Pre-Pathogenic Period of Multisystemic Inflammatory Syndrome: Ecological Triad

Abstract

In this chapter, we discuss Multisystemic Inflammatory Syndrome in children and adults. We begin by mentioning the antecedents and the origin of this disease. We frame this chapter in the ecological triad scheme and present the agent, host, and environment. It is necessary to theorize the new health threats in this scheme, based on a primary health-care approach, to understand how to prevent or inform accordingly. Due to its novelty, this syndrome originated from the SARS-CoV-2 infection still poses many questions. Future directions of this work include understanding the pathogenesis of MIS, including its mechanisms, risk factors, and diversity of outcomes.

1. Introduction

Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2), which causes Coronavirus disease 2019 (COVID-19), emerged in late 2019 in Wuhan, China [1, 2] and has spread to virtually the entire world.

The infection has had a higher impact on older populations (over 40 years of age) and men. For example, Padilla et al. [3] reported that in Mexico, 58.48% of confirmed cases were men, and 97% were aged over 20 years. Children and adolescents are susceptible to SARS-CoV-2 infection but usually develop COVID-19 at lower rates than adults, and the disease is less severe [4, 5].

A fraction of children affected by COVID-19 develop a life-threatening state of hyperinflammation 4 to 6 weeks after the onset of SARS-CoV-2 infection. This condition has been named Multisystem Inflammation Syndrome (MIS-C) [6]. A similar syndrome has been reported in adults (MIS-A), albeit as a rare complication of COVID-19 [7].

MIS-C was initially reported in the United Kingdom in April 2020, where an increase in critically ill children with hyperinflammatory shock and evidence of SARS-CoV-2 infection was described [8]. There are also reports in Spain [9] and New York, USA [10]. The United States Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) developed definitions for this entity [7, 11, 12].

The incidence of Multisystem Inflammatory Syndrome (MIS) in children is estimated to be between 0.05 and 0.1% of children who have been infected with COVID-19. Recent review study has revealed that the majority of MIS cases in children (95.21%) fully recovered while only 1–4% died from this syndrome [13, 14].

Case definitions for MIS have been developed by multiple organizations, including CDC and WHO; however, there is no single test that can demonstrate the diagnosis of MIS [7, 11, 12].

Systemic inflammation is the pathophysiological key to SARS-CoV-2 infection, with a host whose pro-inflammatory cytokines are responsible for the cytokine surge [15]. Table 1 shows the CDC and WHO definitions for MIS-C and MIS-A.

	CDC Children [11]	CDC Adults [7]	WHO Children [12]
Age (years)	< 21	≥ 21	0 a 19
Fever	>1 day	Without comment	>3 days
COVID-19	Yes	Yes (previous 12 weeks)	Yes
Severe disease	Yes	Yes	No
Involvement of extrapulmonary organs	≥ 2	≥ 1 (Extrapulmonary)	≥ 2
Absence of respiratory affection	No	Yes	No
Severe inflammatory evidence by laboratory *	Yes	Yes	Yes
Hospitalization	Yes	Yes	No

Table 1.

Definitions of multisystem inflammation syndrome in children and adults according to CDC and WHO.

^*

Elevated C-reactive protein, procalcitonin, D-dimer, serum ferritin, erythrocyte sedimentation rate, fibrinogen, interleukin-6.

Source: Taken and modified from Refs. [7, 11, 12].

MIS-C occurs in children under 21 years of age with a fever of 1 or more days, with laboratory evidence of inflammation, and in hospitalized patients, with two or more organs involved (cardiac, renal, respiratory, hematological, gastrointestinal, dermatological, and neurological), excluding other causes and RT-PCR/antigen/serology for positive SARS-CoV-2 and COVID-19 within the previous 4 weeks [11].

