%) and rash (n = 372, 56¢2%), were frequently observed. table 4 summarizes laboratory measurements. the mean neutrophil percent was elevated at 80¢7 § 7¢8%, while the mean lymphocyte percent was low at 9¢8 § 0¢8%. c-reactive protein (160 § 6¢9 mg/l), ferritin (977 § 55¢8 ng/ml), and procalcitonin (30¢5 § 2¢1 ng/ml) were markedly increased. cardiac markers, troponin, brain natriuretic peptide, and prohormone of brain natriuretic peptide, were extremely elevated at 494 § 37¢6 ng/l, 3604 § 352 pg/ml, and 5854 § 743 ng/l, respectively. fig. 2 depicts clinical outcomes. four hundred sixty-nine (71¢0%) children diagnosed with mis-c were admitted into the icu. mechanical ventilation and extracorporeal membrane oxygenation were required in 147 (22¢2%) and 29 (4¢4%) patients, respectively. acute kidney injury (aki) occurred in 108 (16¢3%) patients. cardiac outcomes are graphically presented in fig. 3 . echocardiograms were performed in 581 of 662 patients (87¢8%). three hundred fourteen (54¢0%) individuals had an abnormal echocardiogram. the most common abnormality was depressed left ventricular ejection fraction (n = 262, 45¢1%). aneurysms occurred in 47 patients (8¢1%). appendix 3 and 4 summate non-cardiac imaging findings. table 5 summarizes information regarding treatments administered. intravenous immunoglobulin (ivig) therapy was the most common medication (n = 506, 76¢4%), followed by vasoactive agents (n = 347, 52¢3%), and corticosteroids (n = 347, 52¢3%). differences in clinical signs and symptoms between mis-c and covid-19 can be visualized in fig. 4 . the overlap of presentation can be appreciated, but rash, vomiting, and diarrhea are more common in mis-c. in contrary, covid-19 has more upper respiratory symptoms (e.g., cough, rhinorrhea). table 6 compares demographics, laboratory findings, treatments, and outcomes between mis-c and covid-19. children with mis-c had a higher a percentage of neutrophils and lower percentage of lymphocytes. the level of inflammation experienced in this new childhood disease surpasses covid-19. for instance, ferritin is 18fold greater in mis-c (977 § 55¢8 ng/ml vs. 51¢6 § 13¢2 ng/ml). procalcitonin was also much higher in mis-c compared to covid-19 (30¢5 § 2¢1 ng/ml vs. 0¢25 § 0¢0). severe acute respiratory syndrome coronavirus 2 (sars-cov-2) has spread throughout the world at an alarming rate [1]. previous reports suggested that children infected are highly resilient to the disease and generally progress with a mild course [2, 4] . however, as of late april 2020, a new and potentially life-threating childhood disease, referred to as mis-c or pims-ts, emerged [6, 8] . our systematic review focused on describing the clinical presentation and shortterm outcomes of this novel disease. as described by riphagen et al., hyperinflammatory shock is a common element in mis-c [6] . these findings are substantiated in our review as 60¢1% of children required vasopressor support and/or fluid resuscitation, in addition to 71¢0% of children were admitted to the icu. although children were critically ill and had extraordinary inflammation, most responded to prompt administration of anti-inflammatory agents, namely ivig and corticosteroids. a notable finding was that 11 of 662 individuals (1¢7%) did not survive. the death rate in this review is comparable to that observed in adults with severe covid-19 between the ages of 55à64 years (1% to 3%) [29] . while low, it is much higher than the 0.09% mortality rate observed in children with covid-19 [24] . while writing this manuscript a new study was published involving 570 us patients with mis-c [28] . the percentage of deaths for the cohort was comparable to the one observed in this review (n = 10, 1¢8%). among the more concerning findings was that children could still develop mis-c despite an asymptomatic course of coronavirus 2019 disease [20] , [29à31] . the literature reports that mis-c typically manifests 3à4 weeks after sars-cov-2 infection [21, 28] . this may explain why many children had positive antibodies to sars-cov-2, but negative rt-pcr at the time of mis-c evaluation [17,32à36] . an added matter of trepidation was that 52¢0% of individuals (n = 290 of 558) who developed the inflammatory syndrome did not have any underlying medical conditions. more research is needed to understand why some children may be more susceptible to developing mis-c. for instance, our review noticed that there was a higher rate of mis-c in the african american/afro-caribbean population. this may explain the disproportionate rate of deaths in african american us children between the ages of 5à17 [27, 28, 37] . a similar finding is observed in african american us adults, wherein they are more likely to be hospitalized compared to individuals of white race [38] . another population that requires further investigation are children who are overweight or obese. in this review, children who were overweight or obese accounted for 50¢8% (n = 136 of 268) of children with co-morbidities. proposed mechanisms explaining why obesity may be a risk factor for covid-19/mis-c include: an accumulation of inflammatory cells in adipose tissue, fat tissue-associated cytokines are proinflammatory, impaired respiratory function, and adipose cells have more sars-cov-2 binding receptors [39à42] . while children with covid-19 present with upper respiratory symptoms, mis-c is distinguishable by fever (100%), vomiting (68¢2%), and abdominal pain/diarrhea (73¢8%) [24] the abdominal pain in mis-c can be so severe that in several cases patients were presumed to have appendicitis. for instance, patients in studies by belhadjer et al. and dasgupta received urgent abdominal surgery, but ultimately found the patients had mesenteric lymphadenitis [43, 44] . in this review, further imaging of the abdomen (ultrasound, computed tomography, or magnetic resonance imaging) was performed in 14 of the 39 studies. only one of those studies had a normal abdominal evaluation [45] . more common findings included ascites (n = 27 individuals), intestinal/colonic inflammation (n = 16 individuals), and mesenteric adenopathy (n = 15 individuals) [20,26,29,31,32,34,44à51 ]. on one occasion, an 11-year old was diagnosed with pancreatitis secondary to sars-cov-2 [52] . this highlights the vast spectrum of gastrointestinal pathology in mis-c. per the definition of mis-c, neutrophilia and lymphocytopenia were frequent. the average percentage of neutrophils was 80¢7%, a finding that echoed that reported in 99 children from new york (average = 82¢3%) [26] . given the standard deviation of 7¢8% in this report, this implies that 95% of the 662 cases (2 standard deviations) had an elevated neutrophil percent. in contrast, feldstein et al. reported neutrophilia in 67¢7% [21] inconsistency is most likely a reflection of how neutrophilia was defined: we used neutrophil percentage versus feldstein et al. used an absolute number (>7700/ml). of note, laboratory data from feldstein et al. was not used for the calculations in this review as they described their data in a binary format (e.g. above/below a set number) [21] . likewise, our lymphocyte [53] . the degree of separation between the two cell lines may coincide with the severity of inflammation. evidence to support this assumption comes from covid-19 studies that found an association between the percentage of neutrophils, lymphocytes, and the neutrophil to lymphocyte ratio to severity of disease [54, 55] . consistent with the diagnosis of mis-c, multiple inflammatory markers were elevated. examining the trends of some of these values may provide biologic insight to the disease or may serve as potential predictors of mis-c outcomes. in particular, the following analytes were extremely elevated-procalcitonin (203-fold upper limit of normal, uln), interleukin-6 (103-fold uln), and troponin (49-fold uln). we provide brief descriptions of each inflammatory marker and their potential use as future prognosticators. procalcitonin is a glycoprotein that is typically produced by the thyroid gland, but during severe systemic infections it can also be produced by other tissues [56] . in the past, procalcitonin was used to distinguish between bacterial and viral infection, where the thought was that higher levels correlated more with bacterial infections, while viral infections maintained a normal or slightly elevated procalcitonin level [56] . in detail, patients with bacterial septic shock classically had a procalcitonin level >0.10 ng/ml [57] . an average procalcitonin level of 30.5 § 2.1 ng/ml puts into perspective the level of systemic inflammation seen in mis-c cases. in a recent study, italian physicians evaluated the prognostic value of interleukin-6 (il-6) for severe covid-19 and in-hospital mortality [58] . they found that the mean level of il-6 was greater in patients meeting their combined outcome (134¢3 § 19¢5 pg/ml vs. 15¢6 § 14¢8 pg/ml, p<0.01). area under the receiver operator characteristic curve for il-6 for in-hospital mortality was 0¢90 (95% ci 0¢81à0¢95), using a cut-off of 25 pg/ml. providing this context, the average il-6 level in patients with mis-c was 185 § 15¢6 pg/ml. thus, it is logical why patients who did not respond to intravenous immunoglobulin and/or corticosteroids also received immunomodulatory agents known to target the il-6 receptor. the predominance of cardiac manifestations in children with multisystem inflammatory syndrome was striking. many of the patients in this review had an initial echocardiogram that was normal and a few days later showed depressed ejection fraction or dilation/aneurysm of the coronary arteries. we found that the most common cardiac abnormality, on echocardiogram, was a depressed ejection fraction (45¢0%). in line with these findings, a recent study revealed that adults who recently recovered from covid-19 had ongoing cardiac involvement and myocardial inflammation [59] . accordingly, children undergoing evaluation for mis-c should have a baseline echocardiogram, electrocardiogram, and repeat imaging to follow cardiac function and artery changes. close follow-up will be important as the long-term implications of mis-c cardiac involvement are currently unknown. provided the abundance of angiotensin-converting enzyme 2 (ace2) receptors in the heart, and the myocardial changes observed in cardiac imaging, it is no surprise troponin was among the most abnormal mis-c markers [60] . elevated troponin levels in individuals with covid-19 are independent prognostic markers of poor outcome [61] . however, it is unknown if troponin levels correlate or can prognosticate specific cardiac abnormalities (e.g., myocardial dysfunction, coronary dilation, aneurysm) in patients with mis-c. future studies may provide more clarity regarding whether high troponin levels are a reflection of systemic inflammation, direct myocardial changes, vascular stress, or a combination of these injuries. on a positive note, many of the mis-c patients had a down trending troponin and were able to recover their myocardial function by the time of discharge. while mis-c has overlapping features with kd and tss, the inflammatory storm observed in mis-c is much more intense. distinguishing clinical characteristics found in mis-c includes age, vomiting, diarrhea, and abdominal pain. another important difference to highlight between kd and mis-c is that approximately 5% of children with kawasaki's disease presented with cardiovascular collapse [62] . conversely, 60¢2% of children with mis-c presented with shock. the rate of coronary artery aneurysms in 615 japanese children with kd was 1¢3% compared to 7¢1% in this review of mis-c [62] . to date, it is unclear if mis-c patients are at more risk for aneurysms, or if there are key factors, such as genetic predisposition, playing a role in vascular changes. kawasaki disease been implicated in young children <5 years of age, whereas the mean age in mis-c was 9¢3 § 0.4 years [14] . although kd can affect young children of all ethnic backgrounds, there is a clear predilection towards asian populations and young males [63] . in contrast, there was no obvious gender preference in mis-c, yet individuals with african, african american, or afro-caribbean may have a higher risk. the overlapping features between these syndromes suggests that they may share similar pathophysiology and likely explains why these patients respond to similar therapies. as described in this review, most children recovered with standard kd therapies, ivig and glucocorticoids. second ivig administrations occurred in 20¢9% [21, 28, 32] , [64] . even with second dosing of ivig, only a small number of individuals required/were given immunomodulating agents, such as il-1 or il-6 antagonists (8¢5% and 6¢0%, respectively). future longitudinal studies will help delineate if there is a subset of patients with mis-c that would benefit from such medications. for example, patients who may have therapeutic improvement from immunomodulators may include those with persistent elevation in il-1 and/or il-6 despite initial and/or redosing of initial therapies. furthermore, subsequent studies should attempt to examine different features (e.g. demographic, biomarkers) that can predict which patients will need a second dose. a final note, in a study of 26,691 japanese children with kd, the number of deaths was 4, giving a mortality rate of 0¢01% which is much lower than the 1¢7% observed in mis-c [65] . our review has several limitations. first, numerous case reports and case series were included and therefore the level of evidence is low. along the same lines, the risk of bias varied among studies. second, we converted data to mean and standard deviations, which may skew data with outliers. although our prospero protocol does not explicitly state that we were going to include letters to the editor, we did incorporate them. this protocol deviation was performed to offer a more complete portrayal of individuals with mis-c and to optimize the number of patients in this review. however, we did not include letters to the editor that were perspectives or commentary pieces that did not describe pediatric cases of mis-c. we were rigorous in our search but there is a possibility we may have missed studies. we removed patients and/or studies that did not describe patients presenting with fever, a cardinal characteristic of mis-c [66à68]. in addition, to reduce duplication of information we removed studies in which individuals were or may have been included in larger or studies that were more comprehensive [6,69à72] . our review is mainly descriptive, and inferential statistical conclusions cannot be drawn from it. we are cognizant of the numerous listed limitations, but we believe the summative data is clear, concise, and communicates our intent to describe the clinical picture of patients with mis-c. most importantly, we hope this report is clinically useful and may impact patient care. we reviewed and summarized the clinical presentation of a new childhood disease that is most likely linked to sars-cov-2 infection. mis-c is a dangerous systemic infection characterized by extreme inflammation, fever, abdominal symptoms, conjunctivitis, and rash. children will typically show signs/symptoms of mis-c three to four weeks after covid-19 infection and many will progress rapidly into shock and cardiorespiratory failure. families should seek immediate medical care as children with this condition decompensate quickly and most children will need management in an intensive care unit. overall, children will survive this hyperinflammatory condition with administration of ivig, steroids, a multidisciplinary team of healthcare providers, and in some cases immunomodulatory agents. mis-c