key: cord-0766795-ftdq340u
authors: Blatz, Allison M.; Randolph, Adrienne G.
title: Severe COVID-19 and MIS-C In Children & Adolescents
date: 2022-01-10
journal: Crit Care Clin
DOI: 10.1016/j.ccc.2022.01.005
sha: 64d14576c5d6dfce73a53cc6d7591e19f35dc4b9
doc_id: 766795
cord_uid: ftdq340u

Severe complications related to COVID-19 occur infrequently in children and adolescents. The two major types of life-threatening complications are acute respiratory failure from acute COVID-19 and Multisystem Inflammatory Syndrome in Children (MIS-C). MIS-C is a post-infectious complication occurring approximately 3-6 weeks after an asymptomatic or mild SARS-CoV-2 infection. For both types of complications, supportive ICU care is provided. For MIS-C critical illness, immunomodulation is prescribed to reverse hyperinflammation and its cardiac and other sequelae.

Background:

In April 2020, case series emerged from the UK, Italy and later from New York State in the US describing children admitted to the hospital for persistent fever, diffuse inflammation, and shock that appeared similar to Kawasaki disease (KD) or Toxic Shock Syndrome (TSS) which are described in Table 1 . [14] [15] [16] [17] These patients presented differently than most children with KD; they were older, had markedly increased frequency of cardiovascular shock and most had gastrointestinal symptoms. Children presented approximately one month after surges of COVID-19 cases in the general population in a region, so it was suspected to be a post-infectious complication. 18 MIS-C has now emerged in many countries across the world, and national and international public health registries have been tracking this life-threatening disease. Early identification and aggressive treatment strategies have become the standard of care, aimed at decreasing the risk of fatal and long-term cardiovascular sequelae.

In mid-May of 2020, the U.S. Centers for Disease Control and Prevention (CDC) developed diagnostic criteria for MIS-C as did the World Health Organization (WHO). 19 There are similarities and differences in these criteria, which are listed in Table 2 . 20 In the UK, the term "Pediatric Inflammatory Multisystem Syndrome Temporally related to COVID-19" (PIMS-TS) is used to describe the syndrome. 21 It is important to highlight that children diagnosed with MIS-C must have fever, evidence of inflammation, at least two organs involved, no other active infection that could explain their J o u r n a l P r e -p r o o f condition, and a plausible epidemiologic link to SARS-CoV-2 through a positive laboratory test (PCR, antigen or antibody) or a confirmed exposure. MIS-C is a clinical diagnosis based on symptomology and laboratory features. The CDC definition requires hospitalization, which is used to define the disease as severe, whereas the WHO definition does not. 19 Differential Diagnosis:

Sepsis is the most common condition to be ruled out prior to diagnosing a patient with MIS-C.

Bacterial pathogens must screened for using blood and other cultures or rapid testing (Table 3 ).

In particular, Toxic Shock Syndrome from Staphylococcus aureus or Streptococcus spp. should be considered (Table 1) given the acute presentation of shock, fever, diffuse inflammation, hepatitis and skin changes such as erythroderma. Rocky Mountain Spotted Fever due to Rickettsia rickettsiae should be another consideration in certain geographic areas in the summertime, especially in patients with hyponatremia, thrombocytopenia and a palmar rash.

Overlap exists in the diagnosis of MIS-C and KD, and approximately 40% of MIS-C patients will meet diagnostic criteria for KD (Table 1) . 18 Approximately 30% of patients with MIS-C will have a positive respiratory test for SARS-CoV-2. 5 Inflammation and coagulopathy can be features of both acute COVID-19 and MIS-C, and multiorgan involvement is common in critically ill patients with acute COVID-19. The definition of MIS-C is broad, and it is likely that some patients diagnosed with MIS-C have acute COVID-19, especially in those with cardiorespiratory involvement (see Table 3 ). A comparison of children and adolescents with the two diagnoses showed that patients with MIS-C were overall more inflamed with higher C-reactive protein (CRP) and neutrophil to lymphocyte ratio (NLR), that thrombocytopenia (<150,000 platelets per microliter) was more common in MIS-C, and patients with acute COVID-19 tended to be more often 0-4 or 13-17 years of age. 5 In addition, those with J o u r n a l P r e -p r o o f acute COVID-19 were much more likely to have underlying medical conditions whereas the majority of patients with MIS-C were previously healthy. 22

