The Challenges of Unravelling Long Covid

The Challenges of Unravelling Long Covid

Mixed into the collective tangle of agony and loss caused by the ongoing covid-19 pandemic are the “long-haulers” — people who become or continue to feel sick after their initial encounter with the virus. But the road to understanding what’s now become known as long covid will take time, nuanced inquiry, humility, and empathy.

There are numerous theories behind the bodily dysfunction that’s causing people’s symptoms, which range from losing your sense of smell to being so tired that you can no longer carry out daily activities like work or exercise. Many of these explanations could complement one another, yet others may not. The data collected on long covid patients so far is still frustratingly incomplete.

Some doctors are also starting to raise concerns over what they view as a potentially misleading and inaccurate narrative — the idea that even mild covid-19 infections are causing chronic illness and frightening symptoms like psychosis in a large proportion of survivors. In at least some of these cases, they argue, people’s distress related to the pandemic or from the experience of having had covid-19 could be more to blame than the direct aftereffects of infection. At the other end, long covid patients and their advocates fear that their symptoms will be dismissed as nothing more than mass delusion and that they will be abandoned by the medical establishment, as other patients with little-understood chronic illnesses often are.

Underlying all these fraught issues is the question of what we owe to one another in times of great suffering.

The toll of the ongoing covid-19 pandemic is too immense to describe with the weight it deserves.

As of mid-April, there have been over 137 million reported cases and around 3 million deaths attributed to covid-19 worldwide (both underestimates), while millions more have been hospitalised. In the U.S, which has reported over a half million covid-19 deaths to date, it’s estimated that one in every three Americans personally know someone who died from the viral illness, including 40,000 children who have lost a parent. And though some countries have weathered their outbreaks better than others, all have experienced economic and societal disruption in the pandemic’s wake.

Even as the pandemic was in the middle of its first wave around March and April last year, scientists were warning that covid-19 could have health impacts beyond the acute illness it causes, based on history alone. Past pandemics such as the 1918 flu, for instance, have been linked to spikes of neuropsychiatric symptoms or other illness that followed in its wake. And it soon became obvious that covid-19 was capable of causing a lot of bodily havoc that could have lasting effects.

Within months, some patients started to talk about the symptoms they were experiencing following their initial bout of covid-19. Despite the isolation imposed by restrictions on public indoor spaces to stem the pandemic’s spread, they sought each other out on social media and shared their common experiences. By late spring, journalists had begun to write about these cases, popularising the term “long-hauler” that those in the community had adopted for themselves.

Advocates haven’t only talked about their ordeals; they’ve also been at the forefront of collecting data on it. Patient-led surveys were some of the first to provide a broader scope of long covid and what it can entail. The list of health problems attributed to long covid is expansive and can vary widely from person to person, with surveys indicating as many as 50 different symptoms. But common ones include constant fatigue, trouble breathing, pain, appetite loss, and cognitive impairment, the last of which is often referred to as brain fog.

Scientists too have started to map out the destruction that infection can leave behind, especially in severe cases, often using the term “post-acute covid-19 syndrome” as their label for long covid. The lungs of those with acute respiratory distress syndrome (ARDS) become flooded with fluid, for instance, and this flooding effectively drowns us, depriving the body of necessary oxygen. Heart attacks, strokes, and diabetic shock have also been linked to severe covid-19 infection. Slowly but surely, we’ve gotten better at pulling covid-19 patients back from the brink of death, but many survivors who escape their critical condition can still be left with lingering harm, while hospitalisation or intensive care treatment itself can leave lasting marks.

Detectable damage in someone’s lungs or heart caused during infection could neatly explain their inability to breathe or exercise as easily as before. But many researchers are now investigating the factors behind long covid in people for whom that doesn’t appear to be the case.

