It's the early days of the pandemic in and doctor Daniel Cherto has a new patient, a twenty six year old male who was hospitalized with chance pain. He did not present with the typical COVID symptoms, you know, the shortness of breath, for fever and all this other stuff. It was justice comfort and he tested negative on on
multiple occasions. Dan runs the Emerging Pathogen Section at the National Institutes of Health in Bethesda, Maryland, and if you're a COVID case his lab, you're not there for treatment, you're the subject of an autopsy. Dan and his team are studying this young man as part of a big emission to figure out where in the body the coronavirus goes. He thinks that by tracing the virus's path and seeing what it does, it can understand why it's causing disease
and how to stop it. Think of it like he's detective, trying to collect evidence and looking for the m O of a killer before it can strike again. Primary questions that were I to address the initial questions are really the cellular distribution of the virus across the body and the brain. So, in other words, exactly where does the virus go, what cell types does it back and really, really importantly, how long does the virus stay there. Dan and his technique to work fast to get participants like
his new patient. They have about twenty four hours after someone has dyed to study them certain tissues to grate quickly after death, destroying the evidence. Getting these patients in that time has become a massive logistical undertaking. They first talked to the family to get their approval. From there, they make arrangements with a funeral home to transport the remains to the NIH Clinical Center and Bethesda at least set up a call schedule where I might hear about
these cases. At two o'clock in the morning, communicate with our amazing, amazing admissions department, who would facilitate our contract funel home and going out in the middle of the night bringing bodies here so that my team would be suited up. At nine o'clock in the morning on this spring day in twenty Dan and his team are in a secure along chamber wearing astronaut and spied protective gear
as they examine their new patient. The man died at the hospital and tests were negative for the coronavirus, so he doesn't fit the definition of a COVID related fatality. Instead, he died of something called viral myokiditis or inflammation of the heart muscle. But dances there was a reason he
still wanted to study him. And at that time you probably remembered there were a number of reports in the literature, and there were some articles coming out and of imaging of the hard and some autopsies, you know, and but case reports of viral mild cardiitis being an unusual but but present complication of COVID. As they examine his body and heart, Dan says there's good evidence COVID is the culprit. Not only that the patient offers clues about another condition
link to the coronavirus. It's called multi system inflammatory syndrome. It occurs mostly in children after a saska v TO infection, but it's been reported in adults as well. Dan says it's a condition that can arise unexpectedly after a mild case of COVID. They show up later with sometimes life threatening inflammation in different oregans. So in a way he
fits into that category. And so well, what's driving and that is the point of Dan's work performing these autopsies is like recreating police sketches and more and more detail. With every autopsy, the picture gets clearer of what COVID is capable of doing across our bodies and what impact it may have on them in the long run. Is there going to be, you know, some low level or subclinical injury to your heart that then may manifest differently
later in life. I don't know. Is there going to be some subclinical effect on your brain that are going to cause nerve cognitive issues later in life that perhaps are not immediately noticeable or detectable. If you're going to begin to conceive of ways to prevent or treat those manifestations, either in the group that the next group that might be exposed or among the group that are suffering, you, you need to understand mechanism. You need to understand what
the drivers are. But this work has a long way to go. Scientists like Dan are just starting to learn the biological means by which siskov two managers to affect virtually every organ system in the body. Those infected and experience symptoms lasting months and potentially years. The condition is called long covid, and Dan's research could help us understand how to better combat it. But science is an iterative process.
New information or clues have to be checked and validated before they're accepted as proof, and right now there's a ton of information but not a lot of admissible evidence. Conflicting theories have popped up over the last year and a half, which only shows how much more fact gathering needs to be done and resources for critical research like autopsies that help us understand new diseases have been stretched in It means disease detectives have fewer tools to use
in that pursuit of the killer. I'm not here to service of fear manger. I mean that's not that's not much. It's just that these are some under answered questions. I'm Jason Gale, chief biosecurity correspondent and a senior editor at Bloomberg News. From the Prognosis podcast. This is breakthrough. Pathology is one of the sort of fundamental building blocks of medicine. This is Dr Linda Isles. She's the head of Forensic
Pathology Services at the Victorian Institute of Forensic Medicine. It's like a medical examiner's office, but this one in Melbourne is the largest of its kind in Australia. Linda is as heat bespectacled woman with short, salt and pepper hair. She finished medical school at the University of Tasmania more than twenty years ago and then went on to train
in anatomical pathology. She estimates she probably did two hundred three d autopsies during her training, which if you compare that to kind of really old school back in the day, then that might not seem like very many. But if you compare that to anaton called pathology trainees now, then that is a very large amount. These days, pathology trainees aren't even required to do autopsies. Fundamentally, autopsies are expensive procedures.
