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Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with COVID-19

2.5 Contact Hours including 2.5 Advanced Pharmacology Hours
This peer reviewed course is applicable for the following professions:
Advanced Registered Nurse Practitioner (ARNP), Clinical Nurse Specialist (CNS), Licensed Practical Nurse (LPN), Licensed Vocational Nurses (LVN), Midwife (MW), Nursing Student, Other, Registered Nurse (RN), Respiratory Therapist (RT)
This course will be updated or discontinued on or before Thursday, November 24, 2022
Outcomes

92% of participants will identify and manage MIS-C.

Healthcare professionals should become more familiar with MIS-C, including what we do and do not know about MIS-C, epidemiology, transmission, pathogenesis, the case definition for MIS-C according to the CDC and WHO, risk factors, clinical evaluation, differential diagnosis, management and treatment, reporting, maintaining well-child and childhood immunizations during the COVID-19 pandemic, outcomes, how the CDC is investigating MIS-C and tips to protect children during a COVID-19 outbreak.

Objectives

After completing this course, the participant will be able to:

  1. Characterize MIS-C.
  2. Outline the potential risk factors and markers for severe disease.
  3. Illustrate the signs and symptoms of COVID-19 and MIS-C.
  4. Select the clinical management of MIS-C.
  5. Relate tips to protect children during a COVID-19 outbreak.
  6. Recognize the outcome for MIS-C.
CEUFast Inc. did not endorse any product, or receive any commercial support or sponsorship for this course. The Planning Committee and Authors do not have any conflict of interest.

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To earn of certificate of completion you have one of two options:
  1. Take test and pass with a score of at least 80%
  2. Reflect on practice impact by completing self-reflection, self-assessment and course evaluation.
    (NOTE: Some approval agencies and organizations require you to take a test and self reflection is NOT an option.)
Author:    Pamela Downey (MSN, ARNP)

Introduction

Coronaviruses are important human and animal pathogens. At the end of 2019, a novel coronavirus was identified as the cause of a cluster of pneumonia cases in Wuhan, a city in the Hubei Province of China. It rapidly spread, resulting in an epidemic throughout China, followed by an increasing number of cases in other countries worldwide. In February 2020, the World Health Organization (WHO) designated the disease COVID-19, which stands for coronavirus disease 2019.1 The virus that causes COVID-19 is designated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The WHO declared COVID-19 a pandemic on March 11, 2020.2

In children, COVID-19 is usually mild. However, in rare cases, children can be severely affected, and clinical manifestations may differ from adults. In April of 2020, reports from the United Kingdom (UK) documented a presentation in children similar to incomplete Kawasaki disease (KD) or toxic shock syndrome.3,4 Since then, there have been reports of similarly affected children in other parts of the world.5-12 This new syndrome had been termed Multisystem Inflammatory syndrome in Children (MIS-C). Children who present with clinical features of MIS-C should be tested for SARS-CoV-2 and referred promptly to a specialist in pediatric infectious disease, rheumatology, cardiology, or critical care.

Clarifying Terminology

According to the U.S. Centers for Disease Control and Prevention (CDC), there are multiple types of coronaviruses, some of which commonly cause mild upper-respiratory tract illnesses. "Coronavirus" is a generic term that includes a large family of viruses. Seven types of coronavirus infect humans, three of which evolved from animal strains. Because there are many coronavirus types, referring to it simply as "coronavirus" is very general.

The CDC and WHO encourage experts to use COVID-19 when referring to this new disease:

  • COVID-19 is a new coronavirus that has not previously been seen in humans.
  • COVID-19:
    • ‘CO’ stands for ‘corona.’
    • ‘VI’ for ‘virus.’
    • ‘D’ for disease.
    • 19 indicates the year that it was discovered.
  • Previously, SARS-CoV-2 was referred to as 2019-nCoV.

SARS-CoV-2 is the specific virus that causes COVID-19 (the disease).

  • The syndrome has been termed multisystem inflammatory syndrome in children (MIS-C).
  • MIS-C has also been referred to as:
    • Pediatric multisystem inflammatory syndrome (PMIS).
    • Pediatric inflammatory, multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS).
    • Pediatric hyperinflammatory syndrome.
    • Pediatric hyperinflammatory shock.
  • SARS-CoV-2 is genetically related to the SARS-associated coronavirus (SARS-CoV), causing an outbreak of severe acute respiratory syndrome (SARS) in 2002-2003. It is not, however, the same virus.

Virology

Coronaviruses are enveloped positive-stranded RNA viruses. Full-genome sequencing and phylogenic analysis indicated that the coronavirus that causes COVID-19 is a betacoronavirus in the same subgenus as the SARS virus (as well as several bat coronaviruses) but in a different clade.

The Coronavirus Study Group of the International Committee on Taxonomy of Viruses has proposed that this virus be designated SARS-CoV-2.13 The Middle East respiratory syndrome (MERS) virus, another betacoronavirus, appears more distantly related.14,15 The closest RNA sequence similarity is to two bat coronaviruses, and it appears likely that bats are the primary source. It remains unknown whether the COVID-19 virus is transmitted directly from bats or through some other mechanism (e.g., through an intermediate host).16

The host receptor for SARS-CoV-2 cell entry is the same as for SARS-CoV, the angiotensin-converting enzyme 2 (ACE2).17 The cellular protease TMPRSS2 also appears important for SARS-CoV-2 cell entry.18

SARS-CoV-2 binds to ACE2 through the receptor-binding gene region of its spike protein. A study that monitored amino acid changes in the spike protein of SARS-CoV-2 isolates included in a large sequence database identified a D614G (glycine for aspartic acid) substitution that became the dominant polymorphism globally over time.19 In vitro, pseudotyped viruses harboring the G614 variant resulted in higher viral titers than those with the D614 variant. While the emergence of G614 as the dominant variant could be related to relative infectiousness, other explanations for the observation, such as sampling bias, cannot be ruled out. The clinical implications of these findings remain uncertain. The G614 variant did not appear to be associated with a higher risk of hospitalization.

Epidemiology

Geographic Distribution and Case Counts

Globally, more than 20 million confirmed cases of COVID-19 have been reported. Since the first reports of cases from Wuhan at the end of 2019, cases have been reported in all continents, except for Antarctica.

The reported case counts underestimate the overall burden of COVID-19, as only a fraction of acute infections are diagnosed and reported. Seroprevalence surveys in the U.S. and Europe have suggested that after accounting for potential false positives or negatives, the rate of prior exposure to SARS-CoV-2, as reflected by seropositivity, exceeds the incidence of reported cases by approximately 10-fold or more.20-22

While the incidence of MIS-C is uncertain, it appears to be a rare complication of COVID-19 in children. In one report, the estimated incidence of laboratory-confirmed SARS-CoV-2 infection in individuals < 21 years old was 322 per 100,000, and the incidence of MIS-C was 2 per 100,000.23 The initial reports of MIS-C emerged from the UK in April 2020.3,4 Since then, there have been reports of similarly affected children in other parts of the world, including Europe, Canada, the U.S., and South Africa.5-7,9-12,23-27 It is important to note that there have been no MIS-C reports from China or other Asian countries with high rates of COVID-19 early in the pandemic.

While many children with MIS-C meet complete or incomplete KD criteria, the epidemiology differs from classic KD. Most MIS-C cases have occurred in older children and adolescents who were previously healthy.3,9-12,24,25,28 Black and Hispanic children appear to be disproportionally affected. In contrast, classic KD typically affects infants and young children and has a higher incidence in East Asia and Asian descent children.

The epidemiology of MIS-C also differs from that of acute COVID-19 illness in children, which tends to be most severe in infants < one year of age and children with underlying health problems. The first report of MIS-C was a series of eight children seen at a tertiary center in South East England.3 In subsequent larger case series from the UK (n = 78) and the U.S. (n = 186), the majority of children were previously healthy (78% in the UK series, 73% in the U.S. series).12,29 The most common comorbidities were obesity and asthma. The median age was 8 to 11 years (range 1 to 20 years).

The risk of developing MIS-C appears to vary by race and ethnicity:

  • Black and Hispanic children accounting for a disproportionally high number of cases
  • Asian children accounting for a small number of cases
  • In three large case series12,23,29:
    • 25% to 45% of patients were Black
    • 30% to 40% Hispanic
    • 15% to 25% Caucasian
    • 3% to 28% Asian

In most studies, there was a lag of several weeks between the peak of COVID-19 cases within communities and the rise of MIS-C cases.9,10,12,23,30 As an example, in London, the peak of COVID-19 cases occurred in the first to second weeks of April, while the spike of MIS-C cases occurred in the first to the second week of May.10,30 This three-to four-week lag coincides with the timing of acquired immunity. It suggests that MIS-C may represent a postinfectious complication of the virus rather than acute infection, at least in some children.

Can Children Get COVID-19?

Children of all ages can get COVID-19. Children appear to be affected less commonly than adults.31-36 In surveillance from various countries, children typically account for 1% to 8% of laboratory-confirmed cases.37-42 In the U.S., children < 18 years account for approximately 8% to 9%.43,44 The American Academy of Pediatrics provides information about the number of cases in children in individual states.44 Additional information related to COVID-19 activity in the U.S. (e.g., outpatient visits, hospitalization) is available through the CDC's COVIDView.

How Do Children Get COVID-19?

Most cases in children result from household exposure, usually with an adult as the index patient.34,40,45-48 However, healthcare-associated outbreaks have been reported.49,50 Cases of possible transmission from teachers or school staff to students and among students in the school setting have also been reported.51,52 In retrospective studies of transmission of SARS-CoV-2 from China, the household secondary attack rate among pediatric contacts has ranged from 4% to 7%.53,54 In a review of cases from New York state (excluding New York City), the secondary attack rate among children < 18 years was 27%.55

Do Children Transmit COVID-19 to Others?

The role of children in transmission to others is not clear.56,57 Although infected children shed SARS-CoV-2 virus with nasopharyngeal viral loads comparable to or higher than those in adults58, limited evidence suggests that children's transmission, particularly young children, is uncommon perhaps because of viral interference or milder symptoms.40,52,57,59-65 Older children and adolescents appear to be able to transmit SARS-CoV-2 effectively.63,66-69

Age Distribution

Children of all ages can get COVID-19.31-36,70 Early in the pandemic, it appeared that children were less likely than adults to be infected with SARS-CoV-2 and, if infected, most had mild to moderate illness. Then MIS-C cases began to appear in children weeks after they had COVID-19, and sometimes when a child had no prior SARS-CoV-2 infection. Current data indicate that the average age of children with MIS-C is eight years.71 In a multicenter cohort of 582 European children < 18 years of age with laboratory-confirmed SARS-CoV-2 during April 2020 (the early peak of the European pandemic), the age distribution was as follows70:

  • < one month – 7%
  • One month to one year – 22%
  • one to two years – 10%
  • two to five years – 11%
  • five to ten years – 16%
  • > ten years through 18 years – 34%

Early in the pandemic in the U.S., infants < 12 months also accounted for a large proportion of pediatric cases (15%), but they were not disproportionately represented in cases in the general (i.e., all-age) population (0.27% of cases; 1.2% of the general population).34

As of September 3, 2020, the CDC received reports of 792 confirmed cases of MIS-C and 16 deaths in 42 states, New York City, and Washington, DC. Additional cases are under investigation.7 Most cases are in children between the ages of one and 14 years, with an average age of eight. Cases have occurred in children from < one year old to 20 years old. More than 70% of reported cases have occurred in children who are Hispanic/Latino (276 cases) or Non-Hispanic Black (230 cases). 99% of cases (783) tested positive for SARS-CoV-2, the virus that causes COVID-19. The remaining 1% was around someone with COVID-19. Most children developed MIS-C 2 - 4 weeks after infection with SARS-CoV-2. Slightly more than half (54%) of reported cases were male.

Age of reported MIS-C cases as of September 3, 2020, per the CDC, are: (note: two of the 792 cases did not report age data).

  • < one year of age: 4%
  • one – four years of age: 24%
  • five – nine years of age: 32%
  • ten – 14 years of age: 24%
  • 15 – 20 years of age: 15%

Race/Ethnicity

Among adult patients with COVID-19, racial and ethnic minority groups are disproportionately affected, perhaps related to underlying health conditions and economic and social conditions (e.g., poverty, multigenerational households, employment in essential industries, lack of paid sick leave, limited access to medical care).72-74

Children from racial and ethnic minorities also appear to be disproportionately affected.75-78 The CDC's COVID-NET provides race/ethnicity information for COVID-19-associated hospitalizations in children.77,79 Among children hospitalized with COVID-19 from 14 states, the cumulative hospitalization rate by late July 2020 was:

  • 16.9 per 100,000 population in Hispanic or Latino children
  • 10.5 per 100,000 in non-Hispanic Black children
  • 2.1 per 100,000 population among Caucasian children.77

As of September 3, 2020, most MIS-C patients have been Hispanic/Latino or Non-Hispanic Black per the CDC. Hispanic/Latino and Non-Hispanic Black populations are also disproportionately affected by COVID-19 overall. Additional studies into MIS-C are needed to learn why certain racial or ethnic groups may be affected in greater numbers and what risk factors may contribute to this phenomenon.71

Race and ethnicity of reported MIS-C cases as of September 3, 2020, per the CDC, include71: (note: 121 of the 792 cases did not report race/ethnicity data).