One theory argues that infection could trigger a harmful immune response that continues to attack the body, including the brain, after it’s long gone. Many symptoms of acute severe covid-19 are already caused by a too-harsh immune system, and there’s evidence patients can develop autoantibodies that resemble those seen in lupus, a chronic condition with plenty of varying symptoms. Some studies have found that the coronavirus can survive in the gut after it’s been cleared from the respiratory tract, leaving open a way it could hurt people after acute illness. And however it’s happening, one theory posits that covid-19 can cause something similar to dysautonomia, a condition where the autonomic nervous system, the network of nerves that govern our involuntary bodily functions, is thrown completely out of balance. Some have also noticed the possible connection between long covid and other complex, chronic ailments linked to viral infection, such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

As critical as this early work is, though, there are still many important mysteries about long covid. And in these gaps of information, doctors like Adam Gaffney worry that we may be getting ahead of ourselves.

“There’s absolutely no question that covid-19 can have long-term consequences. And I just want to really emphasise that, because the last thing I would want is someone to think I’m downplaying the potential for lingering symptoms from this illness,” Gaffney, a critical care pulmonologist who has treated pandemic patients in the ICU, as well as a public health researcher at Harvard Medicine, told Gizmodo by phone. “I think the real question is: Can a mild infection — something we would classify as mild — cause a unique, new, chronic, and potentially lifelong multi-organ syndrome that isn’t associated with other conditions like stroke? I think that is an unknown. And for some of the assertions that are being made right now, I think they’ve gone beyond the available evidence.”

In his writing about his concerns, Gaffney is careful to say that he doesn’t mean long covid patients are faking their illness. Rather, many of the symptoms associated with long covid are non-specific, meaning they can be caused by many different things. And the elephant in the room is that while a uniquely dysfunctional immune system caused by infection could explain many of the symptoms linked to long covid, so could psychological factors like anxiety, stress, and depression experienced by survivors related to their illness or from the trauma and grief that many people have experienced during the pandemic for a variety of reasons, like losing their job or being isolated from their loved ones for months. In some cases, it’s possible that people experiencing long covid may not have gotten covid-19 at all.

Many of the earliest studies of long covid have relied on self-reported cases of covid-19, rather than cases confirmed through PCR or antibody testing. Of course, during the first wave, testing throughout much of the world, including the U.S., was limited and possibly less accurate, making it hard for people to confirm whether they had contracted the virus. But when studies have been able to account for confirmed cases, a perplexing pattern has emerged.

A survey of thousands of long covid patients last December, for instance, found that only around 30% of those who reported getting antibody testing were positive for antibodies to the virus, a trend that’s been seen with other similar surveys. Another study published this past March focused on self-identified long-haulers and characterised the pattern of neurological symptoms they continued to experience. But half of the patients included were those who had tested negative for covid-19 from PCR or antibody testing.

Rehabilitation specialist David Putrino and his colleagues at Mount Sinai were some of the first doctors to set up a specialised clinic for long-haulers in the U.S.. Putrino’s team in particular has helped patients for whom there isn’t clear evidence of what might be causing their symptoms, and that’s included patients with negative test results. But those results aren’t irrefutable proof that they never had covid-19, he notes.

“You can get a negative PCR test and still have covid-19 very, very easily,” Putrino said, referring to evidence that PCR testing can have a small but meaningful false negative rate (roughly 10%, according to a review in January). “On the antibody side of things, we’re telling people to get tested months down the road, and by that point there’s a solid body of scientific literature to suggest that your antibody titers may have faded to the point where they’re not detectable now.”

There is some evidence that people’s antibodies to the coronavirus do remain detectable in a majority of patients for up to eight months and longer, though rates can vary from around 70% to 90% depending on the test. But Putrino’s larger point is that it’s not helpful to treat patients without these test results any differently from other long covid patients.

“It’s bad science and also bad medicine, to say, ‘Oh, you didn’t have covid-19, so we’re not going to treat you,’” he said, adding that it’s an attitude that he’s seen from doctors on more than one occasion.