is rare but the potential long-term sequelae from this disease are currently unknown. the authors declare that the data collected was gathered from publicly available databases and is available upon reasonable request. we declare no competing interests. funding sources: parker b. francis; pilot grant 2r25-hl126140. funding agencies had no role in the writing of the manuscript or the decision to submit. supplementary material associated with this article can be found in the online version at doi:10.1016/j.eclinm.2020.100527. severe acute respiratory syndrome coronavirus 2 (sars-cov-2) infection in children and adolescents: a systematic review clinical, laboratory and imaging features of covid-19: a systematic review and meta-analysis systematic review of covid-19 in children shows milder cases and a better prognosis than adults sars-cov-2 infection in children hyperinflammatory shock in children during covid-19 pandemic guidance: paediatric multisystem inflammatory syndrome temporally associated with covid-19. www.rcpch.ac. uk/resources/guidance-paediatric-multisystem-inflammatory-syndrome-temporally-associated-covid-19 an outbreak of severe kawasaki-like disease at the italian epicentre of the sars-cov-2 epidemic: an observational cohort study emergency preparedness and response: 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children sars-cov-2-induced kawasaki-like hyperinflammatory syndrome: a novel covid phenotype in children case report: systemic inflammatory response and fast recovery in a pediatric patient with covid-19 cardiac mri of children with multisystem inflammatory syndrome (mis-c) associated with covid-19: case series [published online ahead of print immune-inflammatory parameters in covid-19 cases: a systematic review and meta-analysis neutrophil-to-lymphocyte ratio as an independent risk factor for mortality in hospitalized patients with covid-19 clinical value of immune-inflammatory parameters to assess the severity of coronavirus disease 2019 procalcitonin as a marker of the systemic inflammatory response to infection diagnostic value of procalcitonin, interleukin-6, and interleukin-8 in critically ill patients admitted with suspected sepsis interleukin-6 as prognosticator in patients with covid-19 outcomes of cardiovascular magnetic resonance imaging in patients recently recovered from coronavirus disease 2019 (covid-19) high expression of ace2 receptor of 2019-ncov on the epithelial cells of oral mucosa a nomogram to predict the risk of unfavourable outcome in covid-19: a retrospective cohort of 279 hospitalized patients in paris area changes in clinical and laboratory features of kawasaki disease noted over time in daejeon the riddle of kawasaki disease paediatric multisystem inflammatory syndrome temporally associated with sars-cov-2 mimicking kawasaki disease (kawa-covid-19): a multicentre cohort descriptive epidemiology of kawasaki disease in japan pediatric crohn disease and multisystem inflammatory syndrome in children (mis-c) and covid-19 treated with infliximab spectrum of imaging findings on chest radiographs, us, ct, and mri images in multisystem inflammatory syndrome in children (mis-c) associated with covid-19 horizontal transmission of severe acute respiratory syndrome coronavirus 2 to a premature infant: multiple organ injury and association with markers of inflammation paediatric inflammatory multisystem syndrome: temporally associated with sars-cov-2 (pims-ts): cardiac features, management and short-term outcomes at a uk tertiary paediatric hospital sars-cov-2-related paediatric inflammatory multisystem syndrome, an epidemiological study cardiac mri of children with multisystem inflammatory syndrome (mis-c) associated with covid-19: case series multisystem inflammatory syndrome in children associated with severe acute respiratory syndrome coronavirus 2 infection: a multi-institutional study from new york city key: cord-354608-1me3nopu authors: rabinowicz, shira; leshem, eyal; pessach, itai m. title: covid-19 in the pediatric population—review and current evidence date: 2020-09-19 journal: curr infect dis rep doi: 10.1007/s11908-020-00739-6 sha: doc_id: 354608 cord_uid: 1me3nopu purpose of review: coronavirus disease 2019 (covid-19) pandemic has major health and economic impacts. we review disease characteristics in children. recent findings: children comprise 1–2% of the diagnosed cases, and typically suffer mild disease. the median age of infected children is 3.3–11 years, and male/female ratio is 1.15–1.55. common symptoms in children include upper respiratory symptoms (26–54%), cough (44–54%), fever (32–65%), and gastrointestinal (15–30%) symptoms. substantial proportion (4–23%) are asymptomatic. death rates are up to 0.7%. risk factors associated with severe disease are neonatal age group, male gender, lower respiratory tract disease, and pre-existing medical conditions. vertical transmission was reported. multisystem inflammatory syndrome (mis), characterized by fever, multisystem organ involvement, and laboratory markers of inflammation, causes critical illness in > 50% of cases and is increasingly reported from endemic countries. indirect effects of the coronavirus epidemic include higher rates of psychiatric morbidities, education loss, unhealthy lifestyle changes, and increased child neglect. vaccines are in clinical trials and immunogenicity has not yet been shown in children. summary: overall, covid-19 has lower incidence and causes milder disease in children compared with adult patients. mis is a rare severe complication more common in children. more data on the efficacy and safety of antivirals in children are needed. emerging in late 2019, coronavirus disease 2019 (covid -19) has been spreading worldwide, with major health and economic impacts. by mid-august 2020, the world health organization reported over 23 million confirmed cases of infection with sars-cov-2 (severe acute respiratory syndrome coronavirus 2), resulting in more than 710,000 death worldwide [1] . according to current data, children show lower incidence of symptomatic disease and develop a milder course [2] [3] [4] [5] . we review the current evidence of epidemiology, clinical presentation, treatment, and indirect health consequences of sars-cov-2 on children. (pids) for references. the search was restricted to english language publications during january-august 2020. pathophysiology sars-cov-2 is an enveloped, positive sense single-stranded rna virus with a glycoprotein spike (s) on the surface. cell entry requires binding of the s protein to the cellular receptor ace-2 (angiotensin-converting-enzyme-2) and priming of the s glycoprotein by the host cell serine protease tmprss2 [6] . the milder morbidity in children, despite similar or higher viral loads compared with adults [7, 8] , is the focus of multiple studies but has yet to be fully understood. the differences may be partly explained by several characteristics of the pediatric immune system. according to the hypothesis by carsetti et al., the immune system of children is highly prepared to novel pathogens, due to high levels of innate igm antibodies and the ability to rapidly produce natural antibodies with broad reactivity, in addition to the production of the antiinflammatory interleukin (il)-10 by neonatal b cells [9] . additional suggested explanations are alterations in t cell populations in adults due to continuous antigen stimulation and thymic involution, varied levels of ace-2 expression in children, and the simultaneous presence of other viruses in the respiratory mucosa of children, competing with sars-cov-2 [10] . furthermore, children have fewer comorbidities and a stronger pulmonary regenerative potential than adults [11] . disease burden of covid-19 in children is difficult to determine because case definitions for screening, testing, and disease severity in children are not universal and the proportion of asymptomatic infected children is high. in addition, young children attending daycare may contract several febrile and respiratory illnesses in a course of a few months [12] , and it is plausible that sars-cov-2 test is not routinely performed. in reports from countries that were severely affected early in course of the pandemic, children comprise 1-2% the diagnosed covid-19 cases, underrepresented compared with other age groups [3, [13] [14] [15] . the median age of the diagnosed children ranges from 3.3-11 years in different reports, and data shows that children younger than 1 year are disproportionally represented [2, 3, [15] [16] [17] . like in the adult population, there is a male predominance [2, 3, [15] [16] [17] ( table 1) . the contribution of children in spreading the virus through the community is a field of uncertainty, mainly due to the high rates of asymptomatic infection at younger age groups. a recent report found that in only 8% of households of 40 sick children, the child was the suspected index case. in the reminder, the child developed the symptoms following or together with a sick adult [18] . the same finding was seen in a cohort of sick children from china [19] . however, these cohorts may have been evaluated when educational institutes were closed, so children were less likely to contract the disease outside the house. in addition, recent reports show outbreaks in a high school and a summer camp [20, 21] . this is an issue of concern considering recent evidence of equivalent or higher amounts of viral nucleic acid in children < 5 years with mild to moderate disease, compared with older children and adults [8] . as schools worldwide are set to reopen, proposed adjustments of the education system include universal masking, breaking classes into capsules, attendance on alternate days, outdoors classrooms, online lessons, temperature checks, and reconfiguration of ventilation and air conditioning systems [22, 23] . the rate of asymptomatic children, ranging from 4.4-23% of confirmed cases, is higher than reported in adults and most probably represents a significant underestimation as many asymptomatic children are not screened [2, 3, 16, 17] . the clinical presentation in adults ranges from mild illness to severe pneumonia. severe cases may suffer complications including acute respiratory distress syndrome (ards), acute cardiac injury, and thromboembolic complications. patients with severe disease have evidence of hyperimmune response with persistent fevers, elevated inflammatory markers (d-dimer, ferritin), and elevated proinflammatory cytokines [24, 25] . in children, respiratory symptoms are the most common, followed by fever and gastrointestinal symptoms [3, [16] [17] [18] (table 1) . anosmia and ageusia are commonly described in adults [26] but may be more difficult to elicit in young children and thus underreported [27] . the rate of children with critical illness ranges from 0.4-9% of confirmed cases, probably reflecting population bias since some reports include mainly patients diagnosed in hospitals [3, 4, [15] [16] [17] . data from the usa indicates a hospitalization rate of 8 per 100,000 population in children < 18 years, much lower than 164.5 per 100,000 in adults. however, a third of the hospitalized children required admission to the intensive care unit (icu) [28] . the analysis of critical patients may indicate which children are at higher risk. in various reports, half of the children admitted to the icu had an underlying medical condition [15-17, 28, 29] . factors associated with icu admissions were neonatal age group, male gender, lower respiratory tract disease, and pre-existing medical conditions [17] . infants aged < 3 months comprised 19% of the hospitalized children in a recent report from the usa. however, this may have been due to the diagnosis of neonatal fever and not due to disease severity [28] . because these data are driven from potentially biased datasets with over representation of symptomatic children, the association of young age and severity needs to be further investigated. death ensued in 0-0.7% of diagnosed children [2, 3, [14] [15] [16] . in the european cohort of 582 children aged 0-18 years, four children died, all were older than 10 years, two had no pre-existing medical conditions, one had undergone human stem cell transplant (hsct) 15 months earlier, and the other patient's condition was not specified [17] . in a multinational study from north america on children hospitalized in the icu, two patients, aged 12 and 17 years, died; both had unspecified pre-existing comorbidities and 1 had also prior gram-negative sepsis [29] . in a cohort from new york, one patient with metastatic malignancy died [30] . two cohorts from china reported one death each-a 10-month-old baby with intussusception [16] and a 14-year-old boy with no further details [2] . because mortality rates in pediatric cohorts are low, it is difficult to define risk factors and disease course leading to fatal result in pediatric population. a more distinct population among the pediatric population are neonates. early reports showed that infants of mothers infected in the last trimester have normal course and that amniotic fluid, umbilical cord blood, throat swab, and breast milk were negative to the virus [31, 32] . however, more recent reports show clinical infections in neonates and suggest prevention procedures, such as isolation of the infant and physical barriers after the delivery [33] [34] [35] . recently, vertical transmission with high placental viral load and neonatal compromise requiring resuscitation was documented [36] . when screening neonates, a possible contamination of the neonatal swab by maternal sars-cov-2 should be taken into account [37] , in addition to transmission of an undiagnosed maternal infection after birth. in a review of cases in the neonatal period, most of them were asymptomatic (20%) or had mild (48%) and moderate (20%) signs of clinical infection. the rate of severely ill patients was higher compared with older children (12% vs. up to 9% in the general pediatric population aged < 18 years). dyspnea was the most common sign (40%), followed by fever (32%) and feeding intolerance (24%) [4] . since may 2020, several highly endemic countries reported an exceptional high incidence of multisystem inflammatory syndrome (mis) in children [38] [39] [40] [41] [42] [43] . several case definitions were proposed, all include fever, elevated inflammatory markers, and organ dysfunction not attributed to another infectious cause ( table 2) . a minority of patients had been symptomatic prior to onset of mis onset, and the median interval from covid-19 symptom onset to mis onset is 25 days [44] . the higher rate of positive serologic tests compared with nasopharyngeal reverse transcription-polymerase chain reaction (rt-pcr) is suggestive of a late complication of the disease (table 3 ) [38, 39, 41, 44, 45] . according to the centers for disease control and prevention (cdc) report, in 27% of the patients, both were positive. similar to the acute covid-19 [30] , obesity is a risk factor for mis, present in a quarter of the patients in the cdc report [43] . suggested mechanisms for mis include viral mimicry, formation of immune complexes, and host immune cell activation due to viral superantigen sequences [46] . besides fever, the most common presentations of mis are gastrointestinal (diarrhea, vomiting, abdominal pain), cardiovascular, mucocutaneous (rash, mucus membrane changes, conjunctival injection), respiratory (including sore throat), headache, and limb and periorbital edema [39, 43, 44] . associated laboratory findings are elevated inflammation markers (neutrophilia, c-reactive protein, ferritin, erythrocyte sedimentation rate), thrombocytopenia, lymphopenia, elevated