Multisystem inflammatory syndrome (MIS) or Kawasaki-like syndrome associated with COVID-19

Introduction

Since the early days, SARS-CoV-2 has been highly contagious and virulent, rapidly spread, and led to high morbidity worldwide [1]. Although the virus affected all age groups, children were thought to develop mild SARS-CoV-2 infection. There is statistical evidence that the prevalence of infection in children ranged from 1 to 5% and the vast majority of cases were mild or asymptomatic. However, there have been further reports of pediatric groups who developed severe systemic inflammatory response associated with SARS-CoV-2 [2]. One of the rare but potentially life-threatening complications of COVID-19 is a condition known as multisystem inflammatory syndrome in children (MIS-C), also called Kawasaki-like syndrome or pediatric Kawasaki disease (KD).

This review presents an analysis of relevant studies, including pathogenesis, diagnosis, treatments, and prospects for future research. PubMed, eLIBRARY.RU, and Web of Science databases were searched using the keywords "SARS-CoV-2", "multisystem inflammatory syndrome", and "children". Original studies, literature reviews, and meta-analyses were analyzed.

MIS-C is defined as a febrile syndrome with systemic hyperinflammation, persistent fever, and multisystem organ failure [3].

First cases of MIS-C as a complication of a novel COVID-19-associated hyperinflammatory syndrome in children and adolescents were reported in April 2020 in the UK and Italy. The symptoms included hypotension, multisystem failure, and elevated markers of inflammation [4][5]. The pediatric patients debuted with MIS-C symptoms approximately 4‒6 weeks after the onset of COVID-19. In addition, more than 70% of MIS-C patients were positive for SARS-CoV-2 antibodies. The U.S. Centers for Disease Control and Prevention (CDC) first published a clinical definition of the syndrome on May 14, 2020. It was named COVID-19-associated multisystem inflammatory syndrome in children. This new syndrome was then observed worldwide [5][6]. For example, 26 studies in 2020 and 2021 published 1136 cases of MIS-C (mainly in the USA and Europe). The mean age of the patients was 6–11 years with no significant gender differences.

MIS-C in young children has symptoms similar to KD and toxic shock syndrome (TSS), whereas older children usually have clinical symptoms of shock and cytokine storm syndrome (CSS) or macrophage activation syndrome (MAS) [7]. The U.S. CDC has established the following criteria to improve the diagnosis of MIS-C:

• children under 18 years of age;
• fever;
• laboratory signs of inflammation;
• hospitalization;
• multisystem organ failure;
• laboratory-confirmed SARS-CoV-2 infection or contact with someone who had COVID-19 4–6 weeks before the onset of symptoms and diagnosis [8].

Causative Factors for MIS-C

Researchers find it highly interesting to analyze the studies concerning the causal association between SARS-CoV-2 and MIS-C.

Based on clinical experience in adults, a primary SARS-CoV-2 infection is generally mild in children. However, evidence suggests that MIS-C may be associated with the SARS-CoV-2 infection. The average latency period between COVID-19 symptoms and the onset of MIS-C was 21–25 days. Eighty to ninety percent of MIS-C patients tested positive for SARS-CoV-2 antibodies; however, positive PCR swabs were confirmed in 20‒40% of cases only. In addition, MIS-C patients had higher nasopharyngeal RT-PCR cycle threshold values suggestive of a lower viral RNA load than in patients with severe COVID-19. However, the autopsy of three MIS-C patients documented the SARS-CoV-2 spread across the various tissues including the heart, kidneys, brain, and intestine, which was associated with multisystem organ failure [8, 9]. Thus, historical data suggests that MIS-C may result from a combination of post-infection immune dysregulation, virus-induced cytopathic effects, and inflammation in multiple organ systems.

