These children had Covid-19 beat. Then they got seriously ill

Patrick Davies’ phone wouldn’t stop buzzing. It was April 24 and Davies, a consultant in paediatric intensive care at Nottingham University Hospital, was being inundated with WhatsApp messages from his colleagues. “It was weird,” he says. The first message, from a colleague at a paediatric intensive care unit in London, was soon followed by another from a colleague in Leicester, then one in Nottingham. The doctors were exchanging details of a mysterious new condition, one that was putting a small but significant number of children in intensive care – and it seemingly had a link with Covid-19.

Most of these children had quite severe symptoms: fever, shock, vomiting and diarrhoea were common, some had difficulty breathing and had to be put on mechanical ventilators, around a third had evidence of abnormalities in their coronary arteries. The symptoms had all the hallmarks of a rare but dangerous inflammatory syndrome, but doctors were stumped as to what was causing it. “This was something we’d never seen,” Davies says. “They were so unstable. If you took one wrong turn they would become even more unwell.” Within days of the flurry of WhatsApp messages, Davies had started collating information about these children to try and understand what was happening.

Between April 1 and May 10, England’s 23 paediatric intensive care units recorded each case of this strange new syndrome. This research, published in The Lancet, adds to a small but significant body of evidence shedding light on yet another Covid-19 mystery. In those six weeks in April and May, 78 children were admitted to intensive care units in England with the new inflammatory syndrome, all of them in serious condition and most requiring some form of life support. The vast majority of children made a good recovery and were discharged within one week. Two sadly died.

Almost all the children admitted to hospital with the mystery syndrome had a few things in common. Most were aged between 5 and 15, with a median age of 11. Most children had no underlying health conditions. Around four weeks before being admitted to hospital they all either had mild Covid-19 symptoms or were in the same household as someone who had tested positive. In almost all cases, antibody tests confirmed they had been infected with Covid-19. But, bizarrely, when the children were checked for a current Covid-19 infection, only 22 per cent of them tested positive. In one respect, most of these children had beaten the virus. But in reality, some were fighting for their lives.

Paediatric intensive care units in Europe and North America had no warning that this new mystery syndrome was about to hit. While a small number of children in China had been hit by severe cases of Covid-19, there had been no reports of this kind of illness. England’s paediatric intensive care units had been closely following the progress of Covid-19 as it spread from China to Italy, then France. “We were gearing up to take adults. This whole issue completely blindsided us,” says Davies. “Suddenly all these patients started popping up with a hugely complex illness. The clinical variability was frightening,” Some years earlier, Davies had created the WhatsApp group that sounded the alarm for exactly this sort of situation. Its members represent all 23 paediatric intensive care units in England, allowing colleagues to quickly collaborate and respond to particularly challenging patients. But as the messages flowed, one thing became clear: nobody had seen anything like this before. “We’ve all been doing this job for a while and we know how to treat patients,” Davies says. “And suddenly we were faced with patients who were completely different. It would be easier to understand if it was just a virus doing this. But it’s much more complicated because it’s not just a virus, it’s some after effect.”

Davies and his colleagues had found themselves at the of a medical mystery – the vast majority of children who contract Covid-19 have a mild illness or no symptoms at all. But, for an incredibly small number of children Covid-19 seemingly triggers a delayed and violent immune response. The syndrome has some similarities with other incredibly rare conditions: Kawasaki disease and toxic shock syndrome. It also has similarities with symptoms experienced by some adult patients infected with Covid-19 – inflammation, heart and kidney damage and clotting of the blood, amongst others.

Paediatricians treating children with the mystery syndrome also observed similarities to the immune response seen in some adults in intensive care with Covid-19. These adult patients appear to be making a recovery, only for their own immune system to go into overdrive. This immune response, known as a cytokine storm, wreaks havoc on the human body. The children Davies and his colleagues treated were seemingly suffering from a similar immune response – but unlike the adult cases, the majority of these children weren’t currently infected with Covid-19. This raised a puzzling question: what, precisely, was making these children so ill? Two days after Davies received the first WhatsApp messages, NHS England put out an alert saying there was “growing concern” that an inflammatory syndrome related to Covid-19 was emerging in children in the UK.

