Four years after the outbreak of the Covid-19 pandemic, doctors and researchers are still seeking ways to help patients with long Covid, the persistent and often debilitating symptoms that can continue long after a Covid-19 infection.

In adults, the most common long Covid symptoms include fatigue and brain fog, but for children the condition can look different. A study published last month suggests preteens are more likely to experience symptoms such as headaches, stomach pain, trouble sleeping, and attention difficulties. Even among children, effects seem to vary by age. “There seems to be some differences between age groups, with less signs of organ damage in younger children and more adultlike disease in adolescents,” says Petter Brodin, professor of pediatric immunology at Imperial College London.

While vast sums have been devoted to long Covid research—the US National Institutes of Health have spent more than a billion dollars on research projects and clinical trials—research into children with the condition has been predominantly limited to online surveys, calls with parents, and studies of electronic health records. This is in spite of a recent study suggesting that between 10 and 20 percent of children may have developed long Covid following an acute infection, and another report finding that while many have recovered, some still remain ill three years later.

Now, what’s believed to be the first clinical trial specifically aimed at children and young adults with long Covid is underway, recruiting subjects aged 7 to 21 on which to test a potential treatment. It builds on research that suggests long Covid in children may be linked to the gut.

In May 2021, Lael Yonker, a pediatric pulmonologist at Massachusetts General Hospital in Boston, published a study of multisystem inflammatory syndrome in children (MIS-C), which she says is now regarded as a more severe and acute version of long Covid. It showed that these children had elevated levels of a protein called zonulin, a sign of a so-called leaky gut. Higher levels of zonulin are associated with greater permeability in the intestine, which could enable SARS-CoV-2 viral particles to leak out of the intestines and into the bloodstream instead of being excreted out of the body. From there, they could trigger inflammation.

As Yonker began to see more and more children with long Covid, she theorized that many of the gastrointestinal and neurological symptoms they were experiencing might be linked. But her original study also pointed to a possible solution. When she gave the children with MIS-C a drug called larazotide, an existing treatment for people with issues relating to a leaky gut, the levels of viral particles in their blood decreased and their symptoms improved.

Larazotide works by tightening the junctions between cells in the intestinal lining—making the gut less leaky. Yonker explains that it has been studied and trialed extensively, mostly for celiac disease, and has an excellent safety profile. “So, we thought it would be justified to test larazotide in long Covid.”

Yonker and her colleagues will administer larazotide to 32 patients between the ages of 7 and 21, who will take the drug for eight weeks; a further 16 patients will receive a placebo. To qualify for the trial, patients must have a detectable presence of the Covid-19 spike protein in their blood. The intention is to see whether reducing intestinal permeability can make a noticeable difference to the young patients’ symptoms and quality of life.

Running such a trial has not been straightforward. “It began last year, but we had to put it on pause for a few months because of staffing and drug supply issues,” says Yonker. “One of the requirements is that we need to ensure that the spike protein is present in the blood, which can involve multiple blood draws from these children, which takes time. Because of this I expect it will take one to two more years to recruit all the patients we need, but I would love to move faster.”

The results, when they emerge, will help researchers determine whether a leaky gut is likely to be a major cause of disease in at least a subset of patients, and whether larazotide should be trialed more widely as a possible treatment.

There could be other gut-related involvement: Brodin believes that in some children, the virus lingers in the gut rather than being fully excreted, enabling it to actively damage the intestinal wall and contributing to gastrointestinal problems. He suspects that this viral persistence can then induce an autoimmune reaction in the bloodstream, causing further symptoms.

Yonker’s trial is also encouraging other pediatric long Covid researchers to initiate their own trials, exploring other theories behind the condition. Danilo Buonsenso, a pediatrician at the Gemelli University Hospital in Rome who conducted the first study examining whether children were developing long Covid, described the study as fascinating. He is now trying to get funding for an ambitious trial testing multiple treatments.

Buonsenso’s work includes studies suggesting that blood clots, as well as inflammation within the lining of the blood vessels known as the endothelium, may play a role in driving certain symptoms. Separately, he led a study that found some children with long Covid also struggle with a condition called postural tachycardia syndrome (POTS) that affects many adults with long Covid, too.

“In my opinion, there will not be a single drug that will solve long Covid, as multiple things are being documented,” he says. “We need to investigate the role of low-dose anticoagulants with known effects on reducing endothelial inflammation. But we also need to look at specific drugs for POTS and specific medications for the neurocognitive symptoms like chronic pain and headache.”

Meanwhile, Yonker’s focus on the gut represents a crucial first step. Given the desperation of children suffering from the condition, and their parents, she is hopeful that if her trial proves successful, it will provide an evidence-based treatment option specifically for children. “I think it’s extremely important to advocate for timely treatment advances in children suffering from long Covid rather than wait for trickle-down guidance, based on what we see from trials in adults,” she says.