Coronary arteries modifications in pediatric inflammatory multisystem syndrome associated with SARS-CoV-2

Introduction

Despite the fact that the pediatric population is generally not severely affected by SARS-CoV-2 infection, some children are prone to subsequently developing a multisystemic inflammatory syndrome⁽¹⁾.

According to the World Health Organization (WHO), the multisystemic inflammatory syndrome in children (MIS-C) is defined as follows: a patient aged 0-19 years old who presented a temperature higher than 38 degrees Celsius intrarectally for longer than three days and any two of the following clinical evidence or modified laboratory tests: signs of mucosal or skin inflammation (rash, serous conjunctivitis), hypotension/hypotensive shock, signs of cardiac dysfunction (ultrasound changes, eleva­ted troponin levels, NT-proBNP), signs of coagulopathy (elevated D-dimers, changes in prothrombin time or aPTT), gastrointestinal involvement (diarrhea, vomiting, abdominal pain) WITH biological inflammatory syndrome present (procalcitonin, ESR, C-reactive protein with altered values) in the absence of any septic site, WITH evidence of a history of COVID-19 (RT-PCR, tests, rapid  antigen test or positive SARS-CoV-2 serology) or mentioning a close contact with a patient with confirmed SARS-CoV-2 infection⁽²⁾.

The treatment of patients with MIS-C concentrates on the use of immunoglobulin and corticotherapy, depending on the clinical condition of the patients and their hemodynamic status, without forgetting about the possible installation of thrombotic risk by generalized inflammation, with a possible association of antiplatelet agents or anticoagulants⁽³⁾.

The prognosis is favorable in most cases, with death rates of roughly 2%⁽⁴⁾.

Discussion

The very definition of the multisystemic inflammatory syndrome associated with SARS-CoV-2 infection highlights the possibility of myocardial damage, through myocardial dysfunction, echocardiographic changes and elevated values of NT-proBNP or CK-MB⁽⁵⁾.

The cardiac damage most often encountered in patients diagnosed with MIS-C is represented by acute myocardial dysfunction, with damage to the left ventricle and systolic function⁽⁶⁾.

There are multiple mechanisms that can cause cardiac injury, by affecting the cardiomyocytes following an inflammatory response overstimulated by an “avalanche of cytokines”, viral invasion or dysfunction at the microvascular level, thus producing damage at the cellular level⁽⁷⁾.

But the exact mechanism that leads to the size modification of the coronary arteries or the production of aneurysms in PIMS is not known – inflammatory mediators or direct damage to the arterial vascular wall could be to blame⁽⁸⁾.

Consulting the specialized literature, we found descriptions of multiple cases in which pediatric patients present with dilatation of the coronary arteries.

A study that gathered 186 children from the United States of America, with a mean (or median) age of 8.3 years old, describes an incidence of aneurysms in the target population of 8% (15 of 186 children), with a Z score higher than 2.5⁽⁹⁾.

Likewise, Dufort et al.⁽¹⁰⁾ describe, in another American study led by the New York Department of Health, nine children out of the 99 included in total with aneurysms in the coronary arteries.

In a study that enrolled 58 children (average age: 9 years old) who met the diagnostic criteria for pediatric inflammatory multisystem syndrome (PIMS), children admitted to eight hospitals in the United Kingdom, 100% of those tested (11/11 patients) presented a level high NT-proBNP, and eight children had dilated coronary arteries, with a Z score above 2. Two patients had large aneurysms of the coronary arteries, with a Z score higher than 10. However, the study does not discuss the treatment offered to these patients⁽¹¹⁾.

In another article – this time, a case report – a minor distension of the left coronary artery in a 15-year-old patient was described, with the subsequent discovery of an aneurysm located at the level of the right coronary artery, with the worsening of the dilation of the left coronary artery. The patient received treatment with 80 mg of aspirin daily, intravenous immunoglobulin and corticotherapy with prednisone, being discharged with a treatment plan aimed at the progressive decrease of oral cortisone doses⁽¹²⁾.

Coronary artery dilation in MIS-C is described in another study in which 15 children, with a median age of 8.8 years old, were included. Of these, 14 (93%) had coronary artery abnormalities: objective coronary dilation was described in seven children, the rest presenting hyperechogenic coronary arteries, without dilation – this ultrasound appearance could be caused by endothelial inflammation. All of them received intravenous broad-spectrum antibiotic therapy for minimum five days along with aspirin, with two of them continuing aspirin treatment after discharge. Five patients required corticosteroid therapy and 10 patients received intravenous immunoglobulin. At discharge, six patients had a normal echocardiographic appearance⁽¹³⁾.