troponin and n-terminal pro-b-type natriuretic peptide (nt-probnp), hypertriglyceridemia, and elevated d-dimer and fibrinogen. some patients meet the criteria for macrophage activation syndrome (mas). the disease course is typically severe, with high rates of icu admissions, mechanical ventilation, and death (table 3) . severe course is characterized by shock, and coronary aneurysms [39, 41, 43, 44, 47, 48] . in addition to supportive care, children diagnosed with mis were treated with intravenous immune globulin ± aspirin, glucocorticoids, il-6 receptor antagonist, il-1 receptor antagonist, and tnf-α antagonist [48] . in the larger cohorts, from the usa, 2% of the patients died, one of them reported that half of them had underlying medical conditions [43, 44] . the clinical presentation was compared with that of kawasaki disease. however, children diagnosed with mis were older [38, 39, 44, 47] , showed a greater elevation of inflammatory markers [39] , and more frequent cardiovascular hemodynamic involvement [38, 44, 47] . treatment in children infected with sars-cov-2 consists mainly on supportive care, including oxygen and advanced respiratory support, hydration, and antipyretics [49, 50] . metered dose inhalers are preferred over nebulizers due to the decreased risk of virus dissemination [49, 51] . the inclusion of children in early phase clinical trials of novel agents is usually delayed; hence, trial data regarding efficacy and safety are scarce [52] . antiviral and antiinflammatory drugs may be considered in severely ill children and those at higher risk for severe disease, preferably as part of a clinical trial. severe disease is often associated with hyperinflammation and cytokine storm that may lead to acute respiratory distress syndrome [49, 53] . hence, medications targeted to the immune system were suggested, in addition to antivirals. several medications were used in hospitalized children [28, 29] , but not in the context of a clinical trial, making it difficult to accurately assess their outcome. the antiviral agent remdesivir was suggested as the preferred agent for treating covid-19 in children [50] . this is an adenine nucleoside analogue that interferes with the virus' rna-dependent rna polymerase. remdesivir was used in children suffering ebola infection, but pediatric safety data were not separately reported [54] . studies in adults showed it may have some benefit [55] [56] [57] , and clinical trials including children are ongoing. currently, the nih recommends using remdesivir in adults with severe disease [58] . the drug is available through the us food and drug administration emergency use authorization and compassionate use requests are reviewed by the manufacturer [59] . a clinical trial is currently evaluating the pharmacokinetics in children [58] . dexamethasone was found in the randomized-controlled uk-based recovery trial to reduce mortality in patients who require respiratory support [60] . despite the enrolment of children, it is not clear if the analysis included children, so further data is still needed. the nih guidelines state that dexamethasone may be beneficial in pediatric patients who require mechanical ventilation and suggest treatment according to individual considerations in milder cases [58] . another potential adjunctive therapy for covid-19 is convalescent plasma, with only scarce experience in adults [58, 61, 62] . shekerdemian et al. reported the use of convalescent plasma in a child, but the results were not discussed [29] . currently, there are insufficient data to recommend either for or against the use of convalescent plasma for the treatment of covid-19. clinical trials of covid-19 convalescent plasma in children are ongoing [58] . other drugs were initially suggested for the treatment of covid-19 and their use in infected children was reported [28, 29] . however, current recommendations are against their use due to questionable safety and efficacy [58] . the antiviral lopinavir/ritonavir (kaletra) is a protease inhibitor used for treatment of hiv infection, including young infants. its suggested mechanism of action is inhibition of the sars-cov-2 proteinases papain-like proteinase and 3c-like proteinase, which are key enzymes in polyprotein processing [50] . the nih recommends against its use outside of clinical trials in covid-19 due to lack of proven efficacy and concerns on its pharmacodynamics [63] . hydroxychloroquine was suggested as another potential treatment. it was previously shown to inhibit sars-cov-2 entry into cells and interfere with the glycosylation of the ace-2 receptor (virus' binding site) and inhibit its spread [64, 65] , and has additional host immunomodulatory effects [61] . there is no solid evidence for its efficacy in adults [66] . the drug is available and was previously used to treat children in other indications. due to substantial risk of qt prolongation, it is not recommended combining hydroxychloroquine with azithromycin. patients with known g6pd deficiencies should be monitored for hemolysis [50] . shekerdemian et al. reported its use in almost half of a cohort of children hospitalized in intensive care units in north america, but there is no analysis of the outcome of the specific treatment [24] . the nih recommends against its use except for clinical trials [58] . tocilizumab, an il-6 receptor antagonist, was used in adults with cytokine storm and hyperinflammation due to sars-cov-2 with conflicting results [53, [67] [68] [69] , and in a small number of children admitted to icu, but the outcome was not specified [29] . it is fda approved to treat cytokine release syndrome in children 2 years of age and older, and in the recovery trial used in children > 1 year [52, 70] . screening and monitoring infectious complications especially latent tuberculosis should be performed prior and during therapy [69] . the nih recently recommended against the use of il-6 inhibitors for the treatment of covid-19, except for clinical trials [58] . however, reports suggest its use in children who develop multisystem inflammatory syndrome (discussed later). other potential treatments are currently under evaluation, including antiil-1 (anakinra), interferon-beta, and ivermectin [49, 58, 61] . following the concern regarding the consequences of sars-cov-2 infection in children with chronic diseases, several guidelines were published. a statement endorsed by the us pediatric infectious diseases society has recently proposed that children with severe immunocompromise, severe cardiac, or severe pulmonary diseases may be more likely to experience severe covid-19 disease. obesity and diabetes should be also taken into account, especially with comorbidities [50] . the european academy of allergy and clinical immunology recommends treating children with allergic asthma, allergic rhinitis, or other allergy conditions according to usual guidelines. one exception to this is the advice to withhold biologics (antiil-5rα, il-4rα, and omalizumab) during acute covid-19 disease, since they are directed towards type 2 response, which may counteract the "cytokine storm" seen in severe covid-19 [71, 72] . the global initiative for asthma (gina) recommends continuation of inhaled asthma treatment and treatment with biologic therapies if needed. treatment with oral corticosteroids should be administered in the lowest possible dose in patients at risk of severe attacks [51] . patients with immunodeficiency, either primary, secondary to other diseases or medical treatments, are advised to strictly follow national precaution recommendations and in case of a suspected infection be in touch with their physician [71] . clear data regarding the severity of the disease in immunocompromised children are lacking. previously, immunocompromised children showed increased risk for severe lower respiratory tract disease due to seasonal coronaviruses [73 • ]. on the contrary, a report from bergamo, italy, stated that children who underwent liver transplant did not develop clinical pulmonary disease during the outbreak [74] . in adults, patients with malignancy and solid organ transplant recipients may be at increased risk of severe covid-19 disease and death. evidence regarding other types of immunocompromise is scarce [75] . according to the guidance endorsed by the pediatric infectious diseases experts, patients with mild to moderate immunodeficiency were not proven to be at increased risk, and those severely immunocompromised (e.g., severe combined immunodeficiency, < 100 days post-allogenic-hsct, hiv infection with cd4 count < 15% or < 200/mm 3 , treatment with costimulation inhibitors like belatacept or abatacept, highdose corticosteroids, and more conditions) should be considered for antiviral treatment. the panel suggests reducing t cell immunosuppression in infected children [50] . beyond the physiological manifestation of covid-19, other pediatric health issues during this pandemic bear mention. data show that lockdown, combined with intense fear of covid-19 contagion, led to a dramatic decrease in patients seeking medical care for other emergent issues [76] [77] [78] . in addition, ambulatory and screening services were postponed, including routine immunizations given to infants and children [79] . lower immunization rates may diminish herd immunity for some vaccine preventable diseases and lead to the reemergence of other infectious diseases in children. this trend may wane as the epidemic continues and routine health seeking behaviors resume. masking of the medical staff poses another barrier for the routine medical care of children, making communication with pediatric patients challenging [80] . school closure was a major step of infection control in many countries, affecting over 1.6 billion learners [81] . the consequences to the child's well-being of these steps are numerous: learning loss, (especially for those in low-income settings), lack of access to school-provided social assistance, reduced physical activity, and a significant harm to social life. in low-and middle-income countries, where access to education may be limited, some children may drop out as a result of the indirect impact of the outbreak [81, 82] . following school reopening, frontal teaching is partially replaced by remote online lessons. despite its innovative nature, this mode of studying is impossible to children affected by a lack of resources and requires extreme effort from children dealing with attention deficit hyperactivity disorder (adhd) [83] . a study from china found that children's adhd behaviors significantly worsened during covid-19 outbreak in comparison with their normal state [84] . the european adhd guidance group (eagg) adjusted its protocol, and frontal cardiovascular exam is no longer needed to initiate drug therapy, given normal personal and familial cardiac history and normal blood pressure and heart rate [85] . additional effects of the epidemic on mental health include anxiety and depression [86] [87] [88] . a survey among chinese school-aged children during lockdown revealed higher rates of anxiety and depression than usual [89] . safe, secure, and supportive domestic environment for children requires engaged parenting. however, during these times, parents are challenged by unemployment, remote work, economic instability, home confinement, health worries, and home-learning of their children [90, 91] . thus, children are at higher risk than usual to neglect abuse and domestic violence [91] [92] [93] . despite increased incidence of child abuse and neglect during covid-19 pandemic [93, 94] , the number of official reports to maltreatment lines in a few us states decreased sharply, raising a concern of under-reporting due to decreased contact with the insulted children. spotting signs for abuse and assessing home safety through distance learning should be practiced [93] . the economic impact of the pandemic is likely to deepen unemployment and poverty worldwide. the resultant food insecurity and malnutrition are concerning [95, 96] , particularly in young children who are the most vulnerable to its consequences [97] . on the other hand, in wealthier countries, quarantine, social distancing, and parental difficulties led to unhealthy lifestyle modifications among adolescents with increased consumption of unhealthy foods and reduction in physical activity that may lead to obesity and sleep disorders [98] [99] [100] [101] [102] . suggested steps to encourage physical activity during this period include incorporating physical activity into children's daily routine, using electronic devices for engaging children to physical activity, encouraging family members to join ongoing activities, and avoiding extended sitting [101] . the standard precautions face masks, hand hygiene, and social distancing are extremely difficult to implement in young children. alcohol-based hand sanitizers contain above 60% ethanol, and according to the cdc should be used with adult supervision in children under 6 years of age. the use of masks may be cumbersome in children. the minimal proposed age for mask use is 2 years old. in younger ages, the smaller airways may interfere with breathing and the child may be unable to remove the mask on his own. in older children, size fitted mask and education on appropriate mask removal are needed [103] . over 140 sars-cov-2 vaccine candidates are currently evaluated, including nucleic acid-based, viral vector vaccines, and inactivated or recombinant protein vaccines. most of them focus on immunity against the viral spike (s) glycoprotein [104, 105] . results of three vaccine trials were recently published: a phase 1 trial of an mrna vaccine that encodes the s glycoprotein [105] , a phase 1 trial of a recombinant adenovirus type-5 vectored expressing the s glycoprotein [106] , and a phase 1/2 trial of a chimpanzee adenovirus-vectored vaccine expressing the s glycoprotein (chadox1 ncov-19) [107] . all showed both humoral and cellular immunogenicity to the spike glycoprotein. the most common reported side effects include fatigue, headache, and fever, with higher rates compared with other vaccines [105] [106] [107] . none of the trials included children. in summary, children at any age may be infected with sars-cov-2, with reduced frequency and severity compared with adults, although clear epidemiologic data is still missing. in addition, the recently identified mis may pose an additional threat. data on the outcome of antiviral treatments, the safety and immunogenicity of vaccinations, and better specification of high-risk patients in the pediatric population are still needed. as the pandemic continues to evolve, it is still hard to fully assess or forecast the mid-and long-term effects of the resulting significant changes to society, economics, and human behavior on future child health and well-being. it is important that both medical and social efforts focusing on the pediatric population are undertaken to protect the children of the world allowing them to fulfill their enormous potential. conflict of interest shira rabinowicz, itai m. pessach and eyal leshem declare that they have no conflict of interest. human and animal rights and informed consent this article does not contain any studies with human or animal subjects performed by any of the authors. epidemiology 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play behaviours of canadian children and youth: a national survey promoting healthy movement behaviours among children during the covid-19 pandemic available from reduced physical activity during covid-19 pandemic in children with congenital heart disease to mask or not to mask children to overcome covid-19 draft