Clinical Data, Complications, Sequelae, and Death Causes in MIS-C

Abstract

Multisystem inflammatory syndrome in children (MIS-C) is a potentially life-threatening childhood disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, manifested by the persistence of fever and multiple organ dysfunction, elevated inflammatory markers, and the lack of an alternative diagnosis. Generally, at the time of diagnosis, children had positive antibodies to SARS-CoV-2 but negative nasopharyngeal SARS-CoV-2 polymerase chain reaction (PCR) tests at the time of the MIS-C evaluation. Fever, gastrointestinal, cardiovascular, hematologic, mucocutaneous, and respiratory manifestations are common clinical features. Patients with MIS-C are typically previously healthy, and their most common comorbidity is obesity. Cardiovascular abnormalities, which are the most prevalent complications of MIS-C patients, and thromboembolic events have the greatest influence on the severity of the disease. The majority of patients with MIS-C have a severe course of the disease, requiring intensive care unit admission up to 76%, respiratory support, special care, and vigorous treatment including inotropic drugs; nonetheless, the majority of patients have favorable outcomes, and overall mortality is low.

1. Introduction

Multisystem inflammatory syndrome in children (MIS-C) began to be reported in April 2020 as a new and potentially life-threatening childhood disease that has been temporarily associated with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1].

This condition commonly manifests 2–6 weeks after a typically mild or asymptomatic infection with SARS-CoV-2, with a variety of clinical presentations, the majority of which include persistent fever, multisystem organ involvement, and elevated inflammatory markers in the absence of an alternative diagnosis [2].

Following the publication of these unusual patient presentations, the Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) in May 2020 provided a case definition of this disorder based on clinical manifestations, laboratory features, and findings from additional exams. This disorder was named multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19 2023 [3, 4].

The case definition was updated by the Council of State and Territorial Epidemiologists (CSTE) and the Centers for Disease Control and Prevention (CDC) by developing a new MIS-C surveillance case definition, corresponding case report form, and case report form guidance document to be used starting January 1, 2023 [3].

This case definition includes any illness in a person aged less than 21 years who meets

• the clinical and the laboratory criteria (confirmed), or

• the clinical criteria and epidemiologic linkage criteria (probable), or

• the vital records criteria (suspect)

The clinical criteria in this case definition include.

An illness characterized by all of the following, in the absence of a more likely alternative diagnosis.

• subjective or documented fever (temperature ≥ 38.0°C)

• clinical severity requiring hospitalization or resulting in death

• evidence of systemic inflammation indicated by C-reactive protein ≥3.0 mg/dL (30 mg/L)

New onset manifestations in at least two of the following categories:

Cardiac involvement indicated by

• left ventricular ejection fraction <55% or

• coronary artery dilatation, aneurysm, or ectasia, or

• troponin elevated above laboratory normal range or indicated as elevated in a clinical note

Mucocutaneous involvement indicated by

• rash or

• inflammation of the oral mucosa (e.g., mucosal erythema or swelling, drying or fissuring of the lips, strawberry tongue), or

• conjunctivitis or conjunctival injection (redness of the eyes), or

• extremity findings (e.g., erythema [redness] or edema [swelling] of the hands or feet)

• shock

Gastrointestinal involvement indicated by

• abdominal pain, or

• vomiting, or

• diarrhea

Hematologic involvement indicated by

• platelet count <150,000 cells/μL, or

• absolute lymphocyte count (ALC) < 1000 cells/μL.

The clinical criteria of case definition of MIS-C according to the World Health Organization [4] include children and adolescents 0–19 years of age with fever >3 days and two of the following:

• rash or bilateral non-purulent conjunctivitis or muco-cutaneous inflammation signs (oral, hands or feet)

• hypotension or shock

• features of myocardial dysfunction, pericarditis, valvulitis, or coronary abnormalities (including ECHO findings or elevated Troponin/NT-proBNP)

• evidence of coagulopathy (by prothrombin time-PT , partial thromboplastin time- PTT , elevated d-Dimers)

• acute gastrointestinal problems (diarrhea, vomiting, or abdominal pain)

2. Clinical features of multisystem inflammatory syndrome in children

MIS-C symptoms generally appear 2–6 weeks after infection, and it is common that children with MIS-C would have had no or a few symptoms of COVID-19 [5]. MIS-C seems to develop in the post-infectious stage rather than during the acute infection stage of COVID-19 [6].

