Mark Henning is a self-described redneck who runs at full throttle. “You know those people who make YouTube videos of themselves doing stupid stuff? That’s me,” he says. So when Henning first began developing flu-like symptoms in the summer of 2013, the 47-year-old Nebraska native tried to brush it off. He continued working three jobs and helping friends with construction projects on the weekends. But instead of enjoying a pizza and beer afterwards, Henning went home. His doctor told him it was probably just the flu. After more than a month, Henning finally took off work one Thursday and Friday in early September, hoping that a few days to rest would cure him. Yet on Monday, he only managed a half day at work before returning home. He went to bed for a nap, but instead of falling asleep, he fell into a coma. Henning woke up in the hospital several days later. He had a 104.5° F fever and, finally, a diagnosis: West Nile encephalitis.

“The doctors thought I was going to end up brain dead,” he says. “Down the hall, someone else with West Nile died while I was there.” Henning was in the hospital for a week and off work for two months. After that, his doctors told him that the worst was over. However, Henning’s health problems persisted. His gallbladder ruptured and had to be removed. He developed severe acid reflux for the first time in his life. His short-term memory slipped away from him. And perhaps most frustratingly, his doctors have no idea whether his symptoms might be linked to the West Nile encephalitis that nearly killed him more than two years ago. The idea that seemingly short-lived viral infections could cause long-term symptoms is fairly new to scientists. They long believed that once your body cleared an infection, its symptoms should disappear, too. But that isn’t always the case, says Kristy Murray, an epidemiologist and veterinarian at Baylor College of Medicine’s School of Tropical Medicine. “Some people are developing new problems over time,” Murray says, problems that appear related to their initial infections. More and more, researchers are coming to realize that Henning’s case is far from unique and that his experience isn’t merely paranoia or hypochondria. Some of the world’s most notorious viruses like Ebola, West Nile, chikungunya, and the newcomer, Zika, may cause health problems that linger for months or years, and scientists are only now beginning to grapple with the problem. A Mysteriously Chronic Malady When the New York City Department of Health asked epidemiologists from the CDC to investigate a cluster of encephalitis cases in 1999, Murray was one of the first people on the scene. A member of the CDC’s elite Epidemic Intelligence Service (EIS), her job was to track down the source of the outbreak. Murray’s work, along with a team of epidemiologists and virologists, uncovered West Nile virus as the culprit. Further investigations revealed that those encephalitis cases represented only a tiny fraction of people infected by the West Nile virus. Most people had no symptoms at all, and only 10% developed mild flu-like symptoms. Then, in 2002 and 2003, West Nile began a rapid spread westward across the United States, traveling from the Atlantic to the Pacific in near record time. By that time, Murray had finished her two-year stint in the EIS and had relocated to Houston, where she continued investigating West Nile. In 2002, there were more than 100 cases in the area, giving Murray the opportunity to study the disease in more depth. “Most people had no symptoms, but I was blown away by how ill some were. They were on respiratory support, on ventilators—they had severe paralysis. I was wondering if these people ended up recovering,” she says. To track the effects of West Nile over time, Murray began assembling a cohort of individuals across the spectrum of symptoms: those with the most severe forms of disease like meningitis and encephalitis, those with moderate flu-like symptoms who had tested positive at their doctor’s office, and those who had no symptoms at all and whose infections were identified only through blood bank screening. This initial group of 172 people gave Murray some of the most basic information about West Nile infections that no one had gathered before. She found that those most likely to develop severe infections were older adults with hypertension and that even those with the most severe infections seemed to recover within a few weeks.

“Most people had no symptoms, but I was blown away by how ill some were.”

