Thursday, December 14, 2023

The Priest, the Consultant, the Journalist, and the Epidemiologist

How do we proceed when we still don't really understand Covid?

Researchers have found over 200 symptoms associated with Covid, and no organ untouched by it. A recent review article stated the problem, 

"The mechanisms of Long Covid are unclear. Leading hypotheses include alteration of the immune system, the persistence of residual viral components driving chronic inflammation, endothelial dysfunciton or activation, microembolization, mitochondrial dysfunciton, abnormal metabolites, reactivation of pre-existing chronic viral infection, dysbiosis of microbiota, and unrepaired tissue damage. These hypotheses intersect and overlap."

It's a bugger! The World Health Network is working on a Consensus Statement to help clinicians navigate working with the disease. In the past few days, a few people have written about the conundrum of not being able to really get our heads around how this very serious disease works while trying to work with it. 

An explanation from an epidemiologist:

"We have TWO big problems here. The FIRST problem is that in missing what the REAL Long Covid problem is, this Star article misinforms. The SECOND (real) problem is that we actually don't understand Long Covid prevalence at all. The first part of this thread is about Why. Why there is no uniform case definition for Long Covid. Why we use a variable symptom laundry list, many of which are non-specific. The second part of this thread considers the negative consequences of this knowledge deficit. With a defined disease, we know four things: cause, mechanism, progression, and symptoms. We use these to craft a case definition, which is the yardstick used to diagnose new cases. With Long Covid, we actually don't know any of these. 

Let's start with cause ...Sure, Covid. But how? Direct damage to any number/ combination of organs? Which ones? Is the cause of Long Covid rooted in post-infection inflammation? Or is Covid lingering in some body tissues for months, wreaking havoc? Is Covid activating other latent viruses? Then there is the mechanism. Cumulative cell death? Triggering inflammation to cause harm? Attacking our immune system? Maybe it's causing so much vascular damage with microclots, resulting in oxygen starvation harm? There is some evidence for all of these. Without clear cause or mechanism, we have no diagnostic test. Instead we define Covid with a bunch of observable symptoms. This is called a "syndromic" disease. Some symptoms, like loss of smell, are both unusual and specific to serious infection. But many symptoms, like headache, listlessness, depression, brain fog, are so general that they contribute mostly noise to any data seeking to understand Long Covid. 

Here is where it gets tricky. Much of the damage that Covid can do won't manifest for self-report. We aren't wired to notice cells dying. Even in places like the testes with a lot of pain receptors, damage that could cause infertility is impalpable. Brain fog may indicate brain damage, but it's also possible to have severe cognitive impairment without awareness. So we have a bunch of self-report symptoms that might not be Long Covid, and a bunch of harms that Covid can cause that we don't experience consciously and can't report. And much of Long Covid research is predicated on self-report. It looks a bit like this Venn diagram. 

We are mostly attending to a subset of Covid harms, ones where we can see symptoms. At the same time, we include a lot of cases wrongly attributed to Covid. This has some tragic consequences. The biggest is that infectious disease medicine doesn't like ill-defined, syndromic disease. I don't see ID physicians talk much about Long Covid. Without a sharp, definitive diagnostic test, we aren't going to see buy-in from many physicians that Long Covid matters. A second main problem is the timeline for Long Covid. If vascular damage accelerates vascular disease and causes lots of strokes among people in their 40s a year after infection, what do we call it? This is happening. But it may take years of research to prove Covid dunnit. A third main problem is that nobody seems sure what medical specialty SHOULD own Long Covid, because we can't attach it to one part of the body. A proper approach to Long Covid research and treatment would require an interdisciplinary approach among several specialties. I see a few such efforts out there. But not enough to move the needle. I have endured more than one hoary ID physician shake his fist at me while shrieking "there is no evidence that ..." Sadly they don't realize that absence of evidence is not evidence of absence. 