  • Hispanic or Latino – 41%
  • Non-Hispanic Black – 34%
  • Non-Hispanic White – 13%
  • Other – five%
  • Multiple – three%
  • Asian – two%
  • American Indian/Alaskan Native – one%

Gender

Gender of reported MIS-C cases as of September 3, 2020, per the CDC include71:

  • Male – 54%
  • Female – 46%

MIS-C Cases by Jurisdiction

Since reporting began in Mid-May, 42 States, New York City, and Washington, DC, have reported at least one case of MIS-C to the CDC. Most of those jurisdictions have ten or fewer reported cases. Because of the small number of cases in most states and to protect patients and their families' privacy, the CDC is not reporting individual states’ case counts.

MIS-C Case Ranges by Territory, State, New York City, and Washington, DC71:

  • No reported cases: AK, ID, ME, MT, ND, PR, VT, WV, WY
  • 1 -10 cases: AR, AL, CO, DC, DE, HI, IA, KS, KY, MO, MS, NE, NH, NM, NV, OK, OR, RI, SD, TN, UT, VA, WI
  • 11 – 20 cases: CT, IN, MN, OH, SC, TX, WA
  • 21 – 30 cases: GA, IL, MI, NC
  • 30 cases: AZ, CA, FL., LA, MA, MD, NJ, NY, NYC, PA

How often do children with COVID-19 require hospitalization?

The weekly rate of COVID-19-related hospitalization among children < 18 years of age from 14 states in the U.S. has increased over time, with a cumulative rate of eight per 100,000 population.77 The cumulative rate is highest among children < two years of age (24.8 per 100,000 population).

Despite the trend of increasing hospitalization, a minority of children with COVID-19 require hospitalization.42 Among > 69,700 laboratory-confirmed cases of COVID-19 in children < 20 years of age reported to the CDC by May 30, 2020, the hospitalization rate ranged from 2.5% to 4.1%. Among children hospitalized with COVID-19 from 14 states by late July 2020, approximately 33% required intensive care unit (ICU), and 6% required invasive mechanical ventilation.77 In CDC surveillance of COVID-19 in the U.S., underlying conditions are associated with higher hospitalization and ICU admission rates.42 Age < one year has also been associated with increased rates of hospitalization34, although hospitalization of infants may not reflect the severity of illness. Additional information regarding the hospitalization of children in the United States is available through the CDC's COVIDView.

Transmission

Understanding of the transmission risk is incomplete. Epidemiologic investigation in Wuhan at the beginning of the outbreak identified an initial association with a seafood market that sold live animals, where most patients had worked or visited and which was subsequently closed for disinfection.80 However, as the outbreak progressed, the person-to-person spread was the main mode of transmission.

Person-To-Person Transmission

Direct person-to-person transmission is the primary means of transmission of SARS-CoV-2. It is thought to occur through close-range contact, mainly via respiratory droplets. The virus is released in the respiratory secretions when a person with infection coughs, sneezes, or talks can infect another person if direct contact with the mucous membranes. Infection might also occur if a person's hands are contaminated by droplets or by touching contaminated surfaces, and then they touch their eyes, nose, or mouth. Droplets typically do not travel more than six feet (about two meters). SARS-CoV-2 can also be transmitted through the airborne route (through inhalation of particles smaller than droplets that remain in the air over time and distance), but the extent to which this occurs under natural conditions and how much this mode of transmission has contributed to the pandemic are controversial.81-84 One letter to the editor described a study in which SARS-CoV-2 grown in tissue culture remained viable in experimentally generated aerosols for at least three hours.85 Other studies using specialized imaging to visualize respiratory exhalations have suggested that respiratory droplets may get aerosolized or carried in a gas cloud and have horizontal trajectories beyond six feet (two meters) with speaking, coughing, or sneezing.86-88

Some studies have identified viral RNA in ventilation systems and air samples of hospital rooms of patients with COVID-19, including patients with mild infection.89-93 However, the relevance of these findings to the epidemiology of COVID-19 and their clinical implications are unclear. Studies that attempted to find a viable virus in air and surface specimens in rooms of patients with COVID-19 have either been unsuccessful or have found a virus that ultimately failed to replicate in tissue culture.92,93 Although some reports of clusters of cases have suggested the potential for short-range airborne transmission of SARS-CoV-2 within enclosed indoor spaces94,95, long-range airborne transmission of SARS-CoV-2 has not been documented. Furthermore, in a few reports of healthcare workers exposed to patients with an undiagnosed infection while using only contact and droplet precautions, no secondary infections were identified despite the absence of airborne precautions.96,97 Reflecting on the current uncertainty regarding transmission mechanisms, recommendations on airborne precautions in the healthcare setting vary by location. Airborne precautions are universally recommended when aerosol-generating procedures are performed.

SARS-CoV-2 has been detected in non-respiratory specimens, including stool, blood, ocular secretions, and semen, but these sites' role in the transmission is uncertain.98-104 In particular, several reports have described the detection of SARS-CoV-2 RNA from stool specimens, even after viral RNA could no longer be detected from upper respiratory specimens,101,102 and the live virus has been cultured from stool in rare cases.99,105 Although it would be difficult to confirm, fecal-oral transmission has not been clinically described. According to a joint WHO-China report, it did not appear to be a significant factor in the spread of infection.106 Detection of SARS-CoV-2 RNA in blood has also been reported in some, but not all studies tested for it.98,99,102,107,108 However, the likelihood of bloodborne transmission (e.g., through blood products or needlesticks) appears low. Respiratory viruses are generally not transmitted through the bloodborne route, and transfusion-transmitted infection has not been reported for SARS-CoV-2 or the related Middle East respiratory syndrome coronavirus (MERS-CoV) or SARS-CoV.109 There is also no evidence that SARS-CoV-2 can be transmitted through contact with non-mucous membrane sites (e.g., abraded skin).

Viral Shedding and Period of Infectiousness

The precise interval during which an individual with SARS-CoV-2 infection can transmit the infection to others is uncertain. The potential to transmit SARS-CoV-2 begins before the development of symptoms and is highest early in the course of illness. The risk of transmission decreases after that. After 7 to 10 days of illness, the transmission is unlikely, particularly for otherwise immunocompetent patients with nonsevere infection.

Infected individuals are more likely to be contagious in the earlier stages of illness when viral RNA levels from upper respiratory specimens are the highest.110-114 One modeling study in which the mean serial interval between the onset of symptoms among 77 transmission pairs in China was 5.8 days suggested that infectiousness started 2.3 days before symptom onset, peaked 0.7 days before symptom onset, and declined within seven days.113 In another study that evaluated over 2,500 close contacts of 100 patients with COVID-19 in Taiwan, all 22 secondary cases had their first exposure to the index case within six days of symptom onset. There were no infections documented in the 850 contacts whose exposure was after this interval.115

Prolonged viral RNA detection does not indicate prolonged infectiousness. The duration of viral RNA shedding is variable and may increase with the severity of illness.102,112,116-120 In some individuals, viral RNA can be detected from the respiratory tract months after the initial infection.120 Detectable viral RNA does not always indicate the presence of an infectious virus, and there appears to be a threshold of viral RNA level below which infectiousness is unlikely. In a study of nine patients with mild COVID-19, infectious virus was not detected from respiratory specimens when the viral RNA level was < 106 copies/mL.112 Similarly, in another study, infectious virus was only detected on stored respiratory specimens that had a high concentration of viral RNA (reverse transcription polymerase chain reaction [RT-PCR] positive at cycle threshold [Ct] < 24).121 According to information from the CDC, by three days after clinical recovery, if viral RNA is still detectable in upper respiratory specimens, the RNA concentrations are generally at or below the replication-competent virus levels can be reliably isolated. Additionally, isolation of infectious virus from upper respiratory specimens more than ten days after illness onset has only rarely been documented in patients who had a nonsevere infection and whose symptoms had resolved.112,121-124

An infectious virus has also not been isolated from respiratory specimens of patients who have a repeat positive RNA test following clinical improvement and initial viral RNA clearance. Transmission from such patients has not been documented.125 Occasional reports have described the isolation of infectious virus from respiratory or fecal specimens more than ten days following symptom onset, mainly in patients with severe or critical COVID-19. More studies are needed to understand the frequency and clinical significance of these findings.105,123,126,127

Transmission can occur despite the absence of symptoms. Transmission of SARS-CoV-2 from individuals with infection but no symptoms (including those who later developed symptoms and thus were considered presymptomatic) has been well documented.128-134

The biologic basis for this is supported by a study of a SARS-CoV-2 outbreak in a long-term care facility, in which infectious virus was cultured from RT-PCR-positive upper respiratory tract specimens in presymptomatic and asymptomatic patients as early as six days before the development of typical symptoms.135 The levels and duration of viral RNA in the upper respiratory tract of asymptomatic patients are also like symptomatic patients.136 The extent to which transmission occurs from asymptomatic or presymptomatic subjects and how much it contributes to the pandemic remains uncertain. In an analysis of locally acquired COVID-19 cases in Singapore, transmission during the incubation period was estimated to account for 10 of 157 cases (6.4%). In such cases, the exposures occurred one to three days before symptom development.137

In another study of American passengers on a cruise ship that experienced a large SARS-CoV-2 outbreak, SARS-CoV-2 infection was diagnosed in 63% of those who shared a cabin with an individual with asymptomatic infection, compared with 81% of those who shared a cabin with a symptomatic individual and 18% of those without a cabin-mate.138

The risk of transmission depends on the exposure type. The risk of transmission from an individual with SARS-CoV-2 infection varies by the type and duration of exposure, use of preventive measures, and likely individual factors (e.g., the amount of virus in respiratory secretions). The risk of transmission after contact with an individual with COVID-19 increases with the closeness and duration of contact and appears highest with prolonged contact in indoor settings.

Transmission Among Household Contacts

Limited evidence suggests that transmission from children to household contacts is less common than transmission from adults to household contacts.40,66,67 A study from South Korea reported 248 household contacts of 107 pediatric index cases (defined as the first identified laboratory-confirmed case or the first documented patient within a cluster) during school closure. Only one case of secondary household transmission was identified (secondary attack rate was 0.5%) when infected family members who were exposed to the same source as the pediatric index case were excluded.67

A separate study from South Korea (which included some of the children in the previous study) reported on 10,572 household contacts of 5,706 index patient with COVID-19.66 Although the proportion of positive contacts was greatest (approximately 19%) when the index patient was 10 through 19 years of age, the transmission dynamics were not investigated. The positive contacts and the index patient may have had a common exposure. More than 90% of affected children were household contacts of previously affected adults in other studies of household transmission.139-141 These findings must be interpreted with caution because they occurred after the implementation of strict physical distancing measures, including school closure, which limited the exposure of children to close contacts outside of their household.58

Contact tracing in the early stages of epidemics at various locations suggested that most secondary infections were among household contacts, with a secondary attack rate of up to 15%.106,142-146 Some studies have suggested even higher household infection rates.133,147-149 A large seroprevalence survey from Spain highlighted the greater risk of infection with household contacts.150 The rate of detectable antibodies to SARS-CoV-2 was 31% to 37% (depending on the serologic assay used) among individuals who reported having a household member with confirmed COVID-19, compared with rates of 10% to 14% among those who reported a co-worker, non-household family member, or a friend with confirmed COVID-19.

Transmission in Educational Settings

Limited evidence suggests that transmission by symptomatic preadolescent children is uncommon in educational settings, particularly if the class size is small.62,151-153 In contrast, several studies have documented transmission by adolescents in high school or secondary school151,154,155, but this finding is inconsistent.153 Transmission by presymptomatic children and adolescents also appears to be uncommon in educational settings when effective case-contact testing and epidemic control strategies are implemented.53 In a prospective cohort from Australia where most schools remained open during the first wave of the pandemic, among 752 contacts (649 children and 103 adults) of 12 children who attended primary school, secondary school, or early childhood education while infectious with COVID-19 (defined as 24 hours before the onset of symptoms), only three secondary infections were identified (2 in children and 1 in an adult staff member).

Transmission in Congregate Settings Including Healthcare

Most secondary infections have been described in the following settings:

  • In healthcare settings, personal protective equipment (PPE) was not used (including hospitals156 and long-term care facilities157).
  • In congregate settings where individuals are residing or working in close quarters (e.g., cruise ships158, homeless shelters159,160, and detention facilities161,162).