Researchers have reported the detection of specific human leukocyte antigen (HLA) and toll-like receptor (TLR) loci with HLA-DRB1 and HLA-MICA A4 alleles associated with MIS-C [10]. HLA-B∗46:01 is proposed to be a risk allele for severe COVID-19 infection, whereas people with blood type O have less chance of testing positive for COVID-19. Meanwhile, KD, TSS, or MIS-C is mediated by a genetic variant of HLA, FcγR, and/or antibody-dependent enhancement (ADE), resulting in hyperinflammation with T-helper type 17 (Th17)/Treg imbalance and augmented Th17/Th1 mediators such as interleukin-6 (IL-6), IL-10, inducible protein-10 (IP-10), interferon-gamma (IFN-γ), and IL-17A. The same study provides evidence of lower expression of Treg-signaling molecules, FoxP3, and transforming growth factor (TGF-β), and shows certain similarities and differences in phenotypes, susceptibility, and pathogenesis of MIS-C, by which a physician can provide early protection, prevention, and adequate treatment of the diseases [9].

Risk Factors for MIS-C

The literature-based analysis provides strong evidence of the association between comorbidities and more severe COVID-19. However, it has remained unclear so far if they could play a role in MIS-C. Several authors suggest that pediatric patients with overweight, asthma, or autoimmune disorders may have a higher risk of developing MIS-C [10-12]. However, none of the patients enrolled in the study had congenital heart disease or chronic cardiovascular disease. It has been previously reported that Black and Hispanic patients were more likely to develop MIS-C. There is evidence of a potential association between vitamin D deficiency and MIS-C [13]. Compositional changes in the intestinal and respiratory microbiota/microbiome may also contribute to MIS-C [14]. However, this warrants further investigation.

Based on the above, further investigations are deemed necessary to better understand the role of genetic, socioeconomic, or other factors in the development of MIS-C [15].

Pathogenetic Mechanisms of MIS-C

Currently, the pathophysiology of MIS-C is not well understood. The most recognized theory is based on post-infection immune dysregulation, especially involving the innate immune system. The cytokine storm with upregulation of the IL-1β signaling pathway and elevation of proinflammatory cytokines such as IL-6, IL-8, IL-18, tumor necrosis factor (TNF-α), and interferon γ (IFN-γ) plays a key role. This pathologic cascade trigger damage to many internal organs, particularly to the heart.

Carter et al. have found that acute MIS-C is generally associated with elevated IL-1β, IL-6, IL-8, IL-10, IL-17, and IFN-γ, and decreased T- and B-cells which subsequently return to normal [15]. According to Consiglio et al., compared to MIS-C patients, those with KD had higher IL-6 and IL-17A levels suggesting a pathogenetic difference between these two diseases [3].

Yonker et al. have demonstrated a significant (P=0.004) increase in SARS-CoV-2 S1 protein in MIS-C patients compared to healthy controls [16]. Researchers have shown that MIS-C is typically associated with higher levels of serum zonulin, a protein that plays a crucial role in the regulation of gastrointestinal permeability as a physiological modulator of tight junctions between cells. Zonulin-mediated increased intestinal permeability causes SARS-CoV-2 antigens to pass into the systemic circulation. The SARS-CoV-2 S1/S2 cleavage confirms and has been hypothesized to trigger the MIS-C hyperinflammatory response through interaction with T cell receptors and major histocompatibility complex class II molecules. In addition, Vella et al. performed deep immune profiling in MIS-C patients and demonstrated a robust activation of CX3CR1+ CD8 T cells that correlated with persistent SARS-CoV-2 antigen production [17].

The literature suggests that MIS-C shares some common features with CSS, such as a high expression of CXCLs, interferon-gamma (IFN-γ) induced chemokines. IFN-γ is classically elevated in familial hemophagocytic lymphohistiocytosis, a cytokine storm syndrome; hence, MIS-C may share genetic markers with these conditions.

