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Research & Innovation

Long COVID, ‘Long Cold’: What to Know About Post-Acute Infection Syndromes

BY CARRIE MACMILLAN October 17, 2023

Researchers are exploring how various pathogens cause chronic symptoms.
Poster for video Understanding Long Covid: Post-Acute Infection Syndrome

As researchers learn more about Long COVID and what causes coronavirus symptoms to persist, attention is shifting to other post-acute infection syndromes, including what some are calling “long cold.”

It’s long been known that various viruses can cause symptoms—sometimes mild, sometimes debilitating—to persist for weeks to years after an infection. Historically, however, people’s complaints were poorly understood and not taken seriously. But Long COVID—due to the large number of people it has affected within a relatively short period of time—is helping to change that.

A recent study published in The Lancet’s EClinicalMedicine surveyed more than 10,000 people who had COVID, another respiratory infection, or no infection/sickness at all. The participants were asked if they experienced 16 symptoms found in Long COVID, including fatigue, shortness of breath, dizziness, memory problems, coughing, and sleeping issues.

Those who had been infected with COVID or other respiratory infections were more likely to have new or continuing symptoms more than four weeks after the acute infection than those who had not been infected with COVID or another respiratory virus.

Researchers and clinicians at Yale School of Medicine and Yale Medicine have been working to treat people affected by Long COVID and other post-acute infection syndromes. The Yale New Haven Long COVID Multidisciplinary Care Center evaluates people experiencing Long COVID symptoms and works closely with an array of specialists, including cardiologists, neurologists, pulmonologists, and rheumatologists, to find the best treatments for them.

Yale’s Center for Infection & Immunity aims to provide a better understanding of infectious diseases with a focus on post-acute infection syndromes, such as Long COVID, post-treatment Lyme disease, and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

“Ultimately, the hope is to find a way to prevent post-acute infection syndromes or cure them when they occur, says Akiko Iwasaki, PhD, a Yale immunobiologist and director of the Center for Infection & Immunity. “But to get there, we need to understand the underlying biological mechanisms that cause these diseases. Without that, it's very difficult to design a cure.”

Below, we talked more with Iwasaki about what we know—and don’t know—about Long COVID and other post-acute infection syndromes.

What is post-acute infection syndrome?

Post-acute infection syndrome encompasses chronic illnesses that occur after an infection from a virus, bacteria, or parasite. For example, this could include prolonged symptoms after COVID, caused by the SARS-CoV-2 virus; other infections caused by viruses, bacteria, or parasites; or Lyme disease, which is caused by certain types of bacteria.

“The prevalence of these post-acute infection syndromes differs between pathogens. For COVID, it's estimated to be about 10% of the people who develop Long COVID. With seasonal influenza, the number is likely lower,” Iwasaki says. “We don't know the exact percentages of people who suffer long-term consequences from different infections, but it can certainly happen after different viral infections, and also with bacterial infections like Lyme disease.”

Sometimes, it’s not fully known what pathogen, if any, leads to certain chronic diseases. ME/CFS is a long-term illness characterized by severe fatigue, sleep problems, and other symptoms worsened by physical activity. Scientists believe there may be many causes of ME/CFS, including various viral infections.

Plus, Long COVID and other post-acute infection syndromes can evolve into ME/CFS. “ME/CFS is a disease that lasts at least six months or longer, whereas Long COVID, generally, is defined as four to six weeks of prolonged illness after a presumed COVID infection,” Iwasaki says. “The timeline is different, but many people who developed Long COVID are now also developing ME/CFS—an estimated 50% from the first wave of COVID.”

It's not that everyone who has Long COVID has ME/CFS, but one could turn into the other, she adds. “That's a possibility that researchers are paying attention to, because there's a commonality between these two diseases,” she says.

While different pathogens may trigger Long COVID, ME/CFS, and other post-acute infection syndromes, many of the chronic conditions share similar symptoms, such as fatigue, disrupted sleep, and pain.

What are the possible causes of Long COVID and other post-acute infection syndromes?

Iwasaki says she and fellow researchers have four working hypotheses to explain what triggers post-acute infection syndrome.

“The first hypothesis is a persistent viral infection,” she says. “Even if you clear the virus from your nose and throat, there may be a reservoir of virus somewhere in the body that is continuing to replicate and transmit infection within the body, and that could be triggering chronic inflammation.”

The second hypothesis is autoimmunity, when the body triggers an immune response that leads to inflammation, which occurs continuously. This, Iwasaki says, may be triggered by a viral infection, such as with Long COVID.

The third hypothesis involves latent, or dormant, viruses. “We all carry many viruses, such as herpes, Epstein-Barr, and chickenpox, but they're latent. Sometimes, these viruses wake up from latency and trigger infection in a person,” Iwasaki says. “We are actually seeing Epstein-Barr virus reactivation in a subset of Long COVID patients.”

The fourth hypothesis is that inflammation triggers chronic changes in the tissue and damages it. “We have a mouse model of Long COVID in which animals are infected with a very mild, respiratory-only infection,” Iwasaki says. “That results in chronic changes in the central nervous system. In particular, these immune cells, known as microglia, in the brain become active and then trigger inflammation around them that could be contributing to neurologic symptoms.”

What is the goal of post-acute infection syndrome research right now?

We would like to get to the bottom of the root causes of these diseases, Iwasaki explains.

“For instance, if there's a persistent virus infection that's causing long COVID, can we treat these viruses? That's why we are conducting a Paxlovid trial here with Dr. Harlan Krumholz's group through the Yale LISTEN Study to be able to understand if people benefit from taking Paxlovid, and, if so, determine their biomarkers for success,” she says. “That will allow us to do a larger study in the future by targeting people with the right biomarker to see if Paxlovid or other antiviral agents might help some people with long COVID.”

Understanding the disease mechanism will directly educate us in designing the right kinds of therapy to provide the treatment that these people desperately need, she adds.

What can you do to prevent post-acute infection syndrome?

The best way to prevent some of these chronic diseases is to receive the appropriate vaccine, if available, which is the case for COVID, pneumonia (based on age), flu, respiratory syncytial virus (RSV, also age-dependent), and chickenpox, among others. It’s also important to continue getting certain vaccines seasonally and stay up to date on boosters.

In addition, all the standard prevention measures of masking, staying away from sick people, and handwashing remain the same. As we head into the winter season, when cases of respiratory illness, flu, and COVID tend to spike, another tool could be keeping an eye on the humidity level in your home.

Iwasaki has researched how dry, moisture-free air and cooler temperatures make it easier for airborne particles from viruses, such as COVID, to travel. Furthermore, the ability of the body’s immune system to respond to pathogens is compromised in drier environments, her work says.

Iwasaki recommends using a humidifier to increase the relative humidity level in a room and maintain a level between 40% and 60%.