Pediatric Multi-System Inflammatory Syndrome Temporally Associated with COVID-19. (Kawasaki-like)

[DSeid]

Let’s first get out of the way that this Kawasaki Disease (KD) like illness is not a reason for parents to panic. It is very rare, and as of yet it is not even firmly established that it is a causative association. The reality remains that kids are at much less risk of getting very sick from COVID-19 than they are from influenza. And orders of magnitude less risk than adults.

But I can’t help but wonder if the same factors that make severe COVID-19 so extremely uncommon in children set some very few up for this rare event … and if some of what is already known about those who get KD can provide clues to investigate to why some adults are at greater or lesser risk for severe COVID-19 … ?

KD has been thought of as a response to some infectious disease trigger(s) in genetically susceptible children. It often occurs in clusters and with some seasonality. It is associated with a strong innate immune response and in particular with CD8+ T-cell clonal expansions. Genetically it is ten times more common in those of Japanese ancestry (including those living Western lifestyles) than those of European ancestry and a specific variation at a gene called ITPKC, which has to do with negative regulation of activated T-cells, increase risk significantly. It is not the only gene with association however, just the strongest association.

The SARS-CoV-2 related disease *seems *to be a postinfection sequelae, with the primary infection having been asymptomatic. In some cases the patients’ PCR was negative but they later developed SARS-CoV-2 specific antibodies.

More severe COVID-19 is associated with low WBC counts and in specific “exhausted” CD8+ cells.

The degree and importance of T-cell cross-reactivity is unclear in general and how or even if baseline serologies to common cold causing coronaviruses impact responses to SARS-CoV-2 is to be determined. That said rises in IgG to the common old causing CVs have been seen in the course of response to SARS-CoV-2 as they were in response to SARS-CoV.

Obviously my speculations can go crazy but I’ll go this far out: understanding why some children get that KD-like response (if it is a true causation) will help understanding of why kids in general so rarely get very ill from COVID-19, and that may help identify those adults at higher or lower risk and create treatment targets and impact model predictions/prevention approaches.

[pool]

I’ve only read a little about this with some kids in New York, is it a Kawasaki-like disease or are the two actually directly related somehow?

The only thing I can recall about Kawasaki Disease is that it can cause difficulty with Peristalsis of food is it a very serious disorder?

[DSeid]

My apologies! Did not put in the first general explanation link!

COVID-19 infection leading to critical illness in children remains very infrequent. According to the leaders of the American Heart Association’s Council on Lifelong Congenital Heart Disease and Heart Health in the Young (Young Hearts), a few patients display symptoms found in other pediatric inflammatory conditions, most notably Kawasaki disease. Kawasaki disease is a rare condition that presents with a fever above 102°F to 104°F for at least five days, swelling of the lymph nodes, inflammation, a rash and other symptoms.

Children with this new, possibly COVID-19-related syndrome may have some or all the features of Kawasaki disease. These children have a persistent fever, inflammation and evidence of single or multi-organ dysfunction (shock, cardiac, respiratory, renal, gastrointestinal or neurological disorder) and may or may not test positive for COVID-19.

More here.

And the Lancet article report that brought it to greater attention.

Sorry for not including them in the first place.

On preview - unclear if it is directly related, as discussed in the links.

[nearwildheaven]

I first heard of Kawasaki disease in the early 1980s, when a co-worker’s preschool-aged son was diagnosed with it. All I remember is that she was off work for a week because that’s how long he was in the hospital, and he did make a full recovery except for one thing: they recommended that he see a cardiologist for certain tests once a year for the rest of his life. We were in Des Moines, which is a big enough city to have pediatric cardiologists on top of a medical school, so it wasn’t as much of a burden as it might have been for other families.

It’s also possible that COVID does not cause KD per se, but aggravates a pre-existing condition.

p.s. Mining the recesses of my memory reminded me that she and her husband also liked motorcycles, and talked about Sturgis, something I had never previously heard of. There were a lot of jokes about Honda Disease, Harley-Davidson Disease, etc.

[Dr_Paprika]

I certainly don’t have a pediatrician’s expertise. I have diagnosed a few cases of Kawasaki’s.