The study by Elilarasi et al.⁽¹⁴⁾ describes 65 children diagnosed with MIS-C, the average age being 5.65 years old, with a standard deviation of 3.68 years. Dilation of the coronary arteries was observed in 67% (44/65) of them, and 58% also presented coronary aneurysms, with a Z score above 2.5. All of them received treatment with intravenous immunoglobulin and aspirin, corticotherapy being used in selected cases.

In another observational study from western India, five of the 21 included children had dilated coronary arteries. The average age was 7 years old, with the oldest patient being 14 years old. Four of these five children with coronary changes received anticoagulant treatment with low-molecular-weight heparin, along with antiplatelet therapy with aspirin. All of them had a favorable prognosis, without any death being recorded among them⁽¹⁵⁾.

That is why we consider that is crucial in medical practice that patients who experience signs or symptoms of MIS-C to have an echocardiogram performed, along with the dosage of cardiac inflammatory markers, in order to be able to confirm a possible cardiac disfunction with thrombotic risk.

The studies also point out that the majority of affected children are of school age.

What do the guides recommend?

According to the American College of Rheumato­logy⁽¹⁶⁾, the patients diagnosed with MIS-C who have abnormal values of NT-proBNP and/or troponin need to be closely supervised, and it is necessary to repeat and observe the modified values in evolution until normalization.

It is important that echocardiograms assess valvular and ventricular function, observe whether or not pericardial effusions are present, and evaluate the dimensions of the coronary arteries, using Z-scores.

It is also recommended that echocardiograms should be repeated approximately two weeks and four to six weeks after the initial evaluation and diagnosis. At the same time, when a patient presents with left ventricular dysfunction, with an ejection fraction less than 50%, a cardiac MRI can be performed.

From the point of view of the recommended treatment, the guide mentions, as the first line of therapy, cortisone in low or moderate doses, together with intravenous immunoglobulin (2 g/kg), and in patients where the first line of treatment reveals modest results, the treatment with high doses of cortisone, anakinra or infliximab can be initiated.

Regarding the administration of intravenous immunoglobulin, it is imperative that the cardiac function is evaluated before the dose of intravenous immunoglobulin in patients with reduced ejection fraction, and an association with diuretics may be necessary⁽¹⁷⁾.

In the case of antiplatelet/anticoagulant treatment, 3-5 mg per kg per day of aspirin can be introduced into the treatment regimen until the platelet count and the dimensions of coronary arteries normalize (the contraindications to aspirin introduction are represented by platelet count below 80,000/µL or active bleeding).

The American Heart Association recommends that patients with a highest Z score between 2.5 and 10 be treated with a low dose of aspirin. Once the Z score exceeds 10, they can be treated with a low dose of aspirin and anticoagulants – antifactor X enoxoparin – for at least two weeks.

Returning to the European guidelines, the Italian Guide of the Society of Rheumatology⁽¹⁸⁾ also recommends the administration of intravenous immunoglobulins at a dose of 2 g per kg, together with cortisone – more specifically, methylprednisolone. The second line of treatment consists of biological drugs – anakinra. For the cardiovascular treatment, it is recommended to administer acetylsalicylic acid at a dose of 5 mg per kg, for at least six to eight weeks, if no coronary abnormalities are observed.

If coronary changes occur, one should follow the AHA guideline for Kawasaki disease, which recommends that the patients with small coronary aneurysms be given moderate doses (from 30 to 50 mg per kg per day) to high doses (80 to 100 mg per kg per day) of aspirin until fever remission. In the case of aneurysms with moderate sizes, an antiplatelet agent (e.g., clopidogrel) can be added.

In patients with a Z score higher than 10, a combination of antiplatelet agents with anticoagulants – low-dose aspirin with warfarin or low-molecular-weight heparin – will be used.

Conclusions

The multisystemic inflammatory syndrome in children is a condition with a wide spectrum of possible clinical manifestations, with different degrees of severity. It remains a diagnosis of exclusion. The generalized inflammatory state may impose a thrombotic risk and may require the association of an antiplatelet agent with immunoglobulin therapy or cortisone.

International guidelines recommend antiplatelet treatment, respectively anticoagulant therapy, depending on the size of the arteria coronaria and the presence of possible aneurysms at the coronary level.

 

Conflict of interest: none declared.

Financial support: none declared.

This work is permanently accessible online free of charge and published under the CC-BY licence.