Humoral signatures of MIS-C (antibody-dependent complement deposition and neutrophil phagocytosis) are similar to those seen in adult patients recovering from COVID-19. However, severe MIS-C is associated with persistent high-affinity IgG binding by FcγR that activate inflammatory monocytes/macrophages. Although there was no evidence of hypergammaglobulinemia in children with MIS-C, a selective IgG1 elevation of an unknown cause may occur. Additionally, several authors have reported a relevant difference in antibody levels between pediatric patients with MIS-C and adults with severe COVID-19. For example, Vella et al. showed in their study that children with MIS-C had high titers of anti-SARS-CoV-2 spike antigen-specific IgG antibodies (Abs) and were negative for anti-SARS-CoV-2 N protein antibodies in addition to decreased antibody neutralizing activity. In adult patients with COVID-19, spike-specific IgG, IgM, and IgA antibodies and anti-N protein IgG were positive [17].

Sharma et al. have discussed the role of the complement system in MIS-C pathogenesis. Compared to healthy controls, children with MIS-C and COVID-19 have high plasma levels of soluble C5b-9 [7].

In addition, several studies have reported a potential role of oxidative stress (OS) in MIS-C. OS is crucial in the activation of the NF-κB signaling pathway, which plays a key role in regulating the immune response and inflammation in some viral infections [18] and may be involved in immune thrombocytopenia (IT) secondary to MIS-C. Higher lipid peroxidation levels and deficiency of some antioxidants (vitamin C, glutathione) have been observed in adults with COVID-19. This may be similar to pediatric patients with MIS-C [17-19].

According to Ramaswamy et al., patients with severe MIS-C produce autoantibodies, which bind to endothelial cells, contributing to endothelial dysfunction and multisystem inflammation typical of MIS-C [20]. Although there is currently no consensus as to how endothelin-1 affects this process in patients with MIS-C, its significant role in the disease has not been excluded. Endothelin-1 biosynthesis and release are regulated by transcription through various factors such as p38MAP kinase, NF-κB, PKC/ERK, and JNK/c-Jun. They are upregulated in response to OS, which may be suggestive of the potential of OS in the pathogenesis of MIS-C.

On this basis, the pathogenetic mechanisms of MIS-C need to be thoroughly investigated to better understand the causative factors and drivers of this syndrome. This is absolutely important to choose treatment strategies and therapeutic approaches for patients with severe SARS-CoV-2 infection.

Clinical and Laboratory Findings

In order to better diagnose, manage, and predict treatment outcomes, the following subtypes of MIS-C are currently recognized:

• febrile disorder: it is characterized by persistent fever, headache, fatigue, and elevated markers of inflammation with no evidence of a severe multisystem failure;
• Kawasaki-like syndrome: it meets the criteria for a complete or incomplete set of KD-specific symptoms with no evidence of a severe multisystem failure or shock;
• severe disease: it is characterized by elevated markers of inflammation and severe multisystem failure.

Up-to-date databases present a fairly large number of studies on the clinical features of MIS-C. Currently, it remains unclear how multiple strains of SARS-CoV-2 correlate with the incidence and clinical presentation of MIS-C in children and adolescents [21, 22, 23]. In most cases, the first symptoms of MIS-C show up 3‒6 weeks after COVID-19 disease. Among the most common symptoms of MIS-C, gastrointestinal manifestations in all age groups (more than 80%), coagulopathy, shock and refractory fever, mucosa changes, lymphadenopathy, and/or cardiovascular complications such as myocardial infarction and coronary artery aneurysms have been reported [24-27].

In the study endorsed by the Task Force for Cardiac Imaging and Cardiovascular Intensive Care of the Association for European Pediatric and Congenital Cardiology, myocardial damage (93%), gastrointestinal symptoms (71%), shock (40%), and cardiac arrhythmias (35%) were observed among 286 patients with MIS-C from 17 European countries [28]. All patients had persistent fever (>38 °C) and elevated laboratory markers of inflammation. Most patients were previously healthy and had no comorbidities [3].