landscape of covid-19 candidate vaccines an mrna vaccine against sars-cov-2 -preliminary report safety , tolerability , and immunogenicity of a recombinant adenovirus type-5 vectored covid-19 vaccine : lancet articles safety and immunogenicity of the chadox1 ncov-19 vaccine against sars-cov-2 : a preliminary report of a phase 1 / 2 , single-blind publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord-293367-0fe62h2f authors: henderson, lauren a.; canna, scott w.; friedman, kevin g.; gorelik, mark; lapidus, sivia k.; bassiri, hamid; behrens, edward m.; ferris, anne; kernan, kate f.; schulert, grant s.; seo, philip; f. son, mary beth; tremoulet, adriana h.; yeung, rae s.m.; mudano, amy s.; turner, amy s.; karp, david r.; mehta, jay j. title: american college of rheumatology clinical guidance for pediatric patients with multisystem inflammatory syndrome in children (mis‐c) associated with sars‐cov‐2 and hyperinflammation in covid‐19. version 1 date: 2020-07-23 journal: arthritis rheumatol doi: 10.1002/art.41454 sha: doc_id: 293367 cord_uid: 0fe62h2f objective: to provide guidance on the management of multisystem inflammatory syndrome in children (mis‐c), a condition characterized by fever, inflammation, and multiorgan dysfunction that manifests late in the course of sars‐cov‐2 infection. the task force also provided recommendations for children with hyperinflammation during covid‐19, the acute, infectious phase of sars‐cov‐2 infection. methods: the task force was composed of 9 pediatric rheumatologists, 2 adult rheumatologists, 2 pediatric cardiologists, 2 pediatric infectious disease specialists, and 1 pediatric critical care physician. preliminary statements addressing clinical questions related to mis‐c and hyperinflammation in covid‐19 were developed based on evidence reports. consensus was built through a modified delphi process that involved 2 rounds of anonymous voting and 2 webinars. a 9‐point scale was used to determine the appropriateness of each statement (1‐3, inappropriate; 4‐6, uncertain; 7‐9, appropriate), and consensus was rated as low (l), moderate (m), or high (h) based on dispersion of the votes along the numeric scale. approved guidance statements had to be classified as appropriate with moderate or high levels of consensus, which were pre‐specified prior to voting. results: a total of 128 statements were approved by the task force, which were refined into 40 final guidance statements accompanied by a flow diagram depicting the diagnostic pathway for mis‐c. conclusion: our understanding of sars‐cov‐2‐related syndromes in the pediatric population continues to evolve. this guidance document reflects currently available evidence coupled with expert opinion but is meant to be modified as additional data become available. since its initial description in december 2019 in wuhan china, coronavirus disease 2019 , caused by infection with severe acute respiratory syndrome coronavirus 2 (sars-cov-2), has rapidly evolved into a worldwide pandemic affecting millions of lives.(1) unlike adults, the vast majority of children with covid-19 have mild symptoms. however, there are children who have significant respiratory disease, and some children may develop a hyperinflammatory response similar to what has been observed in adults with covid-19. furthermore, in late april 2020, reports emerged of children with a different clinical syndrome resembling kawasaki disease (kd) and toxic shock syndrome; these patients frequently had evidence of prior exposure to sars-cov-2. (2, 3) subsequent to these initial reports from italy and the united kingdom, multiple case series from europe and the united states have surfaced describing a similar phenomenon.(4-10) while this constellation of symptoms has been given many names, for the purposes of this discussion we will use "multisystem inflammatory syndrome in children" (mis-c). for a number of reasons, there is an urgent need to provide guidance to healthcare providers evaluating patients in whom mis-c is a diagnostic consideration. these reasons include: 1) variable case definitions for mis-c; 2) the clinical description of mis-c is limited to case series; 3) mis-c clinical features may also be seen in infectious, malignant, and other rheumatologic entities; 4) suggested treatment strategies have relied on extrapolation from other inflammatory or rheumatologic conditions presenting similarly; 5) myocardial dysfunction may present insidiously but is a major source of morbidity and mortality in mis-c. in addition, pediatric rheumatologists are often asked to recommend immunomodulatory therapy for patients with a hyperinflammatory state due to acute sars-cov-2 infection. therefore, the american college of rheumatology (acr) convened the mis-c and covid-19-related hyperinflammation task force on may 22, 2020, charged by acr leadership to provide guidance to clinicians in the evaluation and management of mis-c and covid-19-related hyperinflammatory syndromes. clinical guidance generated from this effort is intended to aid in the care of individual patients, but it is not meant to supplant clinical decision-making. modifications to treatment plans, particularly in patients with complex conditions, are highly disease-, patient-, geography-, and time-specific and, therefore, must be individualized as part of a shared decision-making process. this article is protected by copyright. all rights reserved 2020, participants agreed with the importance of addressing these 4 overarching topics as well as the structure of the workgroups. the first webinar was used to confirm the target audience for the guidance, which focuses on clinicians in north america managing pediatric patients with inflammatory syndromes related to recent or concurrent infections with sars-cov-2. notably, the task force deliberately did not attempt to create a new case definition for mis-c as several already exist (table 1) (4) (5) (6) . instead, the task force elected to leverage consensus building to identify the most appropriate diagnostic and therapeutic steps that providers should consider at the present time. all panelists agreed to develop consensus through a modified delphi process that involved 2 rounds of asynchronous, anonymous voting and 2 webinars to discuss voting results. evidence review. from may 22-may 29, 2020, the workgroups developed preliminary recommendation statements within their assigned topic based on expert opinion and evidence reviewed from publications listed in pubmed, scientific briefings from the world health organization (who), health alerts from the centers of disease control and prevention (cdc), and guidance provided by the royal college of paediatrics and child health (rcpch). each workgroup generated an evidence report supporting the recommendations that was shared with the entire task force. this article is protected by copyright. all rights reserved the task force evaluated a total of 125 statements in the first round of voting that addressed the management of mis-c and hyperinflammation in pediatric patients with covid-19. of these, 112 statements met the criteria for approval with a median score of 7-9 and moderate or high consensus while 13 statements were rated as uncertain (median score [4] [5] [6] . after refining the statements based on the input from the initial phase, 128 guidance statements were approved in round 2 voting (supplemental table 1 -4) . these statements were organized into 40 final guidance statements accompanied by 1 figure, which were approved by the entire task force and the acr board of directors. (12) topics covered in the guidance include: 1) diagnostic evaluation of mis-c (table 2, (table 7) . our understanding of sars-cov-2-related syndromes in the pediatric population continues to evolve. the recommendations provided by the task force reflect expert opinion and currently available evidence, which is of low quality and based on a limited number of case series and retrospective cohort studies. thus, this guidance is meant to be a "living document" and will be modified as additional data become available. the recommendations provided in the guidance document do not replace the importance of clinical judgment tailored to the unique circumstances of an individual patient. maintaining a broad differential diagnosis. multiple case definitions for mis-c have been proposed, some of which are broader than others (table 1) . (4) (5) (6) common clinical features of mis-c include fever, mucocutaneous findings (rash, conjunctivitis, edema of the hands/feet, red/cracked lips, and strawberry tongue), myocardial dysfunction, cardiac conduction abnormalities, shock, gastrointestinal symptoms, and lymphadenopathy. (2, (7) (8) (9) (10) (13) (14) (15) (16) (17) (18) there are also increasing reports of neurologic involvement, manifesting as severe headache, altered mental status, cranial nerve palsies, or meningismus, in select patients. (8-10, 13, 14) these findings are non-specific and can occur in other infections as well as non-infectious etiologies such as oncologic or inflammatory conditions. therefore, it is imperative that a diagnostic evaluation for mis-c include investigation for other possible causes as deemed appropriate by the treating provider. mis-c is temporally this article is protected by copyright. all rights reserved associated with sars-cov-2 infections, and clusters of cases have been reported in geographic areas with dense covid-19 disease burden, typically 2-6 weeks after the peak incidence of acute, infectious covid-19 cases. (7, 13, 14, 17) thus, the prevalence and chronology of sars-cov-2 infection in a given location, which may change over time, should also inform the diagnostic evaluation. the incidence of mis-c is unknown; however, it appears to be a rare complication of sars-cov-2 infections with some estimating that mis-c occurs in 2 out of 200,000 individuals under the age of 21 years. (19) the relative rarity of mis-c should also be considered in the diagnostic approach. tier 1 screening evaluation for mis-c. based on our review of the literature and diagnostic algorithms that are publicly available, the task force chose to cast a broad net with respect to the evaluation of patients with possible mis-c while simultaneously balancing the need to reduce indiscriminate over-testing and unnecessary use of resources on pediatric patients who have unrelated causes for fever. (2, 7, 8, 10, 13-16, 20, 21) to date, there are no clear data indicating the pre-test positive or negative predictive probabilities for each clinical symptom or laboratory value in diagnosing mis-c. it should be noted that due to the paucity of data, our recommendations reflect a multidisciplinary consensus that is likely to be revised as these data become available. children with fever, an epidemiologic link to sars-cov-2, and suggestive clinical symptoms should be considered "under investigation" for mis-c while alternative diagnoses that could explain the patient's clinical presentation are also explored ( figure 1) . a tiered diagnostic approach is recommended in patients without life-threatening manifestations; this includes performing an initial screening evaluation (tier 1), and proceeding to a complete diagnostic work-up (tier 2) only in patients with laboratory results from the tier 1 screening that are concerning. tier 1 consists of laboratory studies that are easily obtained at most clinical facilities (complete blood cell count with manual differential, complete metabolic panel, erythrocyte sedimentation rate (esr), c-reactive protein (crp), and testing for sars-cov-2 by pcr or serology). the overwhelming majority of mis-c cases reported in the literature have elevated inflammatory markers, particularly crp, as values higher than 10 mg/dl or even 20 mg/dl are common. (2, 7-9, 13, 14, 17) thus, to enter the second stage of testing, children should have elevated esr and/or crp and at least 1 other suggestive laboratory feature: lymphopenia, neutrophilia, thrombocytopenia, hyponatremia, or hypoalbuminemia. (2, 7-9, 13, 14, 17) this article is protected by copyright. all rights reserved tier 2 evaluation for mis-c. tier 2 encompasses more complex testing that typically requires additional time to complete. reports in the literature and unpublished observations by members of the panel both note that some patients with mis-c can decompensate rapidly; however, the risk factors that predispose patients to such severe and progressive illness have not been identified.(10, 13) accordingly, children with abnormal vital signs, concerning physical examination findings, significantly elevated inflammatory markers, or signs of cardiac involvement will need to be admitted to the hospital for supportive care while tier 2 testing is completed. the panel also noted that mis-c appears to be a continuum of disease that encompasses milder phenotypes that have not been fully represented in the published literature. some patients present with fever, rash, and systemic inflammation and no other organ damage. while these children require close monitoring, they do not always need to be hospitalized. thus, in some cases, well-appearing children with reassuring vital signs and physical examinations may be suitable for outpatient diagnostic evaluations as long as close clinical follow-up can be assured. prominent cardiac involvement has been reported in a proportion of mis-c patients in every retrospective cohort study published to date. (2, 7-9, 13, 14, 17) these include left ventricular (lv) dysfunction, coronary artery dilation or coronary artery aneurysms (caa), and electrical conduction abnormalities. valvular dysfunction and pericardial effusion are less frequently described. among the initial descriptions of mis-c, lv dysfunction was present in 20-55% of cases and coronary artery dilation or caa in ~20%. (2, 7, 13) although the early reports may overestimate the incidence of cardiac features as they likely represent the most severe component of the mis-c spectrum, these numbers nonetheless highlight the significant risk of cardiac involvement in mis-c. for these reasons, ekg and echocardiogram are key components of the full diagnostic evaluation. the echocardiogram should include quantification of lv size and systolic function using end-diastolic volume (and z-score) and ejection fraction (ef). (22, 23) detailed evaluation of all coronary artery segments and normalization of coronary artery measurements to body surface area using z-scores is necessary. (23, 24) cardiac laboratory values at the time of diagnosis, specifically troponin t and btype natriuretic peptide (bnp)/n-terminal-probnp, may help identify patients with cardiac sequelae from mis-c. (7-9, 13, 14, 17) in particular, highly elevated bnp/nt-probnp may be helpful in distinguishing between mis-c patient with and without lv dysfunction; however, mild and transient elevations in these laboratory parameters are likely non-specific and do not necessarily indicate accepted article cardiac involvement. (14, 25, 26) bnp, in particular, is an acute phase reactant and, therefore, may be elevated in inflammatory conditions without cardiac involvement. (25) tier 2 testing should also include further assessment for systemic inflammation. in addition to esr and crp, mis-c patients typically demonstrate other markers of inflammation including high ddimer levels, moderately elevated ferritin (often ranging from 500-2,000 ng/dl), profoundly increased procalcitonin levels in the absence of bacterial infection, and increased lactate dehydrogenase (ldh). (8-10, 13, 14, 17) cytokine panels, when available, can assist in the diagnostic evaluation as il-6, tumor necrosis factor (tnf), or il-10 are often increased; however, cytokine levels measured in this manner should not dictate treatment choices and are not required to determine treatment plans. (8, 9, 13) finally, sars-cov-2 serologies have been reported positive in a greater proportion (80-90%) of mis-c patients than pcr testing (20-40%) and both should be sent to evaluate the epidemiologic link to the infection.