Coronavirus Pandemic Update 58: Testing; Causes of Hypoxemia in COVID-19 (V/Q vs Shunt vs Diffusion)

welcome to another MedCram COVID-19 update we got a lot of news to cover today the United States tops the charts with the number of new deaths at 1867 United States daily new cases is hovering right around 30 thousand also United States daily deaths around 2000 doesn’t seem to be dropping much at this point likewise daily Canadian new cases around 1500 and it looks like Canadian daily deaths are not peaking as yet or stabilizing they continue to increase United Kingdom seem to be hovering around 5,000 cases a day daily deaths also in the United Kingdom are pretty constant here around 750 I wanted to talk a little bit about testing and again I want to review there’s different types of testing that’s going on up to this point we’ve looked at reverse transcriptase PCR and here we’re looking at the RNA of the virus itself this is usually done by a nasal swab and if it’s positive it tells you that you are infected and if it goes from positive to negative generally speaking what you’re trying to find out is whether or not you’re still infective now this is very different than antibody testing so with antibodies you have a antigen presenting cell that has eaten an infected cell and is presenting a portion of the virus on its surface that connects up with a t-cell and once that connection is made there are cytokines which induce that t-cell to do a number of things number one the first possibility are memory cells number two are cytotoxic T cells and number three are b-cells that turn into plasma cells and they create things called antibodies and these antibodies go out and attack the virus so this is different we’re not looking for RNA of the virus we are looking for proteins or specifically antibodies this is not done with a nasal swab but it’s done with a finger and what this tells you is whether or not you have a GG or IgM IGM and igg usually come up maybe around six to seven days generally speaking after the beginning of an infection and they both sort of come up but the IgM will go away and the IgG will be the only one that remains usually and so IgM is usually seen in acute and IgG is chronic one of the things you should understand is just because you have the presence of antibodies it doesn’t mean that you would be negative on the infective state so it’s possible to be both positive on the reverse transcriptase PCR and also be positive on the antibody testing and that would simply mean that your body has made antibodies against the virus but you still have the virus and you’re still infective so understanding that it’s very important when we read articles like this in the Boston Globe titled nearly a third of 200 blood samples taken in Chelsea show exposure to corona virus Mass General researcher says that the results point to a raging epidemic but may also indicate the city is further along the disease curve than some other municipalities so what they did was they went down to Bellingham Square and they tested about 200 Chelsea residents there and they found that 64 of those residents were positive they made sure to exclude those people that have been tested positive using an RT PCR test prior but it’s important to understand that this was not a random sample no in fact Chelsea has the state’s highest rate of confirmed kovat 19 cases at least 39 residents have died from the virus and 712 tested positive as of Tuesday at a rate of about 1,900 cases per 100,000 residents or almost 2 percent so why would there be 30 percent in this sample as we just said this is not a random sample so it may not be representative but boy a third of cases sounds pretty high now as we’ve mentioned before just because you have an antibody that’s positive it doesn’t mean that you’ve cleared the virus still mr. Amberson who is the city manager added here it’s kind of sobering that 30 percent of a random group of 200 people that are showing no symptoms are in fact infected it’s all the more reason for everyone to be practicing physical distancing they also go on to talk about that many work in the hospitality industry and health-related fields where exposure to the virus is greater and a lot of them must go to work during the pandemic just to note that the test that they used here was by biomed omics which is not yet fda-approved but that

Mass General determined that was reliable now here was an article that was published on net archive that has not yet been peer-reviewed that looked at a slightly different situation on the west coast in this situation they reported the prevalence of antibodies to SARS cuff two in a sample of three thousand three hundred and thirty people adjusting for zip code sex race ethnicity so what they found was after they did that adjustment the unadjusted prevalence of antibodies to SARS cough – in Santa Clara County was one point five percent or somewhere between one point one and one and one point nine seven percent and that the population weighted prevalence was two point eight one percent and what they came up with was that this was fifty to eighty five fold more than the number of confirmed cases and so their conclusion was that the population prevalence of SARS cuff to antibodies in Santa Clara County implies that the infection is much more widespread than indicated by the number of confirmed cases population prevalence estimates can now be used to calibrate epidemic and mortality projections but there’s an interesting pair review that was published on medium.com of this article by researchers at Stanford University he talks about how he really hopes that the article is true because of course if it is that widespread then that means the fatality rate is actually a lot less that there may be more people than we think that are infected and this would be closer potentially to widespread immunity and it will allow people to go back to work but he talks about why he is skeptical of this research article for several reasons and he enumerates these reasons here the first one being that the false positive rate of the test is actually too high and basically he says that if