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Life-threatening COVID-associated inflammatory syndrome affects more children in Europe

A new life-threatening inflammatory syndrome associated with COVID-19 has affected 230 children in Europe and killed two so far this year. Reuters Health reports that this is according to the Swedish-based European Centre for Disease Prevention and Control (ECDC) said in a risk report that two children had succumbed to the condition: one in Britain and one in France.

The new coronavirus has so far taken its greatest toll on the elderly and those with chronic health conditions, but reports about the syndrome in children have raised fears it could pose a greater risk to the young than first through. And the World Health Organisation (WHO) has urged clinicians to be alert to the rare syndrome, but cautioned that links to COVID-19 were still unclear.

The condition, known as paediatric inflammatory multisystem syndrome (PIMS), shares symptoms with toxic shock and Kawasaki disease including fever, rashes, swollen glands and, in severe cases, heart inflammation. “I call on all clinicians worldwide to work with your national authorities and WHO to be alert and better understand this syndrome in children,” said WHO director general Tedros Adhanom Ghebreyesus.

The WHO has issued a definition of the syndrome, which it said had become more frequent during the current pandemic but has also appeared in children who did not test positive for COVID-19. “We know so far very little about this inflammatory syndrome,” said WHO epidemiologist Maria Van Kerkhove.

In France, doctors said a nine-year old boy died a week ago in the southern town of Marseille after developing a syndrome akin to Kawasaki disease and being in contact with the coronavirus though not suffering its symptoms. He was hospitalised on 2 May after scarlet fever had been diagnosed. Back home, he suffered from a severe heart ailment and was rushed back to Marseille’s Timone Hospital’s intensive care unit, where he died.

French researchers have reported Kawasaki disease-like symptoms in 17 children admitted to a Paris hospital between 27 April and 7 May, while in an average two-week period they would have expected to see only one such case.

The European Union (EU) health body ECDC added it had agreed to include the syndrome as a possible complication of COVID-19 to be reported for Europe-wide surveillance. Research efforts should aim at determining what role the coronavirus, if any, plays in causing PIMS, it said. The risk of PIMS in children is currently considered low, as is the risk of them contracting COVID-19, the agency said.

The US Centres for Disease Control and Prevention has issued guidance to doctors on how to recognise and report cases of the syndrome, following the reports of cases in Europe and more than 100 in the state of New York.

An article in The BMJ says there has been a surge in cases, following an alert to doctors in the UK at the end of April. Experts have said that the condition may be an “antibody mediated or delayed response” to COVID-19 that happens several weeks after the infection. They also stressed, however, that while doctors must know what to look out for, the syndrome is rare and has good outcomes.

Kawasaki disease is a rare condition which mainly affects children under five and is characterised by a high temperature that lasts for five days or more, a rash, and swollen glands in the neck. It can cause the blood vessels to become inflamed and swollen, and can lead to complications in the coronary arteries.

In the province of Bergamo, Italy, researchers at the Hospital Papa Giovanni XXIII have reported a 30-fold increased incidence of Kawasaki like disease since the start of the COVID-19 outbreak. In a study published in The Lancet they said that between 18 February and 20 April this year, 10 children, with an average age of 7.5, were diagnosed with the syndrome compared with 19 children, with an average age of three, who were diagnosed in the five years leading up to the pandemic (1 January 2015 to 17 February 2020).

Among the post-COVID-19 group, eight of the 10 children were positive for SARS-CoV-2 antibodies – IgG or IgM, or both.

The team reported that the rate of new cases was 0.3 per month in the pre-pandemic group, and 10 per month in the post-pandemic group. Among the COVID-19 group more children had cardiac symptoms (6 out of 10), Kawasaki disease shock syndrome (5 out of 10), macrophage activation syndrome (5 out of 10), and the need for adjunctive steroid treatment (8out of 10). In the pre-covid-19 group only two of 19 children had cardiac involvement and just three required adjunctive steroid treatment.