The alert made international headlines, with news organisations warning of a rare but dangerous syndrome that may be linked to coronavirus. That syndrome now has a name – in fact it has two. In the UK, it is known as Paediatric Inflammatory Multi-System Syndrome Temporally Associated with Sars-CoV-2, or PIMS-TS for short. In the US, it is known as multisystem inflammatory syndrome in children, or MIS-C. The strangeness and complexity of this new syndrome is also reflected in how it is defined: the US, UK and World Health Organisation each have slightly different definitions of it.

The number of children affected by this syndrome is small, but significant. Data from paediatric intensive care units in England going back five years shows that typically one patient a week would be admitted with such symptoms. At its peak, Davies and his colleague recorded 32 intensive care admissions for PIMS-TS in a single week. All those involved in studying and treating children suffering from this syndrome stress how rare it is. If children who contract Covid-19 and end up in intensive care represent a drop in the ocean of this pandemic, then children who suffer from PIMS-TS represent a miniscule fraction of that drop.

“On a scientific level it’s quite fascinating,” says Davies. “We were faced with something completely new that’s not seen in other viruses at all.” And at such an early stage answers are hard to come by. One explanation for PIMS-TS, Davies speculates, is that children suffering from severe cases of the syndrome have mild cases of Covid-19 and beat the virus, but, after the virus is gone, underlying complications start to build up in the background, before cascading into a dangerous illness. Another possibility is that these children catch Covid-19 once, beat it, then catch it again. Faced with a second infection, their immune system gets confused and goes into overdrive. “The body just goes haywire and tries to overcompensate for the second infection,” Davies says. Another possibility is that some children who get Covid-19 are also exposed to other antigens, which change their immune response to the disease and trigger PIMS-TS. But all this is speculation. To date, nobody has found a direct trigger for the illness. But, patient by patient, doctors are getting closer to unlocking its mysteries.

In simple terms, PIMS-TS is an inflammatory condition that causes the body to overreact with potentially dangerous consequences. But this is not a simple syndrome. Children admitted to intensive care with PIMS-TS have serious inflammation throughout their bodies. Inflammation is, in itself, a normal immune response to help fight an infection. But, in some cases, the immune system goes into overdrive and starts to attack the body. When this happens, things get serious. For children with PIMS-TS, this inflammation often spreads to their blood vessels. If this happens around the heart, it can cause serious complications.

As with Covid-19, PIMS-TS is also characterised by its sheer weirdness. Adults with more severe cases of Covid-19 have urinated blood, suffered strokes, heart attacks and kidney failure. Some adults who have had no other symptoms have complained of lesions on their toes, which may be a strange but perfectly healthy response to the virus. Since it appeared in China, Covid-19 has baffled doctors who, at first, thought it was a respiratory illness. Months later, it is now all-too apparent that, in severe cases, Covid-19 is a bizarre, multi-organ disease.

This might help to explain why PIMS-TS almost defies characterisation. “Why is there this lag that’s not part of the acute infection?” says Davies, referring to the month-long gap between surges of Covid-19 infections in the community and children being admitted to intensive care with symptoms of PIMS-TS. “Four weeks for a child is half a lifetime, that’s a long pause between the community surge and the presentations. We don’t understand that yet.” As with Covid-19, studies of PIMS-TS to date have raised more questions than answers. Why does PIMS-TS only affect children? Why, in all studies, does it disproportionately affect children from ethnic minority backgrounds? Why do almost three-quarters of children suffering from the syndrome test negative for Covid-19? And, crucially, what triggers the syndrome?

“There’s something going on in their immune system,” says Adrienne Randolph, senior associate in critical care medicine at Boston Children’s Hospital in Massachusetts. Randolph, like Davies, is part of an international effort to collect as much data as possible about PIMS-TS. Randolph was involved in a US study of the syndrome funded by the Centres for Disease Control. The study, published in the New England Journal of Medicine, found 186 patients with the syndrome in 26 states between March and May. A separate study, published in the same journal but focussed on children in New York State, recorded 95 cases of the syndrome in hospitalised children during the same period. To date, approximately 1,000 cases of the syndrome have been recorded worldwide. “I’m getting reports of cases from other countries,” says Randolph. “Someone from Honduras emailed me to say that they had quite a few cases. So it does seem to be tracking after the virus.”

