Synthesizing multiple studies, pulmonologist Brian Block, MD, reveals which patients are at risk for lasting symptoms from infection with the coronavirus (it’s not who you might think); offers evidence-based categories for the syndrome; defines common symptoms (including mental health issues); and discusses when to start advanced testing and when to refer.
and I was reflecting on how things have changed in the last several months since we last spoke and where we are in the pandemic and what that means about where our attention might have shifted. Or maybe should begin shifting As we think about the next chapter for COVID-19. So I grabbed this today from the new york Times. This is a chart showing the number of cases of confirmed coronavirus reported in the US by day over the last now one year and we're just now on this downslope coming off of our third surge from the winter, which as you all know, was the the biggest surge that we have seen along with the decrease in infections. We've also seen a decrease in the number of people that are in the hospital. And we've certainly seen that here as I expect, you've probably seen in your local practice environments as well. I think one thing that is very different now is that while the total number of new infections is decreasing, the absolute number of cumulative infections is the highest it's ever been. And so last time we connected, it was right here at the start of this third wave. Now we're on the down slope at the right side, But the number of cumulative cases has only kept the cumulative number of COVID-19 cases I should say has only kept increasing. And we're now up to 30 million confirmed cases in the us, which is likely underestimate based on the availability of testing, particularly early in that epidemic. So if we're now dealing with the problem, that's not so much new cases happening, although they very much still are but also having to address the problem of cases of infections that have already occurred. I think a major question that's emerging is what is going to happen to all of these people who have survived Covid 19 and maybe not returned back to their previous level of function. Obviously over half a million people in the US have died of this infection and at the same time many more are recovering well and then there's another segment of the population that had become seriously ill and then maybe has not mounted a full recovery. So this was an opinion piece in the new york times earlier this week, talking about kind of the mounting toll that this is likely to take, written by two people who were themselves infected early on in the pandemic last year describing their experience in recovering from COVID-19 and then also bringing attention to the issue of what some have called long haul covid. So for our talk today, I wanted to focus on a few issues to try to equip you to better understand what is meant by this terminology around long term sequelae of COBA 19. So first of all, it's my goal that by the end of this talk, you'll be able to name three symptoms that are commonly persist in patients who have had COVID-19. I would also like you to understand that long Covid Is best understood as three different entities. Then we're going to talk about risk factors for long covid and I hope that you'll come away understanding two or more risk factors. And finally, I'd like to equip you with a timeline to think about how to approach these patients as they're recovering from coronavirus, decide what is and is not expected and then engage help or additional testing as needed. So I thought it would be helpful to use some examples of cases of patients that had Covid 19 to set the stage. And it was actually very easy for me to come up with these. Unfortunately because I've been seeing so many patients and clinic over the last few months. So these next four patients all with different trajectories are patients that I saw over the span of just one week recently in the clinic. So for one example here's a patient and I've changed some of the details like age and gender here to preserve anonymity. This is a patient in their seventies who had hypertension, Hyperloop anemia asthma had been admitted with severe covid 19 causing a R. D. S. They required ICU level care and were treated with high flow nasal cannula. After three weeks in the hospital, the person was discharged home and had this CT scan of the chest upon discharge. Let me walk through that a little bit more slowly here we can see on these axial images Again, three weeks into their hospitalization evidence of bilateral multifocal capacities in the setting of some more linear or reticulated changes and the suggestion of some areas of traction bronchi exorcists, which is a dilation of the airways. That could be a marker of fiber optic changes. Now, another patient, 60 year old with obesity diabetes, admitted to the acute care hospital less sick, Requiring only six L nasal cannula rather than level care Hospitalized for four days rather than three weeks. I'm sorry. I think I advanced the slide here prematurely. This was the CT scan for the patient with level care evidence of fibrosis on CT. In the former attraction bronchi practices at week three. This next city here is from the patient that was only hospitalist for four days, did not require ICU level care, but standard nasal cannula and was subsequently able to be discharged home. A third patient In their 90s with the history of pulmonary hypertension and prostate cancer was admitted to the step down. So an intermediate level of care did require high flow nasal cannula. It was in the hospital for two weeks with a large amount of recovery, but not back to their baseline. Still requiring two liters of oxygen by nasal cannula. You can see this CT is different with less evidence of vibrate process, but instead, Bilateral multifocal ground glass opacity, ease that are very typical for earlier stages of COVID-19. Finally, Yet another pattern, a patient in their 40s with no past medical history who had actually been a high performance athlete. This woman had had a fever sore throat after traveling and this had occurred early enough in that pandemic last year that they were unable to get access to testing in a timely fashion. So while she and other members of her family were sick, they didn't get immediate access to testing and only a month later were they able to be tested? And all the tests came back negative. Then, in the setting of ongoing symptoms of shortness of breath, we had this CT scan which I hope you can appreciate as normal. These are four patients who all had covid 19 Or at least symptoms consistent with COVID-19. They have all sought care in the setting of those symptoms. They have different patterns of disease on their cat scan, different predisposing conditions and require different levels of care, ranging from not being hospitalized at all to the intensive care unit. So the question is, who out of these four is going to go on to have prolonged symptoms. Is it going to be the older adult who was in the ICU