I'd like to conclude with an easy solution, but there isn't one. It can take many years for large studies to accrue, to prove very clearly what Long Covid is and is not. Even if we soon unravel a LOT about Long Covid, it will still take years. Why? Because it can take two decades for new understanding of diseases to make their way to clinical practice when it conflicts with conventional wisdom. Doctors are educated to be never wrong. So even obvious realities like airborne and asymptomatic transmission are resisted. Consequently we need to wait for the retirement of a whole generation of physicians and physician-researchers who can't acknowledge being wrong, nor by implication, the harms caused by being wrong. 

So what are we to do? 

We need the precautionary principle: assume that Long Covid is a terrible scourge while we prove it. This directly conflicts with physician "there is no evidence..." discourse. Some docs will be mad. So we also need to be public & loud: we need to acknowledge Long Covid. But we also need to fund more research - not easy the self-report kind - that will help move us toward a better understanding of Long Covid causes and mechanisms. As reinfections pile up and take their toll on population health, this will only get more urgent. Some have pointed to a study showing 94% accuracy of self-report predicting actual Long Covid. Except we don't have a valid definition of Long Covid, so we rely on self-report. Self report tends to validate self report. This is circular reasoning. In fact, it elegantly demonstrates an exceedingly gigantic bias toward self-report as "right" way to understand Covid. What about all the harm that isn't consciously perceived? "Everyone who isn't here, put up your hand!"

A call to keep people informed from a journalist in a New York Times article:

"By May 2020, affected patients had already formed support groups thousands strong, coined terms like Long Covid and long-hauler and even conducted research on their own communities. Even that March, people with similar illnesses like myalgic encephalomyelitis (ME/CFS) had warned that the new pathogen would trigger a wave of disability. They knew then what is clear now: People infected by Covid can be pummeled by months or years of debilitating symptoms, including extreme fatigue, cognitive impairment, chest pain, shortness of breath and postexertional malaise (PEM)--a state in which existing symptoms worsen after even minor physical or mental exertion. . . . 

Covering Long Covid solidified my view that science is not the objective, neutral force it is often misconstrued as. It is instead a human endeavor, relentlessly buffeted by our culture, values and politics. As energy-depleting illnesses that disproportionately affect women, Long Covid and ME/CFS are easily belittled by a sexist society that trivializes women's pain, and a capitalist one that values people according to their productivity. Societal dismissal leads to scientific neglect, and a lack of research becomes fodder for further skepticism. . . . Around the world, tens of millions of people are suffering from Long Covid. Some might recover, but most long-haulers don't fully return to their previous baseline. At the same time, the pool of newly sick people will continue to grow since our leaders have rushed us back to an era of unrestrained airborne pathogens and lax public health policies. . . . In this status quo, people are expected to ignore the threat of infection, pay through the nose if they get sick and face stigma and ridicule if they become disabled. 

Journalism can and should repudiate that bargain. We are not neutral actors, reporting on the world at a remove; we also create that world through our choices, and we must do so with purpose, care and compassion. . . . Mental exertion can trigger a loss of energy so profound that I've described it as the annihilation of possibility. An hourlong call could wreck someone for days. . . . Long-haulers saw and predicted the rise of Long Covid before credentialed academics did. Many are patient experts who have read the scientific literature on Long Covid and ME/CFS more deeply than many doctors because they are highly motivated to do so. . . . As the pandemic wore on, many grim outcomes I warned about came to pass, and most societal changes I hoped for did not. I watched two successive administrations make avoidable mistakes, and then make them anew with each successive surge or variant. I witnessed almost every publication that I once held in esteem become complicit in normalizing a level of death once billed as incalculable. It was galling, crushing work that wrecked my faith in journalism and its institutions. 

But the solace that many long-haulers drew from my pieces gave me solace in turn. It convinced me that there is still a point to this horrible work, a purpose in bearing witness to suffering and a reason to continue shouting into the abyss. Sometimes, even if just slightly, the abyss brightens. . . . Contrary to the widespread notion that speaking truth to power means being antagonistic and cold, journalists can, instead, act as a care-taking profession--one that soothes and nurtures. And we are among the only professions that can do so at a scale commensurate with the scope of the crises before us. We can make people who feel invisible feel seen. We can make everyone else look."