Although transmission rates are highest in household and congregate settings, reported clusters of cases after social or work gatherings also highlight the risk of transmission through close, non-household contact.86,163,164 Although outdoor settings are generally considered lower risk for transmission than indoor settings, close contact with an individual with COVID-19 remains a risk outdoors. Nevertheless, clusters of cases have been frequently reported following family, work, or social gatherings where close personal contact can occur.165,166

Epidemiologic analysis of a cluster of cases in the state of Illinois showed probable transmission through two family gatherings at which communal food was consumed, embraces were shared, and extended face-to-face conversations were exchanged with symptomatic individuals who were later confirmed to have COVID-19.165 A report of an outbreak among a choir group, with 33 confirmed and 20 probable cases identified among 61 members who attended a practice session, raised the possibility of a high transmission risk through singing in proximity.95

Transmission while Traveling

Traveling with an individual with COVID-19 is a high-risk exposure145, as it generally results in close contact for a prolonged time. An analysis from China looked at the risk among individuals who traveled by train and were exposed within three rows to individuals later confirmed to have COVID-19.167 The study identified 2,334 primary and 234 secondary cases for an overall attack rate of 0.32%. The risk of secondary infection was highest (3.5%) for individuals in seats adjacent to the index patient and higher for those seated in the same row than those in front or behind. The risk also increased over time of travel. This study could not account for the possibility that individuals seated next to one another could have been from the same household or shared other exposures. The risk of transmission with more indirect contact (e.g., passing someone with an infection on the street, handling items previously handled by someone with infection) is not well established and is likely low. However, many individuals with COVID-19 do not report having had a specific, close contact with COVID-19 in the weeks before diagnosis.168

Transmission by Asymptomatic Children

Although there is little information about transmission of SARS-CoV-2 by truly asymptomatic (as opposed to presymptomatic) children, there are reports of familial clusters that included asymptomatic children and possible transmission from asymptomatic children to adults outside their family.169-171 These reports suggest that asymptomatic children may play a role in transmission.172,173 Asymptomatic transmission by adults is well documented.

Environmental Contamination

Virus present on contaminated surfaces may be another infection source if susceptible individuals touch these surfaces and then transfer the infectious virus to mucous membranes in the mouth, eyes, or nose. The frequency and relative importance of this type of transmission remain unclear. It may be more likely to be a potential source of infection in settings where there is heavy viral contamination (e.g., in an infected individual's household or healthcare settings). Extensive SARS-CoV-2 RNA contamination of environmental surfaces in hospital rooms and residential areas of patients with COVID-19 has been described.89,163,164

In a Singapore study, viral RNA was detected on nearly all surfaces tested (handles, light switches, bed and handrails, interior doors and windows, toilet bowl, sink basin) in the airborne infection isolation room symptomatic mild COVID-19 before routine cleaning.89 Viral RNA was not detected on similar surfaces in the rooms of two other symptomatic patients following routine cleaning (with sodium dichloroisocyanurate). Remember, viral RNA detection does not necessarily indicate the presence of an infectious virus.112

It is unknown how long SARS-CoV-2 can persist on surfaces.85,174,175 Other coronaviruses have been tested and may survive on inanimate surfaces for up to six to nine days without disinfection. A specimen containing SARS-CoV (a virus closely related to SARS-CoV-2) had detectable infectivity at six but not nine days in a study evaluating the survival of viruses dried on a plastic surface at room temperature.175 However, in a systematic review of similar studies, various disinfectants (including ethanol at concentrations between 62% and 71%) inactivated several coronaviruses related to SARS-CoV-2 within one minute.

Simulated sunlight has also been shown to inactivate SARS-CoV-2 over 15 to 20 minutes in experimental conditions, with higher levels of ultraviolet-B (UVB) light associated with more rapid inactivation.176 Based on data concerning other coronaviruses, the duration of viral persistence on surfaces also likely depends on the ambient temperature, relative humidity, and the initial inoculum size.177

Animal Contact

SARS-CoV-2 infection is thought to have been initially transmitted to humans from an animal host, but the ongoing risk of transmission through animal contact is uncertain. There is no evidence suggesting that animals (including domesticated animals) are a major infection source in humans. SARS-CoV-2 infection has been described in animals in both natural and experimental settings. There have been rare reports of animals with SARS-CoV-2 infection (including asymptomatic infections in dogs and symptomatic infections in cats) following close contact with a human with COVID-19.178-180 Moreover, asymptomatic, experimentally infected domestic cats may transmit SARS-CoV-2 to cats they are caged with.181

The risk of infection may vary by species. In one study evaluating infection in animals after intranasal viral inoculation, SARS-CoV-2 replicated efficiently in ferrets and cats. Viral replication was also detected in dogs, but they appeared to be less susceptible to experimental infection.182 Pigs and poultry were not susceptible to infection. Mink appear highly susceptible to SARS-CoV-2. Outbreaks on mink farms have been reported in the Netherlands, and in this setting, a suspected case of mink to human transmission was described.183

Given the uncertainty regarding the transmission risk and the apparent susceptibility of some animals to SARS-CoV-2 infection, the CDC recommends that pets are kept away from other animals or people outside of the household and that people with confirmed or suspected COVID-19 try to avoid close contact with household pets, as they should with human household members, for the duration of their self-isolation period. There have been no reports of domesticated animals transmitting SARS-CoV-2 infection to humans.

Pathophysiology

The pathophysiology of MIS-C is not well understood. It has been suggested that the syndrome results from an abnormal immune response to the virus, with some clinical similarities to KD, macrophage activation syndrome (MAS), and cytokine release syndrome (CRS). However, based on the available studies, MIS-C appears to have an immunophenotype distinct from KD and MAS.184,185 The mechanisms by which SARS-CoV-2 triggers the abnormal immune response are unknown. A postinfectious process is suggested, based on the timing of the rise of these cases relative to the peak of COVID-19 cases in communities.

Many affected children have negative polymerase chain reaction (PCR) testing for SARS-CoV-2. Still, they have positive serology, a finding that further supports the hypothesis that MIS-C is related to immune dysregulation occurring after the acute infection has passed. However, some children do have positive PCR testing.

  • In the available case series, there were 783 children in whom both PCR and serology were performed.9,10,12,26,28,186 Of these:
    • 60% had positive serology with negative PCR
    • 34% were positive on both tests
    • 5% were negative on both tests

Understanding the mechanisms of the exaggerated immune response in MIS-C is an area of active investigation.

Approach to Diagnosis

Infection Control

Given concerns that SARS-CoV-2 may be spread from the upper airway of symptomatic or asymptomatic children187, the Royal College of Paediatrics and Child Health suggests avoiding examination of the oropharynx unless it is essential.188 When examining the oropharynx is necessary (including obtaining oropharyngeal swabs), PPE should be worn, whether the child has symptoms compatible with COVID-19. Detection of other respiratory pathogens (e.g., influenza, respiratory syncytial virus, Mycoplasma pneumoniae) in nasopharyngeal specimens does not exclude COVID-19.70,139,189,190-194 In a systematic review of COVID-19 in 1,183 children from 26 countries, coinfection was detected in 5.6%.

  • M. pneumoniae was most common (58% of coinfections)
  • Influenza (11% of coinfections)
  • Respiratory syncytial virus (11% of coinfections)

Limiting the transmission of SARS-CoV-2 is an essential component of care in patients with suspected or documented COVID-19 and COVID-19-related illnesses, including MIS-C. This includes:

  • Identifying and isolating patients with suspected COVID-19
  • Universal source control (e.g., covering the patient's nose and mouth with a mask to contain respiratory secretions)
  • Use of appropriate PPE when caring for patients with COVID-19
  • Environmental disinfection

All patients with suspected MIS-C should undergo testing for SARS-CoV-2 at the time of presentation.

While specific infection control measures may vary from institution to institution, the general approach is as follows:

  • Infection control precautions should be used, pending the results of initial testing
  • If SARS-CoV-2 PCR is positive, infection control precautions should be continued
  • If the initial PCR is negative, a second PCR should be collected ≥ 24 hours from the first
  • Infection control measures can generally be discontinued if the patient has defervesced, and at least two consecutive PCRs obtained ≥ 24 hours apart are negative (regardless of serology results)

Criteria for Testing for COVID-19 in Children

Laboratory testing is necessary to confirm the diagnosis of COVID-19 because no single symptom or combination of symptoms reliably differentiates SARS-CoV-2 from other community-acquired viruses and because coinfection is common.195-198 Criteria for testing for COVID-19 vary geographically. In the U.S., guidance provided by the CDC, Infectious Diseases Society of America, and the American Academy of Pediatrics may be adapted by state and local health departments depending upon test availability.199-202

Testing criteria suggested by the WHO can be found in its technical guidance online. These are the same criteria used by the European Centre for Disease Prevention and Control.

Outpatient Testing Criteria

The testing approach varies according to test availability and other resources (e.g., some communities have begun to offer COVID-19 testing to residents regardless of symptoms or previous testing). Given limited testing resources, some institutions perform targeted testing in the outpatient setting for children who are evaluated for symptoms consistent with COVID-19 (e.g., fever, persistent cough, shortness of breath, vomiting, diarrhea) or known in-person exposure to a laboratory-confirmed case of COVID-19 within the previous 14 days.

In the emergency department (ED) or urgent care setting, testing is performed for SARS-CoV-2 if the child has an underlying condition that may increase the risk of severe disease.

  • An immune-compromising condition:HIV infection with CD4 count < 15%
  • Primary immunodeficiency
  • Recipients of antineoplastic chemotherapy
  • Recent hematopoietic cell transplantation
  • Solid organ transplant recipients
  • Chronic cardiac disease:
    • Cardiomyopathy
      • Single ventricle physiology
      • Unrepaired cyanotic congenital heart disease
    • Chronic pulmonary disease
      • Requirement for supplemental oxygenation or noninvasive ventilation
      • Severe persistent asthma
  • Former preterm infants
  • Neuromuscular disease with impaired airway clearance
  • Poorly controlled type I diabetes mellitus
  • Severe obesity (body mass index of ≥ 120% of the 95th percentile values
  • Presentation with severe illness:
    • Clinical manifestations of MIS-C
    • New requirement for supplemental oxygen or increased requirement from baseline
    • New or increased need for ventilation [invasive or noninvasive]203

Some institutions have instituted a "drive-thru" assessment center for symptomatic patients (e.g., fever, persistent cough) who are otherwise stable but have either underlying conditions (e.g., immune compromise, chronic cardiac or pulmonary disease), or known in-person exposure to a laboratory-confirmed case of COVID-19 within the previous 14 days.

Inpatient Testing Criteria

Universal testing of hospitalized patients should be performed at the time of presentation, regardless of clinical symptoms or signs of COVID-19. Infants born in an institution to a mother who tested negative for COVID-19 and are admitted to the nursery or neonatal intensive care unit (NICU) are an exception. This strategy was implemented to reduce hospital-associated transmission, given the prevalence of asymptomatic infection in children and frequency of COVID-19 in children with additional diagnoses requiring hospital admission (e.g., diabetic ketoacidosis, sickle cell disease with vaso-occlusive pain).196,204

For hospitalized children whose initial test results are negative and are scheduled for procedures (e.g., endoscopy), retesting within 48 hours of the scheduled procedure should be performed. For patients with the suspected nosocomial acquisition of a respiratory virus, testing for common respiratory pathogens should occur (e.g., via multiplex RT-PCR), as well as COVID-19.

Preoperative

Decisions regarding universal testing of children before elective surgery should be individualized according to the regional prevalence of COVID-19, local testing capacity, and availability of PPE.205 Testing for SARS-CoV-2 should be performed 24 to 48 hours before elective surgical procedures.

In a study of universal preoperative screening for SARS-CoV-2 at three tertiary care children's hospitals, the overall incidence was < one%.205 However, the incidence varied substantially between hospitals (from 0.2% to 2.7%) and within a single hospital (five of nine children who tested positive were from a single township). Although symptoms and known exposure to COVID-19 were more common in children with a positive test, only six of 12 children with a positive test had symptoms (fever, rhinorrhea, cough, diarrhea). Only two had known exposure.

Asymptomatic Individuals

In certain circumstances, testing asymptomatic individuals is important for public health or infection control purposes (e.g., hospital admission in communities with high prevalence, preoperative screening).