the noise from the false positives are high enough it could actually bury the true false positive rate and make it look as though the number of positives are higher than they really should be and he goes through and shows us what the definition of a false positive is but what he really boils it down to is apparently what a gentleman by the name of Geoffrey Spence says he says here in the supplement they say that two out of three hundred and seventy one plus thirty five no negative samples tested positive this means that the 95% confidence interval for the false positive rate is somewhere between 0.06 percent and 1.7 7% and in their samples from Santa Clara County they had 1.5 percent test positive so you see here that the 1.5% fits within the 95% confidence interval that is given for our false positive rate and so what you can see here is that they can’t say with 95% confidence that the positive rate that they got from their antibody tests isn’t all from false positives and what dr. Srinivas on who is the PhD author of this peer review is saying here is that Jeff Lee likely means that 371 plus 30 no negatives here rather than the 371 plus 35 and our confidence interval somewhat differs from his but the conclusions are directionally the same and the author shows this through three progressively more sophisticated ways to estimate the false positive rate which he lists here and he starts with these three and it’s maybe worth your time to look through but probably beyond the scope of what we’re talking about here finally he boils it down to this the main conclusion is that we don’t have a high confidence that the false positive rate is low enough and that this is one possible failure mode the second point he makes is was this really a randomized sample and in fact what they did was they recruited participants via Facebook ads which if you haven’t had any symptoms you probably wouldn’t care but if you had had symptoms and you wanted to find out whether or not you might have had a kovat case maybe a month ago you might be pushed to have an antibody test and that’s exactly the point that he makes here he says here but there’s a problem what if their group of participants was enriched for positives relative to the general population what if their participants had a much higher rate of Cova 19 than normal and as he says to the author’s credit of the original article they did attest to this they say that their study had several limitations first our sampling strategy selected for members of Santa Clara County with access to Facebook and a car to attend drive-through testing sites this resulted in an over-representation of white women between the ages of 19 and 64 and an under-representation of Hispanic and Asian populations relative to our community but the big whopper

here’s here at the end are their biases such as bias favoring individuals in good health capable of attending our testing sites or here’s the key bias favoring those with prior kovat like illnesses seeking antibody confirmation are also possible the overall effect of such biases is hard to ascertain and apparently the authors of the original article didn’t feel that that was a big enough deal but dr. Srinivasan the author of this peer review felt like it was a big deal he says here the first mechanism that could significantly enrich the number of kovat 19 cases in the study is if symptomatic or exposed people use the study to get a test they could get no other way and of course testing is pretty minimal right now in California these states here after all in the Bay Area in early April it was really hard to get a test for people with mild symptoms or exposure so people who thought they were exposed or symptomatic may have signed up for the study to get access to a freak Ovid 19 test they could get no other way and apparently all they needed was 50 out of 3332 exhibit this behavior and then of course people who are exposed may have helped other people who they have direct contact with to get into the study who they could have exposed as well and instead of getting a super spreader you would get what he calls a super recruiter event where one person recruits and other enriched people into the study and that could significantly boost the number of positives behind what you’d see in a random sample of santa clara so at the end he summarizes his conclusions as we talked about the first one was the false positive right the second was there might have been an enrichment of Kovan 19 cases in his sampling the third is that it seems as though in order to produce the visible excess mortality numbers that Kovan 19 is already piling up in Europe in New York City the study would imply that Cova 19 is spreading significantly faster than past pandemics like h1n1 many of which had multiple waves and took more than a year to run their course so why have we taken so much time looking at this I think it’s instructive because number one the original paper that was about to be published or is on met archive does seem to make some very interesting claims claims that show that the virus is far more prevalent than we think number two the pair reviewed by dr Srinivasan is instructive in exactly why peer-review is important sometimes these findings that we see may not be what they seem but what we will see is that time will tell and usually the answer is not on one extreme or the other but somewhere in the middle so I’d be interested to see what comments you have below I wanted to switch gears a little bit now and talk to you about some of the mechanisms of hypoxemia in kovat 19 and in other diseases as well and this has come up because there have been a number of discussions on the internet and on YouTube about physicians talking about the mechanism of how people are getting hypoxemia with kovat 19 and in one video in particular the discussion is about how VQ mismatch and shunt physiology may not describe exactly what’s going on in kovat 19 but that diffusion abnormality seems to be a better explanation so if you don’t understand what those things are you’re going to be completely lost when it comes to discussing this and being able to entertain