Of course, people with confirmed covid-19 are also known to have long covid symptoms, including those with mild infections. Several studies have found that as much as a third of never-hospitalised patients experience symptoms that could fit the criteria for long covid. And some studies have found that patients with milder infections or without antibodies can experience these symptoms about as often as other groups of patients. But those are findings, Gaffney argues, that don’t necessarily make sense if infection from the coronavirus was really their driving cause. And while he does acknowledge the limitations of antibody testing, he thinks it’s unlikely these limitations are enough to entirely explain all the cases where people seem to test negative for having had covid-19.

“All of the suffering and all of the symptoms are real. It’s subjectively real; it’s objectively real. But teasing out the causal effects, that’s really tricky,” he said. “There’s this underlying question — with what certainty can we attribute these chronic symptoms to the viral infection itself?”

In early April, a study of medical records from over 200,000 covid-19 patients (hospitalised and not) found that one in three were diagnosed with neurological or psychiatric symptoms in the six months following their covid-19 diagnosis. These patients were 16% and 44% more likely to have any of these conditions than a control group of patients diagnosed with other respiratory infections or specifically the flu during that same time, respectively. That finding does lend support to the idea that experiencing covid-19 can raise someone’s risk of long-term symptoms. But it also shows that a sizeable number of people who get sick from the flu or a cold will experience these same symptoms later on.

These sorts of observational studies, as the authors admit, aren’t intended to prove that covid-19 or any other infection will directly cause condition A or B. They can only show a correlation, a possible link between the things you want to study, and that’s a critical distinction. In trying to figure out what’s happening to patients with long covid, we have to remember that illness can have many causes (oftentimes, several at once) and we’re not always great at judging where it comes from.

Gaffney isn’t just worried about scientists neglecting the role of mental health in long covid either, but the media as well. He points to recent articles in the New York Times and elsewhere that have reported stories of people experiencing episodes of psychosis weeks to months after their mild initial infection, with little to no critical examination of the possibility that the two conditions may be unrelated in a direct medical sense.

“To me, that’s very irresponsible reporting. Because it’s scary, and it’s frightening, but the cause and effect relationship isn’t quite clear,” he said.

Another example of where we might be overstepping the evidence involves the covid-19 vaccine. Soon after the rollout began expanding in the U.S., reports of long covid patients feeling much better after their shot began to emerge. Some scientists have put forth possible theories for how this could be happening. If their symptoms were tied to lingering remnants of the virus, for instance, the boost in immunity might help the body clear these traces. Yet another plausible explanation hardly ever brought up is that many people, including those with long covid, would understandably feel an overwhelming sense of relief from vaccination — relief that could alleviate, if only for a time, some of the symptoms they’re feeling. Interestingly enough, some long covid sufferers have reported feeling worse following vaccination, while others haven’t felt any change. So there are really no clear indications of whether there is a true cause-and-effect link between vaccination and long covid outcomes right now.

In response to Gaffney’s recent writing about long covid, some researchers and doctors wrote positively about his critiques, while advocates have accused him of claiming that their symptoms are imaginary or “all in their head.” Gaffney isn’t saying the latter, though. But trying to make an impenetrable boundary between our physical and mental health, implying someone can only be physically or mentally sick, isn’t helpful to anyone either, in his opinion.

“We need to move beyond this incorrect mind-body duality. I mean, we only experience pain by experiencing pain in the brain. Even if you got shot in the arm, you would only experience that pain because of neurological processing going on in the brain,” he said. “So yes, we need to keep an open mind about the causes, and I don’t know how all of this is going to pan out. But putting that aside, there’s no question that mental anguish and suffering can cause physical suffering.”

There’s also no question that this past year has provided people no shortage of potential anguish. Many of us have lost people we loved to the pandemic or endured weeks of not knowing whether they would survive. Others have had to face unemployment or other radical life changes for the sake of trying to contain the pandemic’s spread. Most of this has happened, by the way, while living under a presidential administration that abandoned the country to the virus and downplayed its danger at every turn. And for those of us who contracted covid-19 — the viral disease behind the worst pandemic in a century — it’s been worse. In any given year, nearly one in five Americans are thought to experience symptoms of mental illness. But studies have shown that around 25% to 40% of covid-19 survivors have experienced anxiety, depression, trouble sleeping, and PTSD following diagnosis.