The papers are full of pictures of Covid toes and this extremity edema and erythrema is certainly Kawasakiesque. There are probably fevers and maybe organ changes and lymph node swelling. But I am unfamiliar with other symptoms showing up in Covid: conjunctivitis, strawberry tongue, rashes. Are these present too? Has anyone seen enough paediatric cases to know?

[DSeid]

The conjunctival injection, prolonged fever, rash they are having. And the multisystem involvement. The digital involvement doesn’t look very KDish (and not hearing of the desquamation after either), nor the nodes. I think what is making them go to KD is echobrightness of the coronary arteries.

From a Medscape article that I did not link to as it is walled -

… At press time, more cases were reported from the United Kingdom in The Lancet. In London, eight children with hyperinflammatory shock, showing features similar to atypical Kawasaki disease, Kawasaki disease shock syndrome, or toxic shock syndrome, presented within 10 days to Evelina London Children’s Hospital Paediatric ICU, Shelley Riphagen, MBChB, and colleagues revealed.

Clinically, their presentations were similar, with persistent fever, rash, conjunctivitis, peripheral edema, extremity pain, and gastrointestinal symptoms. They all developed warm vasoplegic shock that did not respond to volume resuscitation; noradrenaline and milrinone were administered for hemodynamic support. Seven of the children needed mechanical ventilation for cardiovascular stabilization, although most of them had no significant respiratory involvement.

Of note was development of small pleural, pericardial, and ascitic effusion — “suggestive of a diffuse inflammatory process,” Dr. Riphagen and associates wrote. None of the children initially was positive for SARS-CoV-2; laboratory evidence of infection or inflammation included “elevated concentrations of CRP, procalcitonin, ferritin, triglycerides or d-dimers.”

“A common echocardiographic finding was echobright coronary vessels,” they wrote. “One child developed arrhythmia with refractory shock, requiring extracorporeal life support, and died from a large cerebrovascular infarct.”

As the article went to press, the doctors in that same ICU had seen more than 20 children with similar clinical presentations, Dr. Riphagen and associates reported, and the first 10 tested positive for SARS-CoV-2 antibody, including the 8 described above.

“Most of the children appear to have antibodies to the novel coronavirus, even when they do not have virus detectable in their nose,” said Audrey John, MD, PhD, chief of the division of pediatric infectious diseases at Children’s Hospital of Philadelphia, where clinicians have seen several cases similar to those described by NHS England and the New York City health department. “This suggests that these symptoms are ‘postinfectious,’ likely due to an abnormal immune response that happens after viral infection.”

She noted at the time of her interview, however, that fewer than 100 U.S. pediatric cases appear to have been reported.

“While our understanding is evolving, given the scope of the COVID-19 pandemic, this suggests that this kind of severe disease in children is very rare indeed,” Dr. John said. “Because this syndrome is so newly described, we have to continue to be cautious in attributing this syndrome to COVID-19, as there are many other diseases that look quite similar.” …

[nearwildheaven]

Wow. This is making me wonder if different COVID strains are more or less likely to cause this, the way it seems to have varying degrees of communicability and severity in different areas.

[DSeid]

I cannot find enough about the cases other than those reported in the Lancet article to say whether or not it holds, but more than locations seems to be host factors, i.e. related to ethnicity: of the eight children in their series six were of Afro-Caribbean descent.

[FrillyNettles]

As a veterinarian, I can’t help but wonder how this may or may not be similar to the way the relatively harmless Feline Enteric Corona Virus mutates in a small percentage of young cats to Feline Infectious Peritonitis, which is a multi-system inflammatory disease, and generally fatal. It also strikes me as interesting that GS-441524, a recently studied, and ground-breaking treatment for FIP, is the biologically active component of Remdesivir. Is there anyone in human medicine looking at this potential connection? And if so, do we have reason to fear that the Multi-Organ-Inflammatory-Syndrome in children will have as devastating consequences as FIP in young cats?

[DSeid]

Read up a little on FIP … very interesting. If there is any research investigating anything like that in humans I am unaware of it.

Am I understanding correctly that the thought is that FEP is common and contagious and for some reason has a stable common mutation that occurs but is not transmissible into FIP, which is commonly fatal?

In any case independent of that the syndrome in children has had a couple of fatal outcomes, even though most have resolved. It has overlap with Kawasaki Disease but also very distinct differences.

