After two years, five pandemic waves and at least 1.4 million coronavirus infections, Minnesota might get some answers about the impact of long COVID on the state.

A statewide survey and other efforts planned this year will tally Minnesotans with symptoms that lingered after their initial COVID-19 illness. Estimates put so-called long COVID cases in the hundreds of thousands and the resulting economic costs in the billions, but the figures don't say anything about how sick these Minnesotans are and when — or if — they recover.

"This could be an ongoing chronic condition. That's what we're trying to figure out," said Jay DeSai, manager of the Minnesota Department of Health's chronic disease and environmental epidemiology section. "When you're talking about 10 percent to 35 percent of people having these symptoms [after COVID-19], that's a huge public health issue and we need to be paying attention to it."

The survey of people who had COVID-19 is planned by Minnesota's Long COVID program — the first of its type among states that was launched with $900,000 in federal grants. Gov. Tim Walz has proposed another $10 million over four years to continue its efforts.

And last week, President Joe Biden issued a memorandum to speed up federal research efforts to learn the causes and treatment of long COVID.

The prevalence of long COVID varies with the definition. The federal government calls it PASC — short for post-acute sequalae of SARS-CoV-2 — and defines it as symptoms that persist four or more weeks after coronavirus infection. Severe cases qualify for disability benefits. In contrast, the World Health Organization defines long COVID as symptoms that persist three months after initial infection and aren't explained by another diagnosis.

PASC occurs in 43% of infections worldwide and 57% of hospitalizations, according to a University of Michigan review last fall of available research. The California-based Solve Long COVID Initiative conservatively estimated a 7.1% prevalence among known COVID-19 cases in Minnesota. That would be a total of 391,000 people, including 130,000 with disabling disruptions to work and daily life.

The Rev. Michelle Hargrave is in between. She maintained normal duties at Centenary United Methodist Church in Mankato as it transitioned from virtual to masked to unrestricted services, but the 57-year-old is far from recovered.

"I feel like it aged me a lot and really fast," she said.

Hargrave thought her sister botched Thanksgiving dessert in 2020, but the next day she realized that COVID-19 had ruined her sense of taste. She isolated from her family in the basement and endured the fatigue, fever and respiratory symptoms alone. The infection cleared, but the fatigue remained and new problems emerged.

Words so easy for a preacher to recall became elusive and her thoughts felt jumbled — the "brain fog" often associated with long COVID. Friends slowed down for her on walks.

"It was 14 months after my infection when I finally thought, 'Hey, I can get up the stairs without getting out of breath!'" she said.

Hargrave's experience is characteristic of long COVID. Fatigue and brain fog are most common. The condition appears more likely with age and is reported more among women.

These trends match those of more than 550 long COVID patients who have enrolled in Mayo Clinic's COVID-19 Activity Rehabilitation Program, which helps them return to work and improve their activity levels. Women have stronger immune systems, which put them at greater risk for disorders similar to long COVID in which their own immune systems turn on them, said Dr. Greg Vanichkachorn, medical director of the Mayo program.

Most patients benefit from occupational therapies and pulmonary exercises, but Vanichkachorn said he hopes the same drugs used against autoimmune disorders such as lupus can prove effective against long COVID.

Studies show severe COVID-19 elevates long COVID risks, but many patients in Minnesota's post-COVID therapy programs had mild or even asymptomatic infections. Doctors are concerned that this winter's unprecedented pandemic wave, caused by a fast-spreading omicron coronavirus variant, could fuel long COVID as well.

Omicron pushed Minnesota's known total above 1.4 million coronavirus infections. However, the Centers for Disease Control and Prevention has projected 2.7 million known and unknown infections, based on a reexamination of blood samples from medical tests for COVID-19 antibodies. A record 48.3% of Minnesota's samples in early January contained antibodies.

"I'm sort of waiting for this tsunami of cases to appear," Vanichkachorn said.

Minnesota's progress with COVID-19 vaccinations and boosters could limit the growth of long COVID. Researchers estimate vaccination reduces risks of long COVID symptoms by 50% or more. However, omicron produced a lower rate of severe COVID-19 despite its rapid spread, so it may have produced fewer long COVID cases as well.

Doctors also worry about a silent wave of long COVID among minority members and low-income Minnesotans who haven't reported symptoms or enrolled in rehab programs because they can't afford time off work. The Black Coalition Against COVID, the Yale School of Medicine and the Morehouse School of Medicine issued a report in late March identifying racial disparities in access to diagnosis and treatment of the syndrome.

"These people are out there," Vanichkachorn said. "We don't see them a lot and they are struggling with their symptoms, sometimes dangerously for themselves and the public. Think about a city bus driver. How can we reach them better?"

Minnesota's survey will help by asking known COVID-19 patients to confidentially report their demographics and symptoms.

The federal RECOVER trial will provide answers as well. It missed the omicron wave as an opportunity for recruitment, but it now is enrolling thousands of people with new COVID-19 cases to see which ones develop long COVID over time. Sioux Falls-based Sanford Health is recruiting 100 people.

Research is identifying the physical scars of long COVID, too. A British study last month reviewed imaging scans of 785 people 51 and older and found those with COVID-19 had more markers of tissue damage in the brain and a reduction in gray matter in sections responsible for memory and decision-making.

Lacking physical and diagnostic markers, doctors have diagnosed long COVID by excluding other diseases. So many people have had COVID-19 that some are going to have long COVID while others have unrelated conditions with similar symptoms, said Dr. Shannon Neale, director of family practice for St. Louis Park-based Park Nicollet.

An elderly man in her clinic last week likely had long COVID, having been infected in late January. He appeared to fully recover but later felt dizziness and fatigue. A first step was an electrocardiogram to rule out cardiac disease.

Patients who veer from COVID-19 to full recovery to long COVID are particularly challenging to diagnose, she said.

Fairview Health's Adult Post-COVID-19 Clinic has treated enough people to notice another frustrating phenomenon — second COVID-19 cases after recovery from long COVID.

"Fatigue got worse, activity tolerance got worse. We are heading back to the drawing board with physical therapy and occupational therapy," said Dr. Tanya Melnik, a leader of the Fairview clinic. "I am hoping that their recovery will be faster this time, but it is so heartbreaking to see these patients go for round two."

Depression and anxiety are common, especially among long COVID patients who can't shake cognitive symptoms, Melnik said. Most patients make progress or recover within five months, but even a few from the first pandemic wave in spring 2020 still have symptoms.

Therapy solutions vary. Some patients lose their sense of smell, or they smell rotten fish and smoke everywhere, Melnik said. Olfactory rehab involves placement of scented cotton balls under the nose to retrain the sense of smell.

Park Nicollet's Neale said primary care doctors must play a role because the demands of long COVID will exceed the capacity of specialty clinics. Her colleagues have been trained in diagnosis and management of the condition.

Long COVID is common enough that it affected one of Neale's closest childhood friends — Hargrave, the Mankato preacher.

Hargrave hasn't received treatment for long COVID but has stepped up her exercise to improve her breathing and energy and uses word games like Wordle to stay sharp. Most people wouldn't know she had COVID-19 hangovers, but she still can't taste her once-favorite strawberries and raspberries. Shampoo smells more like pepper.

"My vocabulary took a hit as well. I know I'm middle age, but it's a marked change from where I was two years ago," she said. "I will think, 'Oh, there is a word right there,' and I have no idea what it is."

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