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Why do 'mild' Covid-19 cases sometimes linger for months? Here's what experts say.

Several months into the coronavirus pandemic, providers now know that some patients can experience symptoms for months, even those with mild cases of the disease and those who are young and otherwise healthy—but they're still not sure why.

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The 'extreme' variation in Covid-19 symptoms

According to some estimates, between 40% to 45% of people who become infected with the coronavirus experience no symptoms of Covid-19, the disease caused by the coronavirus. However, the World Health Organization states that "most people infected with the [coronavirus] will experience mild to moderate respiratory illness."

As Axios' "Vitals" reports, commonly reported symptoms of Covid-19 include cough, chest and joint pain, difficulty breathing or feeling short of breath, fever, and headache. CDC also recognizes chills, congestion or runny nose, diarrhea, fatigue, loss of smell or taste, muscle pain, nausea or vomiting, and sore throat as common symptoms of the disease.

But, as CDC notes, the list of possible Covid-19 symptoms extends beyond those listed on the agency's website. For instance, over the past few months, doctors have started to report other emerging symptoms of Covid-19, including injury to the lungs and brain and cardiac symptoms such as myocarditis and irregular heart rhythms. Providers also are commonly reporting kidney damage among Covid-19 patients, as well as blood clots that can travel from patients' veins to their lungs, brains, and other organs.

Some emerging symptoms of the disease are disproportionately impacting younger patients. For example, doctors have reported a rising number of cases of a deadly inflammatory syndrome that afflicts children within days or weeks of coronavirus infection. Doctors also have reported strokes among patients in their 30s and 40s with Covid-19.

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Meanwhile, dermatologists are reporting cases of so-called "Covid toes," which manifests as redness, burning, itching, and/or swelling in the toes of patients with Covid-19, as well as other dermatological issues. In addition, doctors are discovering a growing number of Covid-19 patients experiencing confusion and hallucinations.

The severity of symptoms also varies substantially. Overall, CDC data suggests that one out of five people who contract the virus end up being hospitalized because of the disease. And Aakriti Gupta from the Columbia University Irving Medical Center told Axios that, among hospitalized Covid-19 patients, "the proportion of people in which … multiple organ injury is occurring is higher than anything we've seen before."

The variation in symptoms and manifestations of the disease can make the illness difficult to treat, particularly because providers and researchers don't yet know why Covid-19 can vary so much between patients.

José Ordovas-Montañes, an immunologist at Boston Children's Hospital, explained that providers know infection from the novel coronavirus can result in "an extreme divergence in host responses," but "[w]e don't yet know what is leading to that."

C. Brandon Ogbunu, an assistant professor at Yale University, said, "Even more so than other outbreaksthe variation from person to person, the multisystem nature, the way it hits demographics different, the way the disease manifests differently in national contexts—it defies a simple medical or biomedical narrative."

However, the variation isn't completely unique, according to Amesh Adalja, a senior scholar at the John Hopkins Center for Health Security. Adalja said the novel coronavirus "is proving to be more than just a respiratory virus in terms of the manifestations, which we've seen with other respiratory viruses."

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Length of symptoms also varies

Not only can the novel coronavirus cause a broad range of symptoms, but the length of time that patients experience symptoms also can vary significantly.

At the start of the pandemic, clinicians and researchers assumed that people who contracted the coronavirus and developed Covid-19 "would get better, and then it was over," Michael Peluso, a clinical fellow in infectious diseases at the University of California-San Francisco (UCSF), said.

But  there are Covid-19 patients throughout the world who have reported experiencing symptoms of the disease for months after they initially tested positive for the coronavirus, with some patients even testing positive for the disease months later—and, in some cases, after receiving a negative test result.

For instance, a JAMA research letter found that 55% of surveyed patients in Italy who had been discharged from the hospital after recovering from Covid-19—and who has subsequently tested negative for the disease—were still experiencing three or more symptoms about two months after the disease's onset.

In addition to previously hospitalized patients, doctors are finding that many long-term Covid-19 patients are young and were otherwise healthy, and they had mild to moderate cases of the disease. CDC on Friday published a report acknowledging that Covid-19 "can result in prolonged illness even among persons with milder outpatient illness," noting that up to 35% of patients who did not have to be hospitalized for the disease were not fully recovered three weeks post-diagnosis.

The long-term symptoms patients have reported vary from person to person, and have included breathing problems, cognitive difficulties, elevated heart rates, and gastrointestinal problems. Lekshmi Santhosh, a physician lead and founder of the new post-Covid OPTIMAL Clinic at UCSF, said most of her long-term patients "have either persistent shortness of breath and/or fatigue for weeks to months."