With the rapid spread of the COVID-19 pandemic, a considerable number of MIS-C cases have been reported from almost every country in the world with varying clinical manifestations. A large number of MIS-C-related publications include systematic reviews and meta-analyses that present clinical data, complications, and outcomes of more than a hundred MIS-C cases [6, 7, 8, 9, 10, 11, 12, 13, 14, 15].

According to these studies, males and children aged 7–9 years have a higher risk of developing MIS-C than other age groups and females overall, as shown in Table 1.

Author	Studies included	Number of MIS-C cases	Median age (years)	Gender dominance
Jiang et al., [6]	123	4475	8.1	Male (58.11%)
Santos et al., [7]	48	2144	8.9	Male (58%)
Hoste et al., [8]	68	953	8.4	Male (58.9%)
Radia et al., [9]	35	783	8.6	Male (56%)
Ahmed et al., [10]	39	662	9.3	Male (52.3%)
Dhar et al., [11]	18	883	8.9	Male (56%)
Kornitzer et al., [12]	54	543	8.9	Male (56%)
Williams et al., [13]	18	833	9	Male (57%)
Sood et al., [14]	17	992	7	Male (57%)
Miller et al., [15]	Reported case	4470	9	Male (59.9%)

Table 1.

The characteristics of the study sample by gender and age group.

Most patients with MIS-C do not have any reported underlying medical condition, but in those who do, obesity is the most common [7, 8, 9, 10, 11].

The percentage of reported comorbidities in those studies varies from approximately 3–40% [10, 13]. Apart from obesity being the most frequent, other comorbidities reported include endocrine (diabetes, hypothyroidism, congenital adrenal hyperplasia), respiratory (asthma, chronic pulmonary disease), gastrointestinal (Crohn’s disease), cardiovascular disease, neurologic/behavioral, liver or kidney disease, immunocompromised or immunodeficiency, cancer, immunologic/allergic, hematologic, coexisting infections, acute leukemia, glucose-6-phosphate dehydrogenase deficiency [7, 8, 9, 10, 11].

Patients with MIS-C usually present with persistent fever, abdominal pain, vomiting, diarrhea, skin rash, mucocutaneous lesions or KD-like symptoms and, in severe cases, with hypotension and shock or toxic shock syndrome [15, 16]. Some patients develop myocarditis, cardiac dysfunction, and acute kidney injury [6, 10, 13, 14, 15].

The most common symptoms in reported MIS-C cases [6, 7, 8, 9, 10, 11, 12, 13, 14, 15] are as follows:

Persistent fever, sometimes lasting 3 or 4 days, as a key criterion in the definition of MIS-C, was reported in almost all cases, from 85 to 100%.

Gastrointestinal involvement or symptoms mimicking viral gastroenteritis or mesenteric lymphadenitis are very frequent in 46–86% of cases, including abdominal pain up to 74%, vomiting up to 68%, and diarrhea up to 53%, whereas loss of appetite, emesis, and poor oral intake are less frequent (7–18%).

Cardiovascular involvement or manifestations are frequently seen in patients with MIS-C (23–65%) and manifest as tachycardia (20–56%), myocarditis (13–65%), mild to moderate decreased left ventricular ejection fraction (22–61%), pericardial effusions (15–47%), and abnormalities, dilatation, or aneurysms of the coronary arteries (11–35%).

Most MIS-C patients present with hypotension; in addition, a larger proportion of MIS-C patients (21–65%) developed hemodynamic shock or toxic shock, which is the main reason for using inotropic support.

The majority of MIS-C cases (38–58%) show mucocutaneous involvement or KD-like features, including erythema or rash (20–58%), non-purulent conjunctivitis or conjunctival injection (25–52%), tongue swelling (5–31%), polymorphous exanthema (49%), erythema and edema or swollen of hands and feet (21%), and cheilitis (33%).

Patients with MIS-C are less likely to experience respiratory symptoms (5–43%), which are the primary signs and symptoms of SARS-CoV-2 infection. These symptoms include cough (5–25%), dyspnea or shortness of breath (11–18%), pharyngeal erythema (32%), lung respiratory distress (11%), rhinorrhea or nasal congestion (7%), sore throat (3%), and chest tightness (2%).

