US Pharm. 2020;45(7/8)41-45.
ABSTRACT: In late April 2020, healthcare providers in the United Kingdom and the United States began to recognize a severe inflammatory syndrome in the pediatric population; otherwise-healthy children were presenting with signs of inflammation comparable to Kawasaki disease. In May, the CDC provided a case definition, referring to this novel presentation in pediatric patients as multi-system inflammatory syndrome in children. A small number of studies have been published, providing limited data on presentation and outcomes. There are no definitive guidelines for treatment, but IV immunoglobulin and supportive care are common approaches.
The coronavirus disease 2019 (COVID-19) pandemic, the viral illness caused by severe acute respiratory syndrome–coronavirus-2 (SARS-CoV-2), is an ongoing global healthcare and economic calamity.1 In late November 2019, human infection from the novel SARS-CoV-2 was initially reported in Wuhan province.1 On January 14, 2020, the CDC reported the first human infection within North America.1 The numbers continue to escalate daily, with current reports, at press time, of over 4 million cases in the United States and an estimated 15.8 million globally.2,3 At the beginning of the pandemic, it appeared that pediatric patients were largely not impacted or had mild or asymptomatic cases associated with COVID-19. If infected, the majority of pediatric patients often had few symptoms unless an underlying condition compromised their health.
On April 26, 2020, healthcare providers in the United Kingdom (UK) indicated that there were increasing incidences of otherwise-healthy children who were presenting with signs of inflammation comparable to Kawasaki disease.4,5 As a result, the Royal College of Pediatrics released a statement noting that while the majority of pediatric patients present with mild COVID-19 cases or remain asymptomatic, some pediatric patients are presenting with a considerable amount of inflammation.6 The Royal College of Pediatrics also indicated that while rare, this newly discovered inflammatory syndrome has common clinical features comparable to other inflammatory diseases, including Kawasaki disease, staphylococcal and streptococcal toxic shock syndromes, and bacterial-sepsis and macrophage-activation syndromes. They also noted that patients were experiencing atypical gastrointestinal (GI) symptoms as well as elevations in inflammatory markers.6 The Royal College of Pediatrics also stated that patients affected by this inflammatory syndrome often needed treatment in the pediatric intensive care unit (PICU) and involvement from specialists in pediatric infectious diseases, cardiology, and rheumatology.4,6
After identification in the UK, cases started to appear in New York City and elsewhere in the U.S.4 According to the CDC, the cases in the U.S. occurred in pediatric patients testing positive for current or relatively new infection by SARS-CoV-2 as confirmed by reverse transcriptase polymerase chain reaction (RT-PCR) or serologic assay, or who had an epidemiologic connection to a COVID-19 case.4 The agency also noted that these patients presented with a constant fever and a plethora of other signs and symptoms such as hypotension; multiorgan involvement affecting the cardiac, GI, renal, hematologic, dermatologic, and neurologic systems; and increased levels of inflammatory markers.4-6 Additionally, respiratory symptoms were not experienced by patients in all the cases reported.
The CDC reported that during March and April, cases of COVID-19 began to soar in New York City and New York State. Additionally, during the early part of May 2020, the New York City Department of Health and Mental Hygiene begin to receive reports of pediatric patients with this rare inflammatory syndrome.5 From April 16 through May 4, 2020, fifteen patients aged 2 to 15 years were hospitalized, and many patients in this group were admitted to the ICU. As of May 12, 2020, the New York State Department of Health identified 102 patients with comparable clinical presentations. Several of these patients also tested positive for SARS-CoV-2 infection by RT-PCR or serologic assay. Both New York State and New York City continued to get more reports of possible cases.5 Further reports of pediatric patients presenting with severe inflammatory syndrome with a laboratory-confirmed case of COVID-19 or an epidemiological connection to a COVID-19 case were also noted within the U.S. and by healthcare specialists in other countries.7 On May 14, 2020, the CDC released a health advisory offering the most current known information obtained from the few reported cases. This advisory provided a case definition (TABLE 1) and advised healthcare providers to report cases to local, state, and regional health departments to heighten awareness of risk factors, pathogenesis, clinical presentation, and treatment of this rare inflammatory disorder.5 The CDC is referring to this novel presentation in pediatric patients as multisystem inflammatory syndrome in children (MIS-C).