Studies have reported that the mean age of children diagnosed with MIS-C is 6 to 11 years of age; however, may range from 1 to 18 years of age. There is evidence that the clinical symptoms and incidence of MIS-C may vary by race and ethnicity. Many studies reported that the majority of patients were Black or Hispanic [5][8][17]. According to Irfan et al., approximately 23% of patients had comorbidities, with obesity being the most common, followed by chronic respiratory and cardiovascular diseases. Skin/mucosal symptoms occur in 85% of children from 0 to 5 years of age and 60% of adolescents aged 13–18 years [28]. According to Emeksiz et al., laboratory abnormalities clearly correlate with the severity of the disease [29].

More than half of patients present with hypotension and shock from either systemic hyperinflammation/vasodilation or myocardial involvement, frequently requiring intensive care admission [30-32]. A study of 1733 U.S. patients with MIS-C found that 90.4% of them had complications of at least 4 organ systems, and 58.2% were admitted to intensive care units. The most common symptoms included abdominal pain (66.5%), vomiting (64.3%), rash (55.6%), diarrhea (53.7%), and conjunctival hyperemia (53.6%).

In their study, Dufort et al. reported the results of the New York State Department of Health Surveillance that enrolled 99 patients with documented MIS-C at the beginning of the pandemic [9]. Most of the patients were 6 to 12 years old, and 54% of them were males. Of the 78 patients with known racial data, 40% were Black. Of the 85 patients with reported ethnicity, 36% were Hispanic. Obesity was the most common pre-existing condition (in 29 of 36 patients with comorbidities). Up to 80% of patients were admitted to intensive care units, and 10% required mechanical ventilation. Of the 93 patients with echocardiograms, 52% had abnormalities (mainly ventricular dysfunction), 32% had pericardial effusion, and 9% had coronary artery aneurysms. Two patients died, none of them received intravenous immunoglobulin or glucocorticoids, although one patient was treated with extracorporeal membrane oxygenation.

It should be emphasized that although not a specific feature of MIS-C, respiratory symptoms may arise from shock, cardiogenic pulmonary edema, and direct pulmonary involvement in some cases [19][29][33]. Cardiovascular and neurological involvements are more common in adolescents than in young children [34][35].

Cardiovascular signs are reported in 40–80% of patients and include elevated levels of B-type natriuretic peptide and troponin, ventricular dysfunction, pericardial effusion, coronary artery dilation or aneurysms, and arrhythmias. The mechanisms underlying the cardiovascular effects of MIS-C are still unclear; however, it is suggested that they result from direct viral cardiomyocyte toxicity, microvascular dysfunction, and/or inflammation.

In many cases, myocardial involvement is subclinical, with approximately one-third of patients having a depressed left ventricular systolic dysfunction (defined as left ventricular ejection fraction ≤55%). Ventricular dysfunction is usually identified at admission and appears to be transient: ventricular function returns to normal in >90% of patients in 30 days and 99% in 90 days [28][32]. It is noteworthy that studies are ongoing to identify the long-term cardiovascular effects of MIS-C in children [10][21][28][36][37].

Coronary artery aneurysms are documented in 8–13% of patients with MIS-C, and most (93%) of them are relatively small (a z score of the right coronary or left anterior descending artery <5). Cardiac arrhythmia is a relatively rare complication of MIS-C and occurs in 12% of patients [10][21][28][36][37].

According to Henderson et al., thromboembolic events are more frequent in MIS-C patients than in children admitted for acute COVID-19 (6.5% vs. 2.1%, respectively) [37].

Patients with MIS-C may present with a wide range of neurological symptoms such as altered consciousness, headache, anosmia or ageusia, seizures, or movement disorders. Neurological disorders are transient in most patients, but severe impairments and fatal cases have been reported [7][19].

Diagnosis and Severity of MIS-C

Clinicians highlight the importance of the diagnosis and severity of MIS-C.

