COVID cases keep rising and so does the risk of long COVID. Philly researchers are trying to understand why.

COVID-19 cases are ticking up across the nation again, exposing even the mildly ill to the risk of developing a still poorly understood constellation of health problems known as long COVID.

Researchers at Temple University and the University of Pennsylvania are among those exploring why some people recover from COVID unscathed, while others experience months of incapacitating symptoms. Their ongoing studies examine factors such as blood-vessel abnormalities and the frequency of symptoms.

Despite progress in treating COVID, Penn researcher Nuala Meyer has been frustrated by the reality that “patients’ quality of life could still be pretty poor.”

“The clinician in me wants to know: What can we do a little bit better?” said Meyer, director of the Center for Translational Lung Biology at Penn. “And can we explain it better?”

The phenomenon of lingering side effects from a viral infection is not new to COVID. Similar conditions were reported in some people after infections from Ebola, SARS, and Lyme disease. In those cases, the causes are not fully understood either.

But with COVID, many more are affected due to the sheer number of people infected — an estimated 548 million worldwide, according to the World Health Organization.

“That’s what’s so overwhelming,” said Michael Harhay, a professor of epidemiology and medicine at the University of Pennsylvania, who is also seeking to understand the long-term effects of COVID.

The risk is ongoing. Pennsylvania and New Jersey are both reporting COVID case increases compared with two weeks ago. Although Philadelphia’s counts remain steady, COVID cases have ticked up slightly in recent days in its four bordering Pennsylvania counties, according to the New York Times COVID tracker. Two neighboring New Jersey counties, Camden and Burlington, reported rising cases.

Hospitalizations remain on the decline in Pennsylvania but are rising again in New Jersey.

Nationally, COVID cases are up 4% and hospitalizations are up 10% over 14 days, largely driven by the BA.4 and BA.5 omicron subvariants. The latter is highly infectious and vaccination or previous bouts with COVID provide less protection against mild illness than seen with other strains of omicron.

Brain fog, breathlessness, fatigue, erectile dysfunction, headaches, and lost of taste or smell lasting two months or more after the initial infection are among the symptoms described as long COVID.

Estimates on how often they occur vary widely. The Centers for Disease Control and Prevention has cited research suggesting that one in five people ages 18 to 65 experiences long COVID symptoms after an infection ― and one in four people over 65 ―though other studies have found different results, with one Dutch finding 50% of COVID sufferers can develop long COVID, and another from Veterans Affairs reporting a frequency of just 7%.

Multiple infections appear to increase the chances of developing health problems including long COVID symptoms, according to a recent large study involving U.S. Department of Veterans Affairs health records that gained media attention after being posted online ahead of academic peer review.The effectiveness of vaccination in preventing it is unclear. Some studies have shown vaccines to offer meaningful protection against long COVID, while one recent report found that protection to be minimal.

To look for common factors, Temple researchers are analyzing CT scans taken of about 300 people’s lungs before, during, and after their hospitalizations for COVID. The effort builds on a 2021 study of people hospitalized for COVID-related pneumonia led by Daniel Salerno, Temple University Hospital’s director of critical care services in the respiratory intensive care unit. Salerno found blood vessels in some patients’ lungs were abnormally widened.

He also noted about half of his patients who have had COVID reported some lingering symptoms, even those who didn’t need to be hospitalized, and damage to blood vessels could be a cause.

“COVID can affect blood vessels everywhere,” Salerno said.

» READ MORE: Vaccination can prevent long COVID, and may even alleviate symptoms, studies find

COVID can also inflame a thin layer of tissue lining the blood vessels, called the endothelium, which can lead to clotting.

Such damage can be difficult to detect, Salerno said, particularly in tiny blood vessels.

At Penn, cardiovascular medicine specialist Julio Chirinos is tracking cases of heart failure, strokes, and heart attacks in people hospitalized for COVID to understand if a bout with the virus increases a person’s risks well after the infection clears.

He is still seeking participants for another, wider-ranging study using scans, physicals, and endurance tests to see if abnormalities can be attributed to COVID infections. That study will analyze participants’ livers, brains, lungs, and hearts, as well as their oxygen consumption while exercising. Researchers are hoping to include people with no history of cardiovascular problems.

“I have no doubt that once all this data comes together we’re going to make progress on this,” Chirinos said.

By studying large groups of participants, researchers expect to identify which conditions are the consequences of a COVID infection.

“You can definitely determine whether something’s related to COVID and not part of the background risk of these people,” Chirinos said.

Long COVID complaints like cold fingers or tingling in toes make sense as the result of a blood-flow problem, Penn researchers noted. The Temple team also expects that ongoing studies will find the vascular system is involved in long COVID, along with factors like a damaged or inflamed immune response.

» READ MORE: Philadelphians isolated by long COVID find hope and connection through social media

Penn is also tracking the experiences of 88 former COVID patients for up to two years.

Blood tests every six months measure their protein levels and white blood cell counts, while surveys ask how often patients experience breathlessness, depression, or anxiety. Researchers hope to answer why the severity of the initial COVID infections doesn’t necessarily predict how serious the aftereffects are.

“You might expect they would have more symptoms after ICU stays and hospitalized stays,” Penn’s Meyer said. “There’s still quite a range.”

Another unanswered question is how long the post-COVID symptoms linger. Over the pandemic’s 2½ years, Temple’s Salerno has seen most of his patients improve. But at Penn, researchers have observed the opposite in some cases, seeing people whose lungs become progressively more stiff and scarred after an infection.

“I think it just highlights the complexity of trying to understand what this virus is doing in our bodies,” Meyer said.