MIS-A presents in persons that are 21 years of age or older, with laboratory evidence of inflammation, hospitalized with one or more extrapulmonary organs involved, presenting with hypotension or shock, thrombosis, cardiac involvement, thromboembolism, acute liver injury, exclusion of severe respiratory disease or from other causes, and RT-PCR/antigen/serology positive for SARS-CoV-2 in the previous 12 weeks [7]. It is suspected as an abnormal immune system response to SARS-CoV-2 infection [16], causing systemic vasculitis and multiple organ damage [17].

At the beginning of the pandemic (April 2020), it was reported as a condition like Kawasaki disease [16, 17].

2. Other hyperinflammation syndromes

The first MIS-C and MIS-A cases were confused or considered as Severe Macrophage Activation Syndrome (SMAS), systemic vasculitis with cardiomyopathy, or a disease like Kawasaki disease with coronary artery aneurysm [18].

2.1 Macrophage activation syndrome (MAS)

The erythrocyte sedimentation rate is high in COVID-19 and low in MAS; furthermore, splenomegaly is almost pathognomonic in MAS, whereas it is not detected in MIS-C and the cytokine storm is different in MAS and post-COVID-19 [19].

2.2 Immune complex vasculitis

In MIS-C, there is ischemia due to the occlusion of blood vessels by immune complexes, such as spike proteins and anti-spike immunoglobulins; similar vasculitis is seen in adenosine deaminase 2 deficiency [18].

2.3 Kawasaki disease

Cases of severe hyperinflammation syndrome in COVID-19, resembling Kawasaki disease [20], have been reported in the United Kingdom [21], Italy [22], Spain [9], and the USA [16].

One difference between Kawasaki disease and MIS-C is the significant post-febrile thrombocytosis and coronary artery involvement compared to the myocardial involvement seen in MIS-C [20]. Another difference is that the CDC definition of MIS-C does not include skin rash [11].

Patients with MIS-C could have coronary artery aneurysm. Nevertheless, in most of them, it resolves during MIS-C follow-up; in Kawasaki disease, coronary artery aneurysms are more common and persist longer [23].

A crucial difference is that patients with COVID-19 have gastrointestinal clinical features, usually absent in Kawasaki disease [24].

MIS-C cases showed more pronounced laboratory abnormalities than those reported in Kawasaki disease; in both, the CRP was elevated, and the ferritin levels were elevated but lower in Kawasaki disease [16]; ethnicity was predominant in Afro-Americans in MIS-C, while in Kawasaki disease, it was in Asian descent. Other differences were that the COVID-19 patient developed lymphopenia, decreased platelets, and low albumin levels, while Kawasaki disease did not develop lymphopenia and showed less severe thrombocytopenia [18].

3. Multisystemic Inflammatory Syndrome epidemiology

The prevalence of MIS-C has been estimated at 2 per 100,000 children [10]. Waves of MIS-C cases follow 4–6 weeks after peaks of adult COVID cases [25, 26]. By early January in 2021, 6431 cases of MIS-C had been detected in the United States of America, with 55 deaths [27]. The prevalence of MIS-A is even less clear, and the CDC definitions are used to differentiate MIS-C and MIS-A. Basically, evidence of COVID-19 in the previous 2 weeks, age < 21 years, fever, and respiratory disease in children and absence of fever or respiratory disease in adults [7, 11].

4. Ecological triad

4.1 Agent

The SARS-CoV-2 coronavirus belongs to the order Nidovirales, family Coronaviridae, and genus Betacoronavirus. It can cause Coronavirus disease (COVID-19). The entire population is susceptible, and the forms of transmission include person-to-person contact, as droplets expelled by coughing or sneezing [28, 29].

Aerosol particles may be another form of transmission. There is no evidence of vertical mother-to-child transmission [30].

Coronaviruses are enveloped non-segmented positive-sense RNA [25], and SARS-CoV-2, which causes COVID-19, uses the same receptor, angiotensin-converting enzyme 2, as SARS-CoV, which is expressed in cells from respiratory tract epithelium; is the seventh member of the Coronavirus family to infect humans, and is more infectious than SARS-CoV or the Middle East Respiratory Syndrome Coronavirus (MERS-CoV), since SARS-CoV-2 grows better in the respiratory tract [31].

