Clinical Features of Multisystem Inflammatory Syndrome

Abstract

Multisystem inflammatory syndrome was first detected in pediatric patients in April 2020, related to COVID-19. The clinical manifestations are very broad and overlap with Kawasaki disease. Various organizations have developed guides with case definitions in order to facilitate diagnosis and epidemiological reporting. In this chapter, we present the clinical manifestations of multisystem inflammatory syndrome, considering the case definition of various organizations and case series reports, systematic reviews, and meta-analyses. We also address multisystem inflammatory syndrome in adults in the neonatal period.

1. Introduction

Multisystem inflammatory syndrome (MIS) is a set of symptoms caused by an extreme inflammatory response related to coronavirus disease 2019 (COVID-19) and was first detected in Europe between April and May 2020. The Royal College of Pediatrics and Child Health (RCPCH) of the United Kingdom (UK) referred to this acute condition as pediatric inflammatory multisystem temporally associated with COVID-19 (PIMS-TS). A few days later, the World Health Organization (WHO) and the Center for Disease Control and Prevention (CDC) named it multisystem inflammatory syndrome in children (MIS-C). In June 2020, multisystem inflammatory syndrome was also reported in adults (MIS-A). In June 2021, neonatal multisystem inflammatory syndrome was described (MIS-N) [1, 2, 3].

2. Multisystem inflammatory syndrome in children (MIS-C)

The first cases of COVID-19 due to SARS-CoV-2 in children manifested as mild illness. In April 2020, cases of some children with positive SARS-CoV-2 who presented a severe hyperinflammatory state were reported, considered to be Kawasaki disease (KD), sepsis, bacterial syndromes, or toxic shock, among other diagnoses. This syndrome was called MISC-C, and due to difficulty in establishing the diagnosis, various organizations such as RCPCH, WHO, and CDC, with the opinion of experts, developed documents with the aim of identifying cases and providing advice to doctors on the management of these patients. All of these documents present a case definition that includes clinical manifestations (Table 1).

	RCPCH [1]	WHO [2]	CDC [3]	CSTE/CDC [4]	Molloy et al. [5]
Publication date	May 1, 2020	May, 2020	May, 2020	January, 2023	May, 2023
Denomination	PIMS-TS	MIS-C	MIS-C	MIS-C	MIS-C
Patient age (years)	Child	0–19	<21	<21	<21
Abdominal pain	S	S			S
Cardiac hypotension	M	S			S
Cardiac manifestations			S		S
Confusion	S				S
Conjunctivitis	S	S		S	S
Coronary abnormalities		S			S
Cough	S				S
Dermal manifestations			S		S
Diarrhea	S	S			S
Erythema of the hands or feet				S	S
Fever	A; >38.5° C; Persistent	A; ≥ 3 days	A; ≥38.0°C for 24 hours,; Subjective lasting ≥24 hours.	A; ≥38.0° C; documented or subjective.	A; ≥38.0° C for ≥ days.; Subjective lasting ≥3 days.
Gastrointestinal manifestations			S		S
Headache	S				S
Hematologic manifestations			S		S
Inflammation of the oral mucosa				S	S
Kidney manifestations			S		S
Lymphadenopathy	S				S
Mucus membrane changes	S	S			S
Myocardial dysfunction		S			S
Neck swelling	S
Neurological manifestations			S		S
Oxygen requirement	M
Pericardial effusion					S
Pericarditis					S
Rash	S	S		S	S
Resp symptoms	S	S			S
Seizures					S
Shock		S			S
Sore throat	S				S
Swollen hands and feet	S	S		S	S
Syncope	S
Valvulitis (cardiac)		S			S
Vomiting	S	S
Without another diagnosis that justifies the clinical manifestations and laboratory and imaging findings.	A	A	A	A	A
COVID-19 evidence.	The polymerase chain reaction (PCR) test; positive or negative	Evidence or likely contact	Evidence or likely contact (4 weeks prior)	Detection or close contact (up to 2 months prior)	Evidence or recent exposure
No alternative plausible diagnoses

Table 1.

Clinical manifestations of MIS-C included in case definition of various organizations.

A: all—present in all patients; M: most—present in most patients; S: some—present in some of patients.

