The Epidemiology, Science & Clinical Manifestations of COVID-19: A UCSF Update

good afternoon welcome to the UCSF Department of Medicine Grand Rounds I want to send welcome to our live audience from the UCSF Department of Medicine our other colleagues here at UCSF and our friends at our partner sites in the uses of Health Network I see we already have about 800 participants who have joined us on zoom' I assume we'll have some more we will post this video later on YouTube the Grand Rounds that we did two weeks ago for which this is an update has been viewed about 50,000 times so it's clear that the hunger for up-to-date accurate information about Cova 19 is evident and completely understandable and I'm guessing the today's update will be equally valuable a first a few ground rules for our live audience who are joining us you see them on the screen join the excuse me put your zoom window in full-screen mode and adjust the presentation to fit to window if you have questions submit them through the Q&A box on the bottom that box is being monitored by my colleague 20 Chang and we will try to answer as many of them as we can after the first four speakers speak none of the speakers have any relevant conflicts of interest and the reason all of us are not wearing masks is that we're all sitting alone in our offices which is allowed there is a universal mass policy however at UCSF in our clinical sites right now why are we doing an update after we did a session like this two weeks ago because as you know two weeks is a lifetime in this battle and a lot has changed in the last couple of weeks as you will see as you hear the talks our format today will mirror the one we use two weeks ago four of my colleagues will deliver 12 minute talks covering some of the key issues in this pandemic epidemiology biology and testing clinical aspects of the disease as well as treatment options will then have about a 15 minute QA involving those four speakers that will take us a little past the first hour mark that will be followed by a 30-minute panel discussions with five other used though folks a little bit more on the on the ground experience that we're all having in managing this from variety of viewpoints the entire session will last about an hour and 45 minutes it goes without saying that our hearts go out to the patients and their loved ones who have been affected by this virus last week we lost one of our own dr. John Murray who's was professor emeritus in our pulmonary division and sadly and ironically was one of the people who first described a RDS added seminal research in the disease and he succumbed to Cova 19 in Paris where he was living his obituary was just post in the New York Times so this thing is already affecting all of us in all sorts of ways and sadly to use a baseball metaphor we're probably only in the second or the third inning before we start I really want to send my thanks to everyone here in the UCSF community who's responded to this challenge with a great skill commitment teamwork and courage a salute particularly to the clinicians who are providing direct care both here and around the world also to our research and educational communities who are carrying on it are trying circumstances and particularly the researchers from trying to help us better understand this new disease finally thanks to our leaders who've supported us skillfully in a rapidly swirling and charged environment all of it has made me very proud to be here at UCSF here in San Francisco a combination of early and aggressive action by political leaders corporate leaders including those here at UCSF and the public as well as undoubtedly some good fortune has led to a far flatter curve than we're seeing in many other parts of the country three weeks ago for example our case number in San Francisco was essentially the same as in New York as of this morning there are 450 confirmed kovat cases in all of San Francisco and seven deaths tragically the case count in New York has now topped 50,000 with 1,400 dead it's absolutely vital that we don't let down our guard that what we've done here in San Francisco has been working and we need to keep it up and there are probably some lessons from our experience and that's part of why we're here today the importance of conducting rigorous science and providing accurate information to both professional and lay audiences have never been more evidence and so that is the aim of our session let's start with the first speaker the first speaker is Diane Hagler Diana's professor of medicine and chief of the division of HIV infectious diseases and global medicine based at our Zuckerberg San Francisco general site the goal of her research has developed therapeutic strategies to improve the lives of people living with HIV and other viruses now including the corona virus and she will start us off by giving us an update on the epidemiology of Kovan 19 Diane it's yours thanks very much so we are continuing to exceed an extraordinary expansion in the koba 19 a pandemic we're gonna cross the 1 million barrier over the next 24 hours of reported cases to date and just two weeks ago when I gave this same talk we were really focused on the 80,000 cases that were seen in China so koban 19 a quick review is a new corona virus that's related to the SARS virus and called Tsarskoe v2 across the species barrier between bats and humans in late 2019 this virus can infect cells in the oral pharynx in the upper respiratory tract and the lung and the gut one of its characteristics is that people who are infected at high viral load and are very transmissible before and during symptoms it can be fatal there's no treatment there's no vaccine and the public response public health responses are what we have now next slide so let's look a little bit at the global spread over the last month what are we seeing so the epidemic