While the pathophysiology of MIS-C is not well-understood, various health experts have indicated that the syndrome is the result of an atypical immune response to the virus, with some resemblances to Kawasaki disease, macrophage activation syndrome, and cytokine release syndrome.8 The processes by which SARS-CoV-2 generates the atypical immune response are undetermined. It has been suggested that the timing of the response may indicate a postinfectious complication.8 Currently, health experts believe that the majority of pediatric patients have negative PCR testing results for SARS-CoV-2 but have positive serology, a finding that further substantiates the idea that MIS-C occurs after the acute infection has passed.8 However, some pediatric patients do have positive PCR testing. Data obtained from early case series from the UK, New York, France, and Italy indicate that there were 142 pediatric patients in whom both PCR and serology were completed.5,7 Of these patients, 63% had positive serology with negative PCR, 30% were reported positive on both tests, and 8% were reported negative on both tests.8 It is important to note that one of the major goals of health researchers is to expand knowledge regarding the processes of the amplified immune response in MIS-C as this area of research continues to evolve.8
Patients with MIS-C may present with a continual fever for 3 to 5 days on average; fatigue; signs and symptoms of systemic inflammation, including laboratory-confirmed elevated inflammatory markers and multiorgan system involvement including an array of signs and symptoms involving cardiac, GI, renal, hematologic, dermatologic, and neurologic system involvement.9,10 Not all pediatric patients present with the same symptoms and signs, and in some cases patients may exhibit symptoms not mentioned above.10
A recent cross-sectional study published in JAMA Pediatrics involving 48 pediatric patients in North America who were COVID-19 positive and were admitted to 14 pediatric ICUs in the U.S. was conducted between March 14 and April 3, 2020.1 Of the study participants, 83% of the patient population had previous underlying medical conditions. The study findings indicated that 35 patients (73%) presented with respiratory symptoms, and 18 (38%) needed invasive ventilation; the hospital mortality rate was reported as 4.2%. The researchers concluded that the study findings demonstrated the impact of COVID-19 infection in North American PICUs and also validated that severe infection in pediatric patients is considerable but does not occur as commonly as in the adult patient population. The researchers also noted that prehospital comorbidities seem to be a critical factor in pediatric patients and that their initial findings offer a foundation for further studies involving larger numbers of pediatric patients with COVID-19 infection.1
An observational study published online in May in Circulation reported on a series of pediatric patients with acute heart failure potentially associated with SARS-CoV-2 infection and MIS-C.11 The study involved 35 pediatric patients from France and Switzerland over a 2 -month period who had been exposed to COVID-19 and had an emerging condition with features overlapping toxic shock syndrome. The average age at admission was 10 years (range 2-16 years). Comorbidities including asthma and being overweight were found in an estimated 28%. Additionally, the presence of GI symptoms was common. One-third of participants had a left ventricular ejection fraction of <30%, and an estimated 80% required inotropic support, with 28% treated with extracorporeal membrane oxygenation (ECMO). Moreover, inflammation markers were indicative of cytokine storm (interleukin 6 average was 135 pg/mL) and macrophage activation (d-dimer median was 5,284 ng/mL). The average brain natriuretic peptide level was elevated (5,743 pg/mL). Thirty-one of 35 patients (88%) were confirmed as positive for SARS-CoV-2 infection via PCR of nasopharyngeal swab or serology. All patients received IV immune globulin, and one-third also received adjunctive steroid therapy. Left ventricular function was improved in 25 of the 35 patients discharged from the ICU. There were no reported deaths, and all patients treated with ECMO were successfully removed from ECMO treatment.