Julia Kenny, a consultant in paediatric infectious diseases and immunology at Evelina London Children’s Hospital, said that the Italian findings appear consistent with cases seen in the south east of England. “Evelina has more than 50 children with a similar syndrome and while very few tested positive for the virus on swabs, the majority tested positive for covid-19 antibodies when subsequently tested, suggesting their disease is associated with exposure to the virus,” she said.

At Great Ormond Street Hospital (GOSH), clinicians said they have seen a surge in cases following the alert but stressed that numbers were still small and that parents shouldn’t panic. Paediatric infectious diseases consultant Karyn Moshal said, “There are a number of these children coming through to the district general hospitals and we’re getting calls to discuss them. Although some are well enough to be managed where they are, we are erring on the side of caution and bringing them in, so we can treat them early.”

She said many of the children fall “between toxic shock and Kawasaki disease in terms of their presentation,” but that it does seem to be a distinct syndrome.

Moshal added, “The age group is a much older than the classic Kawasaki patient group, who would be under five with half of them under two. The population we are seeing are seven or eight through to 17, with the majority in their teens, around 13 or 14. The abdominal pain, the diarrhoea, and the gastrointestinal symptoms together with a persistent fever are particularly prominent in this group.”

Sophie Skellett, paediatric and neonatal intensive care consultant at GOSH, said that her department was seeing more patients with toxic shock type symptoms, but with “some sort of heart involvement.” She said that many patients were “presenting with suspected appendicitis.”

Speaking at a press briefing on the syndrome on 13 May, Liz Whittaker, clinical lecturer in paediatric infectious diseases and immunology at Imperial College London, highlighted that the peak in these cases appears to be several weeks behind the peak of COVID-19 across the country. “In London, the peak was estimated around the first or second week of April, and we think we saw the peak of these children this or last week. What we wonder is whether this is an antibody mediated or a delayed response to the virus that is happening several weeks after the infection. That would explain why these children don’t test positive for the virus using polymerase chain reaction tests,” she said. Whittaker said that while the syndrome is referred to as “temporarily associated with SARS-CoV-2” and that they cannot definitely say it is COVID-19 related, “it is happening in the middle of a pandemic so it seems reasonable to suggest they are related.”

Background: The Bergamo province, which is extensively affected by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic, is a natural observatory of virus manifestations in the general population. In the past month we recorded an outbreak of Kawasaki disease; we aimed to evaluate incidence and features of patients with Kawasaki-like disease diagnosed during the SARS-CoV-2 epidemic.

Methods: All patients diagnosed with a Kawasaki-like disease at our centre in the past 5 years were divided according to symptomatic presentation before (group 1) or after (group 2) the beginning of the SARS-CoV-2 epidemic. Kawasaki- like presentations were managed as Kawasaki disease according to the American Heart Association indications. Kawasaki disease shock syndrome (KDSS) was defined by presence of circulatory dysfunction, and macrophage activation syndrome (MAS) by the Paediatric Rheumatology International Trials Organisation criteria. Current or previous infection was sought by reverse-transcriptase quantitative PCR in nasopharyngeal and oropharyngeal swabs, and by serological qualitative test detecting SARS-CoV-2 IgM and IgG, respectively.
Findings: Group 1 comprised 19 patients (seven boys, 12 girls; aged 3·0 years [SD 2·5]) diagnosed between Jan 1, 2015, and Feb 17, 2020. Group 2 included ten patients (seven boys, three girls; aged 7·5 years [SD 3·5]) diagnosed between Feb 18 and April 20, 2020; eight of ten were positive for IgG or IgM, or both. The two groups differed in disease incidence (group 1 vs group 2, 0·3 vs ten per month), mean age (3·0 vs 7·5 years), cardiac involvement (two of 19 vs six of ten), KDSS (zero of 19 vs five of ten), MAS (zero of 19 vs five of ten), and need for adjunctive steroid treatment (three of 19 vs eight of ten; all p<0·01).
Interpretation: In the past month we found a 30-fold increased incidence of Kawasaki-like disease. Children diagnosed after the SARS-CoV-2 epidemic began showed evidence of immune response to the virus, were older, had a higher rate of cardiac involvement, and features of MAS. The SARS-CoV-2 epidemic was associated with high incidence of a severe form of Kawasaki disease. A similar outbreak of Kawasaki-like disease is expected in countries involved in the SARS-CoV-2 epidemic.