epicenter has spread from China Asia on to Europe and the United States and although not certainly not gone Asia the epicenter has really some food subdued I think we can say that Asia really had a what I would call a SARS like response they had experienced SARS before it had devastating helped in very large economic effects to their society so when koban 19 came around they acted fast they did massive ramp up of testing they had already had a culture wearing massive public and they instituted already existing robust contact tracing and quarantine systems so if we look at these graphs here on the screen on the upper left this maps out daily deaths over time and what you can see in February we're seeing these deaths in China they're reduced and then we can see that these are numbers excuse me these are number the confirmed cases not deaths that are rapidly increasing first we see in Italy then in Spain and then you can see in the United States just this remarkable trajectory if we look on the lower graph this is adjusted per population of persons and this helps one see at least in terms of reported cases where the hotspots are and you can see them in Europe and in the United States the next slide ok so now let's move on to deaths the prior slide was four cases and we have had over 40,000 deaths worldwide the countries with the highest number of deaths are Italy Spain the United States followed by France and China we can also look at the trajectory of these deaths and these are a rolling three day average starting in February 17th and this will surprise none of you because we have all heard and seen the just tragic pictures from Italy where they had a rapid increase in their death rate followed by Spain and now the United States below that graph is a graph adjusted per million persons and once again you can see the hard hit regions per million persons in Europe and it's life epidemics were interested in the case fatality rate and that is the number of deaths per cases reported now in the context of an active epidemic these numbers are very dynamic and evolving people on an individual one level want to know if the incidents or they want to know the fatality per incident infection we don't know that right now so let's look at the CF RS or case fatality rate right now the current global range is from point two to seven point seven and in an active-active epidemic it depends on the context the population that's being affected in the state you can imagine for example if an epidemic started in a extended care facility with a very old population the case fatality mate might be very high earlier but it could decrease as it spread to a population with lower age because we are not testing everyone we overestimate the case fatality rate and many in epidemics which is a case of what we're doing now I think one thing we can say with confidence when you look across the globe and if you look at the graph on the upper left which shows case fatality rates by age by four countries which are two in Europe and two are in Asia that the higher ages are associated with higher budget mentality and this is also if people have co-infections I think we don't have data as much data from the United States yet but I think we're certainly seeing it seems like a lot more middle-aged people being infected with the disease so we'll see what's happening I think we can barely say we are not seeing deaths in the younger age groups we know that this particular infection has a much higher case fatality rate compared to the seasonal flu we don't know if it's ten or twenty fold higher will get more date about that and this variability we're seeing will be explained over time looks like so what's happening in the United States we've got over 200,000 cases in over 4,700 deaths the virus entered and spread through the United States the airplanes land and sea on our US response included rationing testing and I think it's fair to say that some confusing and variable public messaging and action and many health care workers got infected we don't know how many nursing homes and cruise ships became sub epidemics and just yesterday the IH IH n E released a model that predicted in the United States somewhere over 80 thousand deaths and we expect to see this death trajectory increasing over this particular month we first heard about cases in Washington State California and some of the coastal states including New York Bob just mentioned incredible escalation of cases that we've seen in the state of New York and in New York City we also have other hotspots in the United States which include Louisiana and there's been speculation that was post Monte Mardi Gras and also in the central United States Michigan Illinois Indiana and possibly Wisconsin next slide so let's look at California in the Bay Area we have nearly 9,000 cases in California this is a heat map which shows cases for a hundred thousand people just to note you can see where the bay area is just to note the dark region in the central eastern border of the state that's just really small numbers and that estimate is not precision so please don't be distracted by that next life so there was a really interesting paper by Charles choose group which was recently released and it addressed one of the questions of what do we know about the introduction of Kovan 19 into Northern California and his group sequenced 29 viral isolates and what had suggested her show that there were multiple independent introductions of co19 the stars Kobe two virus in Northern California and you can look at this map here you can see in San Francisco that we had some viruses with the European lineage we had some viruses with the Washington lineage which was also on the cruise ship Solana conic County had its own lineages that they were seeing and also there were some lineages from China so this is how it has it is