As of October 4 th , 2021, there were 5,217 cases of MIS-C reported to US state public health departments. 23 Additionally, many hundreds of cases have been reported in the United Kingdom, continental Europe and South America. [24] [25] [26] [27] . There are also MIS-C case reports in the literature from Africa and Asia. 28, 29 Overall population incidence estimates for MIS-C range from 2 per 100,000 children in New York State to 3 per 10,000 individuals <21 years of age infected with SARS-CoV-2. 30,31

Incidence after a diagnosis of MIS-C is difficult to determine since so many children are asymptomatic with their initial infection thus not tested. By definition, children with MIS-C are hospitalized, and over two-thirds require admission to the ICU. 32

The most common age of onset is 6-12 years of age, though there are case reports spanning from the neonatal period to early adulthood. 5,22,30,31 . Black and Hispanic children are overly represented in multiple cohorts, as are males. 5,7,30,33 Most children with MIS-C were previously healthy. Some studies report an elevated prevalence of obesity among MIS-C patients.5, 34 There is evidence that some children have an underlying genetic predisposition to hyperinflammation that likely explains their MIS-C. 32, 35 A similar clinical syndrome also exists in adults: Multisystem Inflammatory Syndrome in Adults (MIS-A). It is hypothesized that this is also a post-infectious phenomenon that occurs from a J o u r n a l P r e -p r o o f dysregulated immune response to SARS-CoV-2. The CDC diagnostic criteria for MIS-A are as follows:

1) a severe illness requiring hospitalization in a person aged ≥21 years;

2) a positive test result for current or previous SARS-CoV-2 infection;

3) severe dysfunction of one or more extrapulmonary organ systems; 4) laboratory evidence of severe inflammation; 5) absence of severe respiratory illness. 36 The major difference between criteria for MIS-A vs. MIS-C, aside from age, is that presence of 

The pathogenesis of MIS-C is poorly understood though is hypothesized to be a delayed, overactive immune response to infection with SARS-CoV-2 given its temporal association to SARS-CoV-2 infections in the population (Figure 1 ). It typically develops three to six weeks after exposure to SARS-CoV-2. The initial SARS-CoV-2 infection may go undetected due to no or mild symptoms. Much research aims to elucidate the precise pathogenesis of MIS-C. Both the innate and adaptive immune systems are thought be overly activated 38,39 One theory hypothesized that the SARS-CoV-2 spike protein can act as a "superantigen," activating both T-J o u r n a l P r e -p r o o f and B-cells, leading to hyperinflammatory state and a subsequent cytokine storm, and similar to the staphylococcal endotoxin B implicated in Toxic Shock Syndrome. 40 

MIS-C presents with fever and systemic inflammation that leads to involvement of multiple organ systems, including the cardiovascular, gastrointestinal, neurologic, and mucocutaneous systems (Table 4 ). Involvement can present as follows:

Fever: Children must have persistent fever to meet criteria for MIS-C. Length of fever prior to presentation varies but is usually present for at least 24-48 hours and most commonly 3 days or more. 18 Cardiovascular: Acutely, children can present with cardiovascular instability, decreased cardiac function, arrhythmias including heart block or myocarditis. 41 Approximately 50-80% of children present with shock and approximately half require vasoactive support. 17,18 More than 80% of cases have cardiovascular involvement. 18 Severity of these symptoms range from mild, fluidresponsive shock, shock requiring vasoactive agents, to complete cardiovascular collapse requiring extracorporeal support.

A finding of major concern in MIS-C is the development of a coronary artery aneurysm (CAA) resulting from severe, diffuse inflammation. CAAs in MIS-C are defined as a Z score ≥2.5 in the proximal right coronary artery or proximal left anterior descending coronary artery. The exact mechanism of CAA development is unclear. Multi-center case series suggest that CAA occurs in between 8-14% of cases of MIS-C. 5,42 The majority of these CAAs resolve within 30 days of J o u r n a l P r e -p r o o f hospital admission, therefore most are unlikely to be vasculitis similar to what is identified in patients with KD. 5 Even in severe MIS-C, CAA in the great majority of MIS-C patients is likely to resolve by three-to-six months after diagnosis and treatment. 43 Longer term outcomes of these CAAs related to MIS-C are under study.

