How treating ‘Covisaki’ patients will help doctors understand Kawasaki disease better

Paediatricians in the UK and then the US, started noticing a surge in a little understood childhood disease, the Kawasaki disease, this April. Today, experts believe that Multi-System Inflammatory Syndrome in Children (MIS-C) is a complication or variant of the Kawasaki disease, triggered by SARS-CoV-2 infection, leading to the term ‘Covisaki’. Dr Sagar Bhattad, consultant, paediatric immunologist and rheumatologist, Aster CMI Hospital, Bengaluru explains to Viveka Roychowdhury  what signs major cities in India like Mumbai, Delhi, Hyderabad, Chennai and Bengaluru should watch out for as diagnosis and early treatment can reverse the situation within two to three days. He also cautions that any city or population with a sudden surge of COVID-19 cases in adults must anticipate an increase in MIS-C cases four weeks later

The low number or milder cases of SARS-CoV-2 infection in children was thought to be due to their innate immunity and childhood vaccination schedules. But then came a surge of Kawasaki Disease-like cases, first noticed in the UK and then the US. Are we noticing such cases in India as well? How have these cases changed our understanding of SARS-CoV-2 infection in children as we move into the eighth month of the COVID-19 pandemic?    

Children have been and continue to remain asymptomatic and paucisymptomatic to a larger extent due to primary COVID-19 infection. What has emerged new is the Multi-System Inflammatory Syndrome (MIS-C) syndrome noted in children from the end of April 2020, first described in the UK and later in the US.

Currently, similar cases are being reported from many cities in India. The majority of children with MIS-C are antibody positive (and PCR negative) indicating this is an immune-mediated phenomenon. While adults who developed severe illness had cytokine storm during the active infection, children develop this cytokine storm a month later (when there is no longer an active infection).

So, age has been an important defining factor in the outcome of COVID-19 infection. Why a few children develop this syndrome is under investigation. Several viruses have been implicated in the causation of Kawasaki disease for a long time (including coronaviruses). However, this pandemic is giving us a unique opportunity to study a large number of such cases with a single etiological agent (COVID-19).

Is this the trend in India as well? Which cities, besides Delhi and Mumbai since April 2020, have started to report such cases and similar cases?  

Many cities where there has been a surge of adult COVID cases are reporting this syndrome, however, we do not, so far have robust data across the country. The collection of such data is under process through the aegis of the Indian Academy of Pediatrics (IAP). Such cases are now being reported from Hyderabad and Chennai. A few cases have emerged in Bengaluru over the last two weeks. Bengaluru is likely to see many more cases by this month.

What are the clinical presentation and symptoms of MIS-C related to COVID-19 that paediatricians and paediatric intensivists should watch out for?  

The four major signs are as follows:     

a) Child presenting with fever and rash 

b) Child presenting with fever and pain abdomen

c) Fever and redness of eyes

d) A short history of fever and low blood pressure (likely myocarditis)

What can be the effects of MIS-C?

Some children may have severe myocarditis where the heart muscle is inflamed and the heart pumping is reduced with low blood pressure which can lead to cardiac failure. But an early treatment can reverse the situation within two to three days.

Some may develop multi-organ dysfunction where the organs start malfunctioning. Which is again caused by the cytokine storm.

The heart coronaries get dilated in majority of children. When the dilation happens to a large extent, it leads to a long- term effect. Hence, they would need blood thinners on a regular basis.

What are the current diagnostic criteria of MIS-C? Which is the age group most affected?   

Many international organisations have proposed definitions for MIS-C. I would recommend the WHO criteria. Where the primary syndrome is in less than 19 years old child with fever for at least three days accompanied with rash and redness of eyes and the PRP rate is high in the lab test. Also, they have an antibody or PCR positive or they might had an immediate contact with a COVID-19 positive case.

Other criteria explained by WHO are:

1. Rash or bilateral non-purulent conjunctivitis or muco-cutaneous inflammation signs (oral, hands or feet).
2. Hypotension or shock.
3. Features of myocardial dysfunction, pericarditis, valvulitis, or coronary abnormalities (including ECHO findings or elevated Troponin/NT-proBNP),
4. Evidence of coagulopathy (by PT, PTT, elevated d-Dimers).
5. Acute gastrointestinal problems (diarrhoea, vomiting, or abdominal pain).

The most commonly affected age group:  7 – 15 years.

In MIS-C there is immune dysregulation where there is an immune mediated phenomenon and hence the virus triggers the activation of the immune system abnormally and damages one’s own body. Hence it is an immune mediated disorder because of dysregulated immune response to the virus.

Are there any links to case surges among COVID-19 cases in adults that can be considered early warnings to MIS-C in children in the same population?  

Any city or population with a sudden surge of COVID-19 cases in adults must anticipate an increase in MIS-C cases four weeks later. The same holds true for Bengaluru and many cities in India, where there has been a sudden increase in adult COVID-19 cases over the last month.

What is the pathophysiology of MIS-C? Are certain children more susceptible, besides contact with a COVID-19 positive adult in their circle of contacts? 

As this is an emerging disease, we still do not know the exact mechanism causing MIS-C. There are several hypotheses being proposed to explain this immune-mediated phenomenon.

Following COVID-19 infection, one may produce neutralising antibodies that clear the virus. Another set of antibodies called non-neutralising antibodies are being produced in some individuals, which possibly mediate MIS-C. These antibodies cause enhanced uptake of virus into the cells, causing excessive activation of the innate immune cells, which in turn produce large quantities of cytokines (like IL-6), which cause this inflammatory syndrome. The role of such antibodies causing severe illness in dengue fever is well-known.

What is the current treatment and management protocol for MIS-C? What is the recovery time? What are the chances of recovery? What are the mortality rates in MIS-C?

Current treatment protocols include intravenous immunoglobulin injections, steroids, and biologicals in case of refractory illness. The protocols may get more refined as we treat and understand this illness better.

Doctors from the west (UK and US) have reported excellent outcomes to these protocols. Though many of these children are quite sick at presentation, if treated in the right time, they respond briskly.

On average, the recovery has been noted to occur in one-two weeks. A few children may develop coronary aneurysms which need long term follow-up and management. Overall, mortality seems to be very low (around two per cent).

Going forward, as a consultant in paediatric immunology and rheumatology, how do you feel MIS-C will impact the future growth and well being of children who are diagnosed, treated, and recover from MIS-C? 

MIS-C would have a significant impact on lives of children who get affected. A proportion of them may develop coronary aneurysms (the blood vessels of the heart are severely dilated, or they become huge and can lead to heart failures) and may need long term medications (blood thinners – aspirin/warfarin etc). A small proportion may land up with residual myocardial dysfunction.

This is a very classical complication with Kawasaki disease and this new syndrome, MIS-C, is a lot similar to Kawasaki and people have rephrased it as ‘Covisaki’. Hence, experts believe that it is Kawasaki disease which is getting triggered by this virus. It can be a variant of the Kawasaki disease that is triggered by this virus, but it is not the classical Kawasaki disease but there are features similar to it.

How would this impact their lives?  Will this result in reduced life-span and/or quality of life?

We do not have clear answers to these pertinent questions. We have to follow up these children closely for many years, to understand the consequences, and to treat them at the earliest, in case the need arises.

MIS-C may also help us understand Kawasaki disease better, and may unravel newer therapeutic options for this enigmatic childhood illness!