Dufort et al. [6] reported a case series of 99 patients with MIS-C, younger than 21 years old, admitted to New York hospitals from March 1 through May 10, 2020. Of the 99 patients, 54% were male, 31% of the patients were 0 to 5 years of age, 42% were between 6 and 12 years of age, and 26% were between 13 and 20 years of age. Regarding race, it was found that of 78 patients, 37% were white, 40% were black, and 23% were of other races. Regarding the ethnic group of 85 patients, 36% were Hispanic. Of the 36 patients who presented comorbidities, 29 of them were obese. The 99 patients presented the following symptoms upon admission: fever or chills 100%, chest pain 11%, abdominal pain 61%, nausea or vomiting 58%, diarrhea 49%, rash 60%, swollen hands or feet 9%, conjunctivitis 56%, mucosal changes 27%, headache 29%, altered mental status or confusion 2%, lymphadenopathy 6%, muscle aches or myalgias 17%, joint pain 4%, congestion 13%, sore throat 16%, cough 31%, shortness of breath 19%, wheezing 1%. The vital sign values were; median heart rate 133 beats/min (range: 120–148 beats/min), tachycardia 97%, median respiratory rate 27 breaths/min (range: 23–36 breaths/min), tachypnea 78%, hypotension 32%, median temperature 38.3°C (range: 37.5–39.3°C), temperature ≥ 38.0°C 63%, median oxygen saturation 98 (range: 97–100)%, oxygen saturation < 92% 4% [6].

Davies et al. [7] conducted a multicenter observational study of pediatric patients hospitalized in PICU in the United Kingdom between April 1 and May 10, 2020, who met the requirements of the PIMS-TS case definition published by the RCPCH. Seventy-eight cases of PIMS-TS were reported by 21 of 23 PICUs. Of the 78 patients, 67% were male, with a median age of 11 years (range: 8–14 years). The clinical presenting features were: fever 100%, shock 87% (vasodilated 71%, vasoconstricted 17%), abdominal pain 62%, diarrhea 64%, vomiting 63%, any abdominal symptom (pain, diarrhea, or vomiting) 90%, rash 45%, conjunctivitis 29% [7].

In a systematic literature review that included 56 studies, Yousef et al found 646 pediatric patients diagnosed with MIS-C between April 2020 and October 2020. The average age was 10 years (between 0.5–17 years); 52.2% were male. Of the 646, 51.1% of the cases occurred in the United States, 21.4% were presented in the UK, 8.7% were presented in France and Switzerland combined, and 18.9% were presented in other countries. Of the total patients, 99.5% presented fever, recording an average “max temperature” of 39.4°C (between 38.2 and 41°C). The average duration of fever before presentation to hospital was 5 days (range: 1–12 days).

The frequency of other symptoms was: generalized abdominal pain 77.6%, vomiting 75.4%, diarrhea 63.2%, dyspnea 80%, coryza 60%, cough 55%, sora throat 17%, chest pain 13.6%, headache 30.4%, irritability 57.4%, fatigue 61.5%, and myalgia 16.8%. On physical examination: hypotension 49.7%, tachycardia 93.5%, 67.3% tachypnea, polymorphic rash 57.6%, non-exudative bilateral conjunctivitis 52.9%, lip/oral cavity cracking 37%, hand and feet anomalies 26%, pharyngeal erythema, unilateral cervical lymphadenopathy 13.1%. Abdominal tenderness 51.9%, meningeal signs 21.2%, and bilateral crackles on auscultation 15% [8].

In a system review and meta-analysis, Santos et al. selected 98 studies (2275 patients with MIS-C) published between December 1, 2019, and July 10, 2021. The median age was 8.9 years (range: 0.1 days to 20 years old), and 58% were male. The symptom and clinical characteristics were: fever 100%, gastrointestinal symptoms (not specifics) 82%, abdominal pain 68%, vomiting 66%, cardiac symptoms 66%, shock 60%, hypotension 59%, erythema 59%, diarrhea 58%, conjunctivitis 54%, cough 41%, respiratory symptoms 39%, comorbidity 33%, dyspnea 29%, headache 28%, neurologic symptoms 28%, and sore throat 20% [9].

Jiang et al. did a live systematic review including a schedule of activities covering the period from December 1, 2019, to July 31, 2021. A total of 123 studies that met all the requirements for the final descriptive and risk factor analyses were included, with a total population size of 4475 children with MIS-C. The mean age of MIS-C patients was 8.1 ± 2.37 years, and 58.11% (1856/3184, 95% CI 56.40–59.82%) were boys. Among the 2841 individuals with race/ethnicity data, African black was 24.89%, Hispanic white 25.18%, Asian 23.41%, and non-Hispanic white 19.01%. Prevalent clinical symptoms observed in MIS-C cases were fever 90.85%, not-specified gastrointestinal symptoms 51.98%, rash 49..63%, abdominal pain 48.97%, conjunctivitis 46.93%, vomiting 43.79%, respiratory symptoms 41.75%, diarrhea 40.10%, pharyngeal erythema 31.91%, myocarditis 29.34%, neurologic symptoms 26.92%, erythema and edema of hands and feet 21.00%, and cervical lymphadenopathy 19.11%. Diagnostic criteria of incomplete KD 18.67%, complete KD 15.18%. Shock 37.75% [10].