Since the emergence of the pandemic, the different variants of SARS-CoV-2 have been classified; in December 2020, the Alpha variant with lineage B.1.1.7 was reported [32]. The Beta variant was detected in October 2020 in South Africa, and there was no evidence of increased mortality with this variant [33]. The Gamma variant was detected in Japan in January 2021, and this variant is associated with increased transmissibility and mortality [33, 34] The Delta variant was identified in early 2021 in India and has increased risk of transmissibility and reinfection and became the predominant variant [33, 34]. The Omicron variant was identified in South Africa in November 2021, becoming the most transmissible and dominant worldwide [33].

4.2 Host

Most of the detected cases of MIS-C or MIS-A in the United States were Hispanic or Black (60%) [35]. Evidence suggests that anti-SARS-CoV-2 vaccination makes MIS-C less common among vaccines [36].

Affected children are reported to be between the ages of 2 and 16 years and were previously healthy children with no underlying health conditions [37].

MIS-C differs from MIS-A. In MIS-C, children were generally healthy prior to SARS-CoV-2 infection, and COVID-19 was mild or asymptomatic [10, 17], and reported fever of 1 or more days, with more of one affected body organ, including the respiratory, laboratory data showing inflammation (C-reactive protein, procalcitonin, D-dimer, serum ferritin, erythrocyte sedimentation rate, fibrinogen and interleukin-6) [11, 12] and predominantly in males (73%) [35].

In MIS-A, those affected had underlying health conditions and a history of respiratory disease [7, 38, 39], and generally did not have respiratory involvement, and fever may or may not be reported, and had tested positive for SARS-CoV-2 in the previous 12 weeks, detected by RT-PCR or virus antigen detection [7]. The most common ethnicities reported in MIS-A were Asian (25.4%), Caucasian (23.6%), and Hispanic (21.8%) [40].

The host responds by forming autoantibodies, antibody recognition of viral antigens in infected cells, and hyperinflammatory response due to viral superantigens. It is considered that gender, genetic predisposition, and ethnicity may play a crucial role in the occurrence of the disease syndrome [41].

4.3 Environment

The vast majority of the cases of MIS-C and MIS-A have been reported in hospitalized patients. Nevertheless, it appears that it is not the hospital environment that triggers the syndrome but that they were hospitalized due to the severity of the SARS-CoV-2 infection.

According to the CDC’s definition of MIS-A, one of the criteria is that the patient was hospitalized due to the severity of COVID-19 [7].

5. Conclusion and future directions

The Multisystemic Inflammatory Syndrome originated from the SARS-CoV-2 infection and was first reported in children. Nevertheless, it also appeared to affect adults. Some differences are noted in the chapter. Even as the environment was the hospitals, it may only be the consequence of the COVID-19 severity. As evidence piles up, we will have a clearer picture of this disease and its ecological triad.

Future directions of MIS research include:

• Understanding the pathogenesis of MIS, including its mechanisms, risk factors, and diversity of outcomes. This includes:

  • Immune system characteristics in reaction to SARS-CoV-2

  • The impact of the virus on body’s response to disease and individual variation of response

  • An autoimmune response to the virus.

• Developing better diagnostic tools for the early detection and management of the disease. Currently, there is no single test that can definitively diagnose MIS.

• Developing effective treatments. Supportive care utilized today, such as fluids, electrolytes, and anti-inflammatory drugs, may not work for everyone. Ideally, effective treatments will target the underlying mechanism of MIS onset and prevent serious complications.

• Identifying risk factors for MIS-C and for MIS-A. Developing a risk profile of the people most likely to be impacted by MIS.

• Studying the long-term effects of MIS including heart problems, kidney problems, and neurological complications.