with guards on high flow and has some evidence of fibrosis on scan? Is it the slightly younger person who was hospitalist but not as severely ill, who has multifocal dense opacity, ease on their ct chest? Is it going to be the 90 year old who was in the step down on high flow? Had earlier findings on C. T. Which is to say more ground class without evidence of any fibrosis able to be discharged home on two leaders? Or is it the woman that was never confirmed to have infection but had compatible symptoms, tested negative, was never admitted and has a normal CT scan of the chest. So I want you to think about these four patients as we move through the talk and I'll return at the end to give you some answers on what's happened with each of them. So in thinking about which of those four patients is likely to recover, which is going to have ongoing symptoms and really, what does it mean to recover or to have delayed recovery? It's really important to look at the literature and think about what it tells us about the expected trajectory for patients who are recovering from COVID-19. So, some of the earliest information we have about this comes out of Italy, which you all remember was hit especially hard early in the pandemic. And so in this study, published in Jama last summer, they asked the question of how patients were doing two months after hospital discharge. And this was the study of 143 patients with demographic characteristics, as you can see on the left and in these patients, what did they find? They found that on the left side here, looking at acute symptoms and on the right side, looking at symptoms. Two months later, nearly everyone had symptoms early on. And of course this isn't a hospitalist population, so you wouldn't expect them to be asymptomatic. But what's striking is that even two months later, many, many patients, more than half had certain symptoms like fatigue, shortness of breath, joint pain. In fact, if you look across the coal whole cohort, at the probability of having at least one symptom, 87 had at least one symptom at two months or another way to say this would be only one. Only 13 of people are about one out of eight had no symptoms two months after discharge. So this is one cohort, and it actually agrees with findings from other studies here in the US. This is a study from annals of Internal medicine published last fall That looked at a cohort of patients admitted to one of 38 hospitals in the state of Michigan and so in there, their study, they looked at what happened to these patients on their initial admission. So 24 of those who were admitted to the hospital died While the remainder 75 or so discharged. And of those most were discharged home, but others did not go home and instead went to a facility for ongoing care. Then, just as in the previous study, they assessed how these patients were doing two months, 60 days later, and they were able to contact just over a third of the cohort here. So what did they find? Well, they found that of those who they were in contact with for a survey, two months after hospital discharge, 1/3 159 reported ongoing symptoms and the most common symptoms were breathlessness, cough, loss of taste, or chest tightness. Those are just looking at different physical symptoms if you also add in other domains and think about mental health. About half of the patients reported that they were having different changes in their mental health and half were unable to return to their previous level of function and go back to work. So the C. D. C. Which published is the mmwr had another trial looking at this or study looking at what happens to survivors of Covid 19 asking the question about symptoms at three weeks after their initial diagnosis. And similarly they found that about a third of patients, this is including those who were hospitalized and those who were not hospitalist. So people with more mild initial illness, about a third of them had not returned to their baseline level of function. And among those reporting ongoing symptoms, the most common symptoms were fatigue, cough and shortness of breath, which should be recognizable by now because those have been consistent findings across these studies. But this one ask another question, which is how can we tell up front who is likely to still have symptoms three weeks after their initial diagnosis? So three weeks is not necessarily a time frame that we would identify as long covid or long haulers, but it is a time frame that tells us about some persistence of symptoms, certainly beyond what is normally associated with viral upper respiratory tract infections. And so in this study, they found that people who were over the age of 50 had three or more chronic conditions, people who were obese or those with baseline psychiatric diagnoses were more likely to report ongoing symptoms at three weeks. Each of these factors carrying an odds ratio of about two after adjusting for other characteristics. So how do we put together and synthesize these three studies, one from Italy, one from the state of michigan and one more generally looking across patients who were hospitalized or not Hospitalist here in the US, We can say that ongoing symptoms are common 1-2 months after people are diagnosed with COVID-19. We can also say that among the symptoms that people have the most common symptoms that are manifest our fatigue shortness of breath and cough. And based on that study from the Centers for Disease Control, it does seem like there are some risk factors for going on to develop symptoms at least on the order of several weeks after initial infection, such as obesity psychiatric disease, Age greater than 50 or having multiple comorbidities. So, I guess this all raises the question. What happens after two months if so many people are still having persistent symptoms? So, if we look a little bit further out at the four month outcomes, looking at respiratory function, mobility, and psychiatric outcomes. This is a study that just came out and Jama opened this year and when they looked at these different domains to understand how well we're people's lungs working. How well were they exchanging gas as measured by the DLC? Oh, What were patients functional status measured by their six minute walk distance? And what were their? What was the burden of psychiatric disease? Specifically, post traumatic stress disorder measured by is something called the impact event severity scale. And what they found is that half of people had a decrease in their lungs ability to exchange gas at four months, 54 had a reduction of their walk distance and about one in six had psychiatric outcomes consistent with post traumatic stress disorder. This study has some problems in that there was the potential for selection bias because only a third of subjects who were approached to participate in the study agreed to do so. So you can imagine the cohort would be enriched for people who were having ongoing symptoms. But I think it goes to show that there are still a substantial percentage of people who are having Um symptoms