(7-9, 13, 17) in an early sentinel report from bergamo, the italian epicenter of the covid-19 pandemic, kd and kd-like illnesses were observed at a rate 30 times higher than the pre-pandemic era. this article is protected by copyright. all rights reserved 20% of mis-c patients and at least 3 patients have developed giant caas. (2, 7, 13, 14, 17) it is unknown if the incidence or progression of caas differ in mis-c as compared to kd. importantly, it is clear that mis-c patients without kd symptoms can develop caas, highlighting the need for cardiac evaluation in all patients with mis-c regardless of phenotypic features, and providing support for the treatment rationale discussed below. (14) fourth, although gastrointestinal and neurologic symptoms are reported in kd, the panel felt that these findings were more frequently encountered in the mis-c population. finally, laboratory parameters that differ in retrospective mis-c cohorts compared to historical kd cohorts include lower platelet counts and absolute lymphocyte counts and higher crp levels. (7, 14) children with mis-c will need close clinical follow-up with cardiology. extrapolating data from kd, another condition that can be complicated by caa, the panel recommended that all children with mis-c undergo repeat echocardiograms at a minimum of 7-14 days and then 4-6 weeks after the initial presentation. (22) for those patients with cardiac involvement noted during the acute phase of illness, another echocardiogram at 1 year after mis-c diagnosis could be considered. children with lv dysfunction and caas will require more frequent echocardiograms. although lv function improves rapidly in most mis-c patients, the long-term complications of myocardial inflammation in this syndrome are not known and may include myocardial fibrosis and scarring that has been seen in other forms of pediatric myocarditis.(9, 13, 33) cardiac magnetic resonance imaging at 2-6 months post-acute illness in those patients who had moderate to severe lv dysfunction will allow for evaluation of fibrosis and scarring. electrical conduction abnormalities are increasingly noted in mis-c patients and may develop after the initial presentation; therefore, ekgs should be performed at a minimum of every 48 hours in patients who are hospitalized and at each follow-up visit. (8, 9, 13, 14) if conduction abnormalities are present, the patient should be placed on telemetry while in the hospital and may need holter monitoring at clinical follow-up. immunomodulatory treatment in mis-c. goals of treatment in the mis-c population are to stabilize patients with life-threatening manifestations such as shock and prevent long term sequelae accepted article that may include caas, myocardial fibrosis/scarring, and fixed cardiac conduction abnormalities. there is no available literature that directly compares therapeutic approaches in mis-c. recommendations approved by the task force are derived from experience in managing mis-c patients and higher quality data in other pediatric conditions with similar features. initiation of treatment will often depend on the severity of the patient's presentation. there was consensus among the panelists that patients under investigation for mis-c without life-threatening manifestations should undergo a diagnostic evaluation for mis-c as well as other possible infectious and non-infectious etiologies before immunomodulatory treatment is initiated. this is to prevent the use of therapies that could be potentially harmful in patients who do not have mis-c. further, a subgroup of patients with mis-c will develop progressive cardiac involvement rapidly; therefore, hospital admission and sequential monitoring of inflammatory markers, bnp/ nt-probnp, and troponin t without instituting treatment can sometimes inform the diagnostic evaluation.(10, 13) children with a life-threatening presentation such as shock will clearly require supportive care and may benefit from early initiation of immunomodulatory treatment, sometimes before a full diagnostic evaluation can be completed. in such cases, ongoing diagnostic evaluation should be pursued with a multidisciplinary team in parallel with treatment. finally, the current recommendations address the treatment of mis-c that is uncomplicated by macrophage activation syndrome (mas). importantly, there is a subgroup of patients with mis-c who may also develop overt mas and the treatment of those patients may need to deviate from the recommendations presented in this document. (7) a stepwise approach to immunomodulatory treatment in mis-c is recommended, with intravenous immunoglobulin (ivig) and/or glucocorticoids considered first tier agents. both ivig and glucocorticoids, either alone or in combination, are the most commonly used immunomodulatory medications in mis-c patients reported to date.(2, 7-10, [13] [14] [15] 17) there is insufficient data available to compare the efficacy of ivig vs. glucocorticoids in mis-c or to determine if these treatments should be provided individually or as dual therapy. accordingly, the task force recommended that ivig and glucocorticoids could be used alone or in combination to treat mis-c. evidence for ivig and glucocorticoids in mis-c is also based on their use in kd and fulminant myocarditis, two conditions that resemble mis-c in some aspects. ivig at a dose of 2 gm/kg prevents caas in kd while the benefit of ivig in myocarditis remains unclear; however, case reports of successful use of ivig in coronavirus associated myocarditis have been published. (22, 32, (34) (35) (36) (37) (38) (39) (40) before ivig is given, cardiac function and fluid status should be assessed. if abnormal, the rate of accepted article ivig infusion may be slowed or treatment delayed until cardiac function is restored. glucocorticoids reduce rates of caa development when used in kd patients at high risk for ivig resistance. (41, 42) compared to a historic kd cohort, verdoni and colleagues reported a high rate of ivig resistance in kd patients who presented during the covid-19 pandemic, which may suggest a role for glucocorticoids in mis-c. (7) panelists reported that low to moderate doses (1-2 mg/kg/day) of glucocorticoids were sufficient to treat many mis-c patients. some children with shock, requiring multiple inotropes and/or vasopressors, have responded best to high doses of intravenous severe covid-19 in children. the task force also addressed immunomodulatory treatment in severe covid-19, which panelists felt (given current information) was readily distinguishable from this article is protected by copyright. all rights reserved recovery trial) report that low to moderate dose dexamethasone significantly reduced mortality in covid-19 patients requiring mechanical ventilation; but was reported after voting had occurred.(90, 91) based on these studies that suggest that patients with severe covid-19 pneumonia may benefit from immunomodulation with glucocorticoids, the task force achieved moderate consensus that glucocorticoid treatment could be considered in pediatric patients with severe covid-19 and signs of hyperinflammation. targeted neutralization of inflammatory cytokines is another approach that can be employed to reduce pathologic inflammation in covid-19. in contrast to glucocorticoids, the panel was able to achieve high consensus on considering anakinra (recombinant human il-1 receptor antagonist) for pediatric patients with covid-19 and hyperinflammation. anakinra appears to be safe in severe infections based on results of a randomized controlled trial in sepsis that showed no difference in adverse events in the anakinra arm compared to the placebo group.(49) further, a re-analysis of data from this trial in sepsis showed increased survival in patients treated with anakinra who also had excessive inflammation manifested as hepatobiliary dysfunction and coagulopathy, which is commonly seen in covid-19. our group agreed that the features of severe covid-19 were sufficiently similar between the described adult and pediatric cases to cautiously extrapolate from adult studies. overall, the consensus among panelists was that immunomodulatory treatment should be considered in pediatric patients with hyperinflammation and severe symptoms in the acute phase of illness. while the data are still too sparse to make definitive recommendations based on high quality evidence, the panel favored the use of anakinra in this setting. there has been an evolution in our understanding of sars-cov-2 infections in children. initially, it was believed that covid-19 was almost entirely benign and of little consequence in the pediatric population. there has been a sudden reversal from this stance in the context of the emergence of mis-c cases. the goals of this acr task force were to synthesize available data and expert opinion to provide a resource for clinicians on the frontlines caring for children with inflammatory syndromes due to recent or concurrent infections with sars-cov-2. recognizing the need to address the unique challenges facing children with inflammatory conditions triggered by sars-cov-2 infections, the acr convened the task force to provide guidance in a short period of time. to accomplish this charge, a multidisciplinary panel was assembled that included clinicians from north america with expertise encompassing pediatric rheumatology, cardiology, infectious disease, and critical care. well established methodology in the form of the rand/ucla appropriateness methods was used to achieve consensus. there are limitations inherent in our approach. given the need for expedited decision making, we were unable to provide guidance on all topics of interest. in particular, the task force focused its efforts on providing diagnostic and treatment recommendations for mis-c instead of developing a new case definition for this condition. this choice was made because several case definitions for mis-c exist and the data needed to develop a sensitive and specific set of criteria are not yet available. the guidance provided in this document is targeted to clinicians with access to complex diagnostic tools and biologic treatments. thus, some of the recommendations are not practical in less resource rich settings. the task force recognizes the need to provide support to our international colleagues and this article is protected by copyright. all rights reserved plans to provide additional recommendations for developing countries in subsequent versions of this guidance. in addition, the work product of the task force is considered guidance instead of formal treatment guidelines that must adhere to the strict methodology endorsed by the acr. the guidance provided in this document is supported by reports from the scientific literature and recommendations from public health institutions. yet, available data remains restricted to low quality evidence that often must be extrapolated from the experience in adults. this approach is particularly problematic when confronting clinical questions regarding mis-c, which to date has been reported primarily in children. this unique manifestation of covid-19 in children and adolescents highlights the need to prioritize and fund rigorous research in the pediatric population. for now, our understanding of pediatric sars-cov-2 infections is rudimentary and will continue to change as higher quality evidence becomes available. thus, the recommendations contained in this document should be interpreted in the setting of this shifting landscape and will be modified prospectively as our understanding of covid-19 improves. for these reasons, this guidance does not replace the critical role of clinical judgment that is essential to address the unique needs of individual patients. as the sars-cov-2 pandemic continues to unfold, the acr will support clinicians caring for children with covid-19 by enabling this task force to continue the work of reviewing evidence and providing expert opinion through revised versions of this guidance document. it is the ultimate goal of both the acr and panelists to disseminate knowledge quickly in an effort to improve outcomes for children with sars-cov-2 infections. hu h, ma f, wei x, fang y. coronavirus fulminant myocarditis saved with glucocorticoid and human immunoglobulin. european heart journal. 2020. this article is protected by copyright. all rights reserved the this article is protected by copyright. all rights reserved table 3 . comparing and contrasting features of mis-c and kd. patients with kd that is unrelated to sars-cov-2 will continue to require evaluation, diagnosis, and treatment during the sars-cov-2 pandemic. 1) there is an increased incidence of mis-c in patients of african, afro-caribbean, and possibly hispanic descent, but a lower incidence in those of east asian descent. 2) patients with mis-c encompass a broader age range, have more prominent gi and neurologic symptoms, present more frequently in shock, and are more likely to display cardiac dysfunction (arrhythmias and ventricular dysfunction) than children with kd. 3) at presentation, patients with mis-c tend to have lower platelet counts, lower absolute lymphocyte counts, and higher crp levels than patients with kd. it is unknown if the incidence of caa is different in mis-c compared to serial laboratory testing and cardiac assessment should guide immunomodulatory treatment response and tapering. patients will often require a 2-3-week taper of immunomodulatory medications. high mis-c, multisystem inflammatory syndrome in children; ivig, intravenous immunoglobulin; caa, coronary artery aneurysms this article is protected by copyright. all rights reserved table 6 . antiplatelet and anticoagulation therapy in mis-c. low dose aspirin (3-5 mg/kg/day; max 81 mg/day) should be used in patients with mis-c and kd-like features and/or thrombocytosis (platelet count ≥450,000/ l) and continued until normalization of platelet count and confirmed normal coronary arteries at ≥4 weeks after diagnosis. treatment with aspirin should be avoided in patients with a platelet count ≤80,000/ l. patients with mis-c and documented thrombosis or an ef <35% should receive therapeutic anticoagulation with enoxaparin until at least 2 weeks after discharge from the hospital. indications for longer outpatient therapeutic enoxaparin dosing include: caa with z-score >10.0 (indefinite treatment), documented thrombosis (treatment for ≥3 months pending thrombus resolution), or ongoing moderate to severe lv dysfunction. for mis-c patients who do not meet the above criteria, the approach to antiplatelet and anticoagulation management should be tailored to the patient's risk for thrombosis. high mis-c, multisystem inflammatory syndrome in children; kd, kawasaki disease; caa, coronary artery aneurysms; ef, ejection fraction; lv, left ventricular this article is protected by copyright. all rights reserved table 7 . hyperinflammation in covid-19. medically complex children and those on immunosuppressive medications, including moderate to high dose glucocorticoids, may be at higher risk for severe outcomes in covid-19. children and adults admitted to the hospital with covid-19 present with similar symptoms, including fever, upper respiratory tract symptoms, abdominal pain, and diarrhea. children with severe respiratory symptoms due to covid-19 with any of the following should be considered for