Two studies published yesterday in the Journal of the Pediatric Infectious Diseases Society describe the presentation of the COVID-19–related multisystem inflammatory syndrome in children (MIS-C) and how heavy coronavirus exposure didn't lead to infection in four siblings aged 9 to 12 years.
In addition, an expert review in the same journal recommends best practices for the use of antiviral drugs in infected children.
Severe signs and symptoms, aggressive therapies
In the first study, researchers at Temple University in Philadelphia conducted a systematic review and meta-analysis of 16 case reports and series involving 505 children with MIS-C from Jun 3 to Jul 23. Thirty-two children (14.7%) had characteristic MIS-C signs and symptoms but tested negative for SARS-CoV-2, the virus that causes COVID-19, on reverse transcription polymerase chain reaction (RT-PCR), antibody testing, or both. The rest tested positive.
The most common signs and symptoms were fever (100%), gastrointestinal distress (88%), rash (59.2%), conjunctivitis ("pink eye") (50%), swollen lips and/or tongue (55.7%), swollen and/or red hands or feet (47.5%), and swollen lymph nodes in the neck (42.5%). The latter five signs are characteristic of Kawasaki disease, which is believed to be distinct from MIS-C. Another Kawasaki sign, skin peeling, was also observed in several patients.
Median serum C-reactive protein (indicating inflammation) concentrations and fibrinogen and D dimer levels (indicating blood clots or inflammation) were elevated.
The most common treatments used were immune-boosting intravenous gammaglobulin (78.1%) and the steroid methylprednisolone/prednisone (57.6%). Although blood clots requiring treatment occurred in only 3.5% of patients, 54.4% received anticoagulants.
Major complications included heart muscle dysfunction requiring the use of inotropic agents to strengthen the heartbeat (57.4%) and oxygen added to the blood outside the body (5.3%), respiratory distress necessitating the use of mechanical ventilation (26.1%), and acute kidney injury (11.9%). Seven children (1.4%) died. Median patient age was 9 years (range, 6 months to 20 years).
The authors said that MIS-C is a severe illness that may require aggressive therapy but that empiric, comparative data on the most effective therapies are lacking. "Prospective studies are needed to further define the biochemical and inflammatory changes associated with this syndrome as well as effective therapies," they wrote.
Deliberate heavy exposure but no infection
The second study, led by researchers at the University of Lubeck in Germany, described four schoolchildren in one family who were exposed to SARS-CoV-2 over several days but never had clinical signs and repeatedly tested negative for infection and antibodies to the coronavirus.
The children, three girls and one boy 9 to 12 years old, were identified after their parents became ill after a brief contact with a COVID-19 patient on Feb 27. The mother had a dry cough, limb pain, headache, fever, fatigue, and shortness of breath in mid-March.
Because local authorities announced a 2-week quarantine for all members of households with a COVID-19 infection, which would have meant home quarantine for several months if the four siblings had sequential infections, the family elected to expose the children to the virus. The mother and all four children slept on a mattress in a small bedroom from Mar 13 to 16.
While the parents showed evidence of SARS-CoV-2 antibodies 3 weeks after infection, none of the children did. Noting previous studies that described low secondary COVID-19 attack rates in children, the authors concluded that the novel coronavirus is less likely to infect children than adults.
They said that the study "may have implications for preventive measures such as school closures and social distancing during the SARS-CoV-2 pandemic and encourages further studies on viral cell entry and transmission in children" and that social distancing alone may be "sufficient to control COVID-19 while school closures may reduce peak incidences and contribute to a delayed spread of the virus during the pandemic."
Suggestions amid uncertainties
In the third paper, a panel of pediatric infectious disease specialists and pharmacists from 20 North American centers drafted cautiously worded interim guidance statements on the use of antiviral drugs in children with COVID-19 in the absence of treatments with established efficacy against the coronavirus.
The experts reviewed several randomized trials and other published scientific literature to provide an update to recommendations they published in April.
Children with mild coronavirus illness need supportive care alone, while critically ill children who require supplemental oxygen or mechanical ventilation may be given the antiviral drug remdesivir (Veklury) for 5 days, the authors said. If a patient doesn't improve after 5 days of remdesivir, another 5 days can be considered.
The use of remdesivir should be decided on a case-by-case basis and informed by COVID-19 severity, trajectory, duration of ventilation, hypothesized risk factors for poor clinical outcomes, and the availability of remdesivir. The document recommends that pediatric coronavirus patients be enrolled in clinical trials, when possible.
Remdesivir may be considered in some children with MIS-C, the authors said; however, because the syndrome is not well understood, the drug should be reserved for only certain patients with the condition who test positive for COVID-19 and have ambiguous signs and symptoms, serious illness, or an RT-PCR result suggestive of a high viral load.
Hydroxychloroquine, alone or in combination with azithromycin, and protease inhibitors such as lopinavir-ritonavir are not recommended.
Study results of remdesivir in adult COVID-19 patients have been mixed, and its efficacy in critically ill patients is unknown. Likewise, there are no comparative clinical data on the effectiveness or safety of remdesivir for treating the disease in children.
The US Food and Drug Administration issued an Emergency Use Authorization for remdesivir on May 1 for adults and children with severe or critical coronavirus illness. On Aug 28, the authorization was broadened to include all hospitalized patients.
The authors emphasized that their paper is not an official guideline and that results from ongoing studies and critical review of new literature are needed to inform treatment decisions. They recommend that clinicians review guidelines published by the Infectious Diseases Society of America and the National Institutes of Health.
The panel wrote, "Optimal evidence-based practices surrounding antiviral therapy will undoubtedly continue to change over time as more data are available."