[VOW]

@FrillyNettles

As a veterinarian, I can’t help but wonder how this may or may not be similar to the way the relatively harmless Feline Enteric Corona Virus mutates in a small percentage of young cats to Feline Infectious Peritonitis, which is a multi-system inflammatory disease, and generally fatal. It also strikes me as interesting that GS-441524, a recently studied, and ground-breaking treatment for FIP, is the biologically active component of Remdesivir. Is there anyone in human medicine looking at this potential connection? And if so, do we have reason to fear that the Multi-Organ-Inflammatory-Syndrome in children will have as devastating consequences as FIP in young cats?

This description is exactly what happened to my cat. I first found out about coronaviruses when I did research on the vet’s diagnosis.

The gut infection is very common, and not serious, from what I read. I adopted two littermates from the Humane Society, and they had gut problems from the beginning. I think they picked up every infection from the crowded conditions. One infection was giardia.

Even when they were infection-free, they both suffered from loose stools. Many tests later, we were told they were allergic to wheat. A gluten-free diet helped a great deal, but one of the cats still had loose stools and took to crapping everywhere.

I later noticed that cat had lost a LOT of weight. I could feel each individual vertebra in his back. But he also had an extended belly. The vet diagnosed FIP, and I consented to euthanasia.

His littermate was tested, and he was not infected.

I still grieve for that cat.

And that is how I learned about coronaviruses and their easy ability to mutate.
~VOW

[ThelmaLou]

@VOW

…

I still grieve for that cat.

And that is how I learned about coronaviruses and their easy ability to mutate.
~VOW

I’m so sorry about your cat.

[Jim_Peebles]

Kawasaki disease has been reported as a side effect of at least one vaccine. From Merck’s Patient Information for RotaTeq rotavirus vaccine available at this link:

rotateq_ppi.pdf

“Other reported side effects include:
• allergic reactions, which may be severe and may include face and mouth swelling, difficulty breathing, wheezing, hives, and/or skin rash; and
• Kawasaki disease (a serious condition that can affect the heart; symptoms may include fever, rash, red eyes, red mouth, swollen glands, swollen hands and feet and, if not treated, death can occur).”

[DSeid]

Actually that “report” illustrates the difficulty in attribution of cause.

The background was phase 3 clinical trials. 5 cases of Kawasaki Disease among the roughly 36K who got the vaccine and 1 in the roughly same sized control group. Was not statistically significant but earned to the warning as “reported”. In post marketing surveillance of 1.2 M doses 1 case in the Rotateq group and one in the DTaP control group.

All listed in the package insert. Rare things can create small n issues.

Hence why the experts are hesitant to attribute cause to an association too quickly, even when it appears so.

[monstro]

UK teen dies of Kawasaki-like disease linked to coronavirus

15 US states are investigating cases of children suffering from rare inflammatory syndrome

[DSeid]

A Cuomo quote in the second link really annoyed me when I first read it:

“One of the few rays of good news was young people weren’t affected. We’re not so sure that is the fact anymore,” Mr Cuomo added.

Young people have always been affected … rarely. Rarely compared to adults and rarely compared to how frequently kids are impacted severely by influenza. That has been and remains the case, whether or not this is in fact a COVID-19 consequence.

Surprising to me per that same link that 40% of the New York patients had NO evidence of having had COVID-19 infections.

I would be very surprised if this syndrome is not related to COVID-19, but before concluding that with confidence a minimum is to test a matched demographic of kids without the syndrome for COVID-19 antibodies as well. If statistically similar fractions of both groups test positive then the conclusion we are pretty much all making would have to be questioned.

[nearwildheaven]

@Jim_Peebles

Kawasaki disease has been reported as a side effect of at least one vaccine. From Merck’s Patient Information for RotaTeq rotavirus vaccine available at this link:
https://www.merck.com/product/usa/pi_circulars/r/rotateq/rotateq_ppi.pdf
“Other reported side effects include:
• allergic reactions, which may be severe and may include face and mouth swelling, difficulty breathing, wheezing, hives, and/or skin rash; and
• Kawasaki disease (a serious condition that can affect the heart; symptoms may include fever, rash, red eyes, red mouth, swollen glands, swollen hands and feet and, if not treated, death can occur).”