related to their initial COVID-19 infection even four months after. And so now with knowing that many people have these ongoing symptoms, I guess it's hard to find them. What really is the cut off for long covid. This is not a matter of most people getting better after five or 10 days. Many people take a long time. So then when we're reading about or thinking about or seeing patients who believe they might have long covid, what should we unpack that to really mean? So, I read an editorial last year that I think really changed my thinking about this. And it's the way that I would approach. I would suggest you now begin to think and approach these patients really. What we've kind of grouped together as long Covid is best understood as several different entities. On the one hand, you could have patients with COVID-19 who don't recover their organ function. This could be someone who ends up with fibrosis scarring of their lung. This could be someone who had acute kidney injury and went on to develop permanent need for dialysis. These patients have organ dysfunction, which would be one type of long Covid. A second category would be people with post intensive care unit syndrome or post hospital syndrome. I'm going to give a little bit more information about post ICU syndrome because I think it's an important entity to recognize and it's also the foundation of how we've structured our Covid survivor follow up clinic, which we call the optimal clinic here at UCSF. The other thing people could be having is a post viral fatigue. We know that this happens with other viruses and you may have even experienced this yourself when you've had other viral infections and it feels like it just is taking longer to recover than expected. 1/4 category would be perhaps there's something still going on with the virus. Maybe you're having inflammation triggered by the virus or some other distinct process related to covid that's actually different than viral fatigue related to other infections. So I think it makes the most sense to collapse this into three different categories. And think of long term sick quality categories falling into either the bucket of persistent organ dysfunction, problems related to post intensive care syndrome or post viral fatigue, which has a lot of overlap with the symptoms of long haulers are describing. So what is post ICU syndrome? And I'm going to devote most of the talk to talking about long haul covid because that's a new entity that I thought you'd be most interested in hearing about because it's getting a lot of attention in the media. The post ICU syndrome is also very important. This has become increasingly described over the last decade or so as new impairments that span multiple domains and the primary domains that we're interested in. Our physical dysfunction, cognitive dysfunction and changes in mental health and psychological well being. So, as you can imagine from having seen patients who are critically ill, there's a lot of risk factors for developing debility in terms of prolonged sedation. Um immobility while being on a ventilator are attached to other life support devices. So the physical impairments can be cumulative, particularly in patients with covid 19 where the experiences that the length of stay when they get admitted to the ICU is long on the order of weeks, similarly being in the intensive care unit, receiving many new medications and also the physiologic stresses of shock, hypoglycemia and other disease process are all risk factors for developing cognitive dysfunction, both in the acute term which we would call delirium and then cognitive dysfunction that persists. Finally, there's good data that both patients and their families and caregivers are at high risk for depression, anxiety and PTSD after a family member has been in the intensive care unit. So these are the three core domains of post ICU syndrome and for those of you who are interested in some more writing about this, there was a, I think very impactful article in the new york times last year talking about the experience of covid patients who are experiencing delirium in the intensive care unit. So if we shift away from post ICU syndrome and also shift away from persistent organ dysfunction, that last category of prolonged post viral fatigue or long haul covid is something that certainly was new to me to be seeing in clinic in this last year. I think the first time it came on my radar was in this story, last june in the atlantic. That was the first time I had seen the term long haulers in print. This has since had coverage in local media on numerous occasions. And then, as I mentioned at the outset of this talk just yesterday, there was an opinion piece in the New York Times about the accumulative impact that COVID-19 stands to have now that we're having an increasing number of people who have been infected and survived this infection. So it's actually interesting to think about where this term come from. And I have to say that I have in general avoided using the term long haulers, which I think is quite colloquial and not specific. That's why instead I titled my talk long term sequelae of covid 19, which permits us to them been the types of experiences people are having into the three categories. I suggest few sights ago. But if we think about this terminology is actually very interesting. This is a article from a sociology journal this year talking about how long covid and long haulers where these terms came from emerging on social media, on post that patients were patients. And, you know, the public were Posting after their experience with COVID-19 describing how they weren't feeling better, how this was not expected, how all of the attention was on the acute mortality of people who were hospitalist when many more patients were potentially at risk for developing these other problems. And it's interesting to think about this is potentially what these are, authors argue as the first patient defined illness and an instance similar to past experience of patient activism, to rally support for research around other diseases like HIV and in this case by moving along so quickly in defining this new entity of long covid. You know, now the research institutions are taking are paying attention and the National Institute of Health has said this as a priority area, calling for applications for funding to study what is happening and why these patients are having these long term symptoms. So how would I define long covid or the experience of long haulers? So, in my experience seeing patients like this in our clinic, I'm seeing exactly what we've just heard about in the preceding studies, patients who are having persistent symptoms, the most common being fatigue and shortness of breath, particularly exercise limitation, where they get much more out of breath with much less exercise than they used to. And people even describe things like over doing it one day, for instance, instead of walking around the block, one time trying to walk around the block two times or climate, extra fight of stairs and then being bedridden for several days as they recover. In addition to those cardinal symptoms, some people have also been reported headache, racing heart palpitations, uh fevers and other kind of autonomic findings. So the Centers for Disease Control has a page that I've linked to here that has some more information about the common symptoms experienced by people who are self described long haulers with covid. So, um, there is not great research to date that has taken a lens of looking at all people 19 to understand the burden of persistent symptoms. This study is certainly large and represents people from a large number of countries, asking them by a web based survey About their demographic characteristics. Who are they, what's their background and what symptoms are they having for covid? 