Clinical Manifestations of MIS-C

Presenting Signs and Symptoms

In children of all ages, the symptoms of COVID-19 are similar in children and adults, but the frequency of symptoms varies.42 COVID-19 appears to be milder in children than in adults, although severe cases have been reported.206,207 Among 69,703 laboratory-confirmed cases of COVID-19 in children < 20 years of age reported to the U.S. CDC by May 30, 2020, boys and girls were equally affected.42 In a systematic review of observational studies, including 7,480 children with laboratory-confirmed COVID-19, predominantly from Italy, China, and the U.S., the weighted mean age was 7.6 years.206

Although the clinical findings in children with COVID-19 are diverse, fever and cough are the most common reported symptoms.42,206,207 In case surveillance in the U.S. (through May 30, 2020), information about symptoms was available for 5,188 children aged zero through nine years and 12,689 children aged 10 through 19.42 Among children age zero through nine years, the frequency of symptoms was as follows:

  • Fever, cough, or shortness of breath – 63%
    • Fever – 46%
    • Cough – 37%
    • Shortness of breath – 7%
  • Myalgia – 10%
  • Rhinorrhea – 13%
  • Headache – 15%
  • Nausea/vomiting – 10%
  • Abdominal pain – 7%
  • Diarrhea – 14%
  • Loss of smell or taste – 1%

Among children age ten through 19 years, the frequency of symptoms was as follows:

  • Fever, cough, or shortness of breath – 60%
    • Fever – 35%
    • Cough – 41%
    • Shortness of breath – 16%
  • Myalgia – 30%
  • Rhinorrhea – 8%
  • Headache – 42%
  • Nausea/vomiting – 10%
  • Abdominal pain – 8%
  • Diarrhea – 14%
  • Loss of smell or taste – 10%

Similar clinical manifestations, along with sore throat and fatigue, have been reported in smaller case series.206 Additional symptoms that have been reported in adults include chills or shaking chills.208 Gastrointestinal symptoms may occur without respiratory symptoms.31,209,210 Diarrhea, vomiting, and abdominal pain are the most common gastrointestinal symptoms reported in children.32,34,210-212 Gastrointestinal bleeding has been reported in adults but has not been reported in children.210 Cutaneous findings have been reported infrequently and are not well characterized. They include213-216:

  • Maculopapular
  • Reddish-purple nodules on the distal digits (sometimes called "COVID toes") similar in appearance to pernio (chilblains) are described predominantly in children and young adults. However, an association with COVID-19 has not been established214,217-220
  • Transient livedo reticularis
  • Urticarial
  • Vesicular eruptions

In infants < 12 months of age, additional clinical findings include222-226:

  • Feeding difficulty
  • Fever without an obvious source
  • Respiratory symptoms may be minimal

When present, respiratory symptoms are like those caused by other coronaviruses and influenza, although the cough may be less prominent.227 In a series of 46 infants < 12 months of age from Wuhan Children's Hospital, the disease was asymptomatic or mild in 4, moderate in 40, and severe or critical in 2 patients.228 Only four infants had underlying comorbidities (atrial septal defect, intussusception, hypogammaglobulinemia, brain trauma).

In a systematic review of 25 infants ≤ three months of age with laboratory-confirmed SARS-CoV-2 infection, five were asymptomatic, 12 had mild symptoms, 5 had moderate symptoms, and 3 had severe symptoms.206 Symptoms included fever, cough, dyspnea, vomiting, and feeding intolerance. Two infants were treated in the ICU, and one required mechanical ventilation. In the available case series, MIS-C clinical presentations were similar, including3,6,9-12,23,26,28,29,186,229:

  • Persistent fevers (median duration four to six days) – 100%
    • Most patients present with three to five days of fever, though fewer days of fever have been reported
    • In the largest series, which included 186 patients, 10% had three days of fever, 12% had four days, and 78% had ≥ five days12
  • Gastrointestinal symptoms (abdominal pain, vomiting, diarrhea) – 60% to 100%
    • Gastrointestinal symptoms (abdominal pain, vomiting, diarrhea) are particularly common and prominent, with the presentation in some children mimicking appendicitis27,28,230
    • Some children have been noted to have terminal ileitis on abdominal imaging or colitis on colonoscopy
  • Rash – 45% to 76%

Image 1: Rash

Rash

  • Conjunctivitis – 30% to 81%

Image 2: Conjunctivitis

Non-Purulent Conjunctivitis

  • Mucous membrane involvement – 27% to 76%
    • Redness or swelling of the lips
    • A swollen tongue that looks like a “strawberry”

Image 3: Strawberry Tongue

Strawberry Tongue

  • Respiratory symptoms – 21% to 65%
    • Respiratory symptoms (tachypnea, labored breathing) when present, are most often due to severe shock
    • Cough is uncommon
    • Though some children require supplemental oxygen or positive pressure ventilation for cardiovascular stabilization, severe pulmonary involvement (e.g., acute respiratory distress syndrome) is not a prominent feature
  • Sore throat – 10% to 16%
  • Myalgia – 8% to 17%
  • Swollen hands/feet – 9% to 16% 

Image 4: Swollen Hands

Redness or Swelling of the Hands

  • Lymphadenopathy – 6% to 16%
  • Neurocognitive symptoms (headache, lethargy, confusion) – 29% to 58%12,231
    • Confusion
    • Headache
    • Irritability
    • Lethargy

A minority of patients present with more severe neurologic manifestations, including 12,231:

  • Encephalopathy
  • Seizures
  • Coma
  • Meningoencephalitis
  • Muscle weakness
  • Brainstem or cerebellar signs

Other Clinical Findings

Common clinical findings reported in the available case series include 3,6,9,12,26,28,29,186,229,231:

  • Shock – 32% to 76%
  • Criteria met for complete KD – 22% to 64%
  • Myocardial dysfunction (by echocardiogram and/or elevated troponin or brain natriuretic peptide [BNP]) – 51% to 90%
  • Arrhythmia – 12%
  • Acute respiratory failure requiring noninvasive or invasive ventilation – 28% to 52%
  • Acute kidney injury (AKI) (most cases were mild) – 8% to 52%
  • Serositis (small pleural, pericardial, and ascitic effusions) – 24% to 57%
  • Hepatitis or hepatomegaly – 5% to 21%
  • Encephalopathy, seizures, coma, or meningoencephalitis – 6% to 7%

Different case definitions were used in different studies, explaining some variability in the reported frequency of these findings. As more is learned about MIS-C, it is becoming apparent that there is a wide spectrum of disease severity. The initial case series reported the most severe end of the spectrum, resulting in a high reported incidence of shock, myocardial involvement, and respiratory failure. It is likely that as recognition of milder forms of MIS-C increases, the incidence of shock, left ventricular (LV) dysfunction, respiratory failure, and acute kidney injury will be lower.

Laboratory Findings

Laboratory findings are variable. In a systematic review of laboratory-confirmed cases of COVID-19 in children < 18 years206, this included232:

  • The complete blood count (CBC) was normal in most children
    • 17% had a low WBC count
    • 13% had either neutropenia or lymphocytopenia
      • Severe neutropenia has been described
  • Approximately one-third had elevated C-reactive protein (CRP; defined as > 5 mg/L in most studies) or procalcitonin (defined as > 0.5 ng/mL)
  • Elevated inflammatory markers and lymphocytopenia may indicate MIS-C:
    • Creatine kinase was elevated in 15%
    • Serum aminotransferases were elevated in 12%
  • In a series of 157 children with COVID-19 that was not included in the systematic review, elevated lactic dehydrogenase (LDH) was another common laboratory abnormality233
  • Renal dysfunction may occur in severely ill children
    • In a series of 52 children admitted to a tertiary care hospital, 24 (46%) had serum creatinine greater than the upper level of reference interval (ULRI), and 15 met British Association of Paediatric Nephrology criteria for acute kidney injury (AKI)234
      • Most cases of AKI occurred in children admitted to the ICU and those with MIS-C
      • None of the children with AKI required kidney biopsy or continuous renal replacement therapy
      • Serum creatinine decreased to ULRI in all but one child with AKI during admission

Laboratory abnormalities noted in the available MIS-C case series include3,6,9,12,26,28,29,186,229,235:

  • Abnormal blood cell counts, including:
    • Lymphocytopenia – 80% to 95%
    • Neutrophilia – 68% to 90%
    • Mild anemia – 70%
    • Thrombocytopenia – 31% to 80%
  • Elevated inflammatory markers, including:
    • C-reactive protein (CRP) – 90% to 100%
    • Erythrocyte sedimentation rate (ESR) – 75% to 80%
    • D-dimer – 67% to 100%
    • Fibrinogen – 80% to 100%
    • Ferritin – 55% to 76%
    • Procalcitonin – 80% to 95%
    • Interleukin-6 (IL-6) – 80% to 100%
  • Elevated cardiac markers:
    • Troponin – 50% to 90%
    • BNP or NT-pro-BNP – 73% to 90%
  • Hypoalbuminemia – 48% to 95%
  • Mildly elevated liver enzymes – 62% to 70%
  • Elevated lactate dehydrogenase – 10% to 60%
  • Hypertriglyceridemia – 70%

Laboratory markers of inflammation appear to correlate with the severity of illness. For example, in one series, children who developed shock had higher CRP values, higher neutrophil counts, lower lymphocyte counts, and lower serum albumin than children without shock.10 Additionally, children with shock more commonly had elevated cardiac markers.

Severe Disease in Children

Although severe cases of COVID-19 in children, including fatal cases, have been reported, most children appear to have an asymptomatic, mild, or moderate disease and recover within one to two weeks of disease onset.42,206 In a systematic review of 7,480 children < 18 years of age with laboratory-confirmed COVID-19 infection, information about symptoms and severity was available for 1,475. Among these206:

  • 15% of cases were asymptomatic
  • 42% were mild
  • 39% were moderate (e.g., clinical or radiographic evidence of pneumonia without hypoxemia)
  • 2% were severe (e.g., dyspnea, central cyanosis, hypoxemia)
  • 0.7% were critical (e.g., acute respiratory distress syndrome, respiratory failure, shock)
  • There were six deaths in the entire study population (0.08%).

Why COVID-19 appears to be less common and less severe in children than in adults is unclear. One possibility is that children have a less intense immune response to the virus than adults. Cytokine release syndrome is thought to be important in the pathogenesis of severe COVID-19 infections.189,236 Other possibilities include:

  • Viral interference in the respiratory tract of young children, which may lead to a lower SARS-CoV-2 viral load
  • Different expression of the angiotensin-converting enzyme two receptors (the receptor for SARS-CoV-2) in the respiratory tracts of children and adults31,61,237-239
  • Relatively healthier blood vessels in children than in adults240

Risk Factors for Severe Disease

Children with certain underlying conditions are at greater risk for severe disease (e.g., hospitalization, need for intensive care or mechanical ventilation). These conditions include42,70,207,241-244:

  • Medical complexity
  • Congenital heart disease
  • Neurologic, genetic, or metabolic conditions

Other conditions that increase the risk for severe disease in people of all ages include245:

  • Chronic kidney disease
  • Immune compromise from solid organ transplant246
  • Obesity (body mass index > 95th percentile for age and sex)
  • Sickle cell disease
  • Type 2 diabetes mellitus

Conditions that may increase the risk for severe disease in people of all ages include245:

  • Cerebrovascular disease
  • Chronic pulmonary disease (e.g., cystic fibrosis, moderate to severe asthma, pulmonary fibrosis)
  • Hypertension
  • Immune compromise from hematopoietic cell transplant, primary immune deficiency, HIV, medications (e.g., glucocorticoids)
  • Liver disease
  • Pregnancy
  • Smoking or electronic cigarette use247
  • Thalassemia
  • Type 1 diabetes mellitus

Age < one year also has been associated with increased risk for severe disease31,34,70,243,248,249, but this finding is inconsistent.209,226,245,250 Although immune compromise has been reported as an underlying condition in children with severe COVID-19 disease in some case series, the relationship between immune compromise and severe COVID-19 disease has not been well established. In a review of 178 children with cancer from a single institution in New York City, 20 tested positive for SARS-CoV-2, and only one required admission (noncritical) for symptoms related to COVID-19.251

COVID-19 was similarly mild in small surveys of children who developed COVID-19 while receiving immunosuppressive medications for kidney disease or inflammatory bowel disease.252,253 In the CDC literature review, the evidence is more substantial and more consistent for immune suppression from solid organ transplantation than from other causes of immune suppression.245 In multicenter studies of children admitted to pediatric ICUs, most children had one or more underlying conditions.70,241,242 In a European multinational, multicenter cohort, risk factors for ICU admission included70:

  • Age < one month
  • Underlying medical conditions
  • Lower respiratory tract infection findings at presentation

CDC's COVID-NET provides information about underlying medical conditions in hospitalized children according to age77,79, although robust evidence associating specific underlying conditions with severe illness in children is lacking.203 Among children hospitalized with COVID-19 from 14 states by late July 2020, 42% had ≥ one underlying condition, the most common being obesity (38% of children ≥ two years), chronic pulmonary disease (18%), and prematurity (15% of children < 2 years).190

In a systematic review of 587 hospitalized children and outpatients with laboratory-confirmed COVID-19 and information about comorbidities, 22% had an underlying condition.206 The most common underlying conditions were:

  • Chronic pulmonary disease, including asthma (45%)
  • Chronic pulmonary disease was also the most reported underlying condition in children from the U.S. and Europe with laboratory-confirmed COVID-1942,70
  • Congenital heart disease (23%)
  • Immune suppression (12%)
  • Hematologic or oncologic conditions (6%)

In observational studies, elevated inflammatory markers (e.g., CRP, procalcitonin, interleukin 6, ferritin, D-dimer) at admission or during hospitalization is a potential marker of severe disease in children.209,244,249