The original rotavirus vaccine, and an early vaccine for dengue, both made some people who were exposed to those viruses sicker than they probably would have if they had not had the vax, and both were withdrawn when this was discovered.

OTOH, even if ONE child got KD shortly after being vaxed, that will potentially be listed as a possible side effect.

Remember the brouhaha about the pertussis vaccine? It was later learned that the children who seemed to become brain-damaged after having the original vaccine had a genetic disorder that interfered with sodium metabolism in the brain, and coincidentally it usually showed symptoms around the age of the DPT vaccines - 2 to 4 months.

[monstro]

Doctors in Italian hospital report a 30-fold jump in kids with inflammatory symptoms

[DSeid]

The Lancet article monstro’s link refers to.

“30-fold” is ten cases, eight of whom had positive serologies, two of whom also had positive swabs, two negative for both …

The fact that these clusters, fairly small as they may be, are occurring so coincident with where COVID-19 has run highest and hottest is of course extremely suggestive of a causative correlation.

Keeping the context is the following from the Lancet article:

the Kawasaki-like disease described here remains a rare condition

It however raises many questions of interest both to COVID-19 and to KD.

Specific to KD is this thought in the article:

the cause of Kawasaki disease remains unknown. The most accepted hypothesis supports an aberrant response of the immune system to one or more unidentified pathogens in genetically predisposed patients;21, 22, 23 however, the search for the infectious triggers has been disappointing.24 In Japan, during three epidemics recorded in 1979, 1982, and 1986, the highest Kawasaki disease incidence was seen in January, potentially suggesting that factors during winter months may trigger Kawasaki disease.25, 26…
… In the past 20 years, viruses of the coronavirus family have been proposed as possibly implicated in the pathogenesis of Kawasaki disease. In 2005, a group from New Haven (CT, USA)29 identified a novel human coronavirus, designated New Haven coronavirus (HCoV-NH), in the respiratory secretions of eight of 11 children with Kawasaki disease versus one of 22 controls tested by RT-PCR. A serological test was not done. This report was followed by commentaries expressing a mixed sense of interest and scepticism.30 The arguments against this association were expressed by a group from Japan, who did a retrospective study31, 32, 33 on nasopharyngeal swab samples from 19 children with Kawasaki disease and 208 controls with respiratory tract infections, and found RNA sequences of HCoV-NH in five (2%) of 208 controls versus zero of 19 children with Kawasaki disease.

Another group from Japan explored the association between two different coronaviruses (HCoV-NL63 and HCoV-229E) and Kawasaki disease by serological tests. The immunofluorescence assay detected no difference in HCoV-NL63 antibody positivity between patients and controls, whereas HCoV-229E antibody positivity was higher in patients with Kawasaki disease.34 Given the pathogenesis of the disease, serology testing seems a more reliable tool than RT-PCR in detecting the cause of infection. This suggests that the coronavirus family might represent one of the triggers of Kawasaki disease, SARS-CoV-2 being a particularly virulent strain able to elicit a powerful immune response in the host.

Bolding mine.

While the Rotateq association with KD seems to have been spurious, we do need to be prepared for the possibility that any possible future effective SAS-CoV-2 vaccine could, rarely, trigger this KD-ike response. Eventually knowing the incidence in natural disease and being able to state with confidence what frequency is still less than with natural disease (so still worthwhile doing despite that risk) will be important when we get there.

[Magiver]

@DSeid

Actually that “report” illustrates the difficulty in attribution of cause.

The background was phase 3 clinical trials. 5 cases of Kawasaki Disease among the roughly 36K who got the vaccine and 1 in the roughly same sized control group. Was not statistically significant but earned to the warning as “reported”. In post marketing surveillance of 1.2 M doses 1 case in the Rotateq group and one in the DTaP control group.

All listed in the package insert. Rare things can create small n issues.

Hence why the experts are hesitant to attribute cause to an association too quickly, even when it appears so.

My first thought was a link to vaccines because by their nature they deal with the immune system. If a child reacts badly to covid19 then maybe there’s a side-link to a vaccine because children are closer (in time) to vaccines than adults.

I’m not attributing anything to anything but this was a thought that came to mind.