not just purely from community spread from one string in California excellent so two weeks ago we talked about in all of you who have seen this of trajectories of epidemic and wanting to flatten the curve and the things that we do and we around the world people have initiated population level measures in order to contain the epidemic and those are based what we have now is just to try to prevent the viruses which are in particles to spread from person to person by keeping people farther apart so they don't spread it by talking sneezing spitting or singing or touching surfaces that may also harbor the virus this is a graph which shows over time starting in the first first day of March this is only a month of the absolute number of cases by county and what you can see here is the top County the dark gray is santa clara followed by us in San Francisco then Sal San Mateo and then Alameda what I superimposed on here was the dates of action under our mayor and grant Colfax I'm the director of the Public Health Department over time what was done in San Francisco you can see in March six we declared a local health emergency there was some environmental cleaning suggesting of limit of gatherings and then on march 16th a shelter-in-place order was was released and then finally the most recent mass for health care workers next slide so one of the questions social distancing and the shelter and places measures have been implementing around the world so one question is are people actually doing them and we can actually go to public databases a variety of sources to get some evidence of this so I just want to give three examples what you can see if you look at the percentage of people using percentage of people who are traveling compared to what during this time of year they usually do you can look at these percentages over time and I just showed three cities here San Francisco Boston and Chicago UC San Francisco had the earliest drop in terms of this transportation metric also this is really interesting two nitrogen dioxide which is an intermediary and pollution which really reflects industrial output there's all these satellite images where you can look around the world and you can see is as countries or regions but shelter in place and people were not at these factories working that there were reductions and no.2 emissions and finally this was just kind of interesting online purchase of jigsaw puzzles is actually skyrocketed presumably because more people are staying at home next slide so this is a real key question everybody's entered interventions nothing and are they working well we don't have drugs right now we don't have a vaccine right now so the one thing that we are not uniformly doing is recommending the use of mass in the public domain and of course this assumes we have all of our health care workers protected here are some data to suggest that these barrier methods they're certainly not completely effective but they could resume reduce transmission and provide some protection with certain types of fabrics so there's lots of discussions right now around California around the country about this and the first actually Public Health Department to make a move was in Riverside County two days ago when they when they put out a Public Health order and launched a YouTube video with rather a catchy jingle which was building up what was already being done stay in place maintain your space six feet and cover your face so a couple of cities Los Angeles has recommended the state of California says I think it's a good idea so we'll see what happens with that in terms of any empirical evidence that these these types of interventions work I showed two weeks ago what happened in China with this whole package of interventions that they utilize which did include public masking and I just shared with this with you in Italy these two districts which are similar many characteristics adjacent to each other had two completely different approaches and levels of aggressiveness for shelter-in-place once started February 16 with a very heavy mayoral top-down order and then the other in March 9th and you can see the number of cases really how they dramatically different it's just in terms of we're always measuring cases and certainly when we're looking at hospitalized cases of what happened to three weeks ago so we are still trying to understand exactly what is happening in our cities and cities in the United States but we are going to know more soon next slide so I think one topic that everyone is interested in talking about is what is our breakout plan well if we look at the global experience in China Singapore Hong Kong and Taiwan they have been easing social distance see they have not seen a huge resurgence in cases part of their breakout plan accuses includes mass use also rapid and Universal testing isolation and contact tracing and some border control measures we must a need to understand the immunity to this disease and there's a large effort at UCSF is really I think leading and coordinating much of these efforts to understand which antibody tests are best and we can and should be using this as part of our strategies but let's just say that we find out that the prevalence is only 5% it's going to be tough because there could be 95% of people parties still susceptible so we're fortunate we have strong city and state leadership and we're going to need to deploy these with a multi-sector approach and using the highest tech approaches that we can or some of these rather economy approaches so I think we absolutely the way out of this is with a vaccine but in the meantime we need to continue research for scalable prevention and treatment and to understand more about the virus this isn't going to be the last time with this group of viruses and have a stronger structure for pandemic response thank you great Thank You Diane