It’s not unreasonable to believe that all of these stresses could take a noticeable toll on us that could explain at least some of the pain long covid patients are experiencing — a point that Gaffney has repeatedly made in his writing, noting that we’re still “living through a time of incredible trauma, sorrow, and hardship.”

Something that shouldn’t be forgotten about in all these scientific discussions about long covid, though, is the ordeal that patients are facing right now. Aside from the burden of their symptoms, many patients have reported feeling ignored by doctors, of feeling like their chronic symptoms weren’t treated as real. Even recent history is not kind to the notion that people’s pain will always be seen as valid by doctors, no matter the source.

Studies have shown, for instance, that women wait longer in the emergency room and are given less priority for their pain problems than men; a similar pattern is also found with people of colour. These disparities reflect how doctors’ biases about the people who experience illness can negatively shape the care they offer. And you don’t have to look far to see how a similar sort of dismissal could emerge with long covid.

In a Wall Street Journal opinion piece this March, Jeremy Devine, a psychiatric resident at McMaster University in Canada, argued that long covid was “largely an invention of vocal patient activist groups” and that trying to research it at all would only make the situation worse by encouraging its legitimacy. People in the long covid and ME/CFS community have also criticised Paul Garner, a tropical medicine researcher in the UK who said he experienced and recovered from long covid. In a blog post this January, Garner claimed that he recovered simply because he stopped believing that he would be forever sick and powered through his fatigue with exercise therapy — the implication being that many patients could recover just as easily if they really tried (exercise therapy for ME/CFS also remains a controversial issue, with advocates claiming that it’s unsuitable and actively harmful for many patients).

There does seem to be the risk that by acknowledging long covid as possibly caused more by psychological factors than physical ones, some people would only use that acknowledgment as an excuse to ignore everyone suffering from it. There’s also the worry that even leaving open a debate about its causes for too long will itself do harm to patients suffering from it.

According to Putrino, there’s no doubt that patients’ anxiety or stress could worsen their long covid. But he notes that the very experience of having long covid could be the source of these other symptoms. And he’s opposed to the notion of gatekeeping long covid care or research based on people’s test results.

“Sometimes we run into these moot points of: ‘Well, how do we even know that this person had covid-19?’ Well, you know, excuse my language, but why do I fucking care? This person is coming to me with incredibly debilitating symptoms in extreme distress,” Putrino said. “The clinician in me is going to treat this person. I don’t particularly care, right in that moment, what the pathophysiology of their illness is while I’m trying to make this person in crisis feel better.”

Rachel Pearson, a paediatrician and researcher at the Institute for the Medical Humanities at the University of Texas, has studied the history of complex and medically disputed conditions like chronic Lyme disease as well as written about the ethics of treating these patients. But while she does agree that there’s a potential for harm from overdiagnosing long covid, she’s less worried about that risk at this point.

“If we’re too credulous, there would be different levels to that — there’s the doctor-patient level, and the social and scientific level. And the way that I think about this is that there’s a different kind of harm done, if in approaching my individual patient, I am dismissive of their concerns. That is tactless and mean and harmful,” she said. “But in scientific inquiry, I feel like there’s so much less harm to being more credulous. Especially this early in the game, we might as well cast a broad net of inquiry and see what we find.”

It will take time and careful research to pin down the whys of long covid. More studies are now looking at covid-19 patients prospectively, meaning that they’re being tracked right as they become sick; these studies should give us more clarity about how long covid develops and how often it happens. Scientists have also recently developed easier-to-use tests that look for people’s T-cells specific to the coronavirus, which could provide a valuable and more accurate marker of past infection for long-haulers. Research labs around the world, including at the National Institutes of Health, are studying how covid-19 could cause chronic illness, while specialised clinics and hospitals are preparing to conduct trials of potential treatments, such as immune-modifying drugs.