Practical advice from a biorisk consultant explaining how to take precautions when living with many other people:

"From the outset, it's very important to remember that risk mitigation is absolutely not binary. That is to say, risk mitigation is generally about reducing risk, rather than completely eliminating it - which in many situations (not just avoiding Covid) is simply not possible. The other point to remember is that the risk in this case is nested. By that I mean, the goal is not simply avoiding infection, it is also having as few infections as possible. These are subtly different outcomes. So, Martha is absolutely correct that living with other people creates a route for possible infection. No question of that. If the other people in the household are not taking precautions against infection, or are unable to do so, then the risk of SARS-CoV-2 being brought into the household is higher. 

In this case, passive mitigation in the household will reduce risk. This entails HEPA filtration, ventilation, etc. Also asking other members of the household to test regularly may be useful. However, key point: if one consistently mitigates one's own risk outside the household - such as by wearing a respirator, overall risk drops. This is why infection should never be considered inevitable, and, remembering the nested nature of the risk, if one takes more precautions than the average person, but still has some vulnerabilities (the other people in the household) total infections will still reduce.

To end on a personal anecdote. I have a good friend who convinced himself he was high-risk because he had a large household. That attitude led him to take no precautions, because he thought infection was inevitable. As such, he ended up infecting several members of his household by going to a small gathering unmasked - because he had convinced himself that infection was inevitable... The definition of a self-fulfilling prophecy."

And a helpful metaphor from a priest:

"Long Covid is weird, Some people just don't seem to understand the multifactorial nature of long covid. I don't think there's a grand unifying theory of how it all fits together. It's just covid doing damage to essential core functions of your body and leaving them destabilised. But since your body is a multiplicity of systems, and covid infection messes with so many of them, the possible combination of the interaction of the repercussions is mathematically endless. Your long covid, like you, is unique. 

Picture your beloved timber frame house, invaded by ants. It's just one of many houses on the street suffering this problem. In some of the houses, the ants establish a secret foothold, hidden away in the walls. In some, the ants have hidden away in the walls, and they've eaten the insulation off the electrical wiring. In some the ants found their way into the water system, and they've messed with the pressure. In others the ants have eaten the floorboards and timbers and you have a risk of collapse. And in that one they've also climbed into your computer, and their little anty bodies are short circuiting the wiring. In other houses the ants have been pooping in the pantry, as well as eating the food. That attracts other pests. In some the ants have actually chewed their way through the walls in ways that have changed the very shape of the conduits in the house. They've left pheromone trails that bring flying ants and queens. Some ants fall asleep in the cold temperatures of the fridge, only to awaken months later. Other houses put out so much ant paper and ant poison that the whole house becomes sticky and toxic. The ants stop up the mail box and bite through the telephone line. They bite through the cords that hold the windows open so no air gets in. 

It's all Long Ant, but the effect on all the different combinations of systems is different. Electrical problems, and structural problems, and airflow problems, and communication problems, and metal problems and wood problems and fabric problems and food problems. And there's no one marker for the ant infestation. There's no one cure. The solution is different when they're in the walls and when they're in the pantry. The solution is different when they've damaged wiring and when they've damaged fabric. The ants can get anywhere. And they can keep coming back, which adds damage upon damage. 

If we're going to keep infecting everyone endlessly, we're going to need a hundred solutions. One drug or one treatment won't solve it. The problem of damage is connected but different to the problem of dysfunction is connected but different to the problem of persistence is connected but different to the problem of autoimmunity is connected but different to the problem of metabolic disorders. They all have one cause, Covid infection, and they all have different causes, what Covid does to the different organs and systems and processes and enzyme cascades and... 

And the first and most important solution is to reduce the number of infestations. And the ant mitigations work. And don't forget: Ants are airborne."

(Their names, respectively, for future searching purposes:  Colin Furness, Ed Yong, Conor Browne, and Tern.)

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