Table 2 shows the frequency of signs and symptoms of MIS-C presented by the groups of patients reported by previously mentioned authors.

Clinical manifestation	Dufort et al. [6]; (99 cases)	Davies et al. [7]; (78 cases)	Yousef et al. [8]; (56 studies, 646 cases)	Santos et al. [9]; (98 studies, 2275 cases)	Jiang et al. [10]; (123 studies, 4475 cases)
Fever	100%	100%	99.5%	100%	90.85%
Gastrointestinal symptoms	—	90%	—	82%	51.98%
Abdominal tenderness	—	—	51.9%	—	—
Abdominal paint	61%	62%	77.6%	68%	48.97%
Nausea	58%	—	—	—	—
Vomiting		63%	75.4%	66%	43.79%
Diarrhea	49%	64%	63.2%	58%	40.1%
Rash	60%	45%	57.6%	59%	49.63%
Erythema and edema of hands or feet	9%	—	26%	—	21%
Conjunctivitis	56%	29%	52.9%	54%	46.93%
Coryza	—	—	60%	—	—
Mucosal changes	27%	—	—	—	—
Lip/oral cavity cracking	—	—	37%	—	—
Neurologic symptoms	—	—	—	28%	26.92%
Headache	29%	—	30.4%	28%	—
Confusion	2%	—	—	—	—
Irritability	—	—	57.4%	—	—
Meningeal signs	—	—	21.2%	—	—
Cervical lymphadenopathy	6%	—	13%	—	19.11%
Myalgias	17%	—	16.8%	—	—
Joint pain	4%	—	—	—	—
Fatigue	—	—	61.5%	—	—
Respiratory symptoms	—	—	—	39%	41.75%
Congestion	13%	—	—	—	—
Sore throat	16%	—	17%	20%	—
Pharyngeal erythema	—	—	13%	—	31.91%
Cough	31%	—	55%	41%	—
Shortness of breath	19%	—	—	—	—
Dyspnea	—	—	80%	29%	—
Wheezing	1%	—	—	—	—
Chest paint	11%	—	13.6%	—	—
Bilateral crackles on auscultation	—	—	15%	—	—
Tachypnea	79%	—	—	—	—
Oxygen saturation < 92%	4%	—	—	—	—
Tachycardia	97%	—	93.5%	—
Cardiac symptoms	—	—	—	66%	—
Hypotension	32%	—	49.7%	59%	—
Shock	—	87%	—	60%	37.75%

Table 2.

Frequency of signs and symptoms of MIS-C in groups of patients reported by various authors [6, 7, 8, 9, 10].

3. Multisystem inflammatory syndrome in adults (MIS-A)

In June 2020, a multisystem inflammatory syndrome in adults (MIS-A) was mentioned for the first time, and subsequently, multiple cases have been reported. In MIS-A, it is considered that an abnormal immune repose occurs in a SARS-CoV-2 infection, with various symptoms, usually fever, systemic inflammation that can affect several organs and shock [11, 12].

3.1 CDC case definition for MIS-A

In 2021, through expert opinion, the CDC developed a case definition of MIS-A [11]. The clinical manifestations of this definition are presented in Table 3.

Age	> 21 years
Hospitalization	> 24 hours
Fever	> 38.0°C or subjective.; > 24 hours before or in the initial 3 days of hospitalization.
At least three criteria (one of them primary)
Primary criteria	Cardiac (serious illness): Myocarditis. Pericarditis. Coronary dilation/aneurysm. Ventricular dysfunction (left or right). Second or third-degree atrioventricular block. Ventricular tachycardia.
	Rash,; Non-purulent conjunctivitis.
Secondary criteria	Neurological (new appearance): Encephalopathy. Seizures. Meningeal signs. Peripheral neuropathy.
	Hypotension or shock.
	Gastrointestinal: Abdominal pain. Vomiting. Diarrhea.
	Thrombocytopenia (< 150,000/microliter).
No other diagnosis.
Evidence of SARS-CoV-2 infection (current or recent).

Table 3.

MIS-A case definition developed by the CDC [11].

