Count the American children who have captured COVID-19 since February and you will soon exceed the population of Boston.
Fortunately, most of these 697,000 confirmed or probable cases have had relatively mild illness – and somewhere between 16 and 45 percent of children may not show any symptoms. Yet some in this group – clinically defined as those under the age of 21 – continue to develop a serious condition called multisystem inflammatory syndrome in children or MIS-C.
Thanks to months of urgent research, what began as a mysterious spectrum of symptoms has gathered into a definable disease with early signs that include fever, rash, abdominal pain, diarrhea and vomiting. Although MIS-C is rare ̵
“It’s happening so fast, and kids are so sick that 70 percent will require admission to an ICU,” said Alvaro Moreira, a medical scientist at the University of Texas at San Antonio who recently published an analysis of the results of several scientific articles. in ClinicalMedicine based on 662 cases of MIS-C.
Even when clarity arises around the early stages of the syndrome, there are increasing questions about its true prevalence and its long-term outcomes. MIS-C usually develops several weeks after the classic signs of coronavirus appear in children, such as cough, body aches and runny nose. Studies have also revealed that the condition can occur after an asymptomatic infection with the virus.
“It’s the scary part,” Moreira says. “It can develop even when parents do not know their child has had COVID-19.”
The long-term consequences are also under control after a handful of studies showing that even after clearing the airways, coronavirus can continue to replicate in the digestive system, especially in children. It is a discovery with implications far beyond rare pediatric cases.
“The data show that the virus can linger in the stool for up to a month,” said Siew Ng, associate director of the Center for Gut Microbiota Research at the Chinese University of Hong Kong. Other recent studies of the viral structure may provide clues both about the gastrointestinal effect of the disease and why some patients’ immune systems become haywire. “The implication is that COVID-19 is not just a respiratory disease.”
Coronavirus super antigen
When doctors first encountered children with these strange symptoms, first in Italy and then Britain, they suspected Kawasaki disease, another serious disease in young children that causes inflammation of the blood vessels. While some clinical symptoms overlap, there are clear differences, says Moshe Arditi, an expert on Kawasaki disease and professor of pediatrics and biomedical science at Cedars-Sinai, a medical center in Los Angeles.
Most MIS-C patients are elderly. The median age of those affected is nine, while Kawasaki patients are generally under two. They also have higher levels of biomarkers – proteins found in blood samples – that predict levels of inflammation, and they often experience severe abdominal pain “to the point that [cases] is confused with appendicitis, ”says Arditi.
Together with collaborator Ivet Bahar, a prominent professor of computational and systems biology at the University of Pittsburgh, Arditi went on to look for clues as to how the virus could cause these reactions. SARS-CoV-2 coronavirus has a spherical shape with spikes that attach to a protein on the surface of human cells called ACE2. It looks like a microscopic version of the burrs stuck to your socks after a hike.
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Unlike other known coronaviruses, Bahar and Arditi found that SARS-CoV-2 has a unique function in one part of its tips. This spike fragment is similar to the bacterial toxins known as superantigens – proteins that generate excessive response from T cells, a vital member of the immune system. Other studies show that severe COVID-19 is caused by the immune system overreacting to the coronavirus, causing cascades of excess inflammation that permanently damage many parts of the body. Arditi says the tip fragment may explain why MIS-C appears to be what happens during blood infections such as sepsis or bacterial toxic shock syndrome.
“It simply came to our notice then [spike] region to elicit the same type of very strong reaction [as other super antigens]Says Bahar. This revelation can bridge how and why coronavirus causes other types of hyperinflammation. Arditi says, “We finally found the virus-tip segment that can induce all of these immune responses” – not only in MIS-C, but possibly in adult COVID-19 cases.
A new CDC study, largely overlooked because it came out the same weekend as President Trump’s COVID-19 diagnosis, shows that even adults with the virus can develop a serious condition similar to MIS-C. The report described 27 patients with “cardiovascular, gastrointestinal, dermatological [skin]and neurological symptoms without severe respiratory disease, ”and called the condition MIS-A – for adults.