Researchers concluded that pediatric patients may develop acute cardiac decompensation resulting from inflammation due to MIS-C. They also noted that therapy with immune globulin seems to be correlated with improvement of left ventricular systolic function.11 Additional conclusions drawn from the study include11,12:
• MIS-C in pediatric patients is a novel syndrome that appears to be linked to previous exposure to SARS-CoV-2
• MIS-C appears to have parallels with atypical Kawasaki disease, but major clinical signs are mostly unique
• Myocardial involvement with acute heart failure is probably the result of myocardial stunning or edema instead of inflammatory myocardial damage
• While the early clinical presentation may be serious in some patients who may need circulatory and respiratory mechanical support, swift improvement with the use of immune globulin and steroids is currently seen
• Both initial diagnosis and management appear to result in beneficial clinical outcomes by employing standard therapies
• Further study is warranted to ascertain the broad range of the illness and whether long-term cardiac problems will occur
• The symptoms most frequently noted in the study were high fever; asthenia; GI signs including severe abdominal pain, vomiting or diarrhea, and adenopathy; and rash.11,12
Two studies published online in June by the New England Journal of Medicine added further data. Feldstein and colleagues indicated that of the 186 patients with MIS-C in 26 states, 80% of the pediatric patients who developed MIS-C needed care in the ICU, 20% needed mechanical ventilation, and 2% (representing four of the pediatric patients) died.13 Using New York State data, Dufort and colleagues also found that 80% of the 191 potential cases of MIS-C patients were admitted to ICU; two deaths were reported.14 Both studies reported that clinicians observed that many of the pediatric patients developed cardiovascular and clotting issues; GI symptoms; and dermatologic rashes.
In another recent online publication, results from a review of 131 studies of pediatric patients from 26 countries were released. This systematic review is the largest currently available for pediatric patients and young adults with COVID-19. The study found that 3% of children were asymptomatic; the most frequent symptoms were fever (59.1%) and cough (55.9%); ground-glass opacities in lungs were observed (32.9%). The largest subset of COVID-19 children with underlying health conditions (152 of 233) consisted of those who were immunocompromised or who had respiratory or cardiac diseases; 5.6% of children had coinfections. There were seven reported deaths, and 11 children met criteria for MIS-C. The researchers observed that most children have an uneventful recovery.15 Other studies have also noted that most pediatric patients survive.8,9
To date, there are no definitive guidelines regarding the treatment of MIS-C, and the CDC indicates that no studies have examined the efficacy of various treatment options.10 However, IV immunoglobulin and supportive care have been common approaches, according to a representative of the American Academy of Pediatrics Committee on Infectious Diseases.16 Supportive care may consist of fluids, respiratory and inotropic support, and rarely, ECMO. Treatment should be tailored to manage individual needs depending upon patient symptoms and their severity, and may warrant the use of antibiotics, antivirals, and additional therapies depending upon clinical presentation.8,10,16
Pharmacists can act as patient advocates and educators and provide patients with the most recent and pertinent information about effective means to reduce or prevent the transmission of the COVID-19 virus, such as wearing face masks, routine handwashing, use of alcohol-based hand sanitizers, social distancing, and routinely disinfecting surfaces. Pharmacists can also encourage and remind parents or caregivers to maintain routine healthcare for their children, especially those with preexisting medical conditions, and ensure that these patients remain adherent to any therapies. Until more is learned and there is an FDA-approved vaccine and /or treatment for COVID-19, patient education and awareness are the best defense against this pandemic. Patient resources can be found in TABLE 2. As frontline healthcare providers, pharmacists can direct parents to the educational resources available on the CDC website regarding MIS-C associated with COVID-19. For example, the CDC advises parents to seek emergency care immediately if the patient is exhibiting any of the emergency warning signs or symptoms related to MIS-C including17:
• Difficulty breathing or shortness of breath
• Pressure or discomfort in the chest that lingers
• Signs of confusion
• Lethargy or inability to stay awake
• Bluish color of face or lips
• Severe abdominal discomfort
The full spectrum of MIS-C remains unknown, and more research is clearly warranted. Although severe COVID-19 illness is less frequent in pediatric patients, it is still significant. Further research into MIS-C should offer insight into how COVID-19 affects the immune system and how it can be effectively prevented and treated.
The content contained in this article is for informational purposes only. The content is not intended to be a substitute for professional advice. Reliance on any information provided in this article is solely at your own risk.