I think autopsies have been slightly undervalued by clinicians over a number of years, even decades perhaps, and as less autopsies are requested, less pathologists have experience with autopsies. This points to a big problem happening in modern medicine. Autopsies have been the bedrock of medical science since at least the fifteen hundreds, but today sophisticated imaging and other modern diagnostic tools and hospital cost cutting have turned them into
a dying science. Linda says there are a few reasons why autopsies have started to go out of style. One of them is that facilities are expensive to maintain at a safe standard. So it's this spiral of decreased experience and therefore decreasing confidence and then under utilization of the facilities to some of the facilities essentially being mothballed, and then when you want to reinstat to them, then they're
no longer really safe for modern practice. So it's sort of like this catch twenty two, and now we really left with the generation of pathologists that have really quite limited autopsy experience, and therefore their confidence in performing autopsies safely is significantly diminished. This lack of expertise was only exacerbated during the pandemic. In the first few months of the outbreak, health authorities warned that doctors would become infected
while performing autopsies and handling virus laden tissues. That led to half of these units shutting down. In the US, the same sort of scenario played out across the world. In Germany, initially it was like, no, we will definitely not autopsy these COVID patients, and then a bunch of pathologist said no, we have to do this. Because this
is a new disease process. And then they just did a complete switchero and funded the autopsy program, which is where a lot of the really valuable data has actually come out of Among the first four million fatal COVID cases worldwide, only several hundred were autopsied and the findings reported in medical journals. That delayed getting answers to some crucial questions about COVID nineteen and its effects in the body. The good news is that detailed post mortem investigations are
picking up now. Linda says this could also bring greater awareness the value of autopsy research, whether it's just going to be a sort of short term thing or whether it's going to translate into something kind of more meaningful. I mean, I can only hope that it's going to be the ladder. But you know this, the idea that novel infectious diseases are a thing of the past is you know. I think this has kind of brought this certainly front and center for people. Not all doctors waited
so long before returning to autopsies. Disease detectives like Dancerto accepted the risk early on in the pursuit of answers. Most of the SHOTS team he's made up of trainees, and at the start of the pandemic, he wanted to give them the chance to contribute from home if they felt more comfortable working that way. I said, we're an emerging pathoge in his lab, like there's a pandemic. If you want to work remotely, that's okay. But for those of you that want to be present on SAITE, these
are the things we're going to be focusing on. Selectives stick around and with rare exception, you know, everybody's like we're on deck. Dan himself is used to working in dangerous environments. He was in Liberia during the Ebola crisis, caring for patients and later studying the virus. Before that, he worked on the nineteen eighteen Spanish flu pandemic virus. His experience provided a grounding in bio safety that's carried
through to his personal life. Dan says he takes precautions like wearing a face mask when he can't physically distance to prevent getting SANSKOVI two. I'm not a risk averse person. I'm a believer in calculated and controlled risk, right, but I know that my absolute preference for myself, my family, my loved ones, my colleagues, my kids. I got an eight year old and a twelve year old, my preferences for them not to be infected. Dan says he applied one hey and I was learned from the Ebola outbreak
to understanding kinvid nineteen. It started with this idea that first we gotta go find where this virus is going, what it's doing in those places, and then we got to try to link it back to what we're seeing clinically and what is coming out with volumes and volumes of evidence that we're all struggling to assimilate and trying to put those pieces together to to tell a cohesive story about the mechanisms that are contributing to severe acute illness,
to some mild or asymptomatic disease and others, and in a reasonable portion of the popular sation of survivors long term symptoms that are really distressing. Dan and his group are also trying to figure out how the virus and the body interact, which is another way of saying, in all those locations that you found evidence of RUS, what
was the body's response. Is there an infiltration of immune cells even in the absence of immune cells, is their evidence of damage within those tissues or organs, etcetera, etcetera. To begin to better understand that relationship between the virus and the host the host response. The more you understand that relationship, theoretically, the better equip you will be to design therapies and interventions that might mitigate aspects of the
disease course. These postmoneum exams do carry risk, but the pathologists from the National Cancer Institute actually performing the autopsies have decades of experience. These are the gentlemen of physicians and their trainees that that we're here doing autopsies during the AIDS era, and these guys were in there doing autopsies on hundreds of patients with this new disease, HIV AIDS. So we have now the benefit of working with that
group here now decades later, lots of experience. These aren't typical autopsies though they're done over three hours in a secure facility. That's required for work involving microbes that can cause serious and potentially lethal disease. So our group, the pathologists they design home design a grain box, which is basically plexiglass with a glove it's like a glove box.
