Paediatric inflammatory multisystem syndrome temporally associated with COVID-19 (spring 2021 update)

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Children comprise only a small percentage of cases of acute SARS-CoV-2 infection and usually have mild or moderate symptoms or are asymptomatic ^[1][2]. However, a post-infectious inflammatory syndrome in paediatric patients temporally associated with COVID-19 has been described, and cases have been reported from across Canada and worldwide. Fever is the hallmark of this syndrome, with affected individuals presenting on a spectrum from fever as the sole clinical symptom to patients presenting with or progressing to multisystem involvement. The three broad categories described are: fever and hyperinflammation, Kawasaki disease (KD), and shock or shock-like states. Prominent clinical features can resemble that of Kawasaki disease, and toxic shock syndrome (TSS). In some individuals, symptoms can quickly progress to multi-organ dysfunction with hypotension requiring critical care for ventilatory and inotropic support ^[3]-[15]. 

Several names and case definitions have been used to describe this syndrome, including paediatric multisystem inflammatory syndrome temporally associated with COVID-19 (PIMS-TS) ^[16][17] and multisystem inflammatory syndrome in children (MIS-C) ^[18][19] (see Table 1 for comparative terms). PIMS/MIS-C is used in this practice point, which reviews clinical presentation for the syndrome and the investigations to conduct when considering this diagnosis. Potential treatment options and indications for subspecialty consultation and transfer to tertiary care are also described. The syndrome is currently under active surveillance by the Canadian Paediatric Surveillance Program (CPSP), and cases suspected by paediatricians in Canada should be reported (https://cpsp.cps.ca/surveillance/study-etude/covid-19).  

Initial reports of this syndrome arose from some of the areas hardest hit by COVID-19, where affected children appeared to develop signs or symptoms approximately 2 to 6 weeks following the peak of SARS-CoV-2 cases in their communities ^[20]. Thousands of cases have since been reported. Presentations are similar worldwide, with an estimated incidence of approximately 1 to 2/1000 in SARS-CoV-2-positive paediatric patients in the United States ^[3]-[15]. 

Table 1. Comparison of the case definitions and terms for an emerging inflammatory condition during the COVID-19 pandemic
Differences	RCPCH	CDC	WHO	CPSP
Name	PIMS-temporally associated with COVID-19	Multisystem inflammatory syndrome in children (MIS-C)	MIS-C	PIMS-temporally associated with COVID-19
Length of fever	Not specified	≥24 h	≥3 days	≥3 days
Age	Child	<21 years	0 to 19 years	<18 years
Evidence of inflammation	Yes	Yes	Yes	Yes
Multisystem	Single organ or multisystem	≥2 systems involved	≥2 systems involved	Not specified, but implied
Exclude other causes	Yes	Yes	Yes	Yes
SARS-CoV-2-PCR or antibody or exposure	Not necessary	Necessary	Necessary	Necessary
CDC Centers for Disease Control and Prevention; COVID-19 coronavirus disease 2019; CPSP Canadian Paediatric Surveillance Program; PIMS paediatric multisystem inflammatory syndrome; RCPCH Royal College of Paediatrics and Child Health; SARS-CoV-2-PCR severe acute respiratory syndrome coronavirus 2 polymerase chain reaction; WHO World Health Organization

Association with COVID-19

A temporal association with COVID-19 is clear, with cases of PIMS/MIS-C typically following 2 to 6 weeks after the peak of a COVID-19 outbreak in the local community ^[20]. Little information regarding the sensitivity and specificity of methods used to assess for the presence of anti-SARS-CoV-2 antibodies is contained in the case series published to date. Although only 20% to 40% of affected children tested positive on reverse transcription (RT)-PCR for SARS-CoV-2 using nasopharyngeal (NP) swabs, the vast majority (80% to 100%) of all children tested positive for antibodies to SARS-CoV-2 ^[3]-[15]. For those patients who have tested negative for antibodies and RT-PCR, most have a history of contact with a SARS-CoV-2-positive individual. The early data therefore suggest that this syndrome is not the result of acute infection, but rather of a dysregulated immune response to earlier infection or exposure.