19. And so this could provide some answers to the experience of patients. But It's a very problematic study because as you can see, it was a 257 question study, Uh, that took a median of 70 minutes to complete. So I don't know the last time you took a 70 minute survey. I cannot think of one. It's longer than even most sections on board exams. And so you can imagine that there would be intense selection bias here, where who are going to stick it out and complete this survey are going to be those that are most uh persistent symptoms. So I just mentioned that as a caveat, try to interpret these findings. Nonetheless, I did think it was worth including this because this study has caught some attention and does describe the experience of several 1000 people at least based on what they're reporting. So what did they find? So in this study, which was highly enriched for women, most of whom were under the age of 50. Um, and a large majority under the age of 60. Again, only one quarter with confirmation of covid infection coming back to a limitation like that fourth patient I mentioned to you in my examples above the young woman who had symptoms of covid had not been able to get access to testing because she had been symptomatic early in the pandemic. This is a major problem for this field because there's a lot of people who don't have confirmed covid but now have symptoms that they believe are related to prior covid infection. So among these people, what are the described symptoms? So out of the list of over 200 that they were asked about subjects reported a median of nine symptoms and the most common symptoms very similar to those elicited in prior studies that I've already shared with you were fatigue, post exertion, all malaise, which is distinct from the shorter term symptoms of people who are not following in this long haul group and then cognitive dysfunction, which some people are describing as brain brain fog. There's a couple of figures from this paper, I'll draw your attention to the one on the left, which is asking the question about the average number of symptoms people have displayed here on the Y axis and then the number of months since their onset of illness. So they bifurcated the group into two categories. Those patients who still had symptoms at least 90 days after their initial development of symptoms and those who had recovered. And so you By definition, those who had recovered by 90 days had all recovered by three months. And you could see that there was a steady improvement over time in the number of symptoms that people were reporting. By contrast, among those people who do not get better by three months rather than improving over the initial course, they are accumulating more and more symptoms on average And then perhaps having a gradual improvement, but still far above zero with the median of more than 10 symptoms months later. Now, I mentioned again that this is a highly selective group that chose to participate in this voluntary survey. Three quarters of them actually did not have confirmed COVID-19 infection. But nonetheless, this is what is reported among these people who participated. When we look at what are the symptoms that are most commonly being reported? This is again familiar by now, fatigue, post exertion, all malaise a substantial proportion of people reporting ongoing low grade fevers, sweats, some changes in their uh, sensations in their skin. Other issues that may be related to autonomic dysfunction, like weakness, temperature, liability. So, if these are the symptoms that people are reporting several months after having covid, and we've decided that this is beyond the standard trajectory of covid recovery, which we already recognize can take more than two months in just about everyone who ends up being hospitalized. I guess the question is, who is at risk of developing these long haul symptoms? And thinking back to those four patients that I shared with you at the beginning with different baseline ages, comorbidities, different acute illness severity and different findings on cT scan. What does the data tell us about predicting who's going to go on to develop long term symptoms of COVID-19. So, this is a study also a pre print using data. Um, 1400 patients from a collaborative cohort within the University of California system should say I'm not at all affiliated with this work. The patients in this study all had PCR confirmed coronavirus infection or COVID-19 disease. So that's an improvement in terms of understanding who is included in this study. And then what the investigators did is they did a chart review looking retrospectively to try to understand what were the symptoms that these patients had during their acute illness, meaning day 0 to 10 after their diagnosis with a positive pcR and what symptoms did they have? Greater than two months after that initial diagnosis. So as you can see here, the Cohort was about 2/3 symptomatic, 1/3 of people were asymptomatic during that first period, and when we look at two months down the line, About 27 were endorsing symptoms consistent with what the author is defined as long haulers. So this is one way to say what is the risk of going on to be a long hauler? Although this number seems high and it might be that there's still problems here that limit our ability to infer what the true prevalence or true risk of progressing too long haul covid is. So in this study, they tried to not only define risk factors for long haul covid but also to cluster the types of symptoms that people were experiencing. And I found this interesting in thinking about the patients that I've been seeing in our survivors clinic. Some patients had symptoms that were mostly concentrated around shortness of breath and cough. Other patients had cough and chest pain. Other patients have more gastrointestinal symptoms like abdominal pain and nausea. Some had prominent joint pains like back and other joints. And then there were patients that mostly had anxiety and we're reporting a high heart rate And I will say that I I think I have seen patients now and in all of these categories were having prolonged symptoms after COVID-19 infection. Someone asking what are the factors that put someone at risk for going on to develop