Defining a new syndrome is hard. Michael Levin, a professor of paediatrics and international child health at Imperial College London, compares it to the parable of the blind men and the elephant, with each declaring that the part of the animal they have touched fully defines it. With PIMS-TS, the lack of a trigger for the syndrome is especially problematic – but so is the lack of data on the range of symptoms caused by the syndrome. Studies to date have focussed on hospitals and intensive care units, so by design they are only detecting children with the most severe symptoms. But there are likely other children experiencing far less severe symptoms several weeks after a mild or asymptomatic case of Covid-19. Their symptoms may be mild, but trying to understand how many children are being affected by PIMS-TS will be crucial for understanding more about the syndrome. This would mean that, as with Covid-19 itself, PIMS-TS affects people on a broad spectrum: from those who barely notice they are ill, to those that end up in intensive care fighting for their lives.

But as you slide down the scale of symptoms, syndromes like PIMS-TS become even more difficult to pin down. “We don’t currently have systematic evidence to say what the risk is in mildly affected children and what the risk is in severely affected children,” says Padmanabhan Ramnarayan, senior author on the UK paper and consultant in paediatric intensive care retrieval at Great Ormond Street Hospital in London. “This is a difficult diagnosis to pin down because there isn’t a very clear and precise case definition,” He gives one example of the syndrome’s weirdness. “If you take an adult that has Covid-19 and is critically ill, the primary feature for them is respiratory disease and signs of inflammation. In children with PIMS-TS you see inflammatory changes but no respiratory disease.” He believes that this confusing picture is likely the result of an age-dependent response to Covid-19. “Maybe we are seeing two different sides of the same coin,” he says.

After treating the first wave of patients, researchers are now trying to understand if PIMS-TS has long-term effects on children’s health. “We’re designing follow-up studies,” says Randolph. Such studies will focus on multiple organs to determine how much of a mark PIMS-TS leaves on the children who suffer from it. “Most of these children have, from our perspective, a very mild need for intervention and have been discharged from intensive care,” says Ramnarayan. “But we don’t know if this inflammation has long-term impacts.” For Randolph, the heart is a particular area of concern. In studies in the US and UK, inflammation caused by PIMS-TS has been shown to create abnormalities in the coronary artery. It can also damage the muscle of the heart itself and, in some patients, cause problems with the actual rate or rhythm of the heart. “Does that normalise over time?” asks Randolph. More data on the long-term impacts of the syndrome – and on patients admitted to hospital with it – will also help doctors to intervene earlier and stop some children from becoming seriously ill.

As the data trickles in, there is concern amongst some clinicians that we are only seeing the tip of the iceberg. That’s not to say that this incredibly rare syndrome is not in fact rare, but it could be that there are a significant number of children out there who have far milder symptoms of it and never see a doctor. “I think that is likely,” says Ramnarayan. “But it is difficult to estimate numbers because we don’t have a very precise case definition for the condition.” And those children could, in theory, have complications caused by the syndrome that have not been detected.

To understand that – and so many other things about PIMS-TS – doctors need more data. “It presents in different ways in different patients. It’s likely that there’s more than one thing going on,” says Randolph. Another crucial area of research, Randolph explains, is to collect samples from patients with PIMS-TS to better understand what mechanisms underlie the syndrome. That’s important for two reasons: first, this is an incredibly rare syndrome and gathering enough patient data to make conclusions is hard. Second, the syndrome is wildly heterogeneous.

Ramnarayan echoes the call for more data. In the UK, the British Paediatric Surveillance Unit is currently undertaking a surveillance study and asking paediatricians across the country to report any children who fit the definition of PIMS-TS. With more data will come more insights. This will both help doctors treating this rare syndrome, but also help to explain what causes it. “There are children who may have this who don’t come into hospital,” says Ramnarayan. “So we probably don’t know the true extent of how many children have this condition.”

James Temperton is WIRED’s digital editor. He tweets from @jtemperton

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