Acute SARS-CoV-2 infection in adults has been associated with ‘cytokine storm syndrome’ (CSS), a sudden onset of hyperinflammation and multiorgan disease. CSS is caused by excessive cytokine release from uncontrolled immune activation ^[22]. This response presents in the later stages of acute infection in adults experiencing severe respiratory manifestations from COVID, and is believed to contribute significantly to mortality ^[23]-[25]. By contrast, PIMS/MIS-C appears to be a post-infectious hyperinflammatory syndrome ^[25]. Features similar to PIMS/MIS-C are increasingly being recognized in adults as ‘multisystem inflammatory syndrome in adults’ (MIS-A), often with minimal respiratory involvement and reported deaths ^[26].

Presentation

The hallmark feature of PIMS/MIS-C is the presence of high and persistent fever (>38°C for ≥3 days), unexplained by other causes. Fever, together with laboratory evidence of marked systemic inflammation and a temporal association with higher community prevalence of COVID-19 should raise the index of suspicion for PIMS/MIS-C. The clinical phenotypes of PIMS/MIS-C described to date include: 1) fever with hyperinflammation; 2) KD-like features (Box A); and 3) shock or shock-like states. In addition to features of KD and TSS ^[27] (Box B), the cardiac, gastrointestinal (GI), renal, and neurological systems may be affected ^[6][8]. Persons in all three groups can deteriorate rapidly and develop signs of hypotension and poor perfusion related to severe myocardial dysfunction.

Box A. Diagnostic criteria for classic Kawasaki disease (KD) from the American Heart Association
Complete KD	Incomplete KD
Fever ≥5 days with at least 4 of 5 clinical criteria: Erythema and cracking of lips, strawberry tongue, and/or erythema of oral and pharyngeal mucosa Bilateral bulbar conjunctival injection without exudate Rash: maculopapular, diffuse erythroderma, or erythema multiforme-like Erythema and edema of the hands and feet in acute phase and/or periungual desquamation in subacute phase Cervical lymphadenopathy (≥1.5 cm in diameter), usually unilateral	Fever ≥5 days with <4 clinical features of classic KD   And CRP ≥ 30 mg/L, ESR ≥40 mm/h   With positive echocardiography findings*   Or 3 or more of the following: Anemia for age Platelet count ≥450 x 109/L after 7 days of fever Albumin ≤30 g/L Elevated ALT level WBC ≥15 x 109/L Urine WBC ≥10/hpf
*One of the 3 findings: 1) Z-score of left anterior descending coronary artery or right coronary artery ≥2.5; 2) coronary artery aneurysm is observed; or 3) ≥3 of the following features: (a) decreased left ventricular function, (b) mitral regurgitation, c) pericardial effusion, or d) Z-scores in left anterior descending coronary artery or right coronary artery of 2 to 2.5.
ALT alanine transaminase; CRP C-reactive protein; WBC white blood cell Adapted from reference [33]

Box B. Features of toxic shock syndrome (TSS)

Hypotension with ≥2 of the following clinical and laboratory abnormalities: Fever >38.5°C Rash (diffuse macular erythema with subsequent desquamation) Renal impairment Coagulopathy (platelets < 100 x 109/L or disseminated intravascular coagulation) Liver enzyme abnormalities Acute respiratory distress syndrome Extensive tissue necrosis (including necrotizing fasciitis) Gastrointestinal symptoms

Adapted from reference [27]

Children presenting with PIMS/MIS-C with complete or incomplete KD can experience KD shock syndrome (KDSS) ^[28], which is defined by systemic hypotension and hypoperfusion, and/or macrophage activation syndrome (MAS), which is a form of CSS seen in individuals with underlying inflammatory diseases such as KD ^[29]-[31]. MAS is a potentially life-threatening complication that presents with persistent fever, rash, lymphadenopathy, hepatosplenomegaly and, occasionally, with neurological complications. Affected individuals have characteristic laboratory features, including marked increases in CRP, ferritin, LDH, AST, ALT, triglycerides, and D-dimers, as well as progressive cytopenias. Some children with PIMS/MIS-C who do not fulfill criteria for KD, but have some features of KD, can also present with shock-like states, either due to myocarditis and ventricular dysfunction, or secondarily to MAS ^[4][32].