any of these syndromes? These long haul type clusters of symptoms in this study, there were three that came out as being the most predictive. one was being Caucasian or white race, one was having a female sex and the other was having a normal BMI not being overweight. One thing that they did not find to be associated with the risk of developing long term symptoms was initial illness severity. So, if you remember about a third of patients in this cohort were asymptomatic and about a third of long haulers, we're also asymptomatic. So that suggests that the initial illness severity is actually not a good measure or predictor of who is going to go on to develop long haul symptoms of COVID-19. So that was a finding that was replicated in another study looking at initial illness severity and likelihood of having long haul symptoms of covid. So let's spend a minute trying to understand what this study showed. So this was a single center was a hospital in Dublin. They had looked at 153 patients, all of whom were community dwelling, meaning not coming from a nursing home or other facility. And all of these patients were confirmed to have SARS COV. Two based on PcR among these patients. They put them into three groups. One was those patients who had not been admitted to the hospital. The second group was patients who have been admitted to the hospital that did not require level care. And the third group was patients who had been admitted and required level care. So we could see from their flow diagram here they approached, They considered 715 patients who were positive for stars Kobe too. A little bit over over half of them had not been admitted. Less than half admitted. They excluded patients who had either died on the admitted side, not been able to reach or did not live in the community. They excluded people who they could not reach on the non emitted side. And then they ended up with these groups. They had up with 55 who had been in the intensive care unit and 19 who had been in the non I'm sorry, 55 who had been in the non ICU level of care in the acute care hospital, 19 who had been in the Ido, And 79 patients who had not been hospitalized after their diagnosis. And then they assessed what their symptoms were six weeks following their diagnosis, among those who had not been hospitalized or six weeks following discharge among people who have been admitted to the hospital. So they looked at several different outcomes to try to characterize how patients were doing. On the one hand, they looked at respiratory recovery, which they defined based on radiographic experience appearance on a chest X ray and also functional status as measured by a six minute walk test distance. And then they looked, on the other hand at patients self reported health and quality of life. So what did they find? So for the 115 patients who had a chest X ray six weeks after follow up, They found that 14, so just a little bit over 10 had persistent imaging abnormalities. And if they waited another six weeks, so now three months after their initial illness, Two thirds of those patients got better, meaning that only five out of 115 patients or about four had persistent radiographic abnormalities following their initial illness. Then they looked at 109 patients who did a six minute walk test and they asked the question how many of these patients de saturated below 90 as a marker of lung injury? And they found similar to the radiographic pattern that a very small number, only three out of 109 had a significant d saturation. Yeah, But when they looked at self reported quality of life and health status, They found that of 153 surveyed individuals, 95 or 62 said they were not back to full health and 48 matt criteria that they had defined for fatigue. So this finding is kind of similar to what I shared to you with you earlier in the talk, talking about the two and four month outcomes where fatigue was one of the most common symptoms reported in that italian cohort, the michigan cohort and reported by the Centers for Disease Control. So then the study asked the question, okay, what is the relationship between initial illness severity and those findings? The abnormal chest imaging Abnormal Distance on a six minute walk test or reported shortness of breath? The borG scores a way of measuring how tired and out of breath people are after doing a six minute walk test. So this is where I think that the study really shines. So what did they find? They found that when it came to imaging abnormalities when you compared to patients in the ICU to patients who had not been admitted, those patients in the ICU Were more likely with an odds ratio of 4.9 to have imaging abnormalities. This doesn't quite meet the threshold of statistical significance, but you can see a clear trend here where as you go from the non admitted population to the admitted population that didn't require intensive care to, then the admitted population that did require ICU level care, there is a trend towards worsening imaging findings, meaning that initial illness severity is a predictor in this cohort, not at the statistically significant level, but suggested um, of subsequent imaging abnormalities. Other factors like age, sex and um clinical frailty score. We're not associated either based on odds ratio or P value. So if illness severity were also predictive of six minute walk distance and Dystonia on six minute walk test, we would see a similar trend when we look at the first three rows and these two columns. But instead, what do we see? We see that the main predictor of shortness of breath, again being one of the cardinal symptoms of long haul covid was actually not initial illness severity. None of these findings were significantly associated with the likelihood of being shortness of breath instead having baseline frailty and then female sex were both statistically significantly associated with being at risk for having this. So it suggests just like in that other study I showed you previously that initial illness severity is not a good predictor of who is going to go on to develop long haul symptoms of covid, such as shortness of breath. So I guess the question then, is what is going on with these patients there, clearly suffering. They are not getting better. A fraction of them may slowly be improving, but sometimes the progress is very slow and there could be setbacks where they feel like they're moving in the wrong direction. There's a few theories that I don't have time to get into each individually here, but just to kind of name them so that you're familiar with some of the thought process is out there. One theory would be, do these patients have persistent infection that's not been cleared? Either coronavirus or a new super infection? I think that seems unlikely because we're not finding that immuno compromised as a risk factor for developing these prolonged symptoms. In fact, it's happening more often and younger people who are more likely to have an intact robust immune system. I guess by that measure, then perhaps the problem isn't a