1. Shekerdemian LS, Mahmood NR, Wolfe KK, et al. Characteristics and outcomes of children with coronavirus disease 2019 (COVID-19) infection admitted to U.S. and Canadian pediatric intensive care units. JAMA Pediatr. May 11, 2020. https://jamanetwork.com/journals/jamapediatrics/fullarticle/2766037. Accessed July 16, 2020.
2. CDC. Coronavirus disease 2019 (COVID-19) cases in the U.S. May 29, 2020. www.cdc.gov/coronavirus/2019-ncov/cases-updates/cases-in-us.html. Accessed July 24, 2020.
3. Johns Hopkins Coronavirus Resource Center. https://coronavirus.jhu.edu/map.html. COVID-19 Map. Accessed July 24, 2020.
4. Fornell D, ed. Kawasaki-like inflammatory disease affects children with COVID-19. Diagnostic and Interventional Cardiology. May 20, 2020. www.dicardiology.com/article/kawasaki-inflammatory-disease-affects-children-covid-19%C2%A0. Accessed May 29, 2020.
5. CDC. Multisystem inflammatory syndrome in children (MIS-C) associated with coronavirus disease 2019 (COVID-19). May 14, 2020. https://emergency.cdc.gov/han/2020/han00432.asp. Accessed May 20, 2020.
6. Royal College of Paediatrics and Child Health. Guidance: paediatric multisystem inflammatory syndrome temporally associated with COVID-19. www.rcpch.ac.uk/sites/default/files/2020-05/COVID-19-Paediatric-multisystem-%20inflammatory%20syndrome-20200501.pdf.
7. Verdoni L, Mazza A, Gervasoni A, et al. An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study. Lancet. 2020;395:1771-1778.
8. Son MBF, Friedman K. UpToDate. Coronavirus disease 2019 (COVID-19): multisystem inflammatory syndrome in children. April 2020. www.uptodate.com/contents/coronavirus-disease-2019-covid-19-multisystem-inflammatory-syndrome-in-children/print?topicRef=127488. Accessed May 29, 2020.
9. National Institutes of Health. COVID-19 Treatment Guidelines. Special considerations in children. Updated June 11, 2020. www.covid19treatmentguidelines.nih.gov/overview/children/. Accessed July 8, 2020.
10. CDC. Information for healthcare providers about multisystem inflammatory syndrome in children (MIS-C). May 29, 2020. www.cdc.gov/mis-c/hcp/. Accessed July 8, 2020.
11. Belhadjer Z, Méot M, Bajolle F, et al. Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the context of global SARS-CoV-2 pandemic. Circulation. www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.120.048360. Epub May 17, 2020.
12. Immunotherapy, steroids had positive outcomes in children with COVID-related multi-system inflammatory syndrome. American Heart Association. https://newsroom.heart.org/news/immunotherapy-steroids-had-positive-outcomes-in-children-with-covid-related-multi-system-inflammatory-syndrome. Accessed May 29, 2020.
13. Feldstein LR, Rose EB, Horwitz SM, et al. Multisystem inflammatory syndrome in U.S. children and adolescents N Engl J Med. 2020;583(4):234-346.
14. Dufort EM, Koumans EH, Chow EJ, et al. Multisystem inflammatory syndrome in children in New York State. N Engl J Med. 2020;583(4):347-358.
15. Hoang A, Chorath K, Moreira A, et al. COVID-19 in 7780 pediatric patients: a systematic review. EClinicalMedicine. Published June 26, 2020. www.thelancet.com/journals/eclinm/article/PIIS2589-5370(20)30177-2/fulltext. Accessed July 16, 2020.
16. Jenco M. CDC details COVID-19-related inflammatory syndrome in children. American Academy of Pediatrics. Published May 14, 2020. www.aappublications.org/news/2020/05/14/covid19inflammatory051420. Accessed May 29, 2020.
17. For parents: multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19. May 20, 2020. www.cdc.gov/coronavirus/2019-ncov/daily-life-coping/children/mis-c.html. Accessed July 8, 2020.
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