that kind of language so I wanted to quickly go over exactly what is VQ mismatch shunt and diffusion abnormality so with VQ mismatch one way of looking at this is looking at the blood that is going to the lungs in areas where there is high V Q relationships and areas where there’s low V Q relationships and I’ll explain a little bit more about what that is so you have to understand that with an alveolus it’s very important that the amount of ventilation that’s going in and out of the alveolus is commensurate with the amount of blood that’s going by if there is a difference between the amount of airflow and the amount of blood flow that’s going to cause problems now there always is a slight mal distribution in the lung but it’s a very very small amount what can happen though especially in thrombotic problems where there is blood clots is you can get issues with VQ mismatch of course you can get it with other diseases as well but here’s an example so I’ve drawn this to show you that when deoxygenated blood is coming in to the lungs if there are areas that have more blood going to it and there are areas with less blood by definition q is flow and so if there’s an area here of less blood going to this ventilation units then your VQ ratio are going to be high here on the other hand if there’s more blood coming in and that’s going to increase the denominator then your VQ

ratio is going to be low so you have here is a high VQ ratio and a low VQ ratio and so therefore you have mismatching VQ and so why would that cause hypoxemia it’s simple it’s because in this blood coming back that’s very well ventilated given the amount of blood that’s coming back this is going to be very well oxygenated however the same cannot be said here in this situation you’re going to get oxygenation but not as much because there’s less ventilation perfusion so here 70% saturation is what the blood usually is when it comes in to the pulmonary artery when it goes to the pulmonary vein you have oxygen your blood coming back you might say for instance here have 98 percent saturated blood because it’s very well ventilated but not very well perfused but here you have a very large amount of blood coming back which is not very well ventilated and so here it may only be let’s say 80% saturated well when this blood comes back together it’s good to be normally just an average of these two but it’s gonna be the weighted average based on the blood but because the amount of blood coming back here is so small and the amount of blood coming back here is so large that it’s not going to be the arithmetic mean of these two saturations in other words it’s not going to be 89% no no no actually it’s going to be less than 89% the reason is is that because this has more flow and because the area that has more flow will always have the lowest saturation the average of these two is always going to be closer to 80% or the lower range now if we give a hundred percent oxygen to these patients here and here you can see very quickly that not only is this 98% going to go up to maybe a hundred percent so that’s not a very big deal there but here because there is ventilation because we can get oxygenation into them we’re going to get a hundred percent here and here and so it is possible to improve the oxygen saturation by giving patients a hundred percent oxygen this is encountered distinction to shunt physiology okay let’s show you what’s going on here with shunt physiology same sort of situation start out at seventy percent and in this case we’re just going to say that the shunt physiology is about 50 percent so 50 percent is going here and 50 percent is going here now in this situation we have the lungs up here and let’s just say that the vuq ratios are just fine and so 70 percent blood coming in from this side is going to go here and because it’s going to the lungs it’s going to get well oxygenated and it’s going to come back saturated at 98 percent whereas here this blood coming in to this limb it’s going through a shunt what does that mean well there may be an alveolus that’s here that air could get into and could oxygenate the blood going by but because there’s fluid in here either proteinaceous fluid or it just collapsed there is absolutely no way that that air or that ventilation can get to that area where it can get into the circulation and so as a result of that this blood simply goes right back at 70 percent in other words there’s no oxygenation that occurs it comes in at 70 it leaves at 70 whereas this which goes to the part of the lungs that are being ventilated appropriately will be resat rate at 98% so because this amount of blood is equal to this amount of blood because we said it was a 50% 50% shunts this will be the arithmetic mean of these two so in that case since there’s a difference of 28 points then this will increase by 14 points and the new saturation will be 84% let’s go ahead and put a hundred percent oxygen on this patient 100% here hundred percent here because the ventilation is not getting to it anyway it’s going to be not consequential at all that the patient’s getting 100 percent oxygen it’s getting oxygen here but it’s not able to go anywhere so therefore this will still remain at 70 percent it’s completely blocked whereas up here this is getting ventilated appropriately and so you’re going to super saturate this blood and instead of 98 percent it’s gonna go up to a hundred percent great now let’s do the calculation a hundred percent 70 percent now instead of 84 percent it’s good to be 85 percent and you can see that that’s just a very modest improvement in oxygenation very very small amount of improvement in oxygenation so one of the key things that you should know about shunt physiology is that when you give them a hundred percent oxygen it should not really improve oxygenation what does improve oxygenation in shunt physiology is not increasing the amount of oxygen that you’re giving patients but in fact the amount of pressure that you’re giving it under so if you’re giving High Flow or if you’re giving