failure to clear the infection, but an overreaction to the infection in the form of ongoing inflammation. And here there's some theories that perhaps there's some small vessel inflammation that we're not able to detect on our imaging, standard imaging techniques that's contributing to the symptoms. If you think about who is getting this infection, It's mostly been young women, uh, in their 30s to 50s, that's also the group that is at highest risk for developing autoimmune disease. And it's well recognized that in other autoimmune diseases there can be infectious triggers that are the initiator of the process of inflammation and auto immunity. So could it be that what we're seeing with long haul covid is actually an auto immune disease spurred by the spirit, or unmasked by the initial covid infection. Then there's also a disease called mast cell activation, that is an inflammatory disease that seems to have some overlap with long haul covid in terms of who gets admitted immunological profile of such patients. So, these are just a few kind of potential explanations. Unfortunately, this time we don't know what is the most likely reason for these persistent symptoms. So, you know, there are some other diseases that we can turn to that have some similarities. And I'd say one of the groups that I've been working with and learning from a lot is our Integrative medicine specialists at UCSF, who have been working alongside us to take care of patients, were having persistent symptoms consistent with long haul covid. So chronic fatigue syndrome is uh similar entity that is poorly understood. Seems like it might be triggered by an infection or some sort of immune dis regulation maybe a metabolic problem related to diet or endocrine a pithy. Some overlap with mood disorders, but not clearly explained by such. And it seems to happen in the same people. It seems to happen in young women with a higher socioeconomic status, just as in the predominant pattern that we're seeing in patients with long haul symptoms after covid 19 and the clinical features overlap pretty well with fatigue, cognitive impairment and signs of autonomic dysfunction. So I'm not saying at this point that I'm ready to call these two Syndromes one in the same. Of course, when we have just a syndrome at this time, we actually don't have a constellation of findings. We don't act a specific diagnosis for all these patients to prove that even everyone with long haul covid has the same thing. Or even everyone with chronic fatigue syndrome has the same thing. But I think there are some helpful lessons that we can learn from thinking about this disease model, both in the approach to diagnosis and in terms of risk stratified and understanding who is likely to get this. So these were some proposed diagnostic criteria from the Institute of Medicine published about five years ago about how to diagnose and identify chronic fatigue, chronic fatigue syndrome, which is also called myalgic encephalomyelitis. E And so the cardinal features here you'll recognize as similar to what I've been describing for some patients recovering from COVID 19. They're experiencing substantial reduction, mint reduction or impairment in their ability to engage in their pre illness level of function. They're these systems symptoms are persisting for more than six months. They are accompanied by fatigue, which could be profound. Uh They are also having symptoms that are worsened after exercise, post exertion or malaise. And they're finding that sleep doesn't necessarily make these symptoms better. They're also describing different domains being affected in terms of cognitive impairment or sometimes having features of autoimmune or um autonomic instability, such as Ortho static hypertension and dizziness upon standing. So some clear overlap here and the two syndromes. And I think I'm eager to see as more research comes out Whether approaches to one might be beneficial in the other. And we're certainly starting to borrow lessons from the literature and chronic fatigue syndrome and thinking about how best to care for our patients who have long haul symptoms after COVID-19. So now let's get to the question that you're going to face when you're meeting patients or maybe with Kobe being so common, just talking to friends or family who have had the infection. We're dealing with persistent symptoms and thinking, well, what were you going to do? What am I going to do with this patient who had covid? One week ago, one month ago, six months ago. What types of symptoms are going to be a trigger to do some more investigation or to refer this patient to some specialty care? So let's say that you're meeting Patient # two from the example above and follow up clinic. This just to remind you as a 60 year old who had obesity and diabetes. He had been admitted to acute care. He required six L of Nasal Cannula. He was hospitalized for four days. So let's say it's now a month later and this patient's having persistent cough, exercise limitation. What would you recommend if you're meeting him in clinic? Would this be a time to get lung function testing a ct scan of the chest, an echo Or to re evaluate the patient in three months? I'm gonna keep going because I know we're doing this as a CMI recorded lecture rather than pausing to ask for input here. But the answer I'm looking for is not to do any testing here, But rather to reassure the patient that they're having a trajectory that sounds very consistent with what most people experience most people over 80 in certain cohorts are not back to normal two months after hospitalization and the most common symptoms are cough, shortness of breath, exercise limitation. So on a patient such as this, I think it's important to make sure that there's no red flag scientists, there's a new process. I certainly wouldn't want to see this person getting worse. I wouldn't want to see them feeling like they're needing oxygen now that they didn't need two weeks ago. And if they're actually still on oxygen a month later, I think my index of suspicion for something going on other than Covid would be high unless they were on oxygen before. But barring all of those red flags, I would be most likely upon meeting someone like this to suggest that we meet again in short interval, follow up in 2 to 3 months providing some reassurance that yes, their symptoms are still there and very real. But these are also very much consistent with what others are experience experiencing and as long as their trajectory upwards and they're improving, I wouldn't recommend any testing. So when would I test? Well, you know, if we look back at the other studies that we thought about a couple slides back, I told you about patients with radiographic abnormalities after Covid at six weeks. And those had largely improved by the time they were damaged another six weeks later. That is one answer which is you might want to wait about three months. What about this study here? Published earlier this year, 48 patients who had all of them severe covid requiring I. C. Level care for