The bridge between MIS-C and long-lasting COVID?
Toxic shock has also long been associated with short-term and long-term mental dysfunction, so Bahar wonders whether the superantigen quality of SARS-CoV-2’s peak can also explain the high percentage of neurological symptoms seen in adult COVID-19 patients. One study reported nearly one-third of hospitalized COVID-19 patients experienced altered cognitive function well after discharge.
The hallmarks of both MIS-C and MIS-A are gastrointestinal symptoms. Arditi says that again a hint can be found in the superantigenic region of the virus tip.
Because these symptoms can take weeks to manifest after an initial infection, nasal swabs and genetic tests for the virus – the current methods for confirming the presence of the germ – often return negatively. Some researchers now suspect that the virus is still hiding in the body during MIS-C syndrome, possibly in the gastrointestinal tract.
“Our gut carries the largest immune organ – the gut,” says Ng, as the digestive tract is filled with a variety of immune cells. “We should not ignore it.”
The peak protein of SARS-CoV-2 is structurally similar to Staphylococcal Enterotoxin B (SEB), which is produced by bacteria and is one of the strongest gastrointestinal toxins known in medicine. “A very small amount of it in food will make you very ill with very severe stomach pain and a lot of vomiting,” explains Arditi. Respiratory coronavirus in humans evolved from ancestors known to live in the intestines of bats, and the virus behind the original SARS epidemic in 2002-2003 caused severe gastrointestinal disease.
New research in medical journal Gut adds to this case by showing that the virus persists in the digestive tract long after it disappears from the nose, mouth and lungs. Ng, lead author of the paper, has even developed a coronavirus test for feces because she says it is a better way to screen children and identify possible sources of silent transmission.
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“It is safe and easy to collect samples,” she says. “The poo all the time.” Hong Kong has been using these tests to screen vulnerable travelers since March.
Another small study in June showed that two children had the virus in their feces 20 days after the sore throats came back negative. Similar work from the NGs group found that some COVID-19 patients, including pediatric cases, continued to experience intestinal dysbiosis – the term for microbial imbalance – even after recovering from their initial symptoms.
“We were surprised to see how severe this dysbiosis is, even in patients who had mild or moderate cases,” says Ng, whose team is conducting a clinical trial on whether changing the composition of microbes in the gut can relieve COVID -19.
Your microbiome is constantly changing based on your environment, your diet and your age. But Ng says healthy children typically have a “golden age” of a balanced microbiome that can change from two to twelve years – around the age when tweens begin to respond to COVID-19 as adults. When Ng’s team analyzed patients’ microbiomes as part of a separate paper published in September, they identified the 23 types of intestinal bacteria missing that were associated with increased COVID-19 severity.
“We know most of the functions of these bacteria well. They help us produce short-chain fatty acids, ”she says.
The long efforts
As these issues begin to be teased, it is still uncertain how children with MIS-C will cope. Most will recover if they receive the right treatment, but Moreira found that their hospital stays were long, averaging eight days. And he warns that we do not know the long-term consequences.
“We know that patients with Kawasaki disease can later develop aneurysms, blood clots or blood clots and have an increased risk of high blood pressure and heart attack at a younger age,” he says.
The lasting consequences of the condition can fall unequally on blacks, natives and people of color: Both Moreira’s review and the CDC report on MIS-C showed that, as in adults who have the virus, racial differences were evident. Of the 20 children who died of MIS-C in the United States, 45 percent were Spanish-speaking, 29 percent black, and 4 percent American.
Other risk factors include underlying conditions such as obesity, which can weaken the cardiovascular system. Heart damage appears to occur in many MIS-C cases, raising concerns about lifelong effects, says Joseph Abrams, an epidemiologist at the CDC and author of a recent study on MIS-C.
Although the condition is rare, Abrams says, because the pandemic is so prevalent that it can affect many children. And he adds: “Every child’s death is a terrible and tragic situation.”