Eight years later, Murray once again assessed her group of patients only to discover that many of them had remained ill, a result she wasn’t expecting. Some of the most common complaints were fatigue, weakness, depression, difficulty walking (also known as ataxia), memory loss, paralysis, and blurred vision—symptoms that other West Nile survivors like Henning knew all too well. The symptoms were also frustratingly non-specific, as both Henning and those in the study cohort attested. Their physicians were often stymied by ongoing symptoms with no clear cause. Many of those with fatigue and depression also met the case definition for chronic fatigue syndrome, also known as myalgic encephalitis or systemic exertion intolerance disease. Murray wasn’t prepared for this level of ongoing illness. “After eight years, 70% hadn’t returned to their baseline health status,” she says. The West Nile virus can infect the nervous system and kill neurons, especially in an area of the spinal cord called the anterior horn, which contains the motor neurons that travel to skeletal muscle. If too many of these neurons are damaged by West Nile infection, it could lead to lingering neurological symptoms, says Daniel Pastula, an arbovirus expert at the University of Colorado Denver. “If enough of these cells are killed, there aren’t enough in reserve to do their job,” he says. West Nile virus can also infect the kidneys, and nearly 40% of the Houston West Nile group had developed some form of chronic kidney disease . Until Murray analyzed the data, however, and shared her findings with the study group, almost no one had associated their current kidney disease with their past history of West Nile. Murray could only conclude one thing: the effects of the West Nile virus were lasting for a really long time in otherwise healthy individuals. The root cause remained a mystery. She didn’t know whether the symptoms were the result of the body’s immune response gone haywire or whether some people still harbored remnants of the initial infection that triggered ongoing symptoms.

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Another Outbreak While Murray toiled over her West Nile data, Marc Lecuit was struggling half a world away in his Paris lab to understand a different mosquito-borne disease. On the French protectorate of La Reunion in the Indian Ocean, an outbreak of chikungunya had swept through in 2005 and 2006, sickening more than one-third of the island’s inhabitants. Chikungunya rarely killed, instead causing joint pain so severe infected people often couldn’t sit or stand for several weeks. ( Chikungunya is derived from a Makonde word meaning “that which bends over.”) Similar to West Nile, the virus was known to scientists but had never before caused an outbreak of this magnitude. By 2007, the virus had left La Reunion and moved on, most famously arriving in the Americas in late 2013. But Lecuit, a virologist and epidemiologist at the Pasteur Institute, was hearing from physicians on La Reunion that some of their early chikungunya patients were experiencing joint pain for months, even years, afterward. They asked if Lecuit knew anything about this. He didn’t. Chikungunya virus particles as seen via transmission electron micrography (TEM). Until that point, most of Lecuit’s work had studied whether pregnant women could transmit chikungunya to their fetuses. Indeed they could, and the disease could lead to severe health problems, even death, in the newborn. But he didn’t know much about long-term symptoms in otherwise healthy adults, nor did anyone else, he realized. Lecuit soon arrived at the same question Murray had: Was this a chronic immune response or a chronic infection? “We didn’t really know what was causing this long-term pain,” he says. “There was no hard data proving this.” During the initial infection, the chikungunya virus makes billions of copies of itself in fibroblast cells, which make up the connective tissue commonly found in joints. The virus hijacks the fibroblasts’ cellular machinery, turning them into viral factories. This conversion ultimately kills the cells, which are disposed of by immune cells called macrophages. However, with so many cells and viruses to mop up, the macrophages may leave some debris in and around a patient’s joints for some time. Lecuit thinks the remaining bits of virus could give rise to the chronic condition. “The virus was where the symptoms now are.” People with more severe chikungunya infections are more likely to develop chronic joint pain, which provides some support for Lecuit’s hypothesis given that more severe symptoms are typically caused by a higher viral load. If the body can’t break down pieces of virus, it could lead to a prolonged, localized inflammation. And neither Lecuit nor other scientists have yet to discover any chemical markers in the blood to show that this inflammation is happening throughout the body. Instead, it appears limited to the initial site of chikungunya infection. That might not be the case for what’s happening with West Nile, however. Murray’s research shows that people experiencing prolonged symptoms after West Nile infection do have signs of a persistent, body-wide inflammatory response. And in a few of these individuals, Murray found very low levels of West Nile virus remaining in their urine , which raised the possibility that a West Nile infection had become chronic. Fibroblast cells are found in connective tissue throughout the body. Lecuit isn’t convinced, noting that no other arboviruses had been found to cause long-term infection. To him, the idea that these viruses might set off an uncontrolled immune response was far more likely. Murray says that she hasn’t yet been able to conclusively show that virus is present in every person with long-term symptoms. If any virus is still present, it appears to be causing problems indirectly, by stimulating an ongoing hyperactive immune response, rather than causing symptoms directly. Stephen Maltby, a virologist and immunologist at the University of Newcastle in Australia, says that definitively linking a virus to longstanding symptoms is more difficult than people realize. Finding an association—that people infected by a virus are more likely to develop certain symptoms—is relatively straightforward, but causation is something else entirely. Consider the links between the Zika virus and microcephaly, a birth defect involving small head size, and Guillain-Barre Syndrome (GBS), an autoimmune reaction to an infection that leads to paralysis. While both arise during the infection as opposed to months or years after, they illustrate the difficulty in establishing causation. In countries like Brazil that have been hard hit by Zika, the medical community acknowledges that there have been spikes in babies born with microcephaly and people with signs of GBS. Certainly, signs are there—scientists found fragments of the Zika virus in the fluid that bathes the brains of babies with microcephaly. And a new study in The Lancet of a Zika outbreak in French Polynesia provided some of the strongest evidence to date that infection could lead to GBS. But definitive proof has been much slower to arrive. “There’s a high risk that these kinds of spikes are really just noise, although everyone worries it’s the start of a trend,” Maltby says. “Until I saw some of this most recent data, I thought it might have been just a coincidence. Now I’m more convinced that there really might be something going on.” Following the Data Trail Murray has faced no small amount of skepticism from her fellow scientists that West Nile could create chronic problems. Other viruses, like herpesvirus and hepatitis C, are known for their ability to remain in the body for decades, but nothing in the genomes of West Nile or related viruses hinted at that ability. Beate Sander, a scientist at Public Health Ontario who has studied the long-term effects of West Nile infection, says that these phenomena probably aren’t newly evolved traits, but rather that scientists had never looked for them before. Part of the problem is that many studies on chronic symptoms haven’t been well organized or have suffered from low enrollment. Sander and her colleagues found inconsistencies and methodological problems in the way that 67 studies of chronic West Nile symptoms collected and analyzed their data. The result, Sander said, isn’t that these symptoms don’t exist, but that no one can say with any certainty how common they are or who they are most likely to infect. “If there are only a few cases dispersed over time and space, it’s impossible to gather the kind of data you need,” Sander says. “We didn’t have enough follow-up time until now.” As Sander suggests, that’s beginning to change. So long as viruses like West Nile, chikungunya, and Zika remained in regions where they originally evolved and where, presumably, many people were immune, they caused constant, low-level infections. They were a public health concern, but not a crisis, and that made it difficult for scientists like Murray and Lecuit to monitor chronic symptoms. “To track these kinds of outcomes, you have to see a lot of people get a viral disease,” says Pastula, the arbovirus expert. Yet once the viruses traveled outside that zone and came into contact with people who didn’t have immunity, they caused explosive outbreaks and produced a large number of patients.

