By Warren R. Heymann, MD,

Dermatology World Insights and Inquiries,

Opinion

If there is anything we have learned about SARS-CoV-2 it is that we should expect the unexpected. An analysis from China has shown that children younger than 10 years old account for only 1% of COVID-19 cases, similar to the proportion for SARS-CoV and MERS-CoV epidemics. There is clear evidence that children are susceptible to SARS-CoV-2 infection, but frequently do not have notable disease; why this is so has perplexed researchers. It is conceivable that children could be facilitators of viral transmission. (1) Over recent weeks, however, there has been an increasing number of cases of children linked to the coronavirus that are profoundly ill — despite the media attention, this is still a rare phenomenon.

Over a 10-day span in mid-April, Riphagen et al observed a cluster of 8 previously healthy children (5 boys, 3 girls, age 4 – 14 years) with hyperinflammatory shock with features of Kawasaki disease (KD), atypical KD, or toxic shock syndrome (TSS). Four children had known familial exposure to COVID-19, but all tested negative during the admission.

Clinical presentations were similar, with unrelenting fever (38–40°C), variable rash, conjunctivitis, peripheral oedema, and generalised extremity pain with significant gastrointestinal symptoms. All progressed to warm, vasoplegic shock, refractory to volume resuscitation and eventually requiring noradrenaline and milrinone for haemodynamic support. Most of the children had no significant respiratory involvement, although seven of the children required mechanical ventilation for cardiovascular stabilisation. Other notable features (besides persistent fever and rash) included development of small pleural, pericardial, and ascitic effusions, suggestive of a diffuse inflammatory process.” EKGs were non-specific; however, a common echocardiographic finding was echobright coronary vessels, which progressed to a giant coronary aneurysm in one patient within a week of discharge from pediatric intensive care. One child developed an arrhythmia with refractory shock and died from a large cerebrovascular infarct. Myocardial involvement in this syndrome was characterized by very elevated cardiac enzymes during the course of illness. Following discharge, 2 children tested positive for SARS-CoV-2 infection (including the child who died). (2)

Although the trend of having medical news appear in the media with little opportunity for reflection on peer-reviewed published literature has been accelerating, like so many aspects of our lives, the coronavirus has shattered precedent with alacrity. Despite the ample media coverage of this today (May 7), there is only a solitary reference in PubMed linking the virus to KD. Jones et al described the case of a 6-month-old infant admitted and diagnosed with classic KD, who screened positive for COVID-19 in the setting of fever and minimal respiratory symptoms. The patient was treated with intravenous immunoglobulin (IVIG) and high-dose aspirin (ASA), and subsequently defervesced with resolution of her clinical symptoms. The patient’s echocardiogram was normal, and she was discharged within 48 hours of completion of her IVIG infusion, with instruction to quarantine at home for 14 days from the date of her positive testing for COVID-19. (4)

As this potentially new syndrome with overlapping features of KD and TSS declares itself, it is worthwhile to review classical features of each disorder. For KD, the patient must have fevers for five or more days, with at least four of the following criteria (either all at once or over a series of days):

• Bilateral painless bulbar conjunctival injection without exudate
• Erythematous mouth and pharynx, strawberry tongue or red, cracked lips
• Polymorphous exanthem (morbilliform, maculopapular, or scarlatiniform)
• Swelling of hands and feet with erythema of the palms and soles
• Cervical lymphadenopathy (over 1.5 cm in diameter)

Although we are intimately familiar with the clinical presentation of KD, the etiology remains an enigma. There appears to be a genetic predisposition as genetic markers have been associated with the disease (e.g., HLA-B51 and HLA-Bw22j2 serotypes, chemokine receptor gene-cluster CCR2-CCR5 haplotypes and FCGR3A polymorphism of the IgG receptor IIIa). Various organisms of bacterial and viral origin have been implicated as causative, but to date, no single agent has been identified as the predominant cause. Regardless, over 40% of children diagnosed with KD test positive for viral respiratory pathogens. Presumably these infectious agents trigger a cascade of responses that activates lymphocytes, cytokines, and proteinases, specifically tumor necrosis factor alpha (TNF-a), Interleukin 1, 4, and 6, and matrix metalloproteinases (MMP3 and MMP9), that also result in myocarditis and arteritis with resultant coronary artery aneurysms. Standard therapy focuses on IVIG and aspirin; the use of TNF inhibitors, anakinra, and other biologics is being investigated. (5)