Imaging Findings

Imaging findings are variable and may be present before symptoms.206,254,255 A systematic review that included 674 children with confirmed COVID-19 infection who underwent imaging, approximately 50% had abnormalities.206

Diagnostic imaging may include3,9,10,12,28,186:

  • Echocardiography
    • Echocardiographic findings may include28:
      • Depressed LV function
      • Coronary artery (CA) abnormalities (including dilation or aneurysm)
      • Mitral valve regurgitation
      • Pericardial effusion
    • The frequency of cardiac involvement in MIS-C is uncertain
      • In three large case series, approximately 30% to 40% of children had depressed LV function, and 8% to 19% had CA abnormalities10,12,26
      • These reports included patients with severe MIS-C, as well as milder cases
      • The case series, including severely affected patients, reported considerably higher rates of depressed LV function (approximately 50% to 60%) and CA abnormalities (approximately 20% to 50%). Still, these estimates probably do not reflect the risk in the broader population
  • Chest Radiograph (CXR)
    • Many patients had normal CXRs
    • Abnormal findings included:
      • Small pleural effusions
      • Patchy consolidations
      • Focal consolidation
      • Atelectasis
  • Computed Tomography (CT) of Chest
    • Chest CT (when obtained) generally had findings like those on CXR
      • Among 605 children who underwent chest CT:
        • 33% had normal findings
        • 29% had ground-glass opacities
        • 27% had nonspecific unilateral findings
        • 23% had bilateral findings
  • Lung ultrasonography
    • In a study of eight Italian children hospitalized with documented COVID-19, findings on lung ultrasonography included256:
      • Subpleural consolidations
      • Individual or confluent B lines
        • These findings were concordant with CXR findings in seven of the eight patients
        • They are like findings in adult patients with COVID-19
  • Abdominal Imaging230
    • Findings on abdominal ultrasound or abdominal CT included:
      • Free fluid
      • Ascites
      • Bowel and mesenteric inflammation, including:
        • Terminal ileitis
        • Mesenteric adenopathy/adenitis
        • Pericholecystic edema

Case Definitions

The criteria used for case definition vary slightly between different health agencies.5,7,235 The case definitions put forth by the U.S. CDC and the WHO are summarized below. Both definitions require:

  • Fever (though they differ concerning duration)
  • Elevated inflammatory markers
  • At least two signs of multisystem involvement
  • Evidence of SARS-CoV-2 infection or exposure
  • Exclusion of other potential causes

The CDC case definition requires that the child have severe MIS-C symptoms requiring hospitalization, whereas the WHO case definition does not. These definitions are likely to change as more information becomes available.

CDC Case Definition

According to the case definition put forth by the CDC, MIS-C is defined by meeting all four of the following criteria:

  • Age < 21 years
  • A presentation consistent with MIS-C, including all the following:
    • Fever > 38.0°C (100.4° F) for ≥ 24 hours, or report of subjective fever lasting ≥ 24 hours
    • Laboratory evidence of inflammation including, but not limited to, any of the following:
      • Elevated C-reactive protein (CRP)
      • Elevated erythrocyte sedimentation rate (ESR)
      • Elevated fibrinogen
      • Elevated procalcitonin
      • Elevated D-dimer
      • Elevated ferritin
      • Elevated lactic acid dehydrogenase (LDH)
      • Elevated interleukin-6 [IL-6] level
      • Neutrophilia
      • Lymphocytopenia
      • Hypoalbuminemia
    • Multisystem involvement
      • Two or more organ systems involved:
        • Cardiovascular (e.g., shock, elevated troponin, elevated BNP, abnormal echocardiogram, arrhythmia)
        • Respiratory (e.g., pneumonia, acute respiratory distress syndrome, pulmonary embolism)
        • Renal (e.g., AKI, renal failure)
        • Neurologic (e.g., seizure, stroke, aseptic meningitis)
        • Hematologic (e.g., coagulopathy)
        • Gastrointestinal (e.g., abdominal pain, vomiting, diarrhea, elevated liver enzymes, ileus, gastrointestinal bleeding)
    • Clinically severe illness requiring hospitalization
  • No plausible alternative diagnoses
  • Recent or current SARS-CoV-2 infection or exposure, defined as any of the following:
    • Positive SARS-CoV-2 by RT-PCR
    • Positive serology for SARS-CoV-2
    • Positive antigen test for SARS-CoV-2
    • COVID-19 exposure within the four weeks before the onset of symptoms

Patients who meet these criteria and who also fulfill full or partial criteria for KD should be considered to have MIS-C and should be reported. Also, MIS-C should be considered in any pediatric death with evidence of SARS-CoV-2 infection.

WHO Case Definition

According to the case definition put forth by the WHO, MIS-C is defined by meeting all six of the following criteria:

  • Age zero to 19 years old
  • Fever for ≥ three days
  • Clinical signs of multisystem involvement (at least two of the following):
    • Rash, bilateral nonpurulent conjunctivitis, or mucocutaneous inflammation signs (oral, hands, or feet)
    • Hypotension or shock
    • Cardiac dysfunction, pericarditis, valvulitis, or coronary abnormalities (including echocardiographic findings or elevated troponin/BNP
    • Evidence of coagulopathy (prolonged PT or PTT, elevated D-dimer)
    • Acute gastrointestinal symptoms (diarrhea, vomiting, or abdominal pain)
  • Elevated markers of inflammation (e.g., ESR, CRP, or procalcitonin)
  • No other obvious microbial cause of inflammation, including bacterial sepsis and staphylococcal/streptococcal shock syndromes
  • Evidence of SARS-CoV-2 infection
    • Any of the following:
      • Positive SARS-CoV-2 RT-PCR
      • Positive serology
      • Positive antigen test
      • Contact with an individual with COVID-19

Spectrum of Disease

Initial reports of MIS-C described mostly severely affected children. However, as more is learned about COVID-19 and MIS-C in children, it is becoming apparent that the spectrum of COVID-19-associated disease ranges from mild to severe.10,186 It remains unclear how common each presentation is, how frequently children progress from mild to more severe manifestations and the risk factors for such progression.

Understanding of the full spectrum of MIS-C, including subphenotypes, is evolving. In a study of 570 children with MIS-C reported to the CDC through July 2020, investigators used a statistical modeling technique called latent class analysis to identify different subtypes of the syndrome. The study had important limitations, chiefly that it relied on state public health reports with limited and incomplete clinical data. Nevertheless, the analysis identified three subgroups based on underlying similarities.

MIS-C without overlap with acute COVID-19 or KD group comprised 35% of the cohort. Nearly all patients in this group had cardiovascular and gastrointestinal involvement, and one-half had ≥ four other organ systems involved. Patients in this group were more likely to have shock, cardiac dysfunction, and markedly elevated CRP and ferritin. Nearly all patients in this group had positive SARS-CoV-2 serology (with or without positive RT-PCR).

MIS-C overlapping with severe acute COVID-19 group comprised 30% of the cohort. Many children in this group presented with respiratory involvement, including cough, shortness of breath, pneumonia, and acute respiratory distress syndrome. Most of these children had positive SARS-CoV-2 RT-PCR without seropositivity. The mortality rate was higher in this subgroup compared with the other two subgroups.

MIS-C overlapping with the KD group comprised 35% of the cohort. Children in this group were younger than the other two groups (median age six, verses 9 and 10 years, respectively). They more commonly had a rash and mucocutaneous involvement and less commonly had shock or myocardial dysfunction. Approximately two-thirds of patients in this group had positive SARS-CoV-2 serology with negative RT-PCR, and one-third were positive on both tests. Importantly, the incidence of CA abnormalities was similar in all three subgroups (21%, 16%, and 18%, respectively), highlighting the importance of routine echocardiography in all children with MIS-C, regardless of apparent subphenotype.

Differentiating MIS-C and KD

There is considerable phenotypic overlap with MIS-C and KD. In the available case series, approximately 40% to 50% of children with MIS-C met the criteria for complete (typical) or incomplete (atypical) KD.9,10,12,23,257 However, there appear to be some key differences.

MIS-C commonly affects older children and adolescents, whereas classic KD typically affects infants and young children. In MIS-C, Black and Hispanic children appear to be disproportionally affected, and Asian children account for only a small number of cases. By contrast, classic KD has a higher incidence in East Asia and children of Asian descent. Gastrointestinal symptoms (particularly abdominal pain) are common in MIS-C, whereas these symptoms are less prominent in classic KD. Myocardial dysfunction and shock occur more commonly in MIS-C than classic KD.12 Inflammatory markers (especially CRP, ferritin, and D-dimer) tend to be more elevated in MIS-C than KD. Additionally, absolute lymphocyte and platelet counts tend to be lower in MIS-C compared with classic KD.258

These clinical features can help distinguish MIS-C from KD, but ultimately, the designation of MIS-C versus KD is based on SARS-CoV-2 testing and exposure history. Patients with positive SARS-CoV-2 testing (or with exposure to an individual with COVID-19) who also fulfill criteria for complete or incomplete KD are considered to have MIS-C and receive the standard treatment for KD. However, as the COVID-19 pandemic spreads, distinguishing patients with KD-like MIS-C from those with true KD will be difficult. The baseline incidence rate of true KD will continue as more children are exposed to SARS-CoV-2, with subsequent seroconversion. Accordingly, classifying patients who have KD features and positive antibodies as MIS-C versus KD will be challenging. Ultimately, better characterizing the distinct immunophenotypes of these syndromes may help clinicians distinguish one from the other.184,185

Evaluation

Patients with suspected MIS-C should have laboratory studies performed to look for evidence of inflammation and to assess cardiac, renal, and hepatic function. Testing should also include RT-PCR and serology for SARS-CoV-2. Additionally, patients should be assessed for other infectious or noninfectious conditions that may have a similar presentation. The approach outlined below is generally consistent with the guidance published by the American College of Rheumatology and the American Academy of Pediatrics.258,259

Laboratory Testing

The initial laboratory evaluation of a child with suspected MIS-C depends on the presentation.

  • Moderate to Severe Symptoms
    • For children with moderate to severe symptoms, the following is suggested:
      • CBC with differential
      • CRP and ESR (optional: procalcitonin)
      • Ferritin
      • Liver function tests and LDH
      • Serum electrolytes and renal function tests
      • Urinalysis
      • Coagulation studies:
        • PT/INR
        • aPTT
        • D-dimer
        • Fibrinogen
      • Cardiac markers, if elevated, are followed serially to monitor progression. These include:
        • Troponin
        • BNP or NT-pro-BNP
      • Cytokine panel (if available)
      • Inflammatory markers are measured at the time of admission and then serially to monitor progression. These include:
        • CRP
        • ESR
        • Procalcitonin
        • Ferritin
  • Mild Symptoms
    • For patients presenting with fever for ≥ three days and who are well-appearing (i.e., normal vital signs and reassuring physical examination) with only mild symptoms suggestive of MIS-C, a more limited evaluation initially is suggested. It is suggested to start with the following:
      • CBC with differential
      • CRP
      • Serum electrolytes
      • Renal function tests
    • If these results are abnormal, additional testing is performed (as listed above)
    • The clinician should also assess other common causes of fever (e.g., streptococcal pharyngitis, mononucleosis)
      • While it does not definitively exclude MIS-C, identifying another source of fever makes the diagnosis of MIS-C less likely, particularly in an otherwise well-appearing child

Testing for SARS-CoV-2

All patients with suspected MIS-C should be tested for SARS-CoV-2, including serology and RT-PCR on a nasopharyngeal swab. Approximately 60% of patients have positive serology with negative RT-PCR, and approximately 30% to 35% are positive on both tests. A minority of patients (approximately 5% to 10%) have negative results on both tests. In these cases, the diagnosis of MIS-C requires an epidemiologic link to SARS-CoV-2 (e.g., exposure to an individual with known COVID-19 within the four weeks before the onset of symptoms).

Testing for Other Pathogens

Testing for other viral and bacterial pathogens includes235:

  • Blood culture
  • Urine culture
  • Throat culture
  • Stool culture
  • Nasopharyngeal aspirate or throat swab for respiratory viral panel
  • Epstein-Barr virus serology and RT-PCR
  • Cytomegalovirus serology and RT-PCR
  • Enterovirus RT-PCR
  • Adenovirus RT-PCR

This testing is appropriate for children with moderate to severe MIS-C (i.e., children who require hospitalization). However, an extensive infectious workup is generally not necessary in well-appearing children presenting with mild symptoms. In such patients, microbiologic testing should be done as clinically indicated according to the child's age and his/her specific symptoms (e.g., throat culture if the child has a sore throat, respiratory viral panel if there are respiratory symptoms). Testing should follow the same general approach as is used for fever evaluation more broadly.