Many case series have suggested that a disproportionally high number of Afro-American, Afro-Caribbean, and Hispanic children are affected by PIMS/MIS-C ^{[3][6][8][9][11]-[13]}. It is unclear whether this la is attributable to differences in genetic, socioeconomic, or exposure risk factors. Interestingly, there are few reports from East Asia, the original epicentre of COVID-19.

Some clinical features, particularly non-exudative conjunctivitis, rash, and oral mucosal changes are seen in both PIMS/MIS-C and classic, pre-pandemic KD, although children with PIMS/MIS-C have more significant cardiac dysfunction and more prominent GI features (Table 2). While the major cardiac morbidity associated with KD is the development of coronary artery aneurysms, children with the KD-like phenotype of PIMS/MIS-C have presented with severe myocardial dysfunction and cardiogenic shock. With prompt recognition and recommended initial therapy (corticosteroids + intravenous immunoglobulin (IVIg)) for PIMS/MIS-C-related cardiac dysfunction, cardiac function can improve rapidly ^[4]. Up to one-third of patients with severe presentations of PIMS/MIS-C were reported to have had coronary artery dilatation in the acute phase ^[4][5][8], with giant coronary artery aneurysms only rarely. The clinical significance and evolution of the coronary artery dilatation seen during the acute phase of the illness remain to be determined.

GI symptoms (including acute abdomen, abdominal pain, vomiting, diarrhea) and neurological signs (headache, neck stiffness, altered mental state, lethargy) are also more prominent in PIMS/MIS-C than in pre-pandemic KD.

Table 2. Comparing indicators: Classic, pre-pandemic KD versus PIMS/MIS-C
Indicator or characteristic	Classic pre-pandemic KD	PIMS/MIS-C
Average age at presentation (years)	<5	7 to 9
Ethnicity	East Asian +	African, Hispanic, Afro-Caribbean +
Gastrointestinal symptoms	+	+++
Cardiac dysfunction	+	+++
Coagulopathy	+	++
Shock	+	++
Macrophage activation syndrome	+	++
Markedly elevated CRP (>100 mg/L)	++	++++
Elevated ferritin	+	++
Elevated D-dimers	+	++
Elevated cardiac biomarkers (NT-proBNP, troponin)*	rarely performed	++
Thrombocytopenia	rare	++
Lymphopenia	rare	++
Coronary artery abnormalities	++	+
CRP C-reactive protein; NT-proBNP N-terminal-pro-B-type natriuretic peptide * Biomarkers of interest, with a growing body of data supporting a role in KD and MIS-C. Debate continues [34].

Approach to investigation and management of suspected of PIMS/MIS-C

Because the syndrome of PIMS/MIS-C has only recently been recognized, it is not possible to make evidence-based recommendations about when to undertake laboratory testing in patients who present with unexplained fever. However, certain principles must be kept in mind when suspecting PIMS/MIS-C. While PIMS/MIS-C appears to be rare, children with this syndrome can deteriorate quickly if not appropriately managed, and therefore a high degree of suspicion for the diagnosis must be maintained. It is believed that early recognition and management are important for optimal outcomes in children affected with PIMS/MIS-C. 

Physicians should consider the local epidemiology of COVID-19 (the number of cases and when they occurred) when contemplating a potential PIMS/MIS-C diagnosis, and should include in their history questions to assess the level of risk for exposure to SARS-CoV-2. This approach must be balanced with the knowledge that fever for 3 or more days is a common presenting feature in the paediatrician’s office or hospital emergency department. Therefore, investigations for other causes of fever must be included as clinically indicated.