Bio Engineers on the NIH campus custom build an enclosure that fits over the head and shoulders of the deceased to contain aerosols when the brain is removed, to cut through the skulls. A little bit morbid, but there's aerosolization, right, So you don't want to overly contaminate the environment. So implementing this thing and working, and this takes some time.
The seven also doctors, scientists, and technicians working inside the autopsy suite, where multiple layers of personal protective equipment, usually a plastic apron over a surgical gown, over an impermeable cover, all over surgical scrubs. Sometimes arm sleeve protectors are worn. They also donned three pairs of gloves and two pairs
of shoe coverings, and instead of ninety five masks. They're breathing through controlled air purifying respirators, which provide heaper filtered air under a hood that fits over the head and shoulders. It's cumbersome, but it's not the only aspect of these COVID autopsies that makes the work painstaking. We're sampling way above in the yard. What has done in any sort of diffical We sampled almost a hundred different regions within the body across the whole body and brings a hundred
different areas. And for each one of those areas, we collected and preserved adjacent pieces of tissue in different ways that are amenable to various down stream analysis that preserve the tissues in a better way. It's a ton of time and energy to analyze these samples, but time is important. The first cases of long COVID happened over a year
and a half ago, and only more developing. The sooner we get results from autopsies like Dan's, the Sinner will begin to address the long term effects of COVID nineteen. Dan's are research will not only help us understand what the courses are, but how to counter them. There are many theories on white people continue to suffer from a multitude of symptoms long after a coronavirus infection. Some are
easy to explain, others are a mystery. For example, it's known that if COVID gave you a severe case of pneumonia, your lungs could have scarring that might reduce lung capacity. That's an unfortunate consequence of acute respiratory distress syndrome that can also occur with the flu. If you were unlucky enough to need intensive care, that slinked to muscle weakness, memory problems, and a raft of other conditions referred to
as post intensive care syndrome. And if you were really unfortunate and needed mechanical ventilation that's long been associated with post traumatic stress disorder. But these aren't the problems baffling doctors and researchers. The biggest surprise of COVID is that people who are not in the intensive care unit, people actually who are never needed to be hospitalized, are still having persistent symptoms. This is Dr Walter Kaschatz, who we heard from in our last episode. He heads the National
Institute of Neurological Disorders and Stroke and Bethesda. Walter says it's this group of patients, the ones with unexplained fatigue, brain fog, weird heart palpitations, and body aches and pains, who also represent the largest pool of patients who are persistently unwell as a result of the pandemic. The long
COVID have fatigue. That's the primary, very complaining factor. That's true about the post ice use cases, as well, fatigue is a major problem, but the long COVID symptom complex of fatigue, trouble with memory, travel with thinking quickly, executive function, trouble as sleep pain syndromes sometimes, and exercise and tolerance. Those are the features of this syndrome that we don't
have good explanations for at this point. In some ways, the disease pattern many long COVID suffers experience resembles mono or infectious mononucleosis. It's called glandular fever where I am in Australia, and some people refer to it as the kissing disease, possibly because it's spread through saliva and often occurs in teenagers. The culprit is usually the epstein bea virus. It can cause fever, swollen glands in the neck and armpits,
and a sore throat. Most cases of mono were mild and resol of in their own in one to two months, but Waltera says that's not always the case with infectious mono nucleosis. There is another syndrome which you've probably heard about well, realogic can cephalomi elitis chronic critique syndrome and symptoms are very overlapping between what long COVID folks are complaining of and what happens in NBCFS. It's just that
MBCFS has a six month period. You have to had those symptoms for six months, But it looks like people are moving into that space. Waltera says. Researchers have been trying for years to figure out the causative driver of that longer term illness after infectious morning. Now with the thirty four million people with COVID, it's a tremendous challenge now that we have to take up to try to
figure that out. There is now a greater chance that we're going to figure it out now because we have this opportunity to study so many people and to try and understand what differentiates those who get better quickly versus those who have these persistent symptoms. So the hope is that, you know, we can get some answers that would allow us to try different treatments to see what helps and then potentially also learns something about what causes NBCFS as well.