In a series of 16 cases in patients between 21 and 50 years of age, nine were woman. Seven had some underlying disease (6/16 obese, 2/12 diabetic, 2/16 hypertension, and 1/16 obstructive sleep apnea). Eight patients had documented respiratory illnesses before developing MIS-A symptoms, and eight did not. The initial symptoms and signs that this group of patients presented were fever (75%), cardiac symptoms such as chest pain or palpitations (37.5%), manifestations of cardiac disorders (100%), gastrointestinal symptoms (81.2%), dermatological manifestations (31.2%), including mucositis (18.7%) [12].

In a review of 36 documented cases of MIS-A, the mean age of patients was 33 years, with male predominance (63%). Contracted SARS-CoV-2 infection (47%), suggested by CRP, antibody testing, or clinically. Fever (86%). Gastrointestinal symptoms: nausea (19%), abdominal pain (30%), vomiting (13%), and diarrhea (19%). Sore throat (14%), unilateral cervical pain/swelling (16$). Some patients had predominant visual symptoms. Tachycardia (61%) and hypotension/cardiogenic shock with documented impaired ejection fraction (64%) [13].

4. Multisystem inflammatory syndrome in neonates

Pawar et al. introduced the MIS-N and neonatal MIS-C labels. The MIS-N label was created to differentiate newborns who present with multisystem inflammatory syndrome in the first week after birth secondary to possible maternal COVID-19 infection, with passive transmission of antibodies. Neonatal MIS-C is used to identify newborns who had neonatal, early-onset, or late-onset COVID-19 and who subsequently, between the second and fourth weeks after birth, developed multisystem inflammation. Both MIS-N and neonatal MIS-C are relatively rare [14].

Their case series included 20 suspected MIS-N neonates born to mothers with a history of SARS-CoV-2 infection or exposure to COVID-19 patients. They admitted to seven NICUs in Kolhapur between September 1, 2020, and April 30, 2023. The median maternal age was 26.5 years (range 20–34 years). 20% of the patients were premature <33 weeks, 65% were between 34 and 36 weeks, and 15% were term. There was no difference in distribution by sex. The most frequent clinical manifestations were heart disease, present in 18 (90%) patients (once they had rhythm disorders). Only two newborns (10%) presented fever (both on the first day of life). Eleven patients (55%) had respiratory manifestations. Eight newborns required mechanical ventilation, and three required CPAP. Six (30%) patients had gastrointestinal manifestations. Feeding intolerance and gastric aspirates were seen in six neonates. Two had lower gastrointestinal bleeding. A newborn died [14].

In a systematic review that included 13 papers, 33 cases of newborns with MIS-N were described; 72.7% were premature between 33 and 36 weeks (mean 34 weeks). The average birth weight was 2020 (1890–2620) grams. In all patients, the diagnosis was made in the first 3 days of life, with an average stay of 16 days. The clinical manifestations were fever at 18.2%, cardiovascular at 78.8%, respiratory difficulty at 66.7%, gastrointestinal at 27.3%, neurological at 24.2%, and acute kidney injury at 15.2%. The outcome was favorable in 30 neonates (90.9%). Two neonates die, one from multiple organ dysfunction and the other from necrotizing enterocolitis [15].

Based on the classification of clinical manifestations of COVID-19 in the neonatal period developed by Lakshminrusimha et al. [16], Molloy et al. [5] recommend using the terms early neonatal COVID-19, Late neonatal COVID-19, MIS-N, and MIS-C:

• Early neonatal COVID-19: neonate <7 days after birth at disease manifestation, with respiratory distress, apnea, or asymptomatic, with positive RT-PCR or antigen test from neonate after first few hours (source of SARS-CoV-2 infection: mother).

• Late neonatal COVID-19: age of neonate at disease manifestation typically, 2–3 weeks after birth, with respiratory distress, congestion, apnea, fever. With positive RT-PCR or antigen test from neonate (source of SARS-CoV-2 infection: family members including mother).

• MIS-N: neonate <7 days after birth at disease manifestation, with a neonatal inflammatory illness involving ≥2 organ system involvement (cardiac, gastrointestinal, hematologic, renal, respiratory, and neurological clinic manifestations), suggesting not include fever (which is relatively uncommon in neonates), along with the maternal history of SARS-CoV-2 infection during pregnancy (source of SARS-CoV-2 infection: mother).

• MIS-C: age of neonate at disease manifestation typically, 2–6 weeks after birth, with neonatal inflammatory illness involving ≥2 organ system involvement (cardiac, gastrointestinal, hematologic, renal, respiratory, and neurological clinic manifestations) and fever (source of SARS-CoV-2-infection: self, neonate with neonatal COVID with or without clinical signs).