In all likelihood, this research probably won’t lead to any simple answers. There might be groups of patients with patterns of long covid clearly different from others — different biological pathways that could give rise to their symptoms. But there may be many cases where a mixture of factors are responsible for people’s symptoms, including the psychosocial. Some patients might recover in a matter of months, others will continue to experience some level of impairment, even with supportive care.

There are many scientific puzzles left unsolved about long covid. But perhaps more pressing, there’s the ethical quandary of what these patients need from the medical system as a whole, regardless of the cause of their plight. And on that note, I found wide agreement from all of the doctors and experts I spoke to.

“Everyone, regardless of the exact physiology behind this or any illness, all these patients absolutely and unquestionably deserve top-quality care without financial barriers from whatever specialists and whatever treatments they need,” said Gaffney, who recently ended his term as president of the Physicians for a National Health Program, an advocacy group supporting the formation of a universal, single-payer health care system in the U.S. “There are going to be enormous health needs stemming from this pandemic even beyond the acute illness it causes. And whatever the etiology is of those health needs is not relevant to the question of whether these people need access to quality care and services. They do.”

Tim Lahey, an infectious diseases physician and medical ethicist, agreed with the basic thrust of Gaffney’s plea for caution in long covid research. But he also argues that scientists and doctors need to be humble, especially in how they interact with these patients.

“I think one place where traditional biomedicine sometimes falls down is that we might say: If I can’t find a physiological sequence of cause and effect to explain something, then I might dismiss it as not real or not something that I care about,” he said. “And that can provide an opening for somebody who says that they’ve got the answer for you, and that all you have to do is give them money, and they’ll listen to you and they’ll be sympathetic. So who wouldn’t turn to that person?”

Already, there have been self-proclaimed experts pretending to have all the answers. In February, Goop CEO Gwyneth Paltrow made waves when she said she took care of her long covid through “intuitive fasting” and infrared saunas — statements that soon earned a rebuke from UK government experts. Oftentimes, peddlers of medically dubious treatments will specifically target people with chronic illness, hoping to entice those desperate enough to try anything, and long covid won’t be an exception. Ensuring that patients don’t feel deserted by doctors should help reduce the risk of people turning to worthless and potentially dangerous treatments, Putrino says.

“I think we need to go into this with eyes wide open, understanding there are going to be predatory individuals who view a novel condition as a new market. There are always going to be unscrupulous people who see that as an opportunity to make a quick buck. And so the way that we tend to this is we talk openly with our patients,” he said. “If they want to try something out, we ask to speak with the practitioner first. We share knowledge, we’re open, we’re collaborative, we’re open minded. And we just do our best to be good partners to the patients in terms of their quest to get well.”

No matter where our research into long covid leads, Lahey says, the people at the centre of it deserve just as much empathy and respect as everyone else, especially from doctors.

“I can imagine a universe in which the symptoms have absolutely nothing to do with psychiatric states, and they’re just inflammatory,” he said. “But I can also imagine that it’s more complicated, a mixture of all of the above. And if that’s the case, that old fashioned paradigm of saying that it’s all in your head, which means it’s depression and somehow a black mark on your character, must be avoided — that’s just an outdated way of thinking about things.”

Some of the obligation that doctors have to patients, Pearson says, is the willingness to be there for them even when they don’t have all the answers and to be upfront about the things they do and don’t know.

“Part of our job is to see suffering, see irremediable suffering and to recognise our own smallness — the limitations of our art — in the face of that suffering, which is a deep, profound, and innate part of being a human being. And to say that I will continue to be present and do my best for this person, even so,” she said. “I would add that we also need to be honest and straightforward about our clinical suspicions. And I feel like sometimes we don’t give patients enough credit, to at least acknowledge that there’s a psychological component to their suffering… They’re not nearly as closed off about this concept as physicians are.”


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