immunomodulatory therapy: ards, shock/cardiac dysfunction, substantially elevated ldh, d-dimer, il-6, il-2r, crp, and/or ferritin, and depressed lymphocyte count, albumin, and/or platelet count. glucocorticoids may be considered for use as immunomodulatory therapy in patients with covid-19 and hyperinflammation (as outlined in point above an interactive web-based dashboard to track covid-19 in real time. the lancet infectious diseases hyperinflammatory shock in children during covid-19 pandemic world federation of pediatric intensive and critical care societies media release: expert panel conclusions following the 2 may pediatric intensive care-covid-19 international collaborative conference call multisystem inflammatory syndrome in children and adolescents with covid-19 guidance: paediatric multisystem inflammatory syndrome temporally associated with covid-19 emergency preparedness and response: health alert network an outbreak of severe kawasaki-like disease at the italian epicentre of the sars-cov-2 epidemic: an observational cohort study kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic in paris, france: prospective observational study multisystem inflammatory syndrome related to covid-19 in previously healthy children and adolescents in new york city multisystem inflammatory syndrome in children during the covid-19 pandemic: a case series us agency for health care policy and research office of the forum for quality and effectiveness in health care clinical practice guideline development: methodology perspectives us department of health and human services, public health service, agency for health care policy and research clinical guidance for pediatric patients with multisystem inflammatory syndrome in children associated with sars-cov-2 and hyperinflammation in covid-19 acute heart failure in multisystem inflammatory syndrome in children (mis-c) in the context of global sars-cov-2 pandemic children with a pediatric inflammatory multisystem syndrome temporally associated with sars-cov-2 associated pediatric multi-system inflammatory syndrome septic shock presentation in adolescents with covid-19. the lancet child & adolescent health characteristics, cardiac involvement, and outcomes of multisystem inflammatory disease of childhood (mis-c) associated with sars-cov-2 infection. the journal of pediatrics sars-cov-2-induced kawasaki-like hyperinflammatory syndrome: a novel covid phenotype in children multisystem inflammatory syndrome in children in new york state. the new england journal of medicine covid-19 associated multisystem inflammatory syndrome in children (mis-c) guidelines; a western new york approach. progress in pediatric cardiology. 2020. 21. children's hospital of philadelphia. emergency department, icu and inpatient clinical pathway for evaluation of possible multisystem inflammatory syndrome (mis-c) diagnosis, treatment, and long-term management of kawasaki disease: a scientific statement for health professionals from the american heart association the why and how of z scores recommendations for quantification methods during the performance of a pediatric echocardiogram: a report from the pediatric measurements writing group of the american society of echocardiography pediatric and congenital heart disease council assessment of b-type natriuretic peptide in patients with pneumonia a pilot study of the association of amino-terminal pro-b-type natriuretic peptide and severity of illness in pediatric septic shock. pediatric critical care medicine : a journal of the society of critical care medicine and the world federation of pediatric intensive and critical care societies a new infantile acute febrile mucocutaneous lymph node syndrome (mlns) prevailing in japan nationwide epidemiologic survey of kawasaki disease in japan accepted article this article is protected by copyright. all rights reserved 29 kawasaki syndrome hospitalizations in the united states treatment of kawasaki disease: analysis of 27 us pediatric hospitals from recognition of a kawasaki disease shock syndrome the treatment of kawasaki syndrome with intravenous gamma globulin. the new england journal of medicine cardiovascular magnetic resonance techniques and findings in children with myocarditis: a multicenter retrospective study high-dose intravenous gammaglobulin for kawasaki disease diagnosis, treatment, and long-term management of kawasaki disease: a statement for health professionals from the committee on rheumatic fever, endocarditis, and kawasaki disease, council on cardiovascular disease in the young recognition and initial management of fulminant myocarditis: a scientific statement from the intravenous immunoglobulin therapy for patients with idiopathic cardiomyopathy and endomyocardial biopsy-proven high pvb19 viral load intravenous immunoglobulin treatment for acute fulminant inflammatory cardiomyopathy: series of six patients and review of literature role of intravenous immunoglobulin therapy in the survival rate of pediatric patients with acute myocarditis: a systematic review and meta-analysis treating pediatric secondary hemophagocytic lymphohistiocytosis the use of interleukin 1 receptor antagonist (anakinra) in kawasaki disease: a retrospective cases series high-dose anakinra as treatment for macrophage activation syndrome caused by refractory kawasaki disease in an infant usefulness and safety of anakinra in refractory kawasaki disease complicated by coronary artery aneurysm pulmonary post-mortem findings in a series of covid-19 cases from northern italy: a two-centre descriptive study. the lancet infectious diseases thromboinflammation and the hypercoagulability of covid-19 incidence of thrombotic complications in critically ill icu patients with covid-19 venous thrombosis and arteriosclerosis obliterans of lower extremities in a very severe patient with 2019 novel coronavirus disease: a case report multisystem inflammatory syndrome in u.s. children and adolescents. the new england journal of medicine artery aneurysms in kawasaki disease: risk factors for progressive disease and adverse cardiac events in the us population stenotic lesions and the maximum diameter of coronary artery aneurysms in kawasaki disease thrombosis and embolism in pediatric cardiomyopathy blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis prevention and treatment of thrombosis in pediatric and congenital heart disease: a scientific statement from the children with covid-19 in pediatric emergency departments in italy. the new england journal of medicine sars-cov-2 infection in children. the new england journal of medicine characteristics and outcomes of children with coronavirus disease 2019 (covid-19) infection admitted to us and canadian pediatric intensive care units screening and severity of coronavirus disease 2019 (covid-19) in children in madrid severe covid-19 in children and young adults in the washington, dc metropolitan region. the journal of pediatrics epidemiology of covid-19 among children in china but not tnf antagonists, are associated with adverse covid-19 outcomes in patients with inflammatory bowel diseases: results from an international registry. gastroenterology characteristics associated with hospitalisation for covid-19 in people with rheumatic disease: data from the covid-19 global rheumatology alliance physician-reported registry. annals of the rheumatic diseases the severity of covid-19 the lancet child & adolescent health virus disease 2019 and paediatric inflammatory bowel diseases: global experience and provisional guidance accepted article this article is protected by copyright. all rights reserved 73 incidence of covid-19 in a cohort of adult and paediatric patients with rheumatic diseases treated with targeted biologic and synthetic disease-modifying anti-rheumatic drugs. seminars in arthritis and rheumatism clinical course and risk factors for mortality of adult inpatients with covid-19 in wuhan, china: a retrospective cohort study risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease clinical and immunologic features in severe and moderate coronavirus disease clinical features of patients infected with 2019 novel coronavirus in wuhan clinical characteristics and outcomes of hospitalized and critically ill children and adolescents with coronavirus disease 2019 (covid-19) at a tertiary care medical center dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial effects 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hospitalized patients with covid-19 effect of dexamethasone in hospitalized patients with covid-19: preliminary report blockade is associated with reduced mortality in sepsis patients with features of macrophage activation syndrome: reanalysis of a prior phase iii trial interleukin-1 receptor antagonist anakinra in association with remdesivir in severe coronavirus disease 2019: a case report use of anakinra in severe covid-19: a case report favorable anakinra responses in severe covid-19 patients with secondary hemophagocytic lymphohistiocytosis. cell host microbe targeting the inflammatory cascade with anakinra in moderate to severe covid-19 pneumonia: case series. annals of the rheumatic diseases safety and efficacy of early high-dose iv anakinra in severe covid-19 lung disease interleukin-1 blockade with high-dose anakinra in patients with covid-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study tocilizumab treatment in covid-19: a single center experience effective treatment of severe covid-19 patients with tocilizumab off-label use of tocilizumab for the treatment of sars-cov-2 pneumonia in tocilizumab for the treatment of severe covid-19 pneumonia with hyperinflammatory syndrome and acute respiratory failure: a single center study of 100 patients in brescia impact of low dose tocilizumab on mortality rate in patients with covid-19 related pneumonia tocilizumab for treatment of severe covid-19 patients: preliminary results from smatteo covid19 registry (smacore) this article is protected by copyright. all rights reserved accepted article key: cord-293259-o51fnvuw authors: sinaei, reza; pezeshki, sara; parvaresh, saeedeh; sinaei, roya title: why covid-19 is less frequent and severe in children: a narrative review date: 2020-09-25 journal: world j pediatr doi: 10.1007/s12519-020-00392-y sha: doc_id: 293259 cord_uid: o51fnvuw background: despite the streaks of severity, severe acute respiratory syndrome-coronavirus-2 (sars-cov-2) infection is, in general, less frequent and severe in children than in adults. we searched for causal evidence of this mystery. data sources: an extensive search strategy was designed to identify papers on coronavirus disease 2019 (covid-19). we searched ovid medline, pubmed, embase databases, and cochrane library and carried out a review on the causes of this dilemma. results: our searches produced 81 relevant articles. the review showed that children accounted for a lower percentage of reported cases, and they also experienced less severe illness courses. some potential explanations, including the tendency to engage the upper airway, the different expression in both receptors of angiotensin-converting enzyme and renin–angiotensin system, a less vigorous immune response, the lower levels of interleukin (il)-6, il-10, myeloperoxidase, and p-selectin and a higher intracellular adhesion molecule-1, a potential protective role of lymphocytes, and also lung infiltrations might have protective roles in the immune system–respiratory tract interactions. finally, what have shed light on this under representation comes from two studies that revealed high-titer immunoglobulin-g antibodies against respiratory syncytial virus and mycoplasma pneumonia, may carry out cross-protection against sars-cov-2 infection, just like what suggested about the vaccines. conclusions: these results require an in-depth look. properties of the immune system including a less vigorous adaptive system beside a preliminary potent innate response and a trained immunity alongside a healthier respiratory system, and their interactions, might protect children against sars-cov-2 infection. however, further studies are needed to explore other possible causes of this enigma. the novel coronavirus infection spread rapidly, so that the world health organization (who) declared this epidemic as a pandemic on march 11, 2020 [1] . according to the preliminary data, the overall case fatality rate is about 2.3% and is significantly higher in older patients [2] . also, hospitalization rate increases with age, given the increased risk of nasal colonization and secondary infections [3, 4] . limited initial data exist on the burden of coronavirus disease 2019 in children [5] . thus far, only a small number of severe acute respiratory syndrome-coronavirus 2 (sars-cov-2) infection have involved children, so that they have accounted for only 1-5% of total patients [2, [6] [7] [8] [9] [10] . however, doubt has existed as to whether covid-19 is really less common in children, and some have believed that children are as likely as adults to become infected, but are less likely to be symptomatic or to develop severe symptoms [11] . some have attributed this to a lack of real epidemiological studies in children. however, the recent epidemiological studies have shown that although children are more likely to be affected than those reported previously, children are still less likely to be affected than adults. in iceland, researchers screened 6% of country's population and found that children under 10 years of age had a lower incidence of sars-cov-2 infection than adults [12] . although similar epidemiological results, especially those from serological investigations, are emerging in other countries, such as the netherlands, australia, and china, researchers in china found that children were less likely to catch the covid-19 within households from an affected family member [13] . similarly, of 806 close contacts in 15 schools in australia, only two students have been identified as secondary cases [14] . however, these are three ways that researchers have gauged whether children are less frequently infected by sars-cov-2 infection. the available data also suggest that sars-cov-2 is less severe in children. in a report, among 149,082 cases reported in the united states through april 2, 2020, children experienced less severe symptoms. fever, cough, or shortness of breath were in 73% of children compared to 93% of adults. also, myalgia, sore throat, headache, and diarrhea were less commonly reported by pediatric patients. three deaths were noted among the pediatric patients in this analysis. however, children aged less than 1 year accounted for the highest hospitalization [15] . dong et al. investigated epidemiological characteristics of 2143 suspected pediatric patients. infection was confirmed in 34% of these patients, whereas 94.1% of them were asymptomatic, or had mild to moderate courses, and 4.4% were asymptomatic [16] . these data were similar to previous findings that children with covid-19 may not have reported fever, cough, or sore throat as often as adults [17] . also, dong et al. revealed that the prevalence of severe and critical disease was 10.6% in children aged less than 1 year, 7.3% in those aged 1-5 years, 4.2% in those aged 6-10 years, 4.1% in those aged 11-15 years, and 3% in those aged 16-17 years [16] . however, some patients experienced severe courses of illness. severe sars-cov-2 infection is characterized by a hyperproinflammatory response or cytokine storm state that results to acute respiratory distress syndrome (ards) and multisystem inflammatory syndrome (mis). ards is characterized by hypoxemic respiratory failure with bilateral lung infiltrates often