What We Know Now about the “Kawasaki-Like” Syndrome

By: Larisa Cervenakova, M.D., Ph.D., PPTA Medical Director

May 2020

In the last couple of weeks, media reports have discussed a rare, “Kawasaki-like” disease affecting children and young adults that is potentially linked to COVID-19 [1-3]. The emerging condition, which is not yet well understood, involves a severe, systemic inflammatory immune response that can lead to functional abnormalities in multiple organs, most notably the heart, with fatal consequences if not treated quickly. Cases of the new syndrome have been reported in Europe, the United Kingdom, and the United States. The sudden emergence of this new syndrome and its higher than Kawasaki disease prevalence have raised international concerns. Kawasaki disease can be effectively treated with intravenous immunoglobulin (IVIG) therapy and it seems that current cases of the new syndrome also respond to IVIG treatment. This fact highlights the necessity of continued vigilance with respect to protecting IVIG availability and access.

Kawasaki Disease

Kawasaki disease is a rare illness (frequency 9-20 cases per 100,000 children) of unknown origin that occurs predominantly in children younger than 5 years of age and presents as an acute systemic inflammatory syndrome involving medium-sized arteries (vasculitis) [4]. Patients usually present with high fever, conjunctivitis, rash, irritation, and inflammation of the lips, mouth, and throat, swelling of lymph nodes on the neck, and swelling of hands and feet. In severe cases, if left untreated, patients progress to develop problems with the coronary arteries, including serious aneurysms that can lead to fatal consequences. Kawasaki disease is considered to be the leading cause of acquired heart disease in children in the U.S.

In April, the first case of COVID-19 related Kawasaki disease in an infant was reported in California [5]. The patient had minimal respiratory symptoms and typical signs of Kawasaki disease. The child was successfully treated with IVIG and high-dose aspirin, per treatment guidelines.

The Emerging, New Syndrome

The UK and European Experience (PIMS-TS)
During a short period in April, clinicians in the United Kingdom noticed a sharp increase in the number of patients presenting with a variety of symptoms resembling Kawasaki disease, such as persistent fever, conjunctivitis (inflammation of the conjunctiva of the eyes), and cardiac abnormalities [6]. Strikingly, a disease generally seen in children younger than 5 years old was now occurring in children of all ages. In addition, patients presented with symptoms that were never observed in Kawasaki disease, such as gastrointestinal involvement, abdominal pain, and vomiting. Some patients developed shock and organ dysfunction that required treatment in pediatric emergency care units.

All of the UK patients with this new syndrome tested positive for COVID-19 either by the presence of the SARS-CoV-2 virus (demonstrated by the nucleic acid test − RT-PCR) or antibodies against the virus. Patients also had other common laboratory findings such as increased neutrophil counts and decreased lymphocyte counts; elevated C-reactive protein (an inflammatory marker) and elevated D-dimer (a coagulation pathology marker); elevated ferritin, and decreased albumin levels.

On April 24, the National Health System authorities in the UK issued an alert informing clinicians about this new condition, which was termed Pediatric Inflammatory Multisystem Syndrome – temporally associated with SARS-CoV-2 infection (PIMS-TS). On April 27, the Royal College of Paediatrics and Child Health issued a guidance with a case definition of the syndrome and an approach to clinical management. Among specific recommendations, the use of IVIG together with aspirin is to be considered for early treatment if the patient fulfills the criteria for Kawasaki disease. IVIG treatment is also recommended if the patient fulfills the criteria for toxic shock syndrome.

The U.S. Experience (MIS-C)
On May 4, the New York City Department of Health released a Health Alert on PIMS potentially associated with COVID-19 reporting on 15 patients aged 2-15 years who had been hospitalized from April 17- May 1, 2020.

On May 14, the U.S. Centers for Disease Control and Prevention (CDC) released a Health Alert concerning Multisystem Inflammatory Syndrome in children (MIS-C) (another term for PIMS-TS) associated with COVID-19. In this communication, the CDC provides (1) background information on several recently reported MIS-C cases; (2) a case definition for this syndrome; and (3) a recommendation that healthcare providers report any case of MIS-C to state, local, and territorial health departments to enhance knowledge of risk factors, pathogenesis, clinical course, and treatment of the syndrome. Subsequently, the CDC issued two guidances, one on May 15 with Information for Pediatric Healthcare Providers and one on May 20 with a revision to include Evaluation and Management Considerations for Neonates At Risk for COVID-19. In addition, specific guidance was issued for parents.

The main elements of the CDC’s case definition are:

1. a patient younger than 21 years of age;
2. presenting with fever (>38.0°C for ≥24 hours, or report of subjective fever lasting ≥24 hours);
3. laboratory evidence of inflammation (including, but not limited to, one or more of the following: an elevated CRP, erythrocyte sedimentation rate, fibrinogen, procalcitonin, D-dimer, ferritin, lactic acid dehydrogenase, or interleukin 6, elevated neutrophils, reduced lymphocytes, and low albumin); and evidence of clinically severe illness requiring hospitalization, with multisystem (>2) organ involvement (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic or neurological);
4. no plausible alternative diagnosis; and
5. positive for current or recent SARS-CoV-2 infection by RT-PCR, serology, or antigen test; or COVID-19 exposure within the 4 weeks before the onset of symptoms.