Patients with MIS-C are also less likely to experience meningeal signs, seizures, headache, dizziness, confusion, somnolence, altered mental status, fussiness, or other neurological symptoms (14–32%).

The rarest manifestations of MIS-C patients, although not limited to them, are lymphadenopathy or cervical lymphadenopathy (7–24%), musculoskeletal symptoms or myalgia or malaise (10–30%), and fatigue or drowsiness (9%).

The percentage of reported clinical manifestations in a significant number of MIS-C patients analyzed in this chapter is shown in Table 2.

Clinical features	Percentage (%) according to article
	Jiang et al. [6]	Santos et al. [7]	Hoste et al. [8]	Radia et al. [9]	Ahmed et al. [10]	Dhar et al. [11]	Kornitzer et al. [12]	Williams et al. [13]	Sood et al. [14]	Miller et al., 2021 [15]
Fever	91	96	97	100	100	100	98	96	85	100
Gastrointestinal involvementa	52	46	63	71	74	63	57	86	69	69
Cardiovascular involvementb	30	58	32	40	45	23	NR	65	65	78
Shockc	38	31	44	611	NR	NR2	21	65	40	45
Mucocutaneous involvementd	50	38	49	42	56	NR3	19	58	52	55
Respiratory symptomse	42	25	31	5	18	NR4	14	43	45	29
Neurologic symptomsf	27	23	NR	NR	20	16	14	32	26	45
Musculoskeletal symptomsg	NR	NR	NR	NR	19	NR	10	17	NR	30
Othersh	19	NR	NR	NR	13	NR5	7	24	NR	22

Table 2.

Clinical features of multisystem inflammatory syndrome in children according to reported study [6, 7, 8, 9, 10, 11, 12, 13, 14, 15].

^a

(diarrhea, vomiting, abdominal pain, loss of appetite, emesis, poor oral intake).

^b

(tachycardia, myocarditis, mild or moderate decreased left ventricular ejection fraction, pericardial effusions).

^c

(reported also as a toxic shock, hemodynamic shock, or hypotension).

^d

(tongue swelling, erythema and rash, rash, non-purulent conjunctivitis, polymorphous exanthema, erythema and edema of hands and feet, swollen hands and feet, cheilitis).

^e

(Cough, dyspnea, shortness of breath, chest tightness, sore throat, rhinorrhea, nasal congestion, pharyngeal erythema).

^f

(headache, dizziness, confusion, somnolence, altered mental status, lethargy, fussy, meningeal signs, seizures, sleep disturbance).

^g

(extremity findings, myalgia/malaise, edema to extremities).

^h

(lymphadenopathy, cervical lymphadenopathy, neck swelling, neck pain fatigue or drowsiness, chest pain, periorbital edema).

¹

reported as hypotension.

²

NR (Not reported) reported as most; hypotension.

³

NR (Not reported) reported as some; conjunctivitis, rash, swollen hands and feet.

⁴

NR (Not reported) reported as most; oxygen requirement, some; cough, sore throat.

⁵

NR (Not reported) reported as some; lymphadenopathy, neck swelling.

3. Complications of multisystem inflammatory syndrome in children

3.1 Cardiovascular complications of MIS-C

MIS-C represents a severe complication of COVID-19 in children and a potentially life-threatening illness, the severity of which is primarily influenced by the involvement of the cardiovascular system [15].

The most common cardiovascular abnormalities that occur in patients with MIS-C are cardiac dysfunction, particularly left ventricular dysfunction, coronary artery dilation or aneurysm, myocarditis, pericarditis, and congestive heart failure [6, 7, 8, 10, 11, 13, 14, 15]. Other severe cardiovascular manifestations are hypotension and shock, which are two of the most frequent indications for vasoactive support [6, 7, 8, 10, 11, 13, 14, 15].

Cardiac involvement can occur along a spectrum of disease severity in up to 80% of patients with MIS-C [15]. Ventricular dysfunction is a common finding of MIS-C, with up to 61% of patients affected, from the evidence of ventricular function on echocardiography (26–31% of them have mild or moderate decreased of left ventricular ejection fraction-LVEF , whereas less than 10% have severe decreased LVEF) [8, 10, 11, 13, 14].