5. Comparison with Kawasaki disease (KD)

The MIS-C diagnostic clinical features are general and overlap with those of KD. MIS-C has specific characteristics: it predominates in older children and most frequently affects the respiratory and digestive systems. Patients may present with abdominal pain, vomiting, diarrhea, shock, cardiac complication (myocarditis, left ventricular dysfunction, valvular regurgitation, pericardial effusion, and pericarditis) and have fewer symptoms of conjunctivitis. KD is an acute systemic vasculitis that predominantly affects children under 5 years of age and whose etiology is unknown [17, 18, 19].

Table 4 shows the similarities and differences between MIS-C and Kawasaki disease (KD).

Similarities between MIS-C and KD
Fever; Mucous membrane changes; Rash; Conjunctivitis; Lymphadenopathy; Frequent cardiac involvement; Laboratory tests demonstrating significant inflammation
Differences between MIS-C and KD
MIS-C	KD
Age of affected patients: 5–13 years. More likely to have gastrointestinal manifestations: abdominal pain, vomiting, and diarrhea. Some patients have developed coronary artery dilatation aneurysms (complete resolution at follow-up). Depressed ventricular function and highly elevated brain peptide (BNP) are more typical of MIS-C. Normal blood cell count, lymphopenia, and thrombocytopenia. Troponin increased. Brain natriuretic peptide increased.	Age of affected patients: <5 years. Coronary artery aneurysms or dilation and pericardial effusion are most common. White blood cell count, lymphocytosis, neutrophilia, and thrombocytosis. Troponin usually normal. Brain natriuretic peptide usually normal.

Table 4.

MIS-C and KC: Similarities and differences [5, 17].

Although the presence of a positive test for SARS-CoV-2 is more suggestive of MIS-C, it can also trigger KD in some patients. A positive SARS-CoV-2 antibody test is more difficult to interpret at this given widespread infection and vaccination [5].

Kostik et al. [18] created a score to discriminate MIS-C from KD, which includes five criteria:

• C-reactive protein >11 mg/dl—18 points

• D-dimer >607 ng/ml—27 points

• Patient >5 years—30 points

• Low platelets—25 points

• Gastrointestinal manifestations—28 points

A score > 55 points discriminates MIS-C from KD. This scale has a sensitivity of 87.5% and a specificity of 89.1% [19].

MIS-A shares many similarities with KD. To establish the diagnosis of KD, the patient must present fever for >5 days and at least four of the following signs:

• Conjunctivitis,

• Oropharyngeal mucositis or IgA infiltration of the upper respiratory tract,

• Cervical lymphadenopathy,

• Skin erythema,

• Edema or erythema of the extremities.

KD can present with acute kidney damage or the presence of aneurysms, especially in the abdominal aorta and coronary arteries [13].

To establish the diagnosis of COVID-19 Kawasaki-like syndrome, during or after COVID-19 infection and having ruled out other infections as a cause, the patient must have a fever for >3 days, and at least two of the following signs:

• Rash,

• Hypotension or shock,

• Acute cardiac injury.

Also present coagulation disorders, or acute gastrointestinal symptoms. With elevation of inflammatory markers (CRP, D-dimer, and/or ferritin) [13].

6. Conclusion

Multisystem inflammatory syndrome is a rare disease with a large number of clinical manifestations, both in pediatric, adult, and neonatal presentations. The studies carried out have allowed us to identify the weight of each sign and symptom for the establishment of a timely diagnosis. Without a doubt, clinical guidelines and case definitions will be adjusted as research on this entity continues.

Acknowledgments

We thank Dr. Nicolas Padilla Raygoza for allowing us to participate in this book and Laura Divic for the support provided during the editorial process.

Conflict of interest

The authors declare no conflict of interest.

Nomenclature

CDC	Center for Disease Control and Prevention
CPAP	continuous positive airway pressure
CRP	C-reactive protein
CSTE/CDC	Council of State and Territorial Epidemiologists/CDC
KD	Kawasaki disease
MIS-A	multisystem inflammatory syndrome in adults
MIS-C	multisystem inflammatory syndrome in children
MIS-N	neonatal multisystem inflammatory syndrome
NICU	Neonatal Intensive Care Unit
PICU	Pediatric Intensive Care Unit
PIMS-TS	pediatric inflammatory multisystem temporally associated with COVID-19
RCPCH	Royal College of Pediatrics and Child Health
RT-PCR	reverse transcription polymerase chain reaction
WHO	World Health Organization