necessitating invasive respiratory support. in contrast, this situation occurs less frequently in pediatric patients [18, 19] . in a systematic review of 7480 pediatric patients with confirmed covid-19, only 2% were severe (e.g., dyspnea, central cyanosis, and hypoxemia), and 0.7% were critical (e.g., ards, respiratory failure, and shock) [20] . unexpectedly, there is now a growing cognizance of small reports of pediatric patients with a hyper inflammatory response termed as mis-c or kawasaki-like disease [21, 22] . nevertheless, these two entities are not so common, and the most children experience milder illness. for the first time, we reported two pediatric patients with reactive arthritis who presented with limping following sars-cov-2 infection [23] . the data on laboratory markers in children also revealed lower lymphocytopenia (3-3.5%) than adults (63%) in several studies. also, children generally had lower increased c-reactive protein and procalcitonin levels. thus, the overall prognosis of the disease in children is relatively good [15, 17, [24] [25] [26] . unfortunately, due to the high percentage of missing data, a real statistical evaluation and comparison could not be conducted [27] . however, it seems that symptoms in children are both less frequent and less severe. in this review, we comprehensively investigated the most likely causes of this enigmatic topic, although all the actual causes remain unclear. an extensive search strategy was designed to identify all relevant papers from beginning to august 23, 2020. we used ovid medline, pubmed, embase, and cochrane library and carried out a review on the causes of the lower prevalence and less severity of covid-19 in pediatric patients. the search strategy was constructed based on searching terms 2019 novel coronavirus, covid-19, sars-cov-2 with using and/or, also the terms of child, pediatric, newborn, infant, adolescence, adult, age, age groups, severity, epidemiology, prevalence, difference, immune system, etiology, reasons in title, abstract, and key words. the data were screened and extracted independently by two investigators (the first and corresponding authors) and by one highly experienced librarian; then we proceeded to cross check the results. in addition, we increased the references by using an additional snowballing method. after discussion and consensus, the article was written. the inclusion criteria were: (1) children and adolescents < 19 years of age; (2) all scientific papers and letters, about covid-19; and (3) description of the possible causes of lower prevalence and less severity of diseases. the exclusion criterion is that of ≥ 19 years of age. the search found 994 papers. after removing the duplications and less relevant papers, 81 scientific papers and letters (5-19, 24-69, 84-103) were included. however, several speculations were derived from pathophysiology of disease and defensive mechanisms. the results were categorized into two main groups of causes (immunological and non-immunological considerations), and each group included the six subsets described below. all causes are involved in the less severity of illness, but some (as * ) include the simultaneous and parallel causes of less frequency. the first results stem from some considerations that children have a less vigorous immune response to the virus than adults because the cytokine storm is thought to be important in the pathogenesis of severe sars-cov-2 infections [28] . these results have been suggested from several studies in which elevated inflammatory markers are less common in children, so they experience milder disease than adults [29] . children have a more active innate immune response * of course, this is not in conflict with another hypothesis that children have a more active innate immune response that can be one of the early stages of defense [11] . this can be attributed to the fact that children had more recurrences of recent viral infections [30] . however, if the disease went further extension, a less vigorous immune response may prevent them from the cytokine storm and help to reduce the severity. jeljeli et al. studied the ontogeny of cytokine production in the response of phytohemagglutinin by aging and found a rapid shift from enhanced interleukin (il)-10 secretion capacity at birth toward balanced il-10/t helper (th) 1/ th2/th17 cytokine levels early in life. this change appears to be an essential precondition to fight pathogens and also avoids overwhelming inflammatory reactions [31] . schouten et al. discovered an age-dependent difference in levels of biomarkers in the lungs of ards patients. levels of il-6, il-10, myeloperoxidase, and p-selectin were higher by aging; whereas intercellular adhesion molecule-1 was higher in neonates [32] . however, immunosenescence also may be explain covid-19 age variability. it refers to the gradual deterioration of the immune system (especially adaptive type) brought on by natural age advancement [33, 34] . some studies revealed that with aging, there is a gradual decrease of naïve t cell numbers related to the thymic changes, shrinkage in the collection of t cell clones generated in the thymus, and loss of costimulatory receptor cd28. all these factors may impair the immunological responses with age [35] [36] [37] . shortening of telomeres, especially t cells with cell divisions, might be associated with impaired immune response to new antigens along with increasing the production of proinflammatory cytokines [38, 39] . zhu et al. revealed that among 667 adolescents, the african and the girls had longer telomeres [40] . these findings along with those of other studies can justify the severity of covid-19 in males and also by aging [41] . some have suggested that the constitutional higher percentage of lymphocytes and natural killers (nk) in children may have a defensive role in covid-19 [42] . indeed, increasing proinflammatory cytokines associated with neutrophil function with age, associated with severity of ards and may explain, to some extent, the age-dependent difference [43] . in adult patients lymphocytopenia (especially cd4 + and cd8 + t lymphocytes) has been associated with increased severity or worse outcomes [44] . total leukocyte and neutrophil counts and the neutrophil/lymphocyte ratio can be used as follow-up parameters in covid-19 [45] . at least in three cohorts, the majority of pediatric patients had normal leukocytes and lymphocytopenia accounted for only 3-3.5% of cases [17, 24, 25] . given the central role of lymphocytes and monocytes in the induction of immune responses, their frequency in peripheral blood might be expected to reflect the state of an individual's immune response to infection [46] . in addition, since t cells are required for controlling exuberant innate immune responses, the absence of a potent antivirus t cell response in aged hosts could lead to an exuberant response and damage, which is not seen in children [47, 48] . wynn and colleagues found that 2360 genes in neutrophils, 965 in monocytes, and 109 genes in lymphocytes were up-or down-regulated in pediatric septic shock, referring the data that circulatory lymphocytes are not the main leukocytes population with altered gene profiles during septic shock [49] . other results for a milder disease in children are linked to a trained immunity that represents an immune memory after antigen exposure [26] . interestingly, what have shed light on this under representation comes from two studies that revealed multiple high-titer antibodies against respiratory syncytial virus (rsv) and mycoplasma pneumoniae (mp) in the blood of children appears to offer cross protection against sars-cov-2 infection [50, 51] . several studies have shown that children are more susceptible than adults to infection by rsv and mp [52] [53] [54] [55] . mp has been reported in 10-40% of community-acquired pneumonia cases, and children with 5-15 years age are the most susceptible groups. although, this was documented in children under 4 years by the report of 2010-2011 of european epidemic data [54] . also, rsv is more prevalent in infancy. the who has reported rsv as a causative pathogen for over 30 million new cases of lower respiratory infection episodes, including acute bronchitis in children less than 5 years age [52] . older siblings are a greater source of spreading infection than adults because they spend significant time in nurseries and schools [55] . these events can train the immunity of children so that neutralizing cross-reactive antibodies of mp and rsv may be more common in children than in adults. in a retrospective review of all covid-19 patients treated at wuhan union hospital until march 20, 2020, mi et al. evaluated the correlation between prior exposures to mp and better clinical response in covid-19 patients. the immunoglobulin g (igg) positive patients had a higher lymphocyte, monocyte and eosinophil counts and percentages (p < 0.05) than covid-19 patients without mp igg. in addition, thrombin time and lactate dehydrogenases were better in this group. furthermore, requirement and use of nasal catheter oxygen mask was significantly lower in covid-19 patients with mp igg positivity (p = 0.029). their findings indicate that mp igg positivity is a potential protective factor for sars-cov-2 infection [51] . orange et al. showed that the intravenous immunoglobulin (ivig) manufactured from a plasma pool derived from high-titer, anti-rsv plasma donors contains high titers of antibodies to several common respiratory viruses (influenza a, b, human metapneumovirus, parainfluenza 1, 2, and 3, covoc42 and v299e); this study found a direct correlation between antibody responder status of donors to rsv and their responder status to other viruses (p < 0.05). although, there are, however, a number of considerations, this could be due to higher humoral immune responders in general or especially against intercellular antigens, to diversity in major histocompatibility complex alleles, and finally to donors that might have experienced a greater diversity of viral infection. this can be generalized to the more infections in children and the potential protection effect that results from these infections [50] . cao and colleagues emphasized the role of trained immunity as a new immune model that represents a cross protection against various pathogens. it can be activated also by some vaccines, such as bacillle calmette-guerin (bcg), by generation of immune memory just like what is seen in mp [26] . miller and colleagues found that countries without universal policies of bcg vaccination (e.g., usa, italy) have been affected more severely as compared to countries with universal and long-standing bcg policies. also, countries that have a late start of universal bcg policy (e.g., iran in 1984) had a high mortality, consistent with the idea that bcg protects the vaccinated elderly population. in addition, they found that bcg vaccination reduced the number of reported covid-19 cases in the country. the combination of reduced mortality and morbidity makes bcg vaccine a potential new tool in the fight against covid-19 [56] . however, this cross-protection has been considered, and what argues against this anecdotal assumption is the higher mortality of covid-19 in countries where bcg vaccine is compulsory [47] . myśliwska et al. investigated the relationship between nk activity in the vaccinated population and specific immune protection against influenza virus. they concluded that nk cells activation, which was still significantly elevated after 1 month of vaccination, may allow protection against influenza and other respiratory viral infections [57] . indirect epidemiological analyses also have suggested a protective role of the measles, mumps, and rubella vaccine against covid-19 [58] . because the majority of vaccinated individuals had not protective igg titer against measles after 10 years, hanker et al. hypothesized that age-dependent decline in immunogenicity against measles vaccine could be an explanation for the higher occurrence of covid-19 in adults [59] . there are several issues at this setting. the results show at least six other considerations including some constitutional and behavioral reasons: (1) available data suggest that children may have more upper respiratory tract involvement than the lower. thereafter, viral interference in young children leads to a lower viral load [16] . however, several speculations have emerged at this setting. young children generally, have a healthier respiratory machinery due to their lower exposure to harmful environmental factors. in addition, children have fewer underlying chronic diseases, than what seen in adults [11] ; (2) possible reasons for the disparity in severity between adults and children may be related to the difference in distribution, maturation, and functioning of receptors of renin angiotensin system (ras), angiotensinconverting enzyme 2 (ace-2), and altered inflammatory response to virus [60] . zhu et al. have looked for reasons of this disparity in severity [61] . ace-2 is the receptor of viral endocytosis and also alters the ras activity from proinflammatory to anti-inflammatory response [62] . the ace levels may be altered by several underlying diseases [63] and by age [64] in a murine model, although schouten and colleagues found that there is no marked difference in ace and ace-2 among age groups [32] . however, this speculation should be investigated; (3) xie et al. believe that children are less likely to be exposed to the virus. this may be due to fewer outdoor activities and to less international travel. also, xie et al. considered an under-diagnosis of children that might have resulted from their milder symptoms and therefore yielded fewer laboratory tests [27] ; (4) in attili and colleague's investigation, age-stratified odds ratios showed that the nasal carriage was higher in adult rabbits [65] . this result suggested that the presence of the respiratory nasal bacterial colonization might have more impact in the adult population [49] . in contrast, it is possible that the presence of other viruses in the respiratory tract of young children limits the sars-cov-2 development by direct virus-virus interactions [66] . this hypothesis stems from the greater frequency of viral infection in children and also provides a link between the viral load and covid-19 severity [52] [53] [54] [55] 67] ; (5) in total, some results suggest that children have specific mechanisms that regulate the interaction between their immunological and respiratory systems, which could be contributing to milder disease. as a result, lymphocytes have participated in the inducible bronchus associated lymphoid structure after that respiratory insult has happened [68] ; (6) it was suggested that maturational changes in the axonal transport system may explain the relative resistance to immature mice to poliovirus induced paralysis [69] . this can be generalized to the issue as a complementary reason. knowledge about neonatal outcomes of sars-cov-2 infection is relatively limited. immaturity of both innate and adaptive immune systems make this group highly vulnerable to infection [70] . interestingly, the majority of neonates born to mother with covid-19 were not infected, and to date few reports have suggested that neonates have been affected by covid-19. the possible reasons might be related to surgical delivery and to rapid separation of neonate [71] . levy found that neonatal antigen presenting cells and plasmacytoid dendritic cells have impaired production of interferonand present a bias against the production of th1 cytokines [72] . however, the levels of il-6, il-10, myeloperoxidase, and p-selectin are