The evidence of myocarditis, mainly through the clinical picture of myocarditis and elevated cardiac enzymes, is present in up to 65% of children with MIS-C [13]. Myocarditis is one of the main pathophysiological mechanisms of ventricular dysfunction; however, some MIS-C cases have normal levels of cardiac enzymes but depressed ventricular function, suggesting an alternate pathogenesis such as generalized inflammation or changes in loading conditions [17].

Less common cardiovascular complications, but not limited to, are coronary artery abnormalities (18–39%), dilatation (8–16%), or aneurisms (8–10%) [8, 10, 11, 13, 14].

Pericardial involvement, such as pericardial effusion or pericarditis, is also a common complication of MISC (20–35%) [8, 11, 13, 14, 15] (Table 3).

Article	Complications	Number of cases	Percentage %
Jiang et al., [6]	Shock	1146/3036	38
	Myocarditis	830/2829	29
Santos et al., [7]	Shock	675/1544	44
	Hypotension	890/1697	52
Hoste et al., [8]	Hemodynamic shock or hypotension	416/695	56
	Myocarditis	128/309	41
	Mild or moderate decreased LVEF between 30 and 55%;	211/522	40
	LVEF less than 30%	36/506	7
	Coronary dilatation1	74/638	12
	Coronary aneurysms2	59/572	10
	Pericardial effusion	114/511	22
Ahmed et al., [10]	Shock	398/662	60
	Depressed LVEF	262/662	45
	Depressed LVEF between 30 and 55%	165/662	26
	LVEF less than 30%	33/662	5
	Coronary aneurysms	47/662	8
	Coronary dilatation	50/662	8
Dhar et al., [11]	Myocarditis	191/309	61
	LVEF (<50%)	190/422	45
	Pericardial involvement3	135/436	31
	Coronary artery abnormality	117/681	25
Williams et al., [13]	Shock	363/558	65
	Myocarditis4	363/558	65
	LVEF (<55%)5	368/603	61
	Coronary artery abnormality	96/248	39
	Coronary artery dilatation	108/681	16
	Coronary artery aneurysm6	44/551	8
	Pericardial effusion	166/477	35
Sood et al., [14]	Shock	357/725	49
	Myocarditis	276/870	32
	Left ventricle dysfunction7	337/ 823	41
	Coronary vessel abnormalities	143/802	18
	Pericardial effusion	146/709	20
Miller et all., [15]	Shock8	2018/4470	45
	Myocarditis	665/4470	15
	Cardiac dysfunction9	1296/4198	31
	Pericardial effusion/pericarditis	989/4470	22

Table 3.

Cardiovascular complications of multisystem inflammatory syndrome in children according to reported study [6, 7, 8, 10, 11, 13, 14, 15].

¹

(z-score between 2.0 and 2.5).

²

(z-score above 2.5).

³

Includes asymptomatic, echocardiographic pericardial effusion and pericarditis.

⁴

(clinical and/or biochemical and/or echocardiography).

⁵

Myocardial dysfunction or ejection fraction <55%.

⁶

coronary artery diameter > 2.5 z-score.

⁷

Abnormal ECHO with left ventricle dysfunction.

⁸

Receipt of vasopressors.

⁹

Includes specified left ventricular dysfunction (n = 1151) and right ventricular dysfunction (n = 304); percentages calculated among 4198 persons with an echocardiogram performed.

LVEF; Left ventricular ejection fraction.

3.2 Thrombotic events in MIS-C patients

In addition to the hyperinflammatory state, MIS-C is characterized by hypercoagulability and an increased risk of thrombotic events (TEs), particularly in patients with significant ventricular dysfunction or coronary artery aneurysm [18]. Along with elevated inflammatory markers, the majority of patients with MIS-C have elevated serum D-dimer and fibrinogen concentrations, necessitating anticoagulant medication for the majority of them [19].

Pediatric intensive care unit hospitalization, central venous catheterization, cardiac failure, mechanical ventilation, extracorporeal membrane oxygenation, obesity, or other hematological-associated disorders are also risk factors for thromboembolic events in MIS-C patients [18, 19].