Respiratory: Respiratory symptoms are common in patients diagnosed with MIS-C, reported in about one third to one half of patients in a national cohort. 5,22 These range from mild tachypnea and hypoxemia to respiratory failure with pulmonary infiltrates. Lower respiratory symptoms are more common in severe, acute COVID-19 than in MIS-C (62% vs. 43%, respectively). 5 Some of the respiratory involvement may be cardiogenic, and other patients who have positive respiratory testing for SARS-CoV-2 may be misclassified and have acute COVID-19 with multisystem involvement and hyperinflammation.

Gastrointestinal: Studies report that up to 90% of patients with MIS-C have gastrointestinal symptoms. 5,44 Symptoms include severe abdominal pain with or without emesis, peritonitis, mesenteric lymphadenopathy, and diffuse secretory diarrhea. 45 Abdominal pain has been so severe that cases have been mistaken for acute appendicitis. Terminal ileitis and diffuse colitis have also been observed.

Mucocutaneous: Rashes in MIS-C are variable, and there is not a pathognomonic presentation in MIS-C. More than half of children with MIS-C have a polymorphous exanthem. There have been a variety of lesions described, including maculopapular lesions, annular plaques, and morbilliform eruptions with coalescing papules. 46 47 Most common rash locations include anterior and posterior trunk and extremities. Erythroderma has also been described, along with facial, palmar, and sole erythema and edema. Additionally cracked, dry, erythematous lips are often J o u r n a l P r e -p r o o f present. Non-exudative conjunctivitis has also been well-described (Table 4) . Younger children are more likely to have mucocutaneous findings. 48 Neurologic: CNS involvement can include mild to severe acute encephalopathy, stroke, demyelinating lesions, fulminant cerebral edema, headache, delirium, impaired consciousness, inability to walk or crawl, and neck pain. A recent multicenter study reported that 12% of MIS-C cases had neurologic involvement. CNS findings were generally mild and transient but 8% of patients had severe involvement. 4 Case reports describe head imaging findings that range from normal to mild, diffuse cerebral swelling. Evaluations of cerebral spinal fluid have demonstrated a range of symptoms from normal CSF parameters to pleocytosis that can mimic acute bacterial or viral meningitis. Neurologic dysfunction is more common in MIS-C than in severe COVID-19.

Hematologic: Patients may present with deep venous thrombosis, pulmonary embolus, or coagulopathy. A recent multicenter, retrospective cohort study identified thrombi in 6.5% of patients with MIS-C and found MIS-C to be an independent risk factor for thrombotic events, with most thrombi occurring in children 12 years and over. 3

Multiple laboratory abnormalities are described in MIS-C. Inflammation is required, but other findings need not be present to make a diagnosis. Common laboratory findings are summarized in Table 5 . Polymerase chain reaction (PCR) or antigen testing for SARS-CoV-2 is positive in about 30% of reported cases. Most patients are positive for antibody (IgG) testing, and those who are antibody negative should be investigated fully to identify alternate diagnoses.

In those patients who are PCR positive, often the cycle threshold from a SARS-CoV-2 PCR is J o u r n a l P r e -p r o o f high, indicating a lower viral load and a later stage of infection, though the utility of this test remains controversial. 49 Cardiac studies are frequently abnormal. Case series describe a variety of EKG findings, including normal sinus rhythm, sinus tachycardia, heart block and non-specific ST-wave abnormalities. 41, 42 An echocardiogram may show decreased left ventricular systolic function with an ejection fraction of <55%. Myocardial deformation parameters (such as global longitudinal strain) can be present even with persevered ejection fraction. Coronary artery aneurysms are seen in approximately 8% of patients, especially in delayed or very severe presentation. 41, 42 Recommended Initial Evaluation Initial evaluation should be performed as show in Table 3 . A thorough patient history should be obtained, with focus on presence of fever, close contact with an individual with COVID-19, and occurrence of other symptoms. Careful physical exam should be performed with special attention to findings such as meningismus, mental status, conjunctivitis, dry, cracked lips, abdominal pain, extremity swelling, palmar or sole erythema and rash.

Additional testing to rule out other infectious and non-infectious etiologies should be performed.

Spotted Fever), Toxic Shock Syndrome, Staph Scalded Skin Syndrome or severe adenovirus infection. Clinicians should consider obtaining a blood culture, urinalysis and culture, group A streptococcus testing, PCRs for other respiratory viral pathogens and Rocky Mountain Fever Syndrome or Ehrlichia serologies (depending on geographic location and season).

be considered in the appropriate clinical scenario.