The vast majority of patients with MIS-C present with serological signs of inflammation [31].

In a meta-analysis of 66 pediatric studies that included 9335 children with documented SARS-CoV-2, laboratory findings were (a mean proportion) as follows [29]:

• elevated C-reactive protein (CRP) level, 54%;
• elevated serum ferritin, 47%;
• elevated lactate dehydrogenase, 37%;
• elevated D-dimers, 35%;
• elevated procalcitonin, 21%;
• elevated erythrocyte sedimentation rate, 19%;
• elevated white blood cell count, 20%;
• lymphopenia, 19%;
• lymphocytosis, 8%;
• elevated serum transaminases, 30%;
• elevated creatine kinase-MB, 25%.

In addition, high erythrocyte sedimentation rate (ESR), fibrinogen, ferritin, interleukin 6 (IL-6), as well as thrombocytopenia, hypoalbuminemia, and hyponatremia may be detected.

In their study, Whittaker et al. have shown that mean values of CRP were significantly elevated at 229 mg/L [11]. In another study, the mean ESR was 72 mm/h, and mean ferritin levels achieved 1176 ng/mL. Eight patients (84.5%) were lymphopenic and hyponatremic, while seven (87%) had moderately elevated transaminases (aspartate aminotransferase 87 U/L [SD 70]; alanine aminotransferase 119 U/L [SD 217]) and elevated triglyceride levels. In addition, there were nine cases (90%) of elevated fibrinogen (621 mg/dL [182]) and eight cases of high D-dimer levels (3798 ng/mL [SD 1318]) [29].

The clinical guidelines recommend ECG monitoring, cardiac enzyme tests (troponin, B-type natriuretic peptide [BNP]/N-terminal pro-B-type natriuretic peptide [NT-proBNP]), and cardiac sonography for children with MIS-C. In a study evaluating elevated cardiac enzymes, high troponin was reported in 68% (34/50) of patients, whereas NT-proBNP was elevated in 83% [7][35]. Electrocardiographic findings include atrial and ventricular tachycardia, heart block and isolated ST segment depression or elevation, QT prolongation, and T-wave abnormalities. Sonographic and MRI signs of coronary artery dilation were evident, and there were rare reports of pericarditis, valvulitis, and aneurysm [19][33].

Several studies have discussed hypercoagulability with vascular thrombosis in children with MIS-C. Increased prothrombin time and international normalized ratio, activated partial thromboplastin time, elevated D-dimer levels, and low antithrombin III levels were documented. This can cause disseminated intravascular thrombosis, venous and arterial thrombosis, and pulmonary embolism [4].

Abdominal imaging findings are numerous; often they are non-specific and may include hepatomegaly, splenomegaly, mesenteric adenitis, ascites, ileocolitis, cholecystitis, or appendicitis.

Therapeutic Management of MIS-C

Current treatment guidelines highlight the need for intravenous immunoglobulins (IVIG) and glucocorticoids as first-line therapy. Biologicals may be considered in MIS-C patients with the disease refractory to IVIG and glucocorticoids. However, no formalized clinical guidelines have been established for the management of MIS-C. Fortunately, in most patients, systemic inflammation and cardiac abnormalities eventually resolve with no sequelae. MIS-C-associated mortality remains low [22]. Feldstein et al. reported a mortality rate of approximately 2%. Data from 39 studies including 662 patients with MIS-C showed a mortality rate of 1.7% [34].

However, it should be noted that due to similar mechanisms of pathogenesis of MIS-C and KD, patients with MIS-C are currently treated empirically based on KD treatment protocols.