Any child with unexplained high fever (usually for ≥3 days, when other causes for fever have been excluded) who looks unwell, particularly with any clinical sign suggesting KD, severe abdominal pain, or hypotension, should have appropriate screening investigations (Table 3). PIMS/MIS-C should also be considered in patients with ≥5 days of unexplained fever alone.

Critically ill individuals should receive broad-spectrum antibiotic coverage pending results from their microbiological and hyperinflammatory work-up and be admitted to an intensive care unit (ICU) for inotropic support and mechanical ventilation, as required.

For hospitalized patients with moderate to severe end-organ dysfunction, multidisciplinary team involvement is strongly advised. This team may include general paediatrics, infectious diseases, rheumatology, immunology, ICU, cardiology, and hematology/thrombosis services, delivered in a regional or tertiary care centre.

All hospitalized patients with suspected PIMS/MIS-C should undergo echocardiography, irrespective of the presence or absence of signs or symptoms of cardiac involvement. Features suggestive of cardiac involvement associated with PIMS/MIS-C include signs of heart failure, new cardiac murmur, gallop rhythm, persisting unexplained tachycardia, elevated troponin or NT-proBNP, arrhythmias and other ECG abnormalities, or cardiomegaly on chest radiograph. Patients with PIMS/MIS-C appear to be at risk for developing coronary artery aneurysms. A repeat echocardiogram at 7 to 14 days and at 4 to 6 weeks after presentation is advised for all patients, including those who did not have cardiac abnormalities initially.

Approach to investigation and management of children with PIMS/MIS-C must consider the individual clinical scenario. Children with PIMS/MIS-C present in one of three ways (Figure 1).

Figure 1. Algorithm for investigations and management in PIMS/MIS-C is available as a supplementary file.

1. Fever and hyperinflammation:

When a patient presents with an isolated high fever ≥5 days that is otherwise unexplained OR fever ≥3 days with features of KD, and a history of or potential exposure to COVID-19 based on local epidemiology, screening laboratory tests for hyperinflammation (Table 3) should be considered. When laboratory evidence of significant hyperinflammation is present (Box C), consider additional work-up as available for an evolving picture of CSS/MAS (ferritin, LDH, fibrinogen, D-dimers, PTT, INR, triglycerides), and for cardiac involvement (troponin, NT-proBNP, and ECG). 

When the child appears unwell, or inflammatory markers are markedly elevated, or abnormalities are found in troponin or NT-proBNP, inpatient admission should be considered. Cardiac evaluation and treatment as KD, including IVIG, corticosteroids, and acetylsalicylic acid (ASA), may also be considered (see below for details). When available, consultation with a paediatric rheumatologist or infectious disease physician and a cardiologist may be appropriate.

If hyperinflammation is present but admission is deferred because the patient appears well otherwise, close follow-up and repeat blood work is suggested within 24 to 48 h. Some patients with fever and hyperinflammation may never meet criteria for PIMS/MIS-C.

When the treating physician elects not to perform laboratory investigations, based on local epidemiology, patient history, and clinical assessment, close follow-up is warranted, including reassessment in 24 to 48 h when a fever persists. 

Table 3. Investigations for suspected PIMS/MIS-C cases
Screening hyperinflammation labs	CBC and differential, CRP, albumin
Additional baseline labs	Electrolytes, ALT, CK, urea, serum creatinine, urinalysis
Kawasaki disease	Routine KD labs, troponin, NT-proBNP*, ECG, echocardiogram
Cardiac	Troponin, NT-proBNP*, ECG, CXR, echocardiogram
Microbiology	Bacterial cultures, viral swabs, SARS-Cov-2 PCR, SARS-Cov-2 serology** (draw before administering IVIG)
Additional cytokine storm syndrome/MAS markers	LDH, fibrinogen, D-dimers, PTT, INR, triglycerides
ALT alanine aminotransferase; CBC complete blood count; WBC white blood cell count; CK creatine kinase; CRP C-reactive protein; CXR chest radiograph; CSS cytokine storm syndrome; ECG electrocardiogram; INR international normalized ratio; IVIG intravenous immunoglobulin; LDH lactate dehydrogenase; MAS macrophage activation syndrome; NT-proBNP N-terminal-pro-B-type natriuretic peptide; PTT partial thromboplastin time; SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2 *When available ** When available, or when storage for future testing is available