TSS presents with fever, chills, malaise, rash, vomiting, diarrhea, and hypotension. Diffuse erythema and desquamation may occur later in the disease course. Laboratory assessment may demonstrate anemia, thrombocytopenia, elevated liver enzymes, and abnormal coagulation studies. Diagnostic criteria are available to facilitate the diagnosis, but they should not be relied on for definitive diagnosis. The most common etiologic agents are Staphylococcus aureus and Streptococcus pyogenes. Sources of TSS include postsurgical wounds, postpartum, postabortion, burns, soft tissue injuries, pharyngitis, and focal infections. Symptoms are due to toxin production and infection focus. Treatment involves supportive care and antibiotics (a penicillinase-resistant penicillin, cephalosporin, or vancomycin [in MRSA-prevalent areas] along with either clindamycin or linezolid). (6)

According to Dr. Steven Kernie, chief of pediatric clinical care medicine at Columbia University and New York Presbyterian Morgan Stanley Children’s Hospital, the new syndrome appears to affect the heart differently than classical Kawasaki disease and has a higher rate of a toxic shock complication than classical Kawasaki disease. (2)

This dramatic syndrome is evolving before our eyes. Unlimited questions abound, most notably:

1. What is its precise relationship to COVID-19?
2. What are the earliest warning signs of the syndrome?
3. Do forme frustes of the disorder exist?
4.  Are there any preventive measures?
5. What is the optimal treatment regimen?
6. What are the long-term sequelae — do patients require long-term cardiac follow-up as classical KD patients?

It is impossible to reach any definitive conclusions at this juncture. In my opinion, the term “pediatric multisystem inflammatory syndrome” does not do the syndrome justice, as it does not portray any of its specific features. I favor the term Kawasaki-like Shock Syndrome because it encompasses the full (most consequential) clinical features of this disorder. Inevitably, we will be learning much more about this condition in the coming weeks as it has reached the pinnacle of media attention and concern.

Point to Remember: A new syndrome in children is being reported with features reminiscent of Kawasaki disease and toxic shock syndrome. Its precise relationship to COVID-19 remains to be defined. Children presenting with features suggestive of either Kawasaki disease and/or toxic shock syndrome should be investigated for COVID-19 infection.

1. Kelvin AA, Halperin S. COVID-19 in children: The link in the transmission chain. Lancet Infect Dis 2020 Mar 25 pii: S1473-3099(20)30236-X. doi: 10.1016/S1473-3099(20)30236-X. [Epub ahead of print]
2. Riphagen S, Gomez X, Gonzalez-Martinez, Wilkinson N, Theocharis P. Hyperinflammatory shock in children during COVID-19 pandemic. The Lancet published online May 07, 2020 DOI:https://doi.org/10.1016/S0140-6736(20)31094-1
3. “A new coronavirus threat to children” by Pam Belluck. New York Times May 6, 2020.
4. Jones VG, Mills M, Suarez D, Hogan HA, et al. COVID-19 and Kawasaki disease: Novel virus and novel case.
5. Modesti AM, Plewa MC. Kawasaki disease. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing 2020 – 2019 Jul 24
6. Gottlieb M, Long B, Koyfman A. The evaluation and management of toxic shock syndrome in the emergency department: A review of the literature. J Emerg Med 2018; 54: 807-814.
7. NBC News May 7 “At Least 85 kids across U.S. have developed rare, mysterious COVID-19-linked illness” by Erika Edwards
8. Guidance: Paediatric multisystem inflammatory syndrome temporally associated with COVID-19. Royal College of Paediatrics and Child Health https://www.rcpch.ac.uk/sites/default/files/2020-05/COVID-19-Paediatric-multisystem-%20inflammatory%20 syndrome-20200501.pdf
9. Taddio A, Rossi, ED, Monasta, L, et al. Describing Kawasaki shock syndrome: results from a retrospective study and literature review. Clin Rheumatol (2017) 36: 223-228
10. Dong, Y, Mo, X, Hu, Y, et al. Epidemiology of COVID-19 Among Children in China. Pediatrics (2020);145(6): e20200702
11. https://theconversation.com/us A mysterious illness is striking children amid the coronavirus pandemic-but is it Kawasaki disease. Mark Hicar, MD, PhD. Univer at Buffalo, SUNY May 7, 2020
12. Elakabawi, K, Lin, J, Jiao, F, Guo, N, Yuan, Z Kawasaki Disease: Global Burden and Genetic Background. Cardiology Research (2020) 11, 9-14
13. NBC News May 9, 2020 “Death toll grows to 3 for children in New York with coronavirus-related inflammatory syndrome” by Nicole Acevedo