Lucio Verdoni, Angelo Mazza, Annalisa Gervasoni, Laura Martelli, Maurizio Ruggeri, Matteo Ciuffreda, Ezio Bonanomi, Lorenzo D'Antiga

In the US health officials are advising clinicians about the rare but serious inflammatory condition. The Centres for Disease Control and Prevention (CDC) is calling the condition multisystem inflammatory syndrome in children (MIS-C) and is urging clinicians to report suspected cases so officials can learn more.

The CDC provided a case definition for MIS-C in a health advisory today:
An individual under 21 years presenting with fever, laboratory evidence of inflammation and evidence of clinically severe illness requiring hospitalisation with multisystem (>2) organ involvement (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic or neurological); and no alternative plausible diagnoses; and positive for current or recent SARS-CoV-2 infection by reverse-transcriptase polymerase chain reaction, serology or antigen test; or COVID-19 exposure within the four weeks prior to the onset of symptoms.

The CDC noted the fever should be at least 38 degrees C for at least 24 hours or a subjective fever lasting 24 hours. Evidence of inflammation could include but is not limited to an elevated C-reactive protein, erythrocyte sedimentation rate, fibrinogen, procalcitonin, d-dimer, ferritin, lactic acid dehydrogenase, or interleukin 6, elevated neutrophils, reduced lymphocytes and low albumin.

Clinicians should report suspected cases to their state, local or territorial health departments even if the patient also fulfils all or part of the criteria for Kawasaki disease. MIS-C also should be considered in paediatric deaths with evidence of SARS-CoV-2. Health officials and specialists are monitoring the condition closely to learn more about risk factors and clinical course.

While the CDC did not provide guidance on treatment, Dr Sean T O'Leary a member of the AAP Committee on Infectious Diseases, said intravenous immunoglobulin and supportive care have been common approaches. “I think right now the most important thing is supportive care in an intensive care setting,” he said. “Paediatric intensive care doctors know how to take care of sick children very well and they know how to manage the things that are happening with these kids like low blood pressure and in some cases difficulty breathing, (and) in some cases kidney failure. They’re used to managing those types of conditions even though this is a new phenomenon.”

History and connection to COVID-19
In late April, the UK found increasing reports of children with a severe inflammatory syndrome similar to Kawasaki disease. The children tested positive for SARS-CoV-2 or had been exposed to the virus, according to the CDC.

New York City, which has been hit especially hard by the virus, documented 15 similar cases that occurred between 16 April and 4 May. New York state health officials were investigating 102 cases as of 12 May. “The timing of this syndrome suggests that it’s some kind of immune phenomenon. … The cases of this seem to appear about a month after a community is hit hard with COVID-19,” O’Leary said.

While potentially serious, he emphasised MIS-C appears to be rare, and most cases of COVID-19 in children are asymptomatic or mild.

Advice for parents
O’Leary said his advice for parents has not changed. They should watch for persistent fever in their children and contact their paediatrician if the child appears especially ill. “Parents really shouldn’t be afraid to take their child to their paediatrician if they’re worried they’re sick,” O’Leary said. “They should also, of course, make sure they are keeping up on their well-child care and their vaccinations. The diseases we prevent with vaccines are actually much more severe in children than COVID-19, so we want to make sure to protect children from those diseases.”

[link url=""]Full Reuters Health report[/link]

[link url=""]ECDC rapid risk assessment[/link]

[link url=""]WHO scientific brief[/link]

[link url=""]BMJ article[/link]

[link url=""]The Lancet abstract[/link]

[link url=""]AAP material[/link]

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