mechanical ventilation because of our kids. These patients were evaluated three months after being hospitalized And they were assessed by having a six minute walk test, pulmonary function testing and a high resolution chest ct. And so what did they find here? Let me orient you to the table. So for those patients, they had PFCs for 43 Out of the 48 patients, they found that the absolute value here percentage predicted in the number of patients below the lower limit of normal. We look here at the percentage of predicted column F. e. v. one and forced vital capacity on spy rama tree were normal. The abnormality that they detected in these patients who had been in the intensive care unit was in diffusion capacity for carbon dioxide, a measure more of gas X. Games that could be a finding suggestive of interstitial lung disease or fibrosis related to prior injury. So they found that the spire um a tree was normal. The diffusion capacity was reduced. And they found that their six minute walk test distance was actually pretty good. They were walking about 82 of the predicted distance on average. So What about the imaging that they did at three months? They found that Only two out of 48 people assessed three months after discharged from the ICU. Where they had been on a ventilator. For covid 19 had normal cT scans of the chest, 41, about 80 had persistent ground glass capacities. 32 were about 2/3 had on had evidence of fibrosis. So to me, this suggests that there is very little utility getting lung function testing or a cT scan of the chest and on the time frame of 123 months after someone is discharged from the hospital, particularly if they required intensive care. The problem is that we might very well still find imaging abnormalities. We're also very likely to find abnormalities on their lung function testing and from other diseases. We know that those abnormalities can improve over the next 6 to 9 months. If we look at other A. R. D. S. Literature or literature on recovery from severe pneumonia is including empire imma and things affecting the pleural space space. So because the likelihood of an abnormal test is very high and because there's still a good chance that patients will have recovery in their lung function or improvement in their imaging. There's probably not a lot of utility of doing this kind of testing in the first three months after someone who has been discharged. Unless you're finding that they're having symptoms that are going in the wrong direction. Or you think that there's some process that is making them other making their recovery different from what you would normally expect. So let's say you're in the other camp though and you've decided that yes this is a person who needs to be tested which tests would you do? So here's my approach. I start by getting lung function testing, particularly in younger folks who I don't want to necessarily commit to the imaging with its associated radiation. I'm finding that in addition to getting standard lung function tests, it's also very helpful to get a six minute walk test. Many of these patients anecdotally are having normal lung function tests And on their six minute walk test, they might only walk 40 of the predicted distance or their heart rate might go from 80 to 150 with walking. So I'm finding that even that degree of exercise challenge can be enough to unmask some findings and people, once I've done the lung function testing if their diffusion capacity is low, which is a suggestion that that person might have some fibrosis or other types of damage related to the Covid. That's when I would consider cross sectional imaging with the ct scan of the chest, Then there's also some evidence that people with COVID-19 are at risk for arrhythmias or some changes structural changes in their heart. This does not seem to be very common. If you're interested, you can look at some resources about this, There's some reviews about these processes. I do consider an echo, particularly in someone who has taken cardia on their six minute walk test or is having palpitations, but that's kind of third in line here. From a lab perspective, I like to look and make sure that I'm not missing something else, fatigue could be hypothyroidism. Do they still have infection or evidence of some sort of ongoing inflammation? Like a new rheumatoid logic disease? And S. R. And C. R. P. Can help rule this out if they're normal. Do they have anemia related to their prior illness or an abnormal differential in their white cell count? With a high ES NFL count, again pointing you towards some sort of vasculitis or autoimmune disease. I find that these labs are helpful. You could also consider looking for evidence of muscle enzyme breakdown with the CPK if there was a report of a prominent my Algirdas. So when would you want to go ahead and refer someone for further evaluation and treatment? So let's say you're meeting someone on the front end and, you know, they had a complex hospitalization. They were in the intensive care unit or in addition to having covid they had a pulmonary embolism or a severe vap ventilator associated pneumonia or they had baseline lung disease, putting them at higher risk of having problems after their acute infection or they are not able to come off of oxygen. In this case, I think that initial illness, severity and complexity could be a good reason to engage subspecialty care. I also think that it's appropriate when you have someone with persistent symptoms that you've tried to work up and is still suffering regardless of their initial illness severity. So if you wanted to refer someone here, we'd be happy to see you in our clinic, which again we call the optimal clinic. This is for people who are recovering from covid. We've focused on people who have been hospitalized for their initial COVID-19 infection either at UCSF or elsewhere. And we're also seeing people who are having prolonged symptoms after not being hospitalist. As general pulmonary consults. There's at least six of us faculty now seeing us and I want to give my thanks to Doctor Leslie Santos was right here in the middle who helped set up this clinic and was really helping us pioneer this type of work here at UCSF. What are we doing in our clinic? What's the what's the goal of sending someone? What can we offer? We could go over there hospitalization with them and help them understand what happened in the hospital or review the symptoms and tests that they've already had. Finding that as I've seen more and more of these patients, kind of centralizing our expertise, even if we don't have it in the form of data. But at least in the realm of having seen many of these patients, those of us in our clinic are now getting more comfortable providing some reassurance. We can also offer the value of validating the symptoms that patients are having because many times we'll meet people who have not been believed when they're bringing their symptoms to other people, then we'll assess what's going on with the patient and we'll use some structured instruments to try