higher by aging, whereas intercellular adhesion molecule-1 is higher in neonates [32] . therefore, unlike the infants under 1 year that are at higher risk of infection and hospitalization (17.6% of pediatric cases and 10.6% of critical cases) [16] , neonates are less likely to be infected. in contrast, two known ace-2 and transmembrane protease serine-2 receptors are widely spread in specific cell types of maternal-fetal interface and might be vulnerable to the neonate affecting by sars-cov-2 infection. however, on march 2020, the first case report of possible vertical transmission of sars-cov-2 infection was published [73] . dong et al. speculated the possibility of maternal fetal transmission of virus by demonstrating a higher igm level and abnormal cytokines 2 hours after birth [74] . however, two independent manuscripts described elevated sars-cov-2 specific igm and igg antibodies in the blood of newborns of affected mothers. to date, while maternal infections were observed in the late phase of pregnancy, there may not have been sufficient time for the generation of antibodies. thus, serological investigation for the diagnosis of neonate is still controversial. nevertheless, increased level of igg could be explained by trans-placental transferring from infected mother, while igm strongly indicates a selfimmune response of newborns [74, 75] . thus, the elevated igm might suggest that neonate was infected in utero. in any case, the possibility of vertical transmission has been raised. after birth, the neonates might be involved. zeng et al. reported a series of 33 infants from mothers with covid-19, while three of whom were symptomatic, with a radiological picture of pneumonia. the 31 weeks neonate developed coagulopathy, associated with sepsis. none of the newborns died. the clinical features of infected newborns might be nonspecific and include acute respiratory distress syndrome, temperature instability, gastrointestinal, and cardiovascular dysfunction [76] . however, the age-dependent pattern of immune reactions and other physiological elements may influence the response to sars-cov-2 in the neonatal subpopulation [73] . although covid-19 in children appears largely to present with mild features, a very small percentage of children with sars-cov-2 infection experience mis-c weeks later. however, the mis-c cases usually do not primarily affect the lungs [77] . the recent reports from european countries and the us followed by growing universal reports support the emergence of this novel phenomenon [18] . the clinical presentations of this entity are variable and include persistent fever, severe illness, and involvement of two or more organ systems, in combination with laboratory evidence of both inflammation and sars-cov-2 infection. however, some presentations of mis-c resemble kawasaki disease (kd), toxic shock syndrome, and secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome [18, 19] . of the 191 potential cases reported across 191 hospitals in new york state, 95 patients were classified as confirmed mis-c. the peak in the number of mis-c cases followed the peak in the number of cases of laboratory-confirmed sars-cov-2 infection by 31 days. the researchers stated that based on molecular and serological results, mis-c is probably a post-infectious, inflammatory process related to covid-19 [78] . also, because the majority of patients have had positive serological results for sars-cov-2, with a lesser number of positive rt-pcr tests, this condition may be more a postinfection entity rather than one related to acute early infection state. this hypothesis seems to have emerged for two reasons. first, mis-c cases lagged in time compared with the peak of sars-cov-2 infection. second, children who were involved in mis-c, more often have igg than positive molecular tests. however, mis-c is a delayed immunological response associated with inflammation characterized by elevated levels of proinflammatory cytokines including il-6, il-1β, il-17, tnf-α, and granulocyte colony-stimulating factor. as a hypothesis, because the younger patients have increased number of naïve t cells in different sites to respond to new pathogens [43] , this may prevent severe respiratory disease in children. thus, a low-level, persistent infection in other sites may accumulate over time in some children, resulting in mis-c [19] . one compelling alternative hypothesis for this entity stems from the ability of coronaviruses to block type i and iii of interferon responses, that can result from delayed hyper-inflammatory response in whom that have a high viral load or cannot to control the infection [79, 80] . a mapping systemic inflammation and antibody (ab) responses in mis-c was conducted. they documented that all mis-c patients had igg against sars-cov-2 infection. they identified elevated signatures of inflammation (il-18, il-6), lymphocytic and myeloid chemotaxis and activation (ccl3, ccl4, and cub domain-containing protein-1), and mucosal immune dysregulation (il-17a, ccl20, ccl28). also, a reduction in m-dendritic cells, nk cells, and t cells in blood were seen, suggesting extravasation to affected tissues. also, some disease-associated autoantibodies (anti-la) were seen. these results suggest that autoreactivity secondary to sars-cov-2 infection and the inflammatory innate immune response may be crucial to the pathogenesis of mis-c [81] . interestingly, diorio et al. based on the clinical phenotype, hypothesized that children with mis-c are presenting with a syndrome that is distinct from both kd and severe covid-19 infection. the researchers found that the patients with mis-c had elevated levels of tnf-α and il-10, whereas patients with severe or mild covid-19 had no or minimally elevated levels of these cytokines. this profile for mis-c is distinct from what happens in kd, which is associated with mild elevations of other cytokines (il-1, il-2, and il-6) and not il-10. tnf-α appears to play key role in the pathogenesis of both mis-c and kd. viral cycle thresholds (cts) and burr cells on blood smears also differentiated between patients with severe covid-19 and mis-c. the high cts associated with mis-c support a postinfectious etiology phenomenon that has previously been postulated but not demonstrated [18, 82] . however, children with mis-c have no higher il-10 level, and this may be due to their higher lymphocyte counts hypothetically. in addition, they showed distinct ab responses as compared to adults with severe covid-19 causing ards, and to those who recovered from mild disease. patients with mis-c, often generate igg abs specific for spike (s) protein, while adults with covid-19 showed anti-s, igm, and iga abs, as well as anti-n igg abs. moreover, mis-c patients had reduced neutralizing activity compared covid-19 cohorts, indicating a reduced protective serological response [19] . these results suggest a distinct infection course and immune response in children and adults with severe disease. children appear to have a less severe pulmonary manifestation due to all previous reasons, especially a lower gene expression of the ace-2 receptor. in contrast, adults with severe respiratory failure syndrome due to sars-cov-2 infection, who typically deteriorate near one week later of illness onset, have a dysregulation of immune system as opposed to direct cellular injury from viral infection. the immune dysregulation in adults that experienced respiratory distress is characterized by lymphopenia and a sustained production of proinflammatory cytokines, such as tnf-α and il-6 [83] , giving the basis of immunomodulatory therapies like il-6 blockade at this situation. although, some suggest more conservative treatments, such as ivig or even corticosteroids for mis-c cases, empirical treatment with immunomodulators, such as anakinra or tocilizumab, as a substituted agent in refractory cases are promising [75, 81] . ards is the most severe manifestation of covid-19 in adults. the survival rate of covid-19 patients with ards who are admitted to an intensive care unit (icu) is approximately 25% [18] . in contrast, this situation is uncommon among pediatric patients and is called pards [18, 19] . why some children experience more severe illness? the reasons that children may experience a severe course have not yet been elucidated. here, we summarize some possible causes of this discrepancy. there are some suggestions that several conditions increase the risk of severe disease in children and include hospitalization, mechanical ventilation, congenital heart disease, neurologic, genetic and metabolic conditions [84] [85] [86] . other conditions are related to all ages and include: diabetes mellitus i and ii, immunocompromised due to solid organ transplant and other conditions, cerebrovascular accidents, chronic pulmonary disease (e.g., cystic fibrosis, moderate to severe asthma), chronic kidney disease, liver disease, pregnancy, obesity, smocking, sickle cell disease, thalassemia, and hypertension [87] . in two multicenter studies of children admitted to picu, 40 of 48 and 12 of 17 had an underlying condition [80, 81] . in a systematic review of 587 confirmed pediatric patients, 22% had an underlying condition. most of them were chronic pulmonary disease (45%), congenital heart disease (23%), immune suppression (12%), and hematological and oncological conditions (6%) [20] . it has an important role in development and worse outcome of severity, in both pediatric and adult patients. in the largest ards epidemiologic study of adults, 20.8% and in the pediatric acute respiratory distress syndrome incidence and epidemiology study, 13% of ards cases, had immunosuppression [88, 89] . the higher body mass index has been shown to be an independent factor associated with increased risk of ards development. as a paradox, the underweight patients with ards have higher mortality [90] . in adult population, cigarette smoking is associated with ards in patients with sepsis [91] . this can be generalized to pediatrics as both active and passive smokers. it seems that infants aged less than 1 year are at higher risk of infection and severity [15] . in the largest pediatric population-based study to date with 2143 patients, the proportion of severe and critical cases was 10.6% under 1 year, suggesting the higher risk of severe respiratory failure in infants. in addition to smaller airways, both immaturity of respiratory tract and immune system, alongside with relatively lower trained immunity might contributed to this severity [16, 68, 92] . pediatric studies have not always observed a marked association between ards and both race and ethnicity, perhaps due to limited sample size. however, african and hispanic ethnicity appears to be major risks in mis-c patients [81] . to date, several single-nucleotide polymorphisms have been identified by the increased risk of ards. the most significant variants are surfactant protein-b, ace, angiotensin-2, and il-1r antagonist [93] . the endothelial protein c receptor and thrombomodulin genes were independent factors associated with mortality [94] . il-1 pathway cytokines are associated with ards risk, although this association has not been found in pards studies [95] . the regulatory gene arylsulfatase-d was linked in 22 and 4% of ards cases and controls, respectively. also, xk kell blood group complex membr-3 was present in a minor allele frequency of 37 and 4% of ards cases and controls, respectively [96] . it has been shown that there are five variants of cystic fibrosis transmembrane conductance regulator splicing factor gens that independently are associated with pards in african american children without cystic fibrosis. another variant also was identified in caucasian children with cystic fibrosis, without higher risk of ards development [97] . interestingly, the cluster of mis-c patients in some countries after the peak incidence of coronavirus infection among adults by approximately one month and in contrast no statistically significant difference in japan and korea, suggest a genetic and ethnicity background for these severe cases [22] . however, at this time the extent to which genetics impacts the development of mis-c is unclear. considering the implications of host genes in the cell entry and replication of sars-cov-2 and in mounting the immune system response, it appears that several genes might be involved. the variations within ace-2 gene, the human leukocyte antigen locus, and the genes regulating toll-like receptor and complement pathways seem to influence susceptibility and subsequently the severity of covid-19 [98] . in addition to possible involvement of several other genes (e.g., abo blood type and mediterranean fever gene) [99] , genetic variations in these gateways might be influenced by the societies geographically. using a combinational analysis approach, taylor and colleagues identified 68 protein-coding genes that were highly associated with severe covid-19 [100] . ouyang et al. revealed that the number of differentially expressed genes (degs) increased by disease progression and decreased after initial treatment. all down-regulated degs in severe cases mainly involved th17 activation [101] . researchers identified the 3p21.31 gene cluster as a genetic susceptibility locus in severe covid-19 patients with respiratory failures. the results from comparing 1900 severe covid-19 patients and 1200 healthy blood donors indicated that people with blood group a had a 45% higher risk of infection than others. similarly, they found blood group o was associated with a lower risk of acquiring covid-19 [102] . unexpectedly, some children may have more viral loads without any other reasons. the higher exposure with or without high-risk behavior, alongside the more expression of ace-2 receptors due to the less immaturity, a less previous exposure to coronavirus, influenza and other viruses, not getting the flu vaccine and some other vaccines, a less simultaneous presence of other viruses in body, and a more bacterial nasal colonization, all can be generalized as involved factors at this setting. in addition, some children may have a weaker innate response; while the strong innate response can be due to more exposure to previous viruses and many other reasons. they also, may have a relatively greater adaptive response alongside memory cells like adults [30, 90] . there are several potential reasons that children have relatively milder illness. in addition to a fewer outdoor activity, children have a number of characteristics that protect them against sars-cov-2 infection. they have a healthier respiratory machinery alongside a different expression of receptors in the lower respiratory tract. also, we believe that the collection of immune system specifications including a less vigorous adaptive system beside a preliminary potent innate response, the constitutional higher level of lymphocyte counts, the trained immunity with cross-reactive neutralizing antibodies, the lack effects of aging, and the interaction between the immune system and respiratory tract might be protecting children against sars-cov-2 infection. although, these findings suggest that covid-19 is less common and somewhat milder in children compared to adults, there are now some reports of children presenting with severe types of infection such as mis-c. the exact incidence of mis-c following an asymptomatic or even a mildly symptomatic infection with sars-cov-2 is unclear. however, further investigations are needed to explore other possible causes of less severity of sars-cov-2 infection in the pediatric population. who. who director-general's opening remarks at the media 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