The reported incidence of thrombotic events as a complication of MIS-C ranges from 1.4 to 6.5% (Table 4) [8, 15, 18, 21, 22].

Article	Complications	Number of cases	Percentage %
Hoste et al., [8]	Thrombotic complications1	13/953	1.4
Miller et al., [15]	Thrombotic complications2	38/4470	1
Aronoff et al., [21]	Thrombotic complications3	8/229	3.5
Whitworth et al., [22]	Thrombotic complications4	9/138	6.5
Maniscalco et al., [18]5	Thrombotic complications5	60
	Arterial	42/60	70
	Venous	15/60	25
	Intracardiac	14/60	23
Aronoff et al., [21]	AKI	42/353	12
Ahmed et al., [10]	AKI	108/662	16
Bowen et al., [23]	AKI	535/4470	19
Miller et al., [15]	AKI	849/2818	19
Sood et al., [14]	AKI	151/768	20
Tripathi et al., [20]	AKI	990/4947	20
Williams et al., [13]	AKI	166/477	35
Sood et al., [14]	Pleural effusion	101/625	16
	ARDS	40/594	8
Bowen et al., [23]	Pneumonia	747/2818	27
Miller et al., [15]	Pneumonia	1044/4470	23
	Pleural effusion	954 /4470	21
	Acute respiratory distress syndrome	261/4470	6
Miller et al., [15]	Severe hematologic6	2663/4470	60
	Severe respiratory7	1962/4470	44
	Severe gastrointestinal8	1133/4470	25
	Severe renal9	908/4470	20
	Severe neurologic10	382/4470	9

Table 4.

Other complications of multisystem inflammatory syndrome in children according to a reported study [8, 10, 13, 15, 20, 21, 22, 23].

¹

Including 2 splenic infarctions, (hemorrhagic) cerebral strokes during extracorporeal membrane oxygenation (ECMO) (n = 5), a recognized complication, contributed substantially to thrombotic complications.

²

Deep vein thrombosis/pulmonary embolism.

³

Deep vein thrombosis and/or pulmonary embolism were identified in 8 of 229 (3.5%).

⁴

Deep vein thromboses [7], intracardiac thromboses [1], acute ischemic stroke [1].

⁵

Reports of thrombosis in MIS-C patients published from May 2020 through November 2022.

⁶

Thrombocytopenia (42%), under signs and symptoms or calculated from laboratory results as platelets; Lymphopenia (35%), lymphocyte count <4500 cells/μl if age < 8 months or < 1500 cells/μl if age ≥ 8 months; Neutropenia (47%), absolute neutrophil count; Deep vein thrombosis/pulmonary embolism (1%).

⁷

Oxygen, high flow nasal cannula (17%), Invasive mechanical ventilation (intubation) (9%), Non-invasive mechanical ventilation (8%).

⁸

Free fluid (25%), hepatomegaly/splenomegaly (11%), colitis/enteritis (10%), cholecystitis/gallbladder abnormalities (7%), appendicitis/appendiceal changes (4%).

⁹

Renal failure (3%) and receipt of dialysis (0.9%).

¹⁰

Meningitis (5%), Encephalopathy (4%), Stroke (0.6%).

AKI: Acute kidney injury.

ARDS: Acute respiratory distress syndrome.

Thrombotic events in MIS-C patients might be arterial, venous, or intracardiac, with deep vein thrombosis, pulmonary embolism, cerebral artery thrombosis, and thrombotic renal microangiopathy being the most common [15, 24].

Arterial thrombosis can involve as well as coronary arteries, carotid arteries, peripheral systemic arteries, and the aorta. Deep venous thrombosis can affect the deep veins of the lower and upper limbs, the superior vena cava, the internal jugular vein, and the cerebral sinus vein [18, 19, 21, 22]. Intracardiac thrombosis can occur in any of the heart’s chambers [18].

The splenic infarctions and hemorrhagic cerebral strokes during extracorporeal membrane oxygenation (ECMO) were also reported as thrombotic complications; however, although abnormal coagulation parameters are frequently reported, thrombotic or embolic events were rare, in contrast to adult COVID-19 [8], but with higher mortality rate [17], as shown in Table 4.