to make sure that we're doing this in a systematic reproducible way, asking about breathlessness, asking about anxiety, depression or post traumatic stress disorder and trying to grade their physical function, particularly in people who are recovering from covid uh, that were in the intensive care unit. Then we'll kind of ask the question, okay, is this person recovering as expected? So this is what I usually ask myself when I'm meeting someone in the first month or two after their hospitalization and if things are generally going as expected, the major outcome is that we're providing reassurance if things are not going as expected, that's when we engage additional testing or refer to other colleagues to think about their recovery. The way we've set up our clinic is that we're kind of at the center of this hub and spokes model and we're working with partners in our divisions of Integrative Medicine, cardiology, neurology, which has a special neuro recovery clinic. We're also working with pulmonary rehabilitation and then we set up virtual support groups where patients can have peer to peer contact to understand that others are struggling with the same symptoms that they might have been having. We're also working with our colleagues in psychiatry and behavioral health. And then of course, we're not wanting to supersede the role of the primary care doctor here. We're trying to maintain good streams of contact with them as well. I think one thing that we have also noted and these patients is just as I don't want you to go doing every test for every patient. It's important to recognize that patients could have multiple things going on. And in our referrals for patients who have been described to us as having long term complications of COVID-19 we've made new diagnoses of cancer. We found patients that actually have pulmonary emboli. We found patients that need a home ventilator because it turns out they have respiratory muscle weakness and that's the reason they were short of breath. And we found many other things as well. So I think this is an important lesson that while common things are common, you do want to be looking as appropriate for other potential explanations, particularly when people are not recovering during the along the normal trajectory. What are we offering as far as treatment? And we're suggesting that patients not overdo it because patients are having some post exertion, all malaise. One thing that we're running into is patients that are being counseled to try to push themselves and two more exercise, get back on the bike, go for a run. I think these are very well intentioned pieces of advice, but when it comes to patients that are having long haul symptoms of covid, this is not what we recommend. Instead, we recommend a graded fashion of slowly increasing the amount of exercise they're doing and trying not to overdo it so that they experienced a setback. Our colleagues in pulmonary rehab or physical therapy more generally have been very helpful in this regard. Um, and working with patients who need a jump start or need some supervision or help in their exercise. Finally, I think the support groups that we've set up here have been really important. I think patients feel like they're on this sea of waves where they're getting covid symptoms get better than their symptoms re worsened. They feel like they're getting better, they worsen again and they're out there feeling like they're all on their own suffering in this way and, and from patients that I've seen, they found it very meaningful to connect, either in real, real real time, over video or through social networks, um, to discuss their ongoing symptoms together. So, I wanted to close by telling you what's been happening with those case examples. And then I'm gonna see what questions people have. So at the beginning, I told you about four different patients of different ages with different baseline health status, different acute illness severity. When it came to Covid 19. And I asked you who is going to have prolonged symptoms. This first patient who had evidence of fibrosis on on their CT scan and was discharged home has had severe depression and PTSD. This is most consistent with the post intensive care syndrome and not really as much the long haul symptoms of COVID-19. So yes, she's had prolonged symptoms, but not what we would call long haul Covid. The second patient who had been admitted to the medicine ward for six liters of oxygen with multifocal opacity, ease on ct chest is back to work and having absolutely no symptoms whatsoever. The third patient, 90 year old who had been in the step down with high flow nasal cannula with evidence of ground glass capacities on CT scan and discharged home on two liters of oxygen, has had new organ dysfunction and the setting of Covid developed new atrial fibrillation and has had to be hospitalized. The 4th Patient, the young woman who had been a previous athlete with a high physical performance status had not ever been confirmed to have Covid, but had compatible symptoms, was never admitted and had a normal CT scan now is still having fatigue, cognitive dysfunction described as brain fog and finding that they can't exercise as they were before. So the only one of these patients, number two, did not have prolonged symptoms. The rest of them all have had prolonged the quality of COVID-19. But the point is that they've had different manifestations and all long. Covid is not the same. So I want to close by looking back at our learning objectives. Thinking about symptoms that commonly persist after COVID-19. This would be examples would be shortness of breath, Fatigue, cough and these could persist for 1-2 months. And many people I wanted you to understand that long Covid really should be broken down into three different categories that are distinct entities. On the one hand, people could be having post hospital or post you syndrome. On the other. They could be having persistent organ dysfunction related to their Covid infection. And then finally, they could be having long haul symptoms of covid, which we don't understand as well at this point in terms of risk factors for developing long haul covid. What did we review here? Well, there's substantial overlap with people who develop chronic fatigue syndrome with this primarily being a disease that's affecting working age women who previously had a good functional status. And it turns out that initial illness severity is actually not a risk factor for developing long haul covid. Finally, we talked about when to refer patients for testing or for subspecialty care. And we talked about two categories of indications here. One being people who you're meeting up front who had complex hospitalizations and would be at risk for things like the post intensive care syndrome or for persistent organ dysfunction. The other category being people who have long haul symptoms of covid with symptoms that have not been able to be well described or identified in terms of their source. We're happy to see both of those types of patients