Congress is giving the National Institutes of Health one point one five billion dollars over four years to find answers Ault along with Dr Anthony Felchi from the National Institute of Allergy and Infectious Diseases and Dr Gary Gimmons from
the National Heart Institute are co directing the research. There's a clinical team, that's an autopsy team, that the electronic health record team, I know, there's a big data team, and there's probably a couple of others, So there's I think the estimate was three hundred people have been working
on this project since November. The amount of money Congress has set aside to study long COVID seems a lot, but it pales compared with the trillions of dollars the pandemic has cost already and the economic toller will have decades into the future. Some estimates suggest that more than one billion people around the world have been infected with the coronavirus. We don't know yet what proportion of them will develop long COVID or the duration of their symptoms.
My gut feeling is that you're probably close to a ten percent figuring out about six months out. This is Dr RV. Nath He's the clinical director at the National Institute of Neurological Disorders and Stroke. The one waterheads people do recover or a period of flame on spontaneous people. But most often if you're not better by six months,
then the chances of getting better are become really less. Obviously, says the impact on individuals, families, and societies will be I mean, nobody's gonna do with the calculations for you, but it's a dream on society to get every single level. I mean, it affects women more than then. It affects people and their average ages forty that's the most productive years of your life. And so you can see that the impact worldwide impact of this is unbelievable. You couldn't
translate it to money. The impact is I mean the economic toll, the psychological toll. Every aspect of society is kind of touched. It's why figuring out the cause and waste to treat and prevent long COVID are so critically important. Obviously, there could be two main driving forces behind the clinical manifestations.
One is that the coronavirus manages to persist in the body somewhere somehow, and that it's lingering presence is damaging the body directly, or it's triggering an immune response that's causing the damage. Another hypothesis is that the coronavirus has sent the immune system haywire, and it's this disregulated immune response that's drive long COVID. I think they're all reasonable hypotheses,
but they're not exclusive. They could be interrelated. Have He's been researching chronic fatigue for years and now he's also trying to understand it as well as other elements in long COVID patients. One of the interesting features about this illness is that if you look at it, the people who had were these long haul symptoms are often not the individuals who are hospitalized and we're sicking on and went later and stuff like that. These are individuals who actually,
most often they never went to the hospital. They were at home and during that time they had relatively mild illness in the acute phase and they recovered from it. Obviously, says that the people who were sick enough to require hospitalization probably mounted a strong immune response that helped them to eventually recover and importantly get rid of the virus. But if you had a mild illness, perhaps you never
mounted a strong enough immune response. You thought, oh, you know, I escaped, but in reality you've never got rid of the virus. Viruses can remain in their infectious form and a range of diseases from AIDS to chicken box to a bowler. Some sortists say that the coronavirus may cause a persistent infection in places like the gas and wind, testinal tract, and the nose, but there's no consensus among scientists that that's the case, obviously, says Another possibility is
that what's persisting are viral particles. They may not be completely replicating, butter instead expressing some features of the virus. Now what the body is going to see it as a foreign object, is going to try to mount an immune response against. So you've got this conic immune activation that persists in these individuals, but it's never good enough to get rid of it because they never got river in the first place, but it's enough to start causing
collateral damage. Obviously, the same pattern of immune activation and exhaustion in chronic fatigue or m ec effast patients. They look very much like these long hold COVID patients, and they had the similar problems. They usually start off with some violent infection, then they had cover from it, and
then this thing persists. Whatever. The field of researchers working to unravel COVID's mysteries is growing, and it's bringing in expertise from all kinds of areas neurology, cardiology, horminology, and infectious diseases that includes HIV. Medicine Professor Steve Deetz has been researching a cure for HIV for almost thirty years at the University of California, San Francisco. When the pandemic hit,
Steve took notice. We had no idea what was going to go on with Sariskoby too, but we knew it was a big deal, and we had a good sense that they're probably going to be some long term content places. Everybody was focused on short term. Steve began enrolling patients in a study aimed at identifying how saskov two affects long term health. Subset have long COVID and some don't,
and we're beginning to do the biology. And one of our leading hypotheses is that the virus does persist in some people for some reason, and that that persistent virus initiates an inflammatory process. At the heart of all this has always been the concern that there is something that persists and stimulates that a normal response. Steve thinks the coronavirus might be leaving traces behind. It could be viral protein, strands of its genetic material, or even bits of antigen
that the immune system responds to. We don't think it's virus replication, but I guess it could be virus that's replicating in target cells and tissues. We always thought that that was a potential reason for why this symptoms persists. Steve says Dan's research when it's published, could have significant