3.3 Other severe system involvement in MIS-C patients

Acute kidney injury (AKI) occurs in approximately 12–35% of the patients with MIS-C and is associated with poor prognosis in critically ill children [10, 13, 15, 20]. The incidence of AKI as a complication of MIS-C in a systematic review and meta-analysis with a larger sample size reported by Tripathi et al. is 20% (Table 4).

Dehydration, low cardiac output, cytokine storm, the virus’s direct cytotoxic action on renal tubular cells, and the use of nephrotoxic medications all can contribute to AKI in MIS-C patients [20]. However, renal hypoperfusion is the main trigger of AKI onset in MIS-C patients [20].

In contrast to the typical pediatric COVID-19 infection, which primarily affects the pulmonary parenchyma and manifests as severe pneumonia, respiratory involvement in children with MIS-C is characterized by pulmonary edema and pleural effusions in the context of multiorgan involvement [25].

Severe respiratory involvement, including pneumonia, pleural effusion, and acute respiratory distress syndrome, occurs less frequently 6–27%; however, many MIS-C patients with severe presentation of the disease require any form of respiratory support [15, 23].

Other less prevalent MIS-C complications that have been recorded in a few cases are severe neurological problems 0.6–5% as follows: meningitis, meningoencephalitis, autoimmune encephalitis, encephalopathy, and acute cerebrovascular accidents such as ischemic stroke, intracerebral hemorrhage, subarachnoid hemorrhage, multiple diffuse microhemorrhages, and cerebral sinus venous thrombosis [15, 26].

Reversible splenial lesions, benign intracranial hypertension or pseudotumor cerebri, acute disseminated encephalomyelitis, cranial nerves impairment, transverse myelitis, and fatal cerebral edema have also been reported [26].

Abnormal findings on abdominal imaging, such as free fluid, colitis/enteritis, mesenteric adenitis, hepatomegaly/splenomegaly, gallbladder, and appendix inflammation, are the most prevalent sequelae of severe gastrointestinal involvement 4–25% [15].

4. Sequelae and death causes in MIS-C

The majority of patients with MIS-C had a severe course of the disease that required intensive care unit (ICU) or pediatric intensive care unit (PICU) admission (61–76%), requiring supplemental oxygen via high-flow nasal cannula up to 18%, noninvasive ventilation (8–26%), and invasive mechanical ventilation (9–28%), whereas a small number of cases (4–7%) required ECMO [6, 7, 8, 9, 10, 11, 13, 14, 15].

A substantial percentage of MIS-C cases, up to 63%, need vasoactive support due to hypotension, shock, and cardiovascular involvement [9].

Short-term morbidity is significant in terms of requiring intensive care treatments; MIS-C patients frequently require special care and vigorous treatment. Nonetheless, the majority of patients have favorable outcomes, and overall mortality is low (0.8%–2.41%), as shown in Table 5.

Author		Number of MIS-C cases	Percentage %
Jiang et al., [6]; Number of MIS-C cases; 4475	ICU	2050/3163	65
	MV	666/3901	17
	ECMO	64/2654	2
	Inotropes	971/2565	38
	Deaths	76/3159	2.41
Santos et al., [7]; Number of MIS-C cases; 2144	ICU	1294/1973	66
	(MV/NIV/ HFNC)	731/1919	38
	ECMO	36/641	7
	Inotropes	313/1965	16
	Death	38/1973	2
Hoste et al., [8]; Number of MIS-C cases; 953	ICU	564/769	73
	MV	219/928	24
	NIV	130/503	26
	ECMO	36/953	4
	Severe course1	118/138	86
	Inotropes	477/863	55
Radia et al., [9]; Number of MIS-C cases; 783	ICU	531/783	68
	MV	138/783	18
	NIV	87/783	11
	HFNC	22/783	3
	ECMO	31/783	4
	Inotropes	436/688	63
	Deaths	12/783	1.5
Ahmed et al., [10]; Number of MIS-C cases; 662	ICU	469/662	71
	MV	147/662	22
	ECMO	29/662	4
	Inotropes	347/662	52
	Deaths	11/662	1·7
Dhar et al., [11]; Number of MIS-C cases; 883	Inotropes	458/783	61
	MV	226/813	28
	Deaths	13/833	1·6%
Williams et al., [13]	PICU^c	633/833	76
	MV	208/833	25
	NIV	109/497	22
	HFNC	70/389	18
	ECMO	33/833	4
	Inotropes	508/833	61
	Deaths	18/833	2.1
Sood et al., [14] Number of MIS-C cases; 992	ICU	551/872	63
	MV	183/872	21
	Inotropes	363/872	42
	Deaths	22/992	2.2
Miller et al., [15]; Reported MIS-C case; 4470	ICU	2793/4470	63
	MV	419/4470	9
	NIV	368/4470	8
	HFNC	753/4470	17
	Inotropes	2018/4470	45
	Deaths	35/4470	0.8%