Detection of other respiratory pathogens (e.g., rhinovirus, influenza, respiratory syncytial virus) in nasopharyngeal specimens does not exclude COVID-19. Additional testing for other pathogens may be warranted, depending on the geographic location and exposure history. These may include:

  • Murine typhus
  • Leptospirosis serology

Cardiac Testing

In addition to troponin and BNP/NT-pro-BNP levels, the cardiac evaluation of a patient with suspected MIS-C includes:

  • 12-lead electrocardiogram (ECG)
    • In children with MIS-C, baseline ECGs may be nonspecific, though arrhythmia and heart block have been described3,260
  • Echocardiography
    • Echocardiography is also recommended for children with documented SARS-CoV-2 who do not meet all MIS-C criteria but have either shock or features consistent with complete or incomplete KD
    • Children and adolescents with mild COVID-19 without systemic inflammation signs are unlikely to have CA changes or myocarditis. In such children, echocardiography is generally unnecessary but may be considered if there are specific clinical concerns
    • Findings on initial echocardiography may include3:
      • CA dilation
      • LV systolic dysfunction
      • Pericardial effusion
      • Aneurysm, including giant coronary aneurysms
    • The echocardiographic evaluation includes the following:
      • Quantitative assessment of LV size and systolic function (LV end-diastolic volume, ejection fraction)
      • Qualitative assessment of right ventricular systolic function
      • CA abnormalities (dilation or aneurysm)
      • Assessment of valvar function
      • Evaluation for the presence and size of pericardial effusion
      • Evaluation for intracardiac thrombosis or pulmonary artery thrombosis, particularly apical thrombus in severe LV dysfunction
      • Strain imaging and LV diastolic function (optional)
    • Timing of follow-up echocardiography
      • Echocardiography is performed at the time of diagnosis, with follow-up examinations at the following intervals:
        • A follow-up echocardiogram is performed one to two weeks post-diagnosis in patients who initially have normal function and normal CA dimensions to recheck CA size
        • In patients with CA dilation/aneurysm on initial echocardiogram, echocardiography is repeated every two to three days until CA size is stable and then every one to two weeks for the next four to six weeks
        • The echocardiogram is repeated as clinically indicated for patients with systolic dysfunction/myocarditis and normal CAs on initial echocardiogram, including repeat imaging of the CAs with each study
        • For patients who had evidence of CA involvement or systolic dysfunction/myocarditis in the acute phase, cardiac magnetic resonance imaging (MRI) can be considered at approximately two to six months after the acute illness to assess ventricular function and evaluate for edema, diffuse fibrosis, and scar by myocardial delayed enhancement

Differential Diagnosis

In children presenting with signs and symptoms consistent with MIS-C, the differential diagnosis is broad and includes other infectious and inflammatory conditions. Examples include:

Bacterial Sepsis

Bacterial sepsis is an important consideration in children presenting with fever, shock, and elevated inflammatory markers. All children with suspected moderate to severe MIS-C should have blood cultures sent, and empiric antibiotics should be administered pending culture results. Certain clinical features can help distinguish MIS-C from bacterial sepsis. Cardiac involvement, particularly CA involvement, is uncommon in bacterial sepsis. Ultimately, microbiologic tests (i.e., SARS-CoV-2 testing, bacterial cultures) are necessary to make the distinction.

Complete (typical) versus Incomplete (atypical) Kawasaki Disease (KD)

KD, previously called mucocutaneous lymph node syndrome, is one of the most common vasculitides of childhood.261 MIS-C closely resembles an illness known as KD described by Dr. Tomisaku Kawasaki in 1974. Although the exact cause is unknown, KD is suspected of being related to infection. Alas, in over 40 years, no obvious germ has been identified. Whatever the trigger is, a hyper-exaggerated immune response is kicked off in the body, causing inflammation of blood vessels and organs, thus making children extremely ill. The disease has been an enigma, sickening about 20,000 kids in total across the country each year.

Recently, however, pediatricians started reporting an increase in KD-like cases across the country. On further review, despite several shared features, this has been determined to be related to COVID-19 infection somehow. Although most children have shown positive tests for SARS-CoV-2 or its antibodies, the rate has not been 100%, and many of those kids had no COVID-19 history. This is not unusual, as many children have had COVID-19 without symptoms overt enough to be recognized. Ultimately, the designation of MIS-C versus KD is based on SARS-CoV-2 testing. Patients with positive SARS-CoV-2 testing (or with exposure to an individual with COVID-19) who also fulfill full or partial criteria for KD should be considered to have MIS-C and receive standard treatments for KD. KD rarely occurs in adults.

KD is typically a self-limited condition, with fever and manifestations of acute inflammation lasting for an average of 12 days without therapy.262 However, complications such as CA aneurysms, depressed myocardial contractility, heart failure, MI, arrhythmias, and peripheral arterial occlusion may develop and lead to significant morbidity and mortality. The clinical features of KD reflect widespread inflammation of primarily medium-sized muscular arteries. Diagnosis is based upon evidence of systemic inflammation (e.g., fever) in association with signs of mucocutaneous inflammation.

Toxic Shock Syndrome

Staphylococcal and streptococcal toxic shock syndromes share many similarities with MIS-C. Microbiologic tests (i.e., SARS-CoV-2 testing, bacterial cultures) are necessary to make the distinction.

Appendicitis

Many children with MIS-C present with fever associated with abdominal pain and vomiting, which can mimic acute appendicitis presentation. Abdominal imaging may be necessary to make a distinction.

Other Viral Infections

Other viral pathogens that may manifest with multisystem involvement or myocarditis include:

  • Adenovirus
  • Cytomegalovirus
  • Enteroviruses
  • Epstein-Barr virus

These viruses rarely cause severe multisystem disease in immunocompetent children. Serology and RT-PCR testing can distinguish these from COVID-19-related MIS-C.

Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS)

HLH and MAS are aggressive and life-threatening conditions that have some features in common with MIS-C. HLH/MAS are syndromes of excessive immune activation in previously healthy children (often triggered by an infection) and children with underlying rheumatologic conditions. Most children with HLH/MAS are acutely ill with:

  • Cytopenias
  • Liver function abnormalities
  • Multiorgan involvement
  • Neurologic symptoms

Cardiac and gastrointestinal involvement are less common, and neurologic symptoms are more prominent. The diagnosis of MAS/HLH requires specialized immunologic testing.

Systemic Lupus Erythematosus (SLE)

SLE can present with fulminant multisystem illness. Such patients generally have considerable kidney and central nervous system involvement, which are not common features of MIS-C. Additionally, though patients with SLE may present acutely with fulminant illness, most report feeling fatigued and unwell for an extended time before the onset of severe symptoms. This is not the case with MIS-C, in which most children are completely well before the acute onset of febrile illness.

Vasculitis

Vasculitides other than KD can present with fevers, rash, and elevated inflammatory markers. Rashes seen in COVID-19-associated illness can have an appearance that can mimics vasculitis (e.g., pernio [chilblain]-like lesions of acral surfaces, sometimes referred to as "COVID toes" see image 5), but they are not vasculitis.

Image 5: COVID toes

Covid Toes

Management & Treatment

Setting of Care

The appropriate setting of care is determined by the severity of illness, risk of complications, and follow-up adequacy.

Inpatient Management

Children with moderate to severe signs and symptoms of MIS-C and those at risk for complications should be admitted to the hospital. This includes any of the following258:

  • Abnormal vital signs (tachycardia, tachypnea)
  • Shock
  • Respiratory distress
  • Evidence of cardiac involvement (e.g., elevated troponin or BNP, depressed ventricular function or CA abnormality on echocardiogram, abnormal ECG)
  • Features of KD
  • Neurologic changes (e.g., depressed mental status, abnormal neurologic examination, seizures)
  • Severe abdominal pain or vomiting, especially if unable to tolerate oral feeding
  • Clinical or laboratory evidence of dehydration
  • Laboratory evidence of acute kidney injury, AKI, or coagulopathy
  • Underlying medical condition that may place the child at increased risk for complications (e.g., immunodeficiency, cardiac or pulmonary conditions)
  • Inability to return for follow-up

The severity of illness determines the level of care (ward versus pediatric intensive care unit [PICU]). In the available case series, approximately 60% to 80% of affected patients required PICU care10,12,23,26,29, but this may change as milder cases come to attention.

Admission to a PICU is appropriate for children with:

  • Hemodynamic instability (shock, arrhythmia)
  • Significant respiratory compromise
  • Other potentially life-threatening complications

Outpatient Management

It may be reasonable to manage select patients with mild symptoms in the outpatient setting provided that the child is well-appearing (i.e., normal vital signs and reassuring physical examination), and close clinical follow-up can be assured. It is critical for children managed in the outpatient setting to provide instructions for when to seek care and to ensure appropriate follow-up. Most children should have follow-up within 48 hours if persistently febrile. Follow-up should include clinical assessment and repeat laboratory testing.

Multidisciplinary Care

MIS-C is a multisystem disease, and care for affected children requires coordination of many different specialties. These may include:

  • Pediatric infectious disease specialists
  • Pediatric rheumatologists
  • Pediatric cardiologists
  • Pediatric intensivists
  • Pediatric hematologists

Treatment Based on Presentation

Management of children with MIS-C depends in part on the clinical presentation (distributive shock versus cardiac dysfunction versus KD-like features). These presentations can overlap, and it may be appropriate to provide interventions from more than one category. Additionally, some interventions such as empiric antibiotics, intravenous immune globulin (IVIG), and prophylactic antithrombotic therapy are appropriate for most patients with moderate to severe manifestations, regardless of the predominant presentation type.

Children presenting with shock should be resuscitated according to standard protocols. In the available case series, most children with MIS-C presented with vasodilatory shock that was refractory to volume expansion. Epinephrine or norepinephrine are the preferred vasoactive agents for the management of fluid-refractory shock in children.

Epinephrine is preferred when there is evidence of LV dysfunction. In children presenting with severe LV dysfunction, the addition of milrinone may be helpful.

Patients who meet the criteria for complete or incomplete KD should receive standard therapies for KD, including IVIG, aspirin, and, if there are persistent signs of inflammation or CA dilation/aneurysm, glucocorticoids.

During the acute inflammatory phase of illness, children with cardiac involvement may present with arrhythmias and hemodynamic compromise. Serial echocardiographic assessment of cardiac function and monitoring of BNP and troponin levels can help guide therapy. Management focuses on supportive care to maintain hemodynamic stability and ensure adequate systemic perfusion. IVIG is often used in severe cases, though conclusive evidence of benefit is lacking. Continuous cardiac monitoring is essential so that arrhythmias are promptly detected and treated. Patients with significant LV dysfunction are treated with:

  • Intravenous diuretics
  • Inotropic agents, such as milrinone, dopamine, and dobutamine

In fulminant disease cases, mechanical hemodynamic support may be necessary for the form of extracorporeal membrane oxygenation (ECMO) or a ventricular assist device. Management is generally like that of acute myocarditis.

Antibiotic Therapy

MIS-C can present with signs and symptoms that mimic those of septic shock and toxic shock syndrome. Consequently, patients presenting with severe multisystem involvement, particularly those with shock, should receive prompt empiric broad-spectrum antibiotic therapy pending culture results. An appropriate empiric regimen consists of:

  • Ceftriaxone plus vancomycin
  • Ceftaroline plus piperacillin-tazobactam is an alternative regimen, particularly for children with AKI
  • Clindamycin is added if there are features consistent with toxin-mediated illness (e.g., erythroderma)

Antibiotics should be discontinued once a bacterial infection has been excluded if the child's clinical status has stabilized.

Antiviral Therapy

The role of SARS-CoV-2 antiviral therapies (e.g., remdesivir) in the management of MIS-C is uncertain. Many patients are RT-PCR-negative for SARS-CoV-2, and MIS-C likely represents a postinfectious complication rather than active infection. Some children, however, do have positive RT-PCR testing and may have an active infection.

Thus, antiviral therapy may potentially impact the disease process in some, but not all, patients. Antiviral agents' use is generally limited to children with severe MIS-C manifestations who have active infection evidence. A consultation with an infectious disease specialist is suggested to guide decision-making.

Immune-Modifying Therapies

Intravenous immune globulin (IVIG) is recommended for all patients who meet complete or incomplete KD criteria. Additionally, IVIG is suggested for most patients with moderate to severe MIS-C, even in the absence of KD-like features. This includes any of the following:

  • Shock
  • Cardiac involvement, including any of the following:
    • Depressed LV function on echocardiography
    • CA abnormalities (dilation or aneurysm) on echocardiography
    • Arrhythmia
    • Elevated BNP or troponin
    • Other severe manifestations requiring PICU care

Patients with mild symptoms who lack KD-like features, shock, and cardiac involvement can be initially monitored conservatively. However, if the patient's clinical status worsens or remains persistently febrile with elevated inflammatory markers, including rising ferritin levels, IVIG is typically administered. Dosing and administration of IVIG are as follows:

  • For patients with KD-like features, the dosing is the same as is used for KD (i.e., 2 g/kg administered in a single infusion over 8 to 12 hours)
  • For patients without KD-like features, a lower dose is typically used (i.e., 1 g/kg over 8 to 12 hours). However, some centers use a dose of 2g/kg in this setting
  • For patients with significant LV dysfunction, if there is concern that the patient will not tolerate the full dose-volume load in a single infusion, it can be given in divided doses over two to three days

Patients should have blood drawn for serologic testing for SARS-CoV-2 and other pathogens before IVIG administration. The evidence supporting the use of IVIG in MIS-C is limited to case series in which approximately 70% to 80% of patients were treated with IVIG.3,9-12,23,26,28,229 The vast majority of patients in these series improved and had recovery of cardiac function. Indirect evidence supporting IVIG use comes from studies involving patients with similar conditions, including KD, toxic shock syndrome, and myocarditis.