implications for treatment. If the experts out there tell me, yes, we think that there is a persistent repository of virus protein, nucleic acid, or even virus replication, then for me it's easy to say, okay, well then thousand ways and that can cause long COVID. We need to give people an anti virus. We need to get people antibodies or therapy vaccine and see if they get better. And that's what
we're planning on doing. But we need more rational. We need a paper from the NIH saying, you know, with ni H level standards, yes, indeed some people have virus. And if they tell me that these people virus also had symptoms, well, that would be helpful. Steve says. Circumstantial evidence supports the concept that there's something persistent that's causing
long covids. All these ancdotes out there about people who have long COVID and get a vaccine and get better, and the only way to explain that is that there's persistent virus that's not being cleared by the immune system, and the vaccine makes the immune system better and the virus goes away and they're healthier. And if we can prove it, then me as a as a clinical trial, as can do all the clinical trials, we can look at any of these anthem virals, any of these antibodies,
and these vaccines, they all should help. Well. It's a very important study and I hope it comes out soon. Deep in his lab, Dancoto and his team have amassed more than ten thousand autopsy specimens for meticulous study. Their analysis is beginning to yield some answers to the many
questions around long COVID and what causes it. They know that the research tools will have in years from now will provide even greater insight, which is why a big part of their work as involved careful preservation of the samples collected from each patient. For instance, some tissues go
into a solution that preserves nuclinic asset. The virus is genetic material, and then we use a highly sensitive PCR essay to query presence or absence of all orn and those tissues, and Dance group is going further to see if the virus that's collected from different areas of the body is still infectious. Can we actually get viable virus? Can we grow virus from from these different sites we've done, you know, simply put a much more extensive sampling than
than others have. The data from the biospecimens are also matched with patient records, including genetic tests used to identify certain individual variations in a person's immune system. You have individuals as young as six years old, very very sad to beyond ninety years old. It's diverse, you know, across gender and raise and ethnicity. It's diverse across a really important parameter, which is when we perform the autopsy relevant
to symptom on set from COVID. There have now been dozens of studies published based on autopsy findings that have added data points to a map showing where the virus is going and what it's doing across the body. Others have done a very good job of creating the outline of that map of where the virus goes, what cell types, you know, how long it sticks. We intend to put some more spots on that map, you know, to help to help kind of fill it in both as far
as different locations, different cell types, period of time. You know that that researchers can then use moving forward. It's already clear to day that Sasko vie too spreads through the body wider than previously thought in patients with mild
or even no symptoms. I think we're operating under the impression that for the most part, the virus is contained in the respiery track, perhaps just the upper row story track, never makes it to its lungs and then doesn't go past that right like, it doesn't get into the bloodstream, it doesn't distribute to other parts of the body, and then you clear it, you know, you're better. I'm not
sure that's the case. There's not a lot of evidence in this space, and says some of the patients who died with rather than rome COVID will provide some insight into that. Those are issues that we cannot just assume.
One thing and the implications of that are important because if you are mildly symptomatic or asymptomatic, but you actually do have a period of iramia or the virus tropes to different parts of your body and then you know, you feel better, but actually the virus is persisting for a certain period of time and causing injury or the body's response to clear that virus is contributing to some you know, pathogenic mechanism that is, you know, manifesting as
long COVID symptoms. We gotta we gotta know that, right, We got we gotta know that because without knowing it, how are we going to address it? Right? And so so we got to begin to kind of turn these pages of the book, like peel the layers off the onion and try to answer some of these questions. Dances. A manuscript based on the young man with Manadas is under a valuation by a scientific journal. A paper on what his team found looking specifically at the eye is
undergoing co author review and will be submitted shortly. His larger project, providing a map of where the virus is going in the body, is pending more data across anatomical sites. Dan says he expects this last bit of information shortly and then can finish your manuscript. But evidence pointing to the causes of long COVID are of little help to patience unless the findings in yield ways to help them.
Next week on Breakthrough, doctors and physical therapists in New York are working on strategies to help long haulers manage their symptoms. Even though a cure remains a loop us thinking outside the box. It's bringing a variety of innovative and successful therapeutic options. Some of our patients who have been discharged for the longest, they're experiencing relapses. So is this something you're gonna have to manage for your entire life, or is this something that you're gonna have to manage
for the next five to ten years. Or is this something that we can rehabilitate and we'll discharge you and you will never have to think about it again. So these are all open questions right now. This episode of Prognosis Breakthrough was written and reported by me Jason Gale So for four Heads is our senior producer. Carl Kevin Robinson Jr. Is our associate producer. Theme music was composed and performed by Hannes Brown Rich Shiners editor Franchise get
Leavy is the head of Bloomberg Podcasts. Be sure to subscribe if you haven't already, and if you liked this episode, please leave us a review. It helps others find out about the show. Thanks for listening.