During the initial outbreak of the SARS-CoV-2 Global pandemic, children, in general, appeared to be relatively resilient against the virus, with only 2% of reported cases in patients under 20 years old; and world-wide, epidemiologists identified older populations with underlying conditions as being at most risk (Ludvigsson, J. F. 2020). 

A study of 731 confirmed COVID-19 cases in pediatric populations, described over 90% of patients displaying no symptoms whatsoever.

Kawasaki disease and COVID-19

However, temporally related to COVID-19, is the increase in children exhibiting symptoms of Kawasaki Disease- a rare inflammatory disease typically in children under 5 years of age, which is characterized by inflammation of the blood vessels and the abnormal dilation of the arteries supplying the heart with blood.  These recent cases are now being referred to as Pediatric Multi-Symptom Inflammatory Syndrome partially associated with COVID-19 (PICU-COVID-19 or PMIS). Information about this disease is minimal due to the small number of reported cases, but we are learning more every day. However, there is now clear evidence that infection with SARS-CoV-2 is the underlying cause of PICU-COVID-19 (The Science Times May 15th, 2020).

On April 27th, an alert circulated from the UK describing a small risk in the number of critically ill children displaying multi-system inflammatory disease potentially associated with SARS-CoV-2 exposure. The NYC health department soon followed with a similar alert. By mid-April, 2020, the American Academy of Pediatrics pre-published the first well-documented case of COVID-19 associated Kawasaki Disease in a 6-month old girl. Between April 29th, and May 3rd, over 15 cases were confirmed within NYC and 2 of these patients died, with a total of 64 across the state of NY. An increasing number of confirmed cases of COVID-19 associated Kawasaki disease are now reported in the UK, Spain, and Italy. And since there are currently no definitive blood tests available, there is still a great deal of uncertainty as to how many cases remain unreported. 

CDC advice for treating PICU-COVID-19

In the US, on May 2nd, Dr. Jeff Burns of Boston Children’s Hospital convened a team of pediatric experts to review cases and offer guidelines for clinicians seeing these patients on the frontline. Although rare, this condition has shown to escalate rapidly, and the CDC now advises that in cases of PICU-COVID-19  treatment regimes should be managed across teams of pediatric specialists in infectious disease, rheumatology, and cardiology to help anticipate and address the many aspects of the life-threatening condition (AAP News May 14th, 2020).  

Symptoms of Kawasaki Disease in Pediatric Patients 

The team also suggested that clinicians adopt the following case definition with the goal of more rapidly identifying patients with the condition and preventing more loss of lives:

1. Children presenting with persistent fever, inflammation (neutrophilia and lymphopenia with elevated levels of CRP), and evidence of single or multi-organ dysfunction (shock- particularly gastrointestinal and cardiac, but potentially also respiratory, renal, or neurological).
2. The exclusion of microbial causes such as sepsis, staphylococcal or streptococcal shock syndromes, or enterovirus resulting in myocarditis.
3. SARS-CoV-2 PCR testing may be positive or negative, and most significantly, the serological testing for anti-SARS-CoV-2 antibodies is currently the most reliable diagnostic test. 

Many pediatric patients present several or all symptoms of Kawasaki Disease including fever, rash, conjunctivitis, redness of lips or tongue, with some children also displaying clinical signs of cytokine storm syndrome and toxic shock syndrome, including abnormal cytokine profiles and very low blood pressure.

Identifying the link between COVID-19 and Kawasaki Disease

Serological testing of many of these patients has identified the presence of anti-SARS-CoV-2 antibodies, even though these patients may not test positive for COVID-19 by RT-PCR. Studies in the UK by Dr. Richter and Prof. Cunningham at the University of Birmingham have now clearly demonstrated that the condition is associated with high levels of anti-SARS-Cov-2 IgG antibodies, suggesting that this condition develops weeks after the infection.  

Most cases involve gastrointestinal symptoms rather than the respiratory symptoms displayed in older patients, and in several cases, stool samples from these pediatric patients have tested positive for SARS-CoV-2, even when nasal testing is negative by RT-PCR. Collectively, this indicates that these inflammatory responses were delayed, and only clinically displayed when the virus was no longer detectable on nasal swabs. 

What do we know so far?

We still know so little about this all, and research is now focusing on underlying triggers for this disease. Is it possible that the antibodies being generated in these patients to SARS-CoV-2 are triggering an immune reaction leading to these symptoms? Is there an underlying genetic predisposition to developing PICU-COVID-19? The National Institute of Allergy and Infectious Diseases has now launched the HEROS study to identify and track these patients and their families over time and to better understand the epidemiology of COVID-19 and PICU-COVID-19. It is highly likely that many cases are going unreported because of a lack of awareness or ability to get hospital treatment because of access or because clinicians are not aware of this condition, nor equipped to test for it. 

For those who do require critical care treatment, the current treatment regimes include anticoagulation, IL-1, and IV immunoglobulin infusions, as well as anti-IL-6 treatments and corticosteroids. Crucial to understanding this disease's clinical progression will include characterization of organ function (particularly cardiac, liver, kidney), cytokine profiling, and sequential inflammatory markers, including CBC, CRO, ESR, and coagulation parameters like D-dimer and ferritin.

Current status and next steps

As the number of these cases continues to rise daily, PICU-COVID-19 has been reported in 19 different states and Washington DC.  The good news is that most patients recover without long term organ damage. However, we still don't understand the underlying immunological mechanisms responsible for the disease, and management of the symptoms is on a case by case basis. But serological testing for anti-SARS-CoV-2 IgG appears right now to be a valuable tool in early detection and earlier intervention for better patient outcomes. 

 References:

Ludvigsson, J. F.  Systematic review of COVID-19 in children shows milder cases and a better prognosis than adults. Review Article: Acta Pediatrica. 19th March 2020 - https://onlinelibrary.wiley.com/doi/abs/10.1111/apa.15270 

Jenco, M. AAP News CDC details COVID-19-related inflammatory syndrome in children. May 14th 2020. - https://www.aappublications.org/news/2020/05/14/covid19inflammatory051420

The Science Times: Confirmed! Kawasaki-like Disease in Children is Caused by Coronavirus and Can Only be Diagnosed Using Antibody Testing May 15th 2020. - https://www.sciencetimes.com/articles/25701/20200515/confirmed-kawasaki-disease-children-caused-coronavirus-diagnosed-using-antibody-tests.htm 

Authored by: Dr. Julie Bick

Dr Julie Bick is a medicinal biochemist who has spent close to 7 years with FlowMetric Life Sciences. After receiving her doctorate in Biochemistry at Southampton University in the UK, she began her career as Associate Professor at Rutgers University, NJ, before moving to the west coast to perform biomedical research with Syngenta and Novartis at the Tory Mesa Research Institute in San Diego. Dr. Bick specializes in biomedical engineering of cells and proteins in order to provide innovative therapeutic and diagnostic solutions. She brings to FlowMetric a clinical expertise across a wide range of therapeutic areas from autoimmunity to oncology and chronic inflammatory conditions, acquired over 25 years of research experience in academic, biotechnology and pharmaceutical laboratories. In leading FlowMetric Life Sciences’ innovation initiatives, Dr. Bick has been collaborating with BurstIQ to implement Block Chain solutions into the company’s Contract Research Organization division, with a focus on enhanced big data analytics and process control solutions in the regulated clinical environment. Dr. Bick is committed to working with local Community Colleges to support STEM programs for the next generation of scientists.