Other Therapies

The benefits and risks of adjunctive therapies (glucocorticoids, interleukin-1 [IL-1] inhibitors [e.g., anakinra, canakinumab], IL-6 inhibitors [e.g., tocilizumab], convalescent plasma from recovered COVID-19 patients) are uncertain. Consultation with pediatric infectious disease and rheumatology specialists is advised. Decisions about the use of adjunctive therapies are made on a case-by-case basis, according to disease severity and markers of inflammation or active SARS-CoV-2 infection.

Glucocorticoids are appropriate for patients with features of KD who have a persistent fever after IVIG or CA dilation/aneurysm. Additionally, glucocorticoids can be considered for patients with MAS (also called reactive hemophagocytic syndrome) or Cytokine release syndrome (CRS) (also called cytokine storm). Both MAS and CRS are characterized by:

  • Persistent fever
  • Markedly elevated inflammatory markers (e.g., CRP, D-dimer, ferritin)
  • Elevated proinflammatory cytokines (e.g., IL-6)

Anakinra, canakinumab, and tocilizumab are alternative options for treating MAS or CRS in patients who cannot receive glucocorticoids and those who are refractory to glucocorticoids. The use of these agents should be guided by consultation with a pediatric rheumatologist and should occur in the context of a clinical trial whenever possible.

Antithrombotic Therapy

Patients with MIS-C are at risk of experiencing thrombotic complications. Patients with severe LV dysfunction are at risk for apical LV thrombus. Patients with KD who have large or giant CA aneurysms are at risk for MI. Additionally, patients may be at risk for venous thromboembolism (VTE), including pulmonary embolus, due to hypercoagulability associated with COVID-19.

All patients who meet the criteria for complete or incomplete KD should receive antithrombotic therapy, which, at a minimum, includes low-dose aspirin. Additional antiplatelet or anticoagulant therapy may be warranted in select patients, depending on the degree of CA dilation.

Systemic anticoagulation may be appropriate for patients with moderate to severe LV dysfunction. In patients without KD-like features or significant LV dysfunction, the decision to initiate therapy to prevent VTE is individualized. The diagnosis of COVID-19-related MIS-C itself should be considered a major risk factor for VTE. VTE prophylaxis is generally appropriate for older children and adolescents hospitalized with moderate to severe MIS-C, provided that the bleeding risk is low.

In infants and young children, the decision is made on a case-by-case basis, weighing other VTE risk factors and the patient's bleeding risk. When VTE prophylaxis is used, low molecular weight heparin is generally the preferred agent. Nonpharmacologic strategies for VTE prophylaxis (e.g., intermittent pneumatic compression devices [size permitting] and early mobilization) are encouraged, but MIS-C-related coagulopathy may merit a higher level of intervention.

Investigational Approaches

Numerous vaccine candidates are being evaluated for the prevention of COVID-19.263

These include various types of vaccines, including nucleic acid-based (mRNA and DNA) vaccines, viral vector vaccines, and inactivated or recombinant protein vaccines.264 The different vaccine platforms vary in their potential safety and immunogenicity, speed, cost of manufacturing, and other important features for meeting global demand. A catalog of candidate vaccines and their stages of development can be found on the WHO website. Several of these vaccines have induced binding antibodies, neutralizing activity, and T cell responses in healthy adults during early trials.265-269

Studies of vaccine candidates in nonhuman primates have also reported lower levels or more rapid clearance of viral RNA in respiratory tract specimens following viral challenge in vaccinated animals than unvaccinated controls.270-274 There is also interest in Bacille-Calmette-Guerin (BCG) immunization for the prevention of COVID-19, and clinical trials are underway to evaluate its use among healthcare workers.275 Studies have suggested that, although its primary purpose is to prevent tuberculosis, BCG immunization induces a nonspecific immune response that may have protective effects against non-mycobacterial, including viral infections.276,276 Any impact of BCG immunization on COVID-19 is unknown. The WHO recommends BCG vaccination not to prevent or lessen the severity of COVID-19, pending further data.278

Post-Exposure Prophylaxis

Clinical trials are being conducted in the U.S. and elsewhere to evaluate the safety and efficacy of post-exposure drug prophylaxis against COVID-19.279,280 Monoclonal antibodies developed to neutralize SARS-CoV-2 are also being evaluated for post-exposure prophylaxis.281 No intervention is known to be effective in preventing infection. It is recommended that post-exposure prophylaxis not be attempted outside a clinical trial.

Hydroxychloroquine was one candidate agent for post-exposure prophylaxis, but available data suggest it is not effective in preventing infection. In a double-blind trial, 821 individuals were randomly assigned to hydroxychloroquine or placebo folate tablets within four days of a household or occupational exposure to SARS-CoV-2, defined as contact six feet for more than 10 minutes without an eye shield. Most were also not wearing a medical mask.282

Hydroxychloroquine did not reduce the rate of the combined outcome of RT-PCR-confirmed COVID-19 or consistent symptoms within 14 days. There were also no differences in the separate rates of RT-PCR-confirmed or presumed cases. Side effects were reported in 40.1% of hydroxychloroquine-treated versus 16.8% of placebo-treated subjects. The loss to follow-up in about 11%, a greater treatment discontinuation rate in the hydroxychloroquine group, and the use of self-reported symptoms as a proxy for incident COVID-19 reduce confidence in the findings. Nevertheless, the study did not demonstrate a role for hydroxychloroquine in the prevention of COVID-19.

Immunity and Risk of Reinfection

SARS-CoV-2-specific antibodies and cell-mediated responses are induced following infection. Preliminary evidence suggests that some of these responses are protective, but this remains to be definitively established. Moreover, it is unknown whether all infected patients mount a protective immune response and how long any protective effect will last. Nevertheless, the short-term risk of reinfection (e.g., within the first few months after initial infection) appears low.

Humoral Immunity

Data on protective immunity following COVID-19 are emerging.111,112,283 A case series evaluating convalescent plasma for treatment of COVID-19 identified neutralizing activity in plasma of recovered patients that appeared to be transferred to recipients following plasma infusion.283 Similarly, in another study of 23 patients who recovered from COVID-19, antibodies to the receptor-binding domain of the spike protein and the nucleocapsid protein were detected by enzyme-linked immunosorbent assay (ELISA) in most patients by 14 days following the onset of symptoms. ELISA antibody titers correlated with neutralizing activity.111

However, some data suggest that the magnitude of antibody response may be associated with the severity of disease and that patients with a mild infection may not mount detectable neutralizing antibodies.284,285 Additionally, the durability of neutralizing activity following infection is uncertain, as neutralizing antibodies decline over several months after infection.286-288

In a study of 37 patients who had symptomatic COVID-19, by eight weeks following hospital discharge, neutralizing activity decreased by a median of 12% in 62% of the patients.286 In another study of 149 convalescent patients, 7% had required hospitalization, only 1% had high titers of neutralizing antibodies a mean of 39 days after illness onset.287 In another study, receptor-binding, domain-specific B cells were identified in six patients (all studied). Potent neutralizing antibodies, regardless of the serum-neutralizing titer, were also identified, suggesting that highly protective vaccines could be designed to stimulate such antibodies' production.

Cell-mediated Immunity

Studies have also identified SARS-CoV-2-specific CD4 and CD8 T cell responses in patients who had recovered from COVID-19 and in individuals who had received an investigational SARS-CoV-2 vaccine, which suggests the potential for a durable T cell immune response.289,290 SARS-CoV-2-reactive CD4 T cells have also been identified in some individuals without known exposure to SARS-CoV-2, and some of these CD4 T cells appear to be cross-reactive with antigens from common cold coronaviruses.290-292

Whether these pre-existing immune responses impact the risk or the severity of COVID-19 and whether they will influence SARS-CoV-2 vaccine responses remain unknown.

Protective Immune Response after Infection or Vaccination in Primate Studies

Animal studies have suggested that the immune response to infection may offer some protection against reinfection, at least in the short term.270,271,293,294 In one study of nine rhesus macaques experimentally infected with SARS-CoV-2, all animals developed neutralizing antibodies. Upon rechallenge with the same viral dose 35 days later, all had anamnestic immune responses and, on a nasal swab, had lower viral RNA levels and more rapid viral RNA decline compared with the initial challenge and with challenged naïve control animals.293 Studies evaluating SARS-CoV-2 vaccine candidates in macaques have also suggested that immune responses to vaccination result in lower levels or more rapid clearance of viral RNA in respiratory tract specimens following viral challenge compared with unvaccinated controls.270-274

Testing Positive after Recovery does Not Necessarily Indicate Reinfection

Some studies have reported positive RT-PCR tests for SARS-CoV-2 in patients with laboratory-confirmed COVID-19 following clinical improvement and negative results on two consecutive tests.295-298 However, these positive tests usually occurred shortly after the negative tests, were usually not associated with worsening symptoms, may not represent infectious virus, and likely did not reflect reinfection. Specifically, in a report from the Korean CDC of patients with COVID-19 who had a repeat positive RNA test after being previously cleared from isolation, the infectious virus could not be isolated in cell culture in any of the 108 patients tested.125 Among 790 contacts, there were no new confirmed cases that were traced to exposure during the period of the positive repeat test. Rare cases of probable reinfection have been documented.

An asymptomatic 33-year-old man in Hong Kong tested positive for SARS-CoV-2 on travel-related screening five months after mild laboratory-confirmed COVID-19. Sequencing of viral genomes extracted from saliva specimens collected during each infection indicated two distinct strains, suggesting two distinct infections.298 That the second infection was asymptomatic raises the possibility that immunity from an initial infection could attenuate the severity of reinfection even if it does not prevent it.

Outcomes

The prognosis of MIS-C is uncertain, given that it is a new clinical entity, and our understanding of the disease is still evolving. Though MIS-C has many similarities to KD and toxic shock syndrome, the disease course in MIS-C can be more severe, with many children requiring intensive care interventions. Most children survive, but there have been several deaths reported.3,5,6 Among 570 MIS-C cases reported to the U.S. CDC through July 2020, there were ten deaths (1.8%).26

Case Reporting

Healthcare providers who have cared or are caring for patients younger than 21 years of age meeting MIS-C criteria should report suspected cases to their local, state, or territorial health department. Additional information can be found on the CDC website and the World Health Organization (WHO) website.

The CDC has a dedicated team investigating MIS-C to learn more about this syndrome to communicate information quickly to healthcare providers, parents, caregivers, and state, local, and territorial health departments. The team is working with U.S. and international scientists, healthcare providers, and other partners to learn more about this new syndrome. They are learning how often it happens and who is likely to get it, creating a system to track cases and provide guidance to parents and healthcare providers.298 The team is collaborating with public health agencies around the world to share information and knowledge about cases of MIS-C in other countries, providing local support to New York State’s investigation into MIS-C cases. These staffs understand the clinical course (the way the disease may appear in children) and outcomes of MIS-C cases. Building on existing partnerships across the country to identify additional cases of MIS-C associated with COVID-19, determine risk factors for MIS-C, and support healthcare providers as they care for sick patients. Asking clinical research and surveillance data networks at children’s hospitals to collect and share data on cases of MIS-C.

Preparing Healthcare Providers and Health Departments

A Health Advisory was released on May 14, 2020, through the Health Alert Network. In this advisory, the CDC alerted healthcare providers about MIS-C, issued the case definition developed with the Council of State, Tribal, and Territorial Epidemiologists, and recommended that healthcare providers report suspected cases of MIS-C to local, state, or territorial health departments. The information clinicians and health. Departments will help in understanding this new condition and how common it is. The CDC hosted a webinar for healthcare providers with researchers and clinicians who have treated patients with MIS-C. The CDC set up a method for state and local health departments to report cases of MIS-C.

Keeping Parents and Partners Informed

The CDC is communicating information about what is known, what is not known, and what is being done to learn more to support healthcare providers and parents and caregivers. The CDC is conducting partner outreach activities and educational efforts to increase provider awareness of MIS-C. The CDC is collaborating with other federal agencies, clinical, and professional societies.

Tips to Protect Children During a COVID-19 Outbreak

Based on available evidence, children do not appear to be at higher risk for COVID-19 than adults. While some children and infants have been sick with COVID-19, adults make up most of the known cases to date.

Watch the child/children for any signs of COVID-19 illness.299 COVID-19 can look different in different people. For many people, being sick with COVID-19 would be a little bit like having the flu. People can get a fever, cough, or have a hard time taking deep breaths. Most people who have gotten COVID-19 have not gotten sick. Only a small group of people who get it have had more serious problems. If the child does get sick, it does not mean he/she has COVID-19. People can get sick from all kinds of germs. What is important to remember is that if the child does get sick, the adults at home will seek appropriate healthcare.