 

 

Box C.  Laboratory features suggestive of PIMS/MIS-C

CRP ≥50 mg/L and at least one of the following: ferritin >500 mcg/L platelets <150 x109/L lymphopenia <1.0 x 109/L hypoalbuminemia neutrophilia

2. Kawasaki disease-like presentation of PIMS/MIS-C

Children presenting with complete or incomplete KD should be managed as per standard of care for this patient group. If not already ordered, consider adding ferritin, troponin, and NT-proBNP (when available) to KD evaluation (Table 3), due to risk for cardiac dysfunction and MAS in complete or incomplete KD cases during the COVID-19 pandemic ^[7][8]. An ECG and echocardiogram should be performed upon admission and repeated as indicated by initial results, the child’s clinical picture, and institutional protocols. First-line treatment includes IVIG at 2 g/kg ^[33], to a maximum of 70 g per day (administered in accordance with institutional policy), and acetylsalicylic acid (ASA) (dosing per institutional policy).

Rheumatology or infectious disease and a cardiology consultation should be sought for patients at high risk for complications from KD. These include patients <1 year of age and those with fever for ≥10 days, MAS, KDSS, or the presence of coronary artery abnormalities on baseline echocardiogram ^[33][35][36]. When a diagnosis of KD is suspected, treatment with corticosteroids in conjunction with IVIG may be considered for severe and high-risk cases.

Early administration of IVIG and corticosteroids has been shown to reduce ICU admissions and hospital length of stay ^[37]. Given the concerns about limited IVIG supply, volume overload, and hemolytic anemia, corticosteroids could be considered instead of a second IVIG infusion to re-treat patients who do not respond to an initial dose of IVIG ^[33][35][36]. Whenever possible, perform the echocardiogram before administering IVIG, to better assess function and help determine risk for fluid overload and need for diuretics with IVIG infusion.

Corticosteroids may be given at a dose range of either 1 to 2 mg/kg/day orally or intravenously as prednisone or methylprednisolone, respectively. For more severe organ-threatening disease or failure to improve with lower steroid doses, pulse intravenous (IV) methylprednisolone (MP) therapy can be administered at 10 to 30 mg/kg/day (to a maximum 1000 mg) as an infusion over 1 to 3 h ^[38]. Administering IV MP before IVIG to reduce cardiac inflammation and improve cardiac function may help to mitigate the impact of fluid overload associated with IVIG. Use of furosemide halfway through the IVIG infusion may also be considered. For patients with KD complicated by refractory MAS or KDSS and requiring escalation of therapy beyond pulse IV methylprednisolone therapy, biologic therapy may be considered. Biologic therapy should be directed by a paediatric rheumatologist.

Across Canada, practice variations exist regarding the involvement of rheumatology or infectious disease physicians when diagnosing and managing KD. Given the evolving spectrum of PIMS/MIS-C, consultation with these specialists after initial IVIG treatment fails, even in cases of classic KD, should be considered. Consultation with cardiology, hematology or thrombosis specialists, and the paediatric critical care specialists may also be indicated for complicated or high-risk cases of KD. 