“If there are only a few cases dispersed over time and space, it’s impossible to gather the kind of data you need.”

Sander found that many patients’ ongoing symptoms didn’t necessarily match the ones they experienced when they first developed West Nile, which makes it more difficult for physicians to link these later complaints to their previous infection. As Henning points out, “No one can tell me whether what’s happening to me is a result of West Nile or whether it’s just because I’m getting older.” “The virus doesn’t actually have to be in the system at the time” of the symptoms, Maltby says, since the initial infection could trigger an overactive immune response that lingers long after the body has cleared the virus. “That makes it really hard to prove causation when there’s no virus there anymore,” he says. The wide variety of symptoms, combined with their vagueness, is likely one reason that these effects hadn’t been noticed until recently. Unless someone is specifically looking for them, even in reasonably healthy, well-off Western populations, they’re easy to miss, Sander says. Previously, these viruses were confined to impoverished areas with less healthcare and more disease, especially afflictions like dengue and malaria with symptoms that mimicked these illnesses. “These symptoms have a lot of different causes, which means there’s lots of noise and it’s hard to understand what’s happening clinically,” Pastula says. Even if scientists are able to link Henning’s lingering symptoms to West Nile, it doesn’t necessarily mean that any curative treatments are close at hand. The same is true for Ebola and chikungunya and likely Zika. All too frequently, doctors can only attempt to treat the symptoms. But for Henning, being able to know what’s causing his malaise will go a long way to giving him peace of mind. For now, he tries to stay active, conducting a phone interview while cooking chicken for a charity luncheon at his local firehouse, for example. He still works long hours and hangs out with his buddies as much as his illnesses will allow. But he’s different now, and says he’ll never be able to go back to the person he was before. “The doctors thought I was going to die,” and that changes you, Henning says. “I’d really just like to know what’s going on, even if no one can do anything about it.”

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Photo credits: Dan Bergstrom/Flickr (CC BY-NC) , Cynthia Goldsmith/NIH, James J. Faust and David G. Capco/Arizona State University/NIH