And according to the Wall Street Journal, some patients, including 34-year-old Emily Jensen,  have reported that their symptoms have gotten worse with time and that interfere with their day-to-day lives. Jensen first experienced symptoms of Covid-19 in mid-March, the Journal reports. She had seen improvement, but then experienced relapses in both April and mid-May, which led to her having to go to the ED for a kidney infection.

Now, Jensen, a surfer and runner, has reduced lung capacity as a result of Covid-19, and she told the Journal that she needs to use an inhaler to be able to walk up the stairs. "If I overexert myself it's like I take several steps back and basically can't do anything for several days," she said. "I've never had breathing issues before and now I have to use my inhaler sometimes when I'm having a conversation. It's scary. No one knows: Is this going to be my life for the next two years?"

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What causes long-term symptoms?

Doctors and researchers aren't sure why some patients experience Covid-19 symptoms long term while others don't, but some have developed theories on the matter.

Mount Sinai Health System in May opened a Center for Post-Covid Care that follows patients who were hospitalized with Covid-19 and recovered, as well as people with long-term symptoms of the disease. Currently, the center is following about 1,000 Covid-19 patients who have had symptoms for more than four weeks, with some patients experiencing symptoms for up to 70 days.

David Putrino, director of rehabilitation innovation at Mount Sinai, said he thinks some long-term Covid-19 patients are developing a neurological condition called dysautonomia, which is associated with imbalances in the autonomic nervous system. Symptoms of dysautonomia can include an elevated heart rate, fatigue, and shortness of breath.

Putrino said it's unclear if dysautonomia is triggered by the novel coronavirus or if patients are developing dysautonomia because their immune system overreacts to their coronavirus infection, but he said it is the condition is his "lead theory as to what is going on." Putrino said dysautonomia could affect up to 15% of all Covid-19 patients.

The Center for Post-Covid Care has launched a program for patients with dysautonomia, which emphasizes exercise programs and dietary changes as treatment. The center also is conducting research on patients with long-term Covid-19 symptoms.

Other providers have theorized that chronic fatigue syndrome could be behind some of the persistent symptoms, such as mental fog and fatigue. Symptoms of chronic fatigue syndrome can last for at least six months and can be trigged by stressful events, including viral infections.

Ron Davis, a professor of biochemistry and genetics at Stanford Medical Center, said up to 10% of people with certain viruses can develop chronic fatigue syndrome. "So the concern with this coronavirus is that we will get a large number of cases" of the syndrome, he said.

Meanwhile, Serena Spudich, chief of neuroinfectious diseases and global neurology at Yale, said some long-term Coivd-19 patients experience sensory changes, which she thinks could be related to damage to the nerves that connect to the skin. The issue could be caused by patients' strong immune responses to the coronavirus, she said.

Akiko Iwasaki, a professor of immunobiology at Yale, has three theories about long-term Covid-19 symptoms. Iwasaki said the coronavirus could be lying dormant in the body and reemerging periodically, that traces of the virus in patients' tissues are causing ongoing inflammation, and that some patients' immune systems could be going into overdrive and attacking the patients' cells for extended periods.

However, some doctors think the long-term symptoms simply could be due to damage caused to the body during patient's initial infection periods.

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Hope for treatments?

Peluso said the first step toward effectively treating long-term Covid-19 patients is understanding them.

Many patients have reported that doctors initially were dismissive of their long-term symptoms, telling them that their symptoms were due to anxiety and depression and not the coronavirus.

"It is important that patients know—and that doctors send the message—that they can help manage these symptoms, even if they are incompletely understood," Peluso said. "It sounds like many people may not be being told that."

Multiple organizations across the country, including Mount Sinai and UCSF, are dedicating resources to understand the cause of the long-term Covid-19 symptoms in hopes that the research will lead to an effective treatment plan for such patients.

"I hope that a few months from now, we'll have a sense if there is a biological target for managing some of these long-term symptoms," Peluso said.

Spudich, who is launching a study following Covid-19 patients experiencing neurological problems, said medication could help patients who've experienced nerve damage because of the coronavirus and therefore are having lasting symptoms, though she added that likely won't help patients who've experienced more serious brain injuries.

And Timothy Henrich, a virologist and viral immunologist at UCSF, said there may be fewer long-term patients once treatments for Covid-19 improve, in general. "More effective acute treatments may also help reduce severity and duration of post-infectious symptoms," he said (Owens, "Vitals," Axios, 7/24; Snyder, Axios, 7/23; Reddy, Wall Street Journal, 7/1; Parshley, Vox, 7/14; Hou, "Changing America," The Hill, 7/10; CDC website, 5/13; Carfi, JAMA, 7/9; Edwards, NBC News, 7/24).

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