More Recent and Multinational Perspectives The World Health Organization in its Scientific Briefing on May 15 acknowledged the emergence of MIS-C and also issued a preliminary case definition as follows:

1. children and adolescents 0–19 years of age with fever > 3 days and two of the following:
   1. rash or bilateral non-purulent conjunctivitis or mucocutaneous inflammation signs (oral, hands, or feet),
   2. hypotension or shock,
   3. features of myocardial dysfunction, pericarditis, valvulitis, or coronary abnormalities (including ECHO findings or elevated Troponin/NT-proBNP),
   4. evidence of coagulopathy (by prothrombin time, partial thromboplastin time, elevated D-dimers), or
   5. Acute gastrointestinal problems (diarrhea, vomiting, or abdominal pain);
2. elevated markers of inflammation such as erythrocyte sedimentation rate, C-reactive protein, or procalcitonin;
3. no other obvious microbial cause of inflammation, including bacterial sepsis, staphylococcal or streptococcal shock syndromes; and
4. evidence of COVID-19 (RT-PCR, antigen test or serology positive), or likely contact with patients with COVID-19.

On May 15, the European Centre for Disease Prevention and Control published a Rapid Risk Assessment of PIMS-TS. According to this report, more than 300 suspected cases of the syndrome have been reported in European countries, the UK, and North America, including a few fatalities (UK - 1, France - 1, U.S. - 3 reported in NY). This document is the most comprehensive record to date. It includes the historical encounter of PIMS-TS and a full description, as well as details of Kawasaki disease, treatment options, and reports from various European countries (Spain - 22, Italy - 10, Luxemburg - 5, Sweden - 3, Switzerland - 3, Portugal - 1, UK - at least 48).

The CDC Center for Preparedness and Response organized a May 19 webinar on MIS-C that presented findings based on 37 cases from eight hospitals in England (27 patients tested positive for SARS-CoV-2 or antibodies) and 33 cases from the Cohen Children’s Medical Center in New York (all patients tested positive for SARS-CoV-2 or antibodies; at the time of the webinar, 43 cases were reported to NY State Department of Health). The main clinical features reported by both groups were very similar: fever persisting for a couple of days, shock in three quarters of cases, and cardiac involvement features in approximately half of cases. However, in the U.S., a significantly higher proportion of children had gastrointestinal problems and acute kidney injury, as well as respiratory involvement.

Laboratory findings described for PIMS-TS and MIS-C were also similar. All patients required hospitalization with a high proportion requiring admissions to Intensive Care Units. In regard to treatment, all U.S. patients were treated with at least one dose of IVIG and some received a second dose. More than three-quarters received aspirin. In the UK, a majority of patients (62%) also received IVIG treatment. In both groups, patients were treated with other drugs as well, including steroids, but a smaller proportion of patients received steroids in the UK than in the U.S. (51% vs 70%). In a recent retrospective study from France and Switzerland that included 35 patients, all patients received IVIG therapy, with one-third receiving steroid therapy.

On May 21, the New York State Department of Health conducted a webinar that addressed the experiences of two other New York pediatric healthcare entities: the Mount Sinai Kravis Children’s Hospital (report on 15 patients; one fatality) and the Columbia Irving Medical Center (report on 28 patients). At that time, the Commissioner reported a total of 175 suspected MIS-C pediatric cases and three fatalities in New York. At Mount Sinai, clinicians have been guided by the clinical definition criteria provided by the CDC. At Columbia, clinicians emphasized that only some of the Kawasaki disease criteria were fulfilled in some patients following an SARS-CoV-2 infection (out of 28 patients, only one had Kawasaki-like clinical presentation) and that MIS-C is a unique syndrome, with its own set of defined clinical criteria, which develop two to three weeks following asymptomatic infection or clinical COVID-19. These criteria include high fever for at least three days, severe abdominal pain, neurological symptoms (e.g., severe headache, confusion), shock (seen in half of cases), and rash (seen in some cases). The laboratory findings from both centers overlap to some degree with the data reported from the UK and by the Cohen Children’s Medical Center. IVIG therapy was used in approximately half of the patients at Mount Sinai and in all patients at Columbia. Patients were also treated with other therapies, including steroids. Importantly, both centers reported positive clinical outcomes in patients they treated.

It should be noted that multiple earlier reports from China did not mention the occurrence of a similar condition in pediatric patients and young adults, but recently five COVID-19 pediatric cases with clinical manifestations comparable to MIS-C/PIMS-TS have been described [7].

Conclusion

There is still much to learn about this emerging condition. As our understanding of MIS-C/PIMS-TS continues to evolve, we will likely see more cases of this new COVID-19 associated syndrome. Certainly with time, the specific clinical and laboratory criteria will be refined to guide the best treatment options. IVIG therapy has been, and likely will remain, of high importance to the treatment of this acute condition. Consequently, plasma donations are more important than ever. The plasma protein therapies industry will continue working to fulfill its commitment to patients who rely on these life-saving medicines.

References:

1. Ariana Eunjung Cha and Chelsea Janes, The Girl Who Died Twice, WASHINGTON POST (May 17, 2020).
2. Editorial Board, The Evidence on Kids and Covid, WALL STREET JOURNAL (May 20, 2020).
3. Joseph Goldstein and Jesse McKinley, After 3 Children Die, a Race to Investigate a Baffling Virus Syndrome, NEW YORK TIMES (May 22, 2020).
4. https://www.cdc.gov/kawasaki/index.html
5. Jones VG, Mills M, Suarez D, et al. COVID-19 and Kawasaki disease: novel virus and novel case. Hosp Pediatr. 2020; doi: 10.1542/hpeds.2020-0123.
6. Riphagen S, Gomez X, Gonzales-Martinez C, Wilkinson N, Theocharis P. Hyperinflammatory shock in children during COVID-19 pandemic. Lancet. 2020. Advance online publication, doi: 10.1016/S0140-6736(20)31094.
7. Cai X, , Ma Y, Li S, Chen Y, Rong Z and Li W . Clinical characteristics of 5 COVID-19 cases with non-respiratory symptoms as the first manifestation in children. Front Pediatr 2020 ; 8:258. doi: 10.3389/fped.2020.00258.

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