The American College of Rheumatology has published clinical guidelines for laboratory evaluation and management of patients with suspected MIS-C. The guidelines support the use of high-dose IVIG (2 g/kg) and glucocorticoids (2 mg/kg/day) in divided doses. Glucocorticoids have been shown to have a beneficial effect on the fever curve of MIS-C patients compared to IVIG monotherapy [37]. Low-dose aspirin (3‒5 mg/kg, a maximum daily dose of 81 mg/day) may be considered unless there are contraindications such as thrombocytopenia or active bleeding. MIS-C patients with severe left ventricular dysfunction (EF <35%) usually receive enoxaparin thromboprophylaxis at a pediatric hematologist's discretion. Patients with severe disease (admission to ICU, significant cardiovascular involvement, evidence of macrophage activation syndrome) receive methylprednisolone pulses (30 mg/kg/day × 3 days) followed by glucocorticoids (~2 mg/kg/day in divided doses). Glucocorticoids are discontinued after 2‒3 weeks in mild cases and 4‒8 weeks in more severe cases.

Due to the immune-mediated pathogenesis of MIS-C, biological therapy may be beneficial; tocilizumab (an anti-IL-6 receptor monoclonal antibody), anakinra (a recombinant IL-1 receptor antagonist), and infliximab (an anti-tumor necrosis factor α monoclonal antibody) have been most widely investigated.

Although MIS-C has much in common with KD and TSS, MIS-C may be more severe, and many children are more likely to require intensive care. In a systematic review of 16 case series including a total of 655 patients with MIS-C, 11 deaths (1.7%) were reported. Patients diagnosed with multiple systemic inflammatory syndrome with abnormal BNP and/or troponin T levels should be followed up until their laboratory values return to normal.

There have been increasingly frequent reports of cardiac conduction abnormalities in MIS-C patients. Therefore, ECGs should be recorded at least every 48 hours in patients admitted for MIS-C [25]. Electrocardiographic conduction abnormalities should be continuously monitored. In addition, follow-up Holter ECG monitoring may be considered. It is worth noting that initial and follow-up echocardiography should be performed to measure z scores adjusted for the body surface area and assess ventricular/valve function, pericardial effusion, and coronary artery dimensions.

MIS-C patients require a more thorough post-discharge follow-up by a cardiologist. Approximately 20% of patients with cardiac involvement have refractory heart failure [26]. Long-term complications of myocardial inflammation should be closely monitored for other forms of myocarditis.

In the acute phase of MIS-C, for patients with significant transient left ventricular dysfunction (ejection fraction <50%) or persistent left ventricular dysfunction, follow-up cardiac MRI at 2‒6 months may be advisable to detect/prevent myocardial fibrosis and myocardial scarring [38].

Standards of follow-up and long-term monitoring for a variety of conditions have not been established so far. Many pediatric hospitals are currently conducting studies to evaluate both short- and long-term effects, outcomes, and standardization of MIS-C treatment. Further studies are pursued to examine the subtypes and variety of diseases associated with MIS-C [27].

Conclusion

MIS-C is an absolutely life-threatening hyperinflammatory syndrome that affects multiple organ systems in previously healthy children as a complication of COVID-19. The clinical signs of MIS-C may be similar to KD. However, the inflammatory process is probably peculiar to the SARS-CoV-2 infection and is characterized by reversible myocardial dysfunction and/or coronary artery dilation in some children. Certain laboratory markers, such as elevated serum CRP, ferritin or D-dimer levels, and low albumin, sodium, or ALC levels, may be predictors of more severe disease manifestations [5].

MIS-C treatment generally follows KD treatment protocols. Most patients are treated with intravenous immunoglobulins and glucocorticoids as first-line therapy; in refractory cases, biologicals, such as IL-1 and TNFα inhibitors, may be considered.

At present, timely diagnosis and treatment of MIS-C are critical factors for the highest possible success in this cohort. It should be noted that a multidisciplinary approach to these patients must be based on the cooperative efforts of experienced pediatricians, rheumatologists, cardiologists, hematologists, and intensive care physicians. Thus, larger multicenter studies are required to elucidate a variety of associated disorders, risk factors, the impact of OS, severity, and treatment strategies for MIS-C.