3. Shock or shock-like states:

Children with PIMS/MIS-C may also present with, or progress to, hypotension and shock. In such cases, consultation with paediatric intensive care specialists should be sought immediately. These patients may exhibit some features of KD, most commonly non-exudative conjunctivitis, rash, and oral mucosal changes with isolated but severe organ dysfunction, particularly of the heart or GI tract, or they may present with multi-organ dysfunction. All children presenting with unexplained shock, or a shock-like state, should be screened for PIMS/MIS-C and tested for hyperinflammation (Table 3 and Box C), with additional screening for cardiac involvement, including ECG, echocardiogram, and baseline troponin and NT-proBNP (if available). CSS/MAS markers (Table 3) should also be investigated in patients presenting with shock or a shock-like state. For severe abdominal presentations, input from gastroenterology or general surgery should be requested, along with transfer to a tertiary care centre when clinically indicated. For altered level of consciousness or focal neurological deficits, neurology should be consulted.

Patients presenting with or developing hypotension, severe cardiac dysfunction (including elevated troponin, highly elevated NT-proBNP, abnormal ECG), or another shock-like state (including GI or neurologic presentations) can deteriorate very quickly. They require careful, judicious fluid resuscitation, inotropic support, and possible intubation. Initial broad-spectrum antibiotics are recommended because symptoms overlap with severe bacterial infections. Emergent cardiology and critical care consultation, and transfer for tertiary care, should be pursued.   

If there is evidence of myocarditis, shock, or MAS/CSS, treatment should be discussed with a consulting rheumatologist, and IVIG, corticosteroids, and low-dose ASA (3 to 5 mg/kg/day, to a maximum of 81 mg/day) initiated. Patients with documented thrombosis or an ejection fraction <35% should receive therapeutic anticoagulation with enoxaparin ^[38].

For children with myocardial dysfunction in the ICU setting, initial treatment with a combination of IVIG and methylprednisolone has been associated with faster cardiac recovery and shorter ICU stay compared with IVIG alone ^[4][37]. When clinical response is suboptimal, biologic therapy such as anakinra may be considered, in consultation with paediatric rheumatology.

Follow-up

Patients with PIMS/MIS-C should be followed by cardiology and rheumatology (or general paediatrics with rheumatology guidance) after discharge. Patients treated with corticosteroids or biologics often require 2 to 3 weeks or more of therapy, with tapering of medications guided by clinical and laboratory evaluations. All patients with PIMS/MIS-C who receive IVIG should remain on low-dose ASA (3 to 5 mg/kg/day, to a maximum 81 mg/day) until a follow-up echocardiogram confirms normal coronary arteries >4 weeks post-diagnosis and inflammatory markers return to normal. Cardiology follow-up is recommended for all patients with PIMS/MISC similar to KD, as per institutional policies (i.e., echocardiograms are suggested 7 to 14 days and 4 to 6 weeks post-diagnosis) ^[38]. 

Conclusion

In Canada, the burden of disease from COVID-19 in paediatric patients appears to be low. PIMS/MIS-C has been reported to present 2 to 6 weeks after the peak number of cases of SARS-CoV-2 in the local community. While this syndrome appears to be rare, clinicians must be vigilant in considering this diagnosis. There should be a low threshold for transfer to a regional or tertiary centre for further management and consultations. When PIMS/MIS-C is diagnosed and treated promptly, most children have favourable outcomes.

Information on SARS-CoV-2 related syndromes will be reviewed and updated in CPS documents as the pandemic and its literature evolve.

CANADIAN PAEDIATRIC SOCIETY ACUTE CARE COMMITTEE (2020-2021)

Members: Carolyn Beck MD, Kevin Chan MD (Chair), Kimberly Dow MD (Board Representative), Karen Gripp MD, Kristina Krmpotic MD, Marie-Pier Lirette MD (Resident Member), Evelyne D. Trottier MD
Liaisons: Laurel Chauvin-Kimoff MD (Past Chair 2012-2019), CPS Paediatric Emergency Medicine Section; Sidd Thakore MD, CPS Hospital Paediatrics Section

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References

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Disclaimer: The recommendations in this position statement do not indicate an exclusive course of treatment or procedure to be followed. Variations, taking into account individual circumstances, may be appropriate. Internet addresses are current at time of publication.