The profound dermatological manifestations of COVID-19: Part V – Pediatric multisystem inflammatory syndrome

By Warren R. Heymann, MD
May 13, 2020
Vol. 2, No. 19

Disclaimers: This commentary was written on May 7, 2020 for a publication date of May 13, 2020. The issues related to the COVID-19 pandemic are changing by the millisecond. The content included in this commentary may no longer be factual or relevant by the publication date. Parts I and IV of this series were referenced; Parts II and III were personal reflections; Part V is referenced. The reader is encouraged to stay abreast of developments via the CDC and local government and institutional health care authorities. The AAD has instituted the valuable Coronavirus Resource Center and the COVID-19 Dermatology Registry to help understand the dermatologic manifestations of the COVID-19 virus.

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)

On May 4, 2020 Dr. Demetre Daskalakis, the Deputy Commissioner of the Division of Disease Control of the New York City Health Department, sent the following letter (2020 Health Alert #13: Pediatric Multisystem Inflammatory Syndrome Potentially Associated with COVID-19):

“A pediatric multi-system inflammatory syndrome, recently reported by authorities in the United Kingdom, is also being observed among children and young adults in New York City and elsewhere in the United States. Clinical features vary, depending on the affected organ system, but have been noted to include features of Kawasaki disease or features of shock; however, the full spectrum of disease is not yet known. Persistent fever and elevated inflammatory markers (CRP, troponin, etc.) have been seen among affected patients. Patients with this syndrome who have been admitted to pediatric intensive care units (PICUs) have required cardiac and/or respiratory support. Only severe cases may have been recognized at this time.

The NYC Health Department contacted PICUs in NYC during April 29-May 3, 2020 and identified 15 patients aged 2-15 years who had been hospitalized from April 17-May 1, 2020 with illnesses compatible with this syndrome (i.e., typical Kawasaki disease, incomplete Kawasaki disease, and/or shock). All patients had subjective or measured fever and more than half reported rash, abdominal pain, vomiting, or diarrhea. Respiratory symptoms were reported in less than half of these patients. Polymerase chain reaction (PCR) testing for SARS-CoV-2 has been positive (4), negative (10), and initially indeterminate and then negative (1). Six patients with negative testing by PCR were positive by serology. More than half of the reported patients required blood pressure support and five required mechanical ventilation. No fatalities have been reported among these cases.

If the above-described inflammatory syndrome is suspected, pediatricians should immediately refer patients to a specialist in pediatric infectious disease, rheumatology, and/or critical care, as indicated. Early diagnosis and treatment of patients meeting full or partial criteria for Kawasaki disease is critical to preventing end-organ damage and other long-term complications. Patients meeting criteria for Kawasaki disease should be treated with intravenous immunoglobulin and aspirin.”

On May 6, the New York Times reported that 64 cases had been identified in New York State, with a handful of cases in other states and more than 50 cases in Europe. (3)

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.

Our Expert’s Viewpoint

Anat R. Feingold, MD, MPH
Associate Professor of Pediatrics
Cooper Medical School of Rowan University

Debrah Meislich, MD
Assistant Professor of Pediatrics
Cooper Medical School of Rowan University

As Dr. Heymann has pointed out, the vast majority of reported cases of children with identified COVID-19 infections present with either asymptomatic or only mild disease. However, over the past 2 months European and now U.S. clinicians have reported cases of children with a much more serious clinical syndrome, detailed by Dr. Heymann above. This syndrome has been recognized concurrent with the pandemic of the novel coronavirus SARS-COV2. It is postulated that this newly identified syndrome represents a child’s overly aggressive immune response during or following a COVID-19 infection. Dr. Audrey John, chief of pediatric infectious diseases at Children’s Hospital of Philadelphia, explained that: “We’re all still waiting for the smoking gun to be sure it is associated with COVID-19” but that it’s “certainly suspicious.” (7)

While the descriptions of SARS-COV2-associated pediatric multisystem inflammatory syndrome may have many features of Kawasaki disease, there is also clinical overlap with staphylococcal and streptococcal toxic shock, septic shock, and even macrophage activation syndrome. (8) The clinical manifestations bring to mind Kawasaki shock syndrome (KSS), a rare manifestation of Kawasaki disease which is characterized by systolic hypotension or clinical signs of poor perfusion. In a recent retrospective review in which 84 children with KD were enrolled, 5 met criteria for KSS. When compared to the 79 children with KD, patients with KSS had statistically higher c-reactive proteins, lower Hgb levels, coagulopathy, and increase in cardiac troponins. While the etiology of both KD and KSS remain unknown, the clinical and laboratory findings of KSS are consistent with greater underlying inflammation and more systemic vasculitis and severe myocardial involvement. Of note, the median age in both the children with KD and those with KSS was 25 months. (9) In a recent correspondence by the South Thames Retrieval Service for Children published in the Lancet reported on a cluster of eight cases of “hyperinflammatory shock“ during the COVID-19 pandemic. They suggested that this clinical picture represents a new phenomenon similar to Kawasaki disease shock syndrome. It is interesting to note that the mean age in their series was nearly 9 years, significantly older than the majority of children who develop KS. (10)

As Mark Hicar, assistant professor at the University of Buffalo, SUNY, pointed out, not only the age distribution of the children presenting with this syndrome is atypical for KD, the epidemiology of reported cases is also strikingly different. (11) The incidence of KS varies widely among different nations and is highest in the North-East Asian countries with almost 1 in 100 children in Japan having the disease by age 5. (12)

Despite this epidemiology, the reports of pediatric multisystem inflammatory syndrome temporally associated with COVID-19 have come almost exclusively from Europe and the United States. It is noteworthy that China, a country reporting nearly 83,000 cases since December 2019, has, to date, not reported a single case of an infected child with a Kawasaki-like syndrome. A recent review in Pediatrics, describing the epidemiology of COVID infections among 2,135 Chinese pediatric patients, found that young children, particularly infants, were the ones most likely to present with “severe” disease (defined as early respiratory symptoms, such as fever and cough, which may be accompanied by gastrointestinal symptoms, such as diarrhea). (10)

While we are always unsettled when we do not wholly agree with Dr. Heymann, because of these major differences between Kawasaki disease and the unique nature of these more recently identified critically ill children presenting in Europe and North America in the midst of the COVID-19 pandemic, we prefer the term Pediatric Multi-system Inflammatory Syndrome or coronavirus related inflammatory syndrome, as some have called it. That being said, the important message for physician and other health care providers is that these children should be treated as suspected COVID-19 patients and that they can become critically ill, requiring PICU admission at a facility with specialized pediatric cardiology services and a multidisciplinary team of specialists to care for them. Unfortunately, at the time of this writing, New York officials have just reported 3 deaths in pediatric patients as a result of coronavirus-related inflammatory syndrome. (13)

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