Table 5.

Outcomes of multisystem inflammatory syndrome in children according to reported study [6, 7, 8, 9, 10, 11, 13, 14, 15].

¹

Severe course was defined as the presence of coronary dilatation/aneurysm, shock, death, need for mechanical ventilation, extracorporeal membrane oxygenation (ECMO), renal replacement therapy, inotropes, or PICU admission.

Abbreviations: PICU/ICU, pediatric intensive care unit; MV; mechanical ventilation; NIV; noninvasive ventilation; HFNC, high-flow nasal cannula; ECMO, extracorporeal membrane oxygenation.

Children who have one or more underlying medical conditions, the most prevalent of which is obesity, have a higher mortality rate [23].

Mortality is higher among children who have had a longer duration of the disease prior to being admitted to the PICU, have severe involvement of four to five organ systems, more cardiovascular complications and shock, severe involvement of the respiratory system, and require more mechanical ventilation support and renal replacement therapy [23, 27, 28].

Furthermore, non-survivor patients have more neurological or respiratory symptoms, less diarrhea, and normal nutritional status; they also have higher levels of blood D-dimer, ferritin, lactate, and CRP [27, 28].

Most patients with MIS-C have good outcomes with no significant sequelae one year after diagnosis [3]. Laboratory abnormalities including NTproBNP, troponin-T, lymphocytopenia, thrombocytopenia, and C-reactive protein (CRP), normalize within 1–4 weeks after hospitalization [29].

Almost all cardiac abnormalities, including serum biomarkers and ventricular dysfunction (LV systolic dysfunction, LV ejection fraction, and LV systolic dysfunction), recover within 6 weeks to 6 months of follow-up; however, coronary artery abnormalities in a small percentage of MIS-C patients persist but improve after 6 months [29, 30].

Furthermore, most organ-specific complications resolve by 6 months post-diagnosis; complications persisting at 6 months include muscular fatigue, abnormalities at neurological examination, anxiety, and emotional difficulties [3].

Patients with MIS-C treated with immunomodulators have favorable early outcomes with no mortality, normalization of LV systolic function, recovery of coronary abnormalities, and no inflammation or scarring on cardiac MRI [31].

5. Conclusion

MIS-C is a severe complication of the SARS-CoV-2 infection that generally appears 2–6 weeks after infection and is common in previously healthy children; most of them manifest asymptomatic or mild forms of the COVID-19 infection, and it seems to develop in the post-infectious stage rather than during the acute infection stage of COVID-19.

MIS-C can occur at any age in children, but it is more common in children aged 7–9 years and more frequent in boys and in children with obesity.

The symptom complex of fever, GI symptoms, cardiac involvement, and rash or KD-like symptoms in children with prior symptomatic or asymptomatic SARS-CoV-2 infection, should prompt clinicians to recognize this syndrome early.

The involvement of the cardiovascular system and thromboembolic problems, which are the most prevalent sequelae of MIS-C, have the largest influence on the severity of this illness.

Short-term morbidity is significant in terms of requiring intensive care and vigorous treatment; nonetheless, the majority of patients have favorable outcomes, with no significant sequelae one year after diagnosis, and overall mortality is low.

Acronyms and abbreviations

AKI	acute kidney injury
ECMO	extracorporeal membrane oxygenation
ICU	intensive care unit
LVEF	left ventricular ejection fraction
MIS-C	multisystem inflammatory syndrome in children
PTT	partial thromboplastin time
PICU	pediatric intensive care unit
PT	prothrombin time
SARS-CoV-2	severe acute respiratory syndrome coronavirus 2
TEs	thrombotic events