Take steps to protect children and others.299 Help stop the spread of COVID-19 by doing the same things everyone should do to stay healthy. Teach children to do the same. Clean hands often using soap and water or alcohol-based hand sanitizer. Avoid people who are sick (coughing and sneezing). Put distance between children and other people outside of the home. Keep children at least 6 feet from other people. Children 2 years and older should wear a cloth face covering their nose and mouth when it is difficult to practice social distancing in public settings. This is an additional public health measure that should be taken to reduce the spread of COVID-19 in addition to (not instead of) the other everyday preventive actions previously mentioned above. Clean and disinfect high-touch surfaces daily in common household areas (like tables, hard-backed chairs, doorknobs, light switches, remotes, handles, desks, toilets, and sinks).

Launder items, including washable plush toys, as needed. Follow the manufacturer’s instructions. If possible, launder items using the warmest appropriate water setting and dry items completely. Dirty laundry from an ill person can be washed with other people’s items.

Limit time with other children.299 If children meet in groups, it can put everyone at risk. Children can pass this virus onto others who may be at higher risk, including older adults and people who have serious underlying medical conditions.

Practice social distancing.299 The key to slowing the spread of COVID-19 is to limit contact as much as possible. While school is out, children should not have in-person playdates with children from other households. If children are playing outside their own homes, they must remain 6 feet from anyone who is not in their household. Children may have supervised phone calls or video chats with their friends to help children maintain social connections while social distancing.

Clean hands often.299 Ensure children practice everyday preventive behaviors, such as washing their hands often with soap and water for at least 20 seconds. This is especially important if they have been in a public place.

Change travel plans.299 Revise travel plans if non-essential travel is included.

Limit time with people at the highest risk of severe illness from COVID-19.299 Older adults and those with serious underlying medical conditions are at the highest risk of severe illness from COVID-19. If others in the home are at exceptionally high risk for severe illness from COVID-19, consider extra precautions to separate the child from those people. If the parent(s) cannot stay home with the child while school is out, carefully consider who might be best positioned to provide childcare. If someone at higher risk for COVID-19 will be providing care (older adults, such as a grandparent or someone with a chronic medical condition), limit the children’s contact with other people. Consider postponing visits or trips to see older family members and grandparents. Connect virtually or by writing letters and sending via mail.

Help children learn at home.299 Stay in touch with the child’s school. Many schools are offering lessons online (virtual learning). Review assignments from the school, and help the child establish a reasonable pace for completing the work. The child may need assistance with turning on devices, reading instructions, and typing answers. Communicate challenges to the school. If technology or connectivity issues are faced, or the child is having difficulty completing assignments, inform the school. Create a flexible schedule and routine for learning at home.

  • Have consistent bedtimes and get up at the same time, Monday through Friday.
  • Structure the day for learning, free time, healthy meals and snacks, and physical activity.
  • Allow flexibility in the schedule. It is okay to adapt based on the day.

Consider the needs and adjustments required for the child’s age group. The transition to being at home will be different for preschoolers, K-5, middle school students, and high school students. Talk to the child about expectations and how he/she is adjusting to being at home versus at school. Consider ways the child can stay connected with their friends without spending time in person.

Look for ways to make learning fun. Have hands-on activities, like puzzles, painting, drawing, and other crafts. Independent play can also be used in place of structured learning. Encourage children to build a fort from sheets or practice counting by stacking blocks. Practice handwriting and grammar by writing letters to family members. This is a great way to connect and limit face-to-face contact. Start a journal with the child to document this time and discuss the shared experience. Use audiobooks or see if the local library is hosting virtual or live-streamed reading events. Ask about school meal services. Check with the school on plans to continue meal services during the school dismissal. Many schools keep school facilities open to allow families to pick up meals or provide grab-and-go meals at a central location.

The CDC has offered recommendations to help adults have conversations with children about COVID-19 and ways they can avoid getting and spreading the disease. In the available case series, approximately 60% to 80% of affected patients required PICU care10,12,23,26,29, but this may change as milder cases come to attention. Children may worry about themselves, their family, and friends getting ill with COVID-19. Parents, family members, school staff, and other trusted adults can play an important role in helping children make sense of what they hear in an honest, accurate way and minimize anxiety or fear.

Tips for Talking to Children300

Remain calm. Remember that children will react to both what is said and how it is said. They will pick up cues from the conversations you have with them and with others. Reassure children that they are safe. Let them know it is okay if they feel upset. Share with them how you deal with your stress so that they can learn how to cope. Make yourself available to listen and to talk. Let children know they can come to you when they have questions.

Avoid language that might blame others and lead to stigma. Pay attention to what children see or hear on television, radio, or online. Consider reducing the amount of screen time focused on COVID-19. Too much information on one topic can lead to anxiety. Provide information that is truthful and appropriate for the age and developmental level of the child. Talk to children about how some stories on COVID-19 on the Internet and social media may be based on rumors and inaccurate information. Children may misinterpret what they hear and can be frightened about something they do not understand. Teach children everyday actions to reduce the spread of germs. Remind children to wash their hands frequently and stay away from coughing or sneezing or sick people. Also, remind them to cough or sneeze into a tissue or their elbow, then throw the tissue into the trash. If school is open, discuss any new actions taken at school to help protect children and school staff.

Facts About COVID-19 to Discuss with Children

Try to keep information simple and remind them that everyone is working hard to keep everyone safe and healthy.

  • What is COVID-19?299 COVID-19 is the short name for “coronavirus disease 2019.” It is a new virus. Scientists and doctors are still learning about it. Recently, this virus has made many people sick. Scientists and doctors are trying to learn more so they can help people who get sick. Doctors and health experts are working hard to help people stay healthy.
  • What can I do so that I don’t get COVID-19?299 Healthy habits should be practiced at home, school, and play to help protect against the spread of COVID-19.

Case Study

Scenario/Situation/Patient Description

Lilly Williams, a six-year-old Caucasian female, is transported to the Emergency Room via EMS on August 3, 2020, at 0700 accompanied by her mother, Ester Williams, and father, Bill Williams. Her mother states that she spiked a temperature on Friday, July 31, 2020, to 102.5° Fahrenheit (oral). The child was given Tylenol and Motrin every four hours, but the lowest temperature ever got was 100.5°. The last Tylenol was given at 2400. The child has been eating and drinking little since the previous Friday. Since Saturday, she also has “bloodshot” eyes and a rash on her lower legs/feet. Mother states all five toes on right foot reddened with toes on left foot now turning red. Since Monday, she has been sleeping mostly, and early this morning, she became hard to wake up and stay awake. Lilly spent a full weekend with her grandmother three weeks ago. The grandmother is currently in the upstairs ICU-diagnosis COVID-19.

Current Medical History:

  • None

Past Medical History:

  • None

Past Surgical History:

  • T&A – age 3

Current Medications:

  • None

Interventions/Strategies

Vital signs:

  • BP right arm: 70/35
  • Pulse oximetry: 75% on room air: placed on 2 L per nasal prongs
  • Cardiac monitor shows sinus tachycardia without ectopy

IV access (left forearm): 1000ml 0.9 NS hung at 100 ml/hr.

Bloods drawn:

  • CBC with differential
  • CMP and kidney function profile
  • BNP
  • Troponin
  • Coagulation studies: PT/INR, aPTT, D-dimer, fibrinogen
  • C-reactive protein
  • ESR
  • Ferritin
  • Interleukin-6
  • Procalcitonin
  • ABGs
  • Antigen test for SARS-CoV-2

Other labs sent:

  • RT-PCR via nasopharyngeal swab

Other imaging studies were done:

  • 12-lead ECG
  • CXR

Emergency physician obtained an initial physical examination:

  • Neurologic:
    • GCS was 8
    • Alert. Lethargic
    • Appears confused upon awakening but then can follow simple commands when a question is repeated
    • Speech comprehensible
    • PERRLA, EOMs intact
    • MAEs
    • Muscle strength 5/5 bilaterally
    • No resting tremors, fasciculations, or seizure activity were noted
    • Cerebellar testing deferred at present
  • HEENT:
    • Sclera reddened bilaterally
    • No drainage from the eyes
    • Lips cracked, reddened
    • Mucous membranes dry, reddened
    • Tongue beat red
  • Integument:
    • Fine red rash on her lower legs/feet
    • All five toes on the right foot reddened, with toes on the left foot now a lighter red
  • Cardiac:
    • Sinus tachycardia without ectopy
    • No murmurs, rubs
  • Respiratory:
    • Lung sounds diminished bilaterally without rales, rhonchi, or wheezes
  • GI/GU:
    • Abdomen soft, non-tender with bowel sounds in all quadrants
  • Extremities:
    • +2 pitting edema of lower legs, feet bilaterally

Echocardiogram ordered stat

CT of chest ordered sta.

Cardiology consult ordered stat

Awaiting results of laboratory tests

Notified PICU concerning the need for bed in negative pressure with airborne precautions room.

Discussion of Outcomes

Lilly Williams was monitored in the ED, awaiting chest CT results, cardiology recommendations, and laboratory results. Tentative diagnoses: MIS-C.

Strengths and Weaknesses

Lilly Williams’s health history and physical examination were performed quickly with appropriate orders written. Appropriate interventions implemented.

Summary and Recommendations

Coronavirus disease 2019 (COVID-19) in children is usually mild. However, in rare cases, children can be severely affected, and clinical manifestations may differ from adults. In April of 2020, reports emerged of a presentation in children like KD or toxic shock syndrome. Since then, there have been increasing reports of similarly affected children around the world. The syndrome has been termed MIS-C.

The clinical presentation of MIS-C may include persistent fevers, gastrointestinal symptoms (abdominal pain, vomiting, diarrhea), rash, and conjunctivitis. Patients typically present with three to five days of fever, followed by the development of shock. Laboratory findings include lymphocytopenia, elevated inflammatory markers (CRP, ESR, D-dimer), and elevated cardiac markers (troponin, BNP).

The initial evaluation of a child with suspected MIS-C generally includes the following, though a more limited evaluation may be appropriate for children with mild presentations:

  • Laboratory testing:
    • Blood culture
    • BNP
    • CRP and ESR (optional: procalcitonin)
    • Coagulation studies (aPTT, PT/INR, D-dimer, fibrinogen, antithrombin-3)
    • Complete blood cell count with differential
    • Cytokine panel (if available)
    • Ferritin level
    • Liver function tests and LDH
    • Serum electrolytes and renal function tests
    • Troponin
  • Testing for SARS-CoV-2, including both serology and RT-PCR
  • Testing for other viral and bacterial pathogens
  • Cardiac evaluation including 12-lead ECG and echocardiography

Management of MIS-C includes the following:

  • Multidisciplinary care
    • MIS-C is a multisystem disease, and care for affected children requires coordination of many different specialties. Infectious disease and rheumatology specialists should be consulted early. Pediatric cardiologists should be consulted in patients with myocardial dysfunction or features of KD.
  • Children presenting with shock should be resuscitated according to standard protocols.
  • Empiric antibiotic therapy is appropriate for patients presenting with severe multisystem involvement and particularly those with shock.
  • The use of antiviral therapies (e.g., remdesivir) is generally limited to children with severe MIS-C manifestations and evidence of active SARS-CoV-2 infection. Treatment should be guided by an infectious disease specialist, preferably in the context of a clinical trial.
  • Patients who meet the criteria for complete or incomplete KD should receive standard therapies for KD, including IVIG, aspirin, and, if there are persistent signs of inflammation or CA involvement, glucocorticoids.
  • Management of myocardial dysfunction focuses on supportive care to maintain hemodynamic stability and ensure adequate systemic perfusion.
    • IVIG is often used, though conclusive evidence of benefit is lacking.
    • Continuous cardiac monitoring is essential so that arrhythmias can be promptly detected and treated.
  • Patients with MIS-C are at risk of experiencing thrombotic complications, and antithrombotic therapy is warranted in many cases (e.g., low-dose aspirin in patients with features of KD, systemic anticoagulation in patients with moderate to severe ventricular dysfunction).
  • The benefits and risks of adjunctive therapies (glucocorticoids, IL-1 inhibitors [e.g., anakinra, canakinumab], IL-6 inhibitors [e.g., tocilizumab], convalescent plasma from recovered COVID-19 patients) are uncertain. Consultation with pediatric infectious disease and rheumatology specialists is advisable.
  • Children with cardiac dysfunction or CA abnormalities should have a follow-up with cardiology after discharge, with serial echocardiography to assess for CA aneurysms.

Health care providers who have cared or are caring for patients younger than 21 years of age meeting MIS-C criteria should report suspected cases to their local, state, or territorial health department.

The prognosis of MIS-C is uncertain, given that it is a new clinical entity, and our understanding of the disease is still evolving. Most children survive, though deaths have been reported.

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