I'm sure the issue of the breakout plan and what happens next will come up in the in the questions let's switch over to a Chas so Chas Langley a who is assistant professor in our division of infectious diseases based at ucsf health he also works in the Chan Zuckerberg bio hub his research aims to understand the biology of infectious lung diseases and influence respiratory infection a susceptibility severity and their contribution to lung injury and he has become one of our go-to people as we talk about testing and that's what he'll talk about with us today so jazz well thanks Bob I like to start by just saying that you know testing has really been a cornerstone of the Cova 19 response it's so important for understanding infection prevalence in the community and also in the hospital and for preventing hospital transmitted infections next slide please I'm testing has certainly been an acute issue in our country this is evident if you read the popular press or the scientific press and one of the key issues related to this was with respect to challenges in terms of test availability I think many would argue that lack of of a lack of availability of tests early during this pandemic precluded us from truly appreciating the gravity of the situation and from understanding the degree of community spread next slide please now this is appreciated if we think about test per capita if we look at coronavirus test for million people we can see that the United States this was from a week ago still lags behind many other countries and testing and test availability remain a important challenge in many locations next slide please in terms of the diagnostic test that we have they involved by and large reverse transcriptase PCR which detects components of the viral genome and in particular these tests target at two key locations they're highlighted in red on the slide a schematic of the viral genome is shown towards the bottom of the slide they target the N gene which encodes the nucleic acid protein as well as the e gene which encodes the envelope glycoprotein next slide please and these reverse transcriptase PCR tests have sensitivity that depends on specimen type I'll go into that more in detail in a minute and they're highly specific next slide please with respect to the latter point it's important for everyone to recognize that there isn't cross reactivity with the SARS coronavirus to PCR tests that we use with the other four common corona viruses that circulate in the United States and in many other countries what's shown in the background here is a phylogenetic tree showing the genetic relatedness of coronaviruses and you can see that on there is divergence between the SARS coronavirus too and these other corona viruses and this is just reflected in the in the specificity of these reverse transcriptase PCR tests next slide please so what about testing at UCSF well our University was really one of the first out there to make testing available in-house this is due to efforts from Steve Miller at Thornborough Charles Chu in the clinical microbiology lab and for the past several weeks testing has been humming along at more than a hundred samples a day and increasingly more see our platforms are being employed in part to help alleviate issues with supply chain problems and in part to deliver a faster turnaround so what's shown in the picture here is one of the latest PCR instruments to come online this is a Gen Marquis flex it's actually been deployed at Parnassus this can detect multiple viruses in addition to SARS coronavirus - and can offer a two hour turnaround time so despite the hundreds ample per day output this really wasn't sufficient to meet the demands not only of UCSF but it's a larger Bay Area community next slide please so to address this unmet need leaders at the Chan Zuckerberg bio hub and Jo Durie Z and others helped build a a partnership with the clinical microbiology lab to extend capacity and leverage liquid handling robots in high-throughput instrumentation as well as a whole team of volunteers to help meet the demands for greater capacity right now the there is ability to do more than a thousand tests per day these are PCR based tests targeting the N and E gene and currently serving many UCSF partners including San Francisco General Hospital Department of Public Health and many others and this really is one of the more inspiring examples of teamwork and camaraderie that I think we've had here during this otherwise terrible pandemic next slide please so as I mentioned previously sensitivity of the reverse transcriptase PCR test depends on sampling site and I'll first just start by showing data from the common coronaviruses as we can infer some information from this sampling of the oropharynx seems to have overall the lowest sensitivity nasopharyngeal a bit better a combination can boost that further and then a nasopharyngeal wash which is a procedure gentle more commonly in pediatrics but not so much in adult patients can offer the highest sensitivity this was based on a composite gold standard and using all of these approaches next slide please so what do we know about SARS coronavirus - well no study has been done yet that allows us to accurately calculate sensitivity and specificity but what we do have are several studies now that look at the percent positivity based on swab type and we see a similar trend in that oral pharyngeal sampling has a lower percent positivity compared to other sites and compared to lower respiratory sites now many many of these studies suffered from some bias in terms of patients who received bronchial or Valera lavage likely had more severe disease than some of the others but nonetheless this helps provide an indication of what type of sample is is the best approach next slide please more recent data from Hongkong has provided some insight into lower respiