Articles concerning Kawasaki disease and  COVID-19

This is an outrigger page from a particular part of the main page cv19/#kdarticles  .  The primary purpose of this page is to link to 15 articles about Kawasaki disease (Kawasaki syndrome) and COVID-19 which do NOT mention this crucial research article which enables us to understand its cause, no matter whether it is triggered by COVID-19 or any other condition: extremely low vitamin D levels:

Severe vitamin D deficiency in patients with Kawasaki disease:a potential role in the risk to develop heart vascular abnormalities?
Stefano Stagi et al. Clinical Rheumatology volume 35, pages 1865–1872 (2016)  (Paywalled.)

Google Scholar 13 citations (2020-05-29)

I found another 3 such articles on 2020-06-11: ../#more-KD-articles-1 and wrote to the authors of all of them.  A copy of my message is below:  #msg .

Once you have read this article, and looked at the research I present on these pages:

I believe that you will understand that vitamin D deficiency is the biggest easy-to-correct factor causing severe and deadly outcomes with COVID-19 in general, and with Kawasaki disease (whatever the trigger) for babies, children and adolescents.

If and when some such articles appear which do cite Stefano Stagi et al. 2016, I will add them to a second list here. 

I found these articles entirely with Google Scholar.  I did not chase references or look for web pages such a of health authorities, blogs etc.

Robin Whittle .   2020-05-30  Last update 2020-06-11 11:00 UTC

To the main COVID-19 page of this site:
Be sure to read the Disclaimer!

List of articles concerning Kawasaki disease AND COVID-19 which do NOT cite Stefano Stagi et al. 2016

I may have missed one or two, but as far as I can tell, this is all the articles listed on Google Scholar concerning COVID-19 and Kawasaki disease, at the end of 2020-05-29.  None of the articles mention Stefano Stagi et al 2016.  Nor do they mention vitamin D, the word "vitamin" or anything concerning nutrition.

There's no particular order.  The first block of articles are those I added on 2020-05-30. 

COVID-19 and Kawasaki Disease: Novel Virus and Novel Case
Veena G. Jones et al. Hospital Pediatrics  2020-04-07

Google Scholar 21 citations

We describe the case of a 6-month-old infant admitted and diagnosed with classic Kawasaki disease (KD), who also screened positive for COVID-19 in the setting of fever and minimal respiratory symptoms.

The cause of KD remains unknown, despite several decades of investigation.
Some evidence suggests an infectious trigger, with winter-spring seasonality of the disease, and wave-like spread of Japanese epidemics of KD.  Various studies have described an association between viral respiratory infections and KD, ranging from 9% to as high as 42% of patients with KD testing positive for a respiratory viral infection in the 30-days leading up to diagnosis of KD.

With regards to her COVID-19 infection, our patient’s clinical course and presentation were mild.  Throughout her hospitalization, she did not have any notable respiratory symptoms and repeat chest x-ray was not obtained.

Upper extremity erythema and edema.  Maculopapular rash.  Elevated C-reactive protein (CRP W) 13.3mg/dl.  (Normal range to 0.3.) Normal platelets.  Erythrocyte sedimentation rate [W] 118mm/hr (ref range up to ~10mm/hr) indicates inflammation and that the blood is in a coagulative state.   No mention of lasting harm, though they will continue to monitor her heart.

Kawasaki-like disease: emerging complication during the COVID-19 pandemic
Russell M Viner and Elizabeth Whittaker, The Lancet 2020-05-13
Google Scholar 2 citations

Kawasaki disease is a rare acute paediatric vasculitis, with coronary artery aneurysms as its main complication.  The diagnosis is based on the presence of persistent fever, exanthema, lymphadenopathy, conjunctival injection, and changes to the mucosae and extremities.  Verdoni and colleagues describe ten cases (seven boys, three girls; aged 7·5 years [SD 3·5]) of a Kawasaki-like disease occurring in Bergamo, Italy, at the peak of the pandemic in the country (Feb 18 to April 20, 2020), a monthly incidence some 30-fold higher than observed for Kawasaki disease across the previous 5 years.

Anecdotally, clinicians across Europe have identified clusters of similar cases. In the UK, paediatricians have identified a small group of children presenting with shock and a multisystem inflammation to critical care units, some of whom have coronary artery aneurysms, and a further group of less severely ill children with a Kawasaki-like disease, who respond to a variety of immunomodulatory treatments, including intravenous immunoglobulin, corticosteroids, and biologics such as infliximab and anakinra (Whittaker E, unpublished).  Long-term echocardiogram data on coronary artery aneurysms are pending.  In response to this cluster in London, UK, we notified the National Health Service of the emergence of an unusual disorder, and an alert was issued on April 25.  On the basis of the review of clinical and laboratory features, a case definition of the syndrome we have provisionally called paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) was formulated by experts in the UK and published by the Royal College of Paediatrics and Child Health.

. . . the mechanism for the Kawasaki-like disease described here and PIMS-TS might represent post-infectious inflammatory syndrome, which might be antibody or immune-complex mediated, particularly because in this Italian cohort there was little evidence of viral replication.

Missed or Delayed Diagnosis of Kawasaki Disease During the 2019 Novel Coronavirus Disease (COVID-19) Pandemic
Ashraf S. Harahsheh et al. J Pediatr. 2020 May 3
Google Scholar 6 citations

As best I understand this letter, the authors are concerned that with the focus on COVID-19 patients and the difficulty of bringing children to hospital, that children suffering from Kawasaki disease may not be diagnosed in a timely manner.  As far as I know, they are not suggesting that COVID-19 might be triggering Kawasaki disease - but perhaps that is assumed knowledge.

Without timely treatment, Coronary Arterial Aneurisms could occur in up to 25% of children with Kawasaki disease.

Association Between COVID-19 and Kawasaki Disease: Vigilance Required From Otolaryngologists
Henya Sandhaus et al.  Otolaryngology–Head and Neck Surgery 1–2  2020-05-19

Several reports have recently highlighted a spike in the incidence of KD in the COVID-19-positive pediatric population.  These presentations of KD may occur weeks after the diagnosis of COVID-19 and possibly once the patient has recovered from the virus.

The etiology of KD is unknown.  However, there have been theories related to infectious triggers.

COVID-19 and Kawasaki Disease: Finding the Signal in the Noise
Alan R. Schroeder et al. Hosp Pediatr. 2020; doi: 10.1542/hpeds.2020-000356

On April 26, an alert was sent to general practitioners in London advising them of rising numbers of cases of a multisystem inflammatory state in children with overlapping features of toxic shock syndrome (TSS) and atypical KD. These cases were subsequently described in a correspondence in the Lancet on May 7, 2020, which detailed 8 children with critical illness characterized by severe inflammation, though not all had confirmed COVID-19 infection or exposure. 

In Bergamo, Italy, KD was diagnosed in 20 children over a short period, roughly equivalent to the total number of cases that region sees over 3 years.  The French health minister reported that around 15 children were hospitalized in Paris hospitals with symptoms of KD.  On May 4, 2020, the New York City health department issued a health alert describing 15 cases
of a multi-system inflammatory syndrome with features of KD or TSS.  Since then, media reports have increased dramatically in the New York City area and now include Detroit and Chicago . . .

Outbreak of Kawasaki disease in children during COVID-19 pandemic: a prospective observational study in Paris, France
J Toubiana et al.

A total of 17 children were admitted for KD over an 11-day period, in contrast with a mean of 1.0 case per 2-week period over 2018-2019. Their median age was 7.5 (range, 3.7-16.6) years, and 59% of patients originated from sub-Saharan Africa or Caribbean islands.  Eleven patients presented with KD shock syndrome (KDSS) requiring intensive care support, and 12 had myocarditis.  All children had marked gastrointestinal symptoms at the early stage of illness and high levels of inflammatory markers.  Fourteen patients (82%) had evidence of recent SARS-CoV-2 infection (positive RT-PCR 7/17, positive IgG antibody detection 14/16).

Everyone knows that dark skinned people living in Europe are likely to have low vitamin D levels, unless they take supplements.  The clinicians ran a battery of lab tests, but 25OHD was not one of them. 

This proves beyond reasonable doubt that the clinicians did not consider vitamin D deficiency as a possible cause, or even association, with Kawasaki disease.

Kawasaki disease (KD) is the most common primary vasculitis in childhood, affecting predominantly medium and small-sized arteries.  KD annual incidence is the highest in Japan, with more than 300 per 100,000 children < 4 years of age, compared to 25 per 100,000 children < 5 years of age in North America.  One of the most severe complications of KD is coronary artery aneurysm.  KD shock syndrome (KDSS) is a rare form of KD, frequently associated with myocarditis and requiring critical care support during the acute phase of illness.  Although the aetiology of KD remains unclear, a role of a viral trigger on some genetically predisposed children has been hypothesised . . . 

All patients had high inflammatory parameters, including leukocytosis with a predominance of neutrophils, and high levels of C-reactive protein (CRP), procalcitonin (PCT), and serum interleukin-6.  Anaemia was common with a median haemoglobin level reaching 8.1 (range, 5.3-12.2) g/dL.  All patients had hyponatraemia (<135 mmol/L), and hypoalbuminaemia (<32 g/L) except one patient with mild KD.

I was surprised by the low sodium, but I am not a doctor.  I wrote on ../cv19/ about excessive salt intake worsening immune system dysregulation, based on articles such as
Where there is sodium there may be sepsis  PMC6735289 .

All but one of our patients had no suggestive symptoms of acute Covid-19 disease and most had positive serum IgG responses, suggesting that the development of KD in these patients is more likely to be the result of a post-viral immunological reaction.

The observation of a higher rate of patients originating from sub-Saharan Africa and the Caribbean islands is consistent with recent findings reported by Riphagen et al., suggesting either adverse social and living conditions or genetic susceptibility.  KD is rarely reported in sub-Saharan Africa, but it may be more common than previously thought.

These clinicians seem never to have heard of vitamin D deficiency in dark-skinned people who move to less sunny, urban, environments such as Paris!  The parents' origins were:

Kawasaki disease from COVID-19 in Paris, early 2020

Multisystem inflammatory syndrome with features of Atypical Kawasaki disease during COVID-19 pandemic: Report of a case from India
Rauf A, Vijayan A, John ST, Krishnan RA, Latheef A  2020-05-22

5-year-old boy from a COVID-19 hotspot area in Kerala state of India who presented in late April 2020 with acute febrile illness with abdominal pain and loose stools followed by shock.  On examination, child had bulbar conjunctivitis and extremity edema.

Inflammatory parameters were high (CRP- 120 mg/l, ESR 70 mm/hr, Ferritin 600 mg/dl) and serum creatinine (1.35 mg/dl) and liver enzymes were elevated (AST-85 U/L, ALT-60 U/L). Serum Albumin was low (2.1 gm/dl) and hyponatremia (124 mEq/L) was also present.

Covid-19 and Kawasaki syndrome: should we really be surprised?
Rohit S Loomba et al. Cardiology in the Young PDF date 2020-05-14

While the etiology of Kawasaki Disease has been considered elusive for some time, there is substantial data pointing to a likely viral etiology.  Many have hypothesized that some children may be genetically predisposed to a more robust inflammatory response to specific viruses.  Once exposed to the specific virus, children then mount this exaggerated inflammatory response which clinically manifests as what is now defined to be Kawasaki Disease.

Viruses associated with Kawasaki Disease include Influenza, Enterovirus, Adenovirus, Parvovirus, Rhovirus, RSV, Varicella, Epstein-Barr, measles, and dengue.  Association with previous coronavirus has also been demonstrated. With this in mind why should Kawasaki Disease with Covid-19 come as a surprise?

Additionally, hyperinflammatory response to Covid-19 has been reported at length in adults.  Elevated inflammatory and reactive markers including C-reactive protein, procalcitonin, ferritin, and D-dimer amongst others.  In fact, these have prognostic value as more ill Covid-19 patients have higher values.  In adults. accumulating evidence suggests that a subgroup of patients with severe COVID-19 have a "cytokine storm syndrome" in which a cascade of activated cytokines leads to harmful auto-amplifying hyperinflammatory cytokine production.  Adult patients with worse illness and greater evidence of inflammation also had a higher incidence of cardiac findings such as troponin leak and ventricular dysfunction.  Thus, these findings also may simply be inherent to more severe Covid-19 secondary to overall inflammatory response. This has been noted in viremia from other agents as well, particularly in the form of myocarditis.

Hyperinflammatory shock in children during COVID-19 pandemic
Shelley Riphagen et al. The Lancet 2020-05-23
Google Scholar 28 citations

South Thames Retrieval Service in London, UK, provides paediatric intensive care support and retrieval to 2 million children in South East England.  During a period of 10 days in mid-April, 2020, we noted an unprecedented cluster of eight children with hyperinflammatory shock, showing features similar to atypical Kawasaki disease, Kawasaki disease shock syndrome, or toxic shock syndrome (typical number is one or two children per week).

So every year, from a population of 2,000,000 children, there are normally 75 or so cases of Kawasaki disease. 

None of this would be happening if the children had reasonable vitamin D intakes.  The official UK recommendations ../#NHS-advice are too low for adults - and for children with adult-sized bodies - but they are probably fine for infants and younger children.

Why haven't the doctors thought of this? 

Clinical presentations were similar, with unrelenting fever (38–40°C), variable rash, conjunctivitis, peripheral oedema, and generalised extremity pain with significant gastrointestinal symptoms.

Most of the children had no significant respiratory involvement, although seven of the children required mechanical ventilation for cardiovascular stabilisation.

One child developed arrhythmia with refractory shock, requiring extracorporeal life support, and died from a large cerebrovascular infarct

A 14 year old Afro-Caribbean boy (95kg) died of stroke.   He was killed by his own immune system, triggered by a virus which would not cause such trouble if he was properly nourished so that his immune system was stronger and better regulated.

With sufficient micronutrients, including especially vitamin D (and he would probably need 5000 to 8000IU a day to be replete, with that weight) he would have been much healthier, and would never have succumbed to Kawasaki disease.

Why is supplementation so difficult compared to these ICU heroics and death?  Why to the doctors not mention vitamin D?  There are surely reasons, but none of them are good.

Features of COVID-19 post-infectious cytokine release syndrome in children presenting to the emergency department
Temima Waltuch et al. American Journal of Emergency Medicine 2020-05-20

This is a detailed case report concerning three boys 5, 10 (asthma) and 13 (hypothyroid) one girl 12 in New York.  All survived.

Common laboratory findings among hospitalized [adult] patients with RT-PCR positive SARS-CoV-2 infection include lymphopenia, elevated lactate dehydrogenase levels, elevated inflammatory markers (ferritin, C-reactive protein, and erythrocyte sedimentation rate), elevated procalcitonin and elevated D-dimer.  The same laboratory findings were seen in these four children with COVID-19 post-infectious cytokine release syndrome. 

Additionally, all four children had an exaggerated cytokine storm with a profoundly elevated IL-6 and elevated IL-8 and TNF-α.  Elevations in these cytokines can lead to increased vascular hyperpermeability, multiorgan failure and eventually fatality if the cytokine concentrations remain unabated over time.  The mechanism of injury during cytokine storm is poorly understood, but an exaggerated initial response that persists over time is associated with poor outcomes.  Treatment with tocilizumab was initiated in all four patients to directly inhibit the IL-6 cytokine storm.

Interestingly, three of these four patients presumably had asymptomatic COVID-19 infections, as they reported no recent symptoms of illness yet had positive antibody testing.  It is possible that the mechanism of COVID-19 post-infectious cytokine release syndrome in children is a post-infectious phenomenon related to an antibody complex mediated reaction.

Pediatric coronavirus disease 2019 (COVID-19): An insight from west of Iran
Jafar Soltani et al. 2020-05-04 North Clin Istanb 2020;7(3):284–291

30 children aged one day to 15 years, 23 with no predisposing conditions.  All survived except an 11 year old girl who was undergoing chemotherapy for Acute Lyphocytic Leukemia.

Severe COVID-19 in Children and Young Adults in the Washington, DC Metropolitan Region
Roberta L. DeBiasi et al. 2020-05-06 Journal of Pediatrics

Higher representation of African American and Latino/Hispanic patients.  177 patients to age 25.  44 in hospital of whom 9 were critically ill.  Asthma was common, but not more so in hospitalised patients than in those at home.

Only one patient - a 4 year old boy - was diagnosed as having Kawasaki disease.  He recieved PRVC ventilation.  All survived.

Systemic inflammatory response and fast recovery in a pediatric patient with COVID-19
Adam Klocperk et al.  2020-05-14

This is a case report from Prague concerning an 8 year old girl with severe inflammatory symptoms who received mechanical ventilation and at one point lapsed into a coma.  She recovered fully. 

Her IL-6 was not particularly high.  The report goes into some detail about neutrophils, and mentions eosinophils being elevated at one point.

COVID-19 and Kawasaki Like Disease: The Known-Known, the Unknown-Known and the Unknown-Unknown
Aurélie Morand, Diego Urbina and Alexandre Fabre 2020-05-09

They propose that some children are genetically predisposed to this condition, which differs from ordinary Kawasaki disease in some ways - in particular gastrointestinal symptoms - and from adult COVID-19 by absence of lung symptoms.

The cause of Kawasaki disease is still unknown.

An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study
Lucio Verdoni et al.  2020-05-14 The Lancet
Google Scholar 18 citations

These researchers in Bergamo compared previous years' Kawasaki cases with a group of 10 cases coinciding with the recent COVID-19 outbreak there.   The recent group was older and had more severe symptoms than and which differed somewhat from those of the earlier group.  The recent group had a high proportion of hyponatremia which was not present in the earlier group.

The rate of incidence, from a child population of about 1 million, was 30 times that of the average over previous years.  All the new patients survived.

They estimate the condition affects no more than 1 in 1000 children exposed to SARS-CoV-2.

Despite half a century having passed since Tomisaku Kawasaki first reported his 50 cases in Japan, 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; however, the search for the infectious triggers has been disappointing.  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.

Vitamin D!!!


Here is what I wrote to the authors on 2020-06-11:

Dear Clinicians and Researchers,

I am writing to you because you are the corresponding author of one of the 18 articles on Kawasaki disease and COVID-19 which I found recently - none of which mention vitamin D.

Please see this 2016 research from Italy which shows that children with Kawasaki disease averaged 9.2ng/ml 25OHD and that the worst affected averaged 5.8ng/ml:

Severe vitamin D deficiency in patients with Kawasaki disease: a potential role in the risk to develop heart vascular abnormalities?
Stefano Stagi et al. Clinical Rheumatology volume 35, pages 1865–1872 (2016)  (Paywalled.)
Age-matched controls averaged 23.3ng/ml.  These children's 25OHD levels were 20% to 13% of the 46ng/ml levels of hunter gatherers in Africa:

Even without this Italian report, or the recent reports of sub-30ng/ml 25OHD levels strongly correlating with the risk of severe COVID-19 symptoms (Alipio and death ( Raharusun et al., it should be obvious to anyone with an understanding of vitamin D's role in immune system regulation that vitamin D deficiency plays a strong causative role in severe symptoms of COVID-19 for both adults and children.  I have linked to and quoted from some of this research at .

Please let me know any arguments you are aware of against the hypothesis that vitamin D deficiency plays a strong and frequently decisive role in the incidence of Kawasaki disease (once triggered by an infection) and in the severe symptoms of COVID-19.

I have CCed Stefano Stagi and colleagues and Mary Van Buesekom.

  Best regards

    Robin Whittle

../ to the main COVID-19 page of this site.

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