Most children with moderate to severe COVID-19 will improve with supportive care alone. Data are lacking regarding optimal treatment strategies of children with COVID-19 as severe disease in children is very uncommon and children were not enrolled in prior published clinical trials. 50 The Pediatric Infectious Diseases Society suggests use of five-day course of remdesivir in children with severe COVID-19. 51 Pharmacokinetic/pharmacodynamic clinical trials are ongoing to determine optimal dosing strategies (NCT04431453). 52 Dexamethasone has been widely used in children with severe disease, given results in adults from the RECOVERY trial, and while considered safe, efficacy data are lacking children. 53 Other immunomodulatory therapies such as tocilizumab, anakinra and baricitinib have also been given to some children following some successful results in adults, but no data exist to support their use.

There is no evidence to support the use of azithromycin, hydroxychloroquine, ivermectin, other antiviral therapies or convalescent plasma in children.

Similar techniques of ICU management including optimal ventilation strategies, proning and other optimal intensive care unit management of ARDS has also been used in children. Status asthmaticus is managed with standard asthma protocols. 54 Fluid management is essential.

Adolescents are often anticoagulated, as are those who are obese or have another coexisting condition.

For treatment and outcomes of the overlapping phenotype between MIS-C and severe COVID-19, these children generally receive hybrid treatment strategies including steroids both for antiinflammatory effect and ARDS. IVIG and/or remdesivir may also be used.

An estimated 5-20% of cases require hospitalization, and about 2% of cases require admission to the intensive care unit versus the general pediatric floor. Of those admitted to the intensive care unit, the mortality rate was <2% even in a large national multicenter study. 5 Long term pulmonary outcomes are unknown given that this is a novel disease.

Treatment: A recent US based study of very severe patients in the Overcoming COVID-19 US Network (47% were on vasopressors and 41% had impaired ejection fraction) showed improved outcomes when given IVIG plus steroids on the first day of treatment. 55 Addition of other immunomodulatory treatments after the initial treatment day was also significantly decreased.

However, the Best Available Treatment Study (BATS) which was international, showed no difference in recovery from MIS-C when comparing groups given IVIG alone, corticosteroids alone, or IVIG and corticosteroids together. 56 The BATS study population used a broader definition for MIS-C, and their patients were markedly less ill than the US cohort. Therefore, in critically ill patients it is likely prudent to treat more aggressively initially to resolve the cardiovascular complications more quickly. Other immunomodulatory therapies have been trialed such as anakinra, an IL-1 inhibitor, and tocilizumab, an IL-6 inhibitor, though data are lacking whether these are effective. Some institutions have used anakinra for refractory MIS-C that has not responded initially to steroids and/or IVIG. A recent single-center study reported quicker recovery in children given IVIG plus infliximab (a TNF-a inhibitor). 57 In addition to immunomodulatory therapies, anticoagulation is typically administered to patients with laboratory markers consistent with a hypercoagulable state, given potential CAA and risk of thrombosis. While hospitalized in the ICU, low-molecular weight heparin is usually initiated. In some centers, patients are also given low-dose aspirin, as is the standard of care in KD.

Ultimate duration of optimal anticoagulation remains unclear. Most institutions continue anticoagulants until after discharge when a follow up echocardiogram has been obtained and longer if the patient has a CAA.

Supportive care is always provided, including vasoactive support if needed and careful fluid management. Echocardiograms should be performed serially to follow decreased cardiac function. Antibiotics are usually administered until the blood and other cultures report back as negative as sepsis must be ruled out.

The great majority of children with MIS-C have recovered. The mortality rate in the US in MIS-C patients is 1-2%. 5,23 A recent UK case series showed that six-to-twelve months after diagnosis, most patients had resolution of their hyperinflammatory state. 43 For cardiac outcomes. 4-17.5% percent of patients have had coronary aneurysms diagnosed while hospitalized, and at 90-day follow up, the majority of these coronary aneurysms have resolved. 5,39,42 Data are still being collected about long-term outcomes of these children, though data suggest that full recovery typically occurs after aggressive treatment upon presentation. Studies are ongoing to determine the longer-term effects on the heart. Children who are diagnosed with MIS-C are often followed by a multidisciplinary team after discharge including rheumatology, cardiology and in some cases, infectious disease specialists. 

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