peep on later then that could potentially pop open very nicely those alveoli and allow ventilation to go in and down and now you can actually oxygenate and ventilate these alveoli to the point where you can improve oxygenation that tells you that it’s shunt phenomenon so shunt phenomenon again the characteristic is is that increasing oxygenation will not change the resulting saturation but increasing positive pressure will do that however what a lot of these emergency room physicians who are on the front lines seeing these patients are saying is that patients are coming in extremely hypoxic they’re being put on oxygen and they are improving so they feel that shunt physiology doesn’t explain it as well and they’re saying that maybe VQ physiology mismatch doesn’t explain it so what some people have proposed out there is diffusion abnormality so what is diffusion abnormality it’s very simple diffusion abnormality is when you have an alveolus and you have a pulmonary artery going into a pulmonary vein through a capillary so this is the pulmonary artery this is the pulmonary vein and remember again at the pulmonary artery has deoxygenated blood and that is going to oxygenated blood and here you have an alveolus and you’ve got ventilation you’ve got carbon dioxide an oxygen coming in but what you have here is this very thin layer which is made up of the cell bodies of the endothelium on this side and the epithelium on this side so this is extremely thin and what can happen is if there is fluid sometimes fluid can accumulate in here and make it thicker and that can cause a diffusion abnormality it’s so it’s harder for oxygen and carbon dioxide to diffuse back and forth through this now as it turns out carbon dioxide is not as affected as oxygen because of its ability to diffuse much more quickly because of its molecular structure whereas oxygen has a much harder time diffusing in these things and so if you slow down the ability of oxygen to diffuse then it’s possible that the red blood cells as they are passing by will not equilibrate instead of having 70% here going to a hundred percent they may go from seventy percent to only eighty five percent why because the red blood cell is going by too quickly normally speaking just so you’re aware in a resting situation the red blood cell spends about 0.75 seconds in the capillary membrane as it goes by of course if you do exercise the cardiac output is going to increase and the red blood cell is going to whip by even faster and so it might spend only 0.5 seconds now for a collaboration to occur this can occur very very quickly if you have a very fine-tuned and thin barrier for oxygen to diffuse through and so you may only need point 4.5 seconds for oxygen to diffuse but if you have a diffusion abnormality which causes a barrier now it might take instead of 0.4 0.5 seconds it may take a full seconds in some situations or at 0.75 seconds for that oxygen to diffuse and if you start to exercise you can see that the red blood cell is going to spend less time because it’s going faster and it will not be able to completely take on all the oxygen that it should so that is diffusion abnormality and I would say that if you want to have a fuller understanding of these three and another two types of hypoxia or the mechanisms of hypoxemia please go to med cram comm for a whole course on the different mechanisms of hypoxemia and that is completely free there’s two more points that i want to make regarding all of this VQ mismatch shunt and diffusion abnormality the first point is you should not fall into the trap of thinking that one type of disease only causes one mechanism let me give you an example for instance if somebody had mild congestive heart failure mild congestive heart failure would first cause an accumulation of fluid right here between the alveolus and the pulmonary capillary membrane and so it’s possible to have a mild diffusion abnormality in very early congestive heart failure but as the congestive heart failure gets worse and worse and worse not only will the fluid be in the capillary membrane but if you look over here on shut it could fill up the entire alveolus so it was completely full of fluid when it’s more severe and then instead of having a diffusion abnormality you would have a shunt phenomenon so that’s just a simple explanation in fact in a lot of different diseases you might see a bit of diffusion abnormality you might see some shunting you might see some VQ mismatch so that brings me to the second point and that is this it’s possible to actually quantitatively find out exactly what’s going on in terms of the human

smach shunts and diffusion abnormality and the technique is called multiple inert gas elimination technique this is where they put inert gases intravenously and they’re able to see how they are cleared the description of how this works goes well beyond the ability to describe it here and in this forum but it’s well noted here that in addition to quantifying ventilation perfusion inequality and pulmonary shunting mig t or multiple inert gas elimination technique and identify and quantify diffusion limitation of oxygen exchange when present as well as explain the contributions of extra pulmonary influences such as inspired oxygen concentration ventilation cardiac output hemoglobin concentration body temperature and acid-base State on arterial oxygenation so what I would propose to the scientific community is to see if it’s possible to get one of these patients one of these patients that many of the physicians have been saying are not acting like your typical a RDS patient to see if they could quickly identify who they are and do multiple inert gas elimination technique but there is another point that I would make this kovin 19 disease is much like an elephant in a dark room and we are trying to feel the animal to see what kind of animal it is and depending on where we’re standing in the room it might feel like a tree trunk it might feel like a rope but at the end of the day it’s all one animal it may be presenting as different things to different people please come and see us at met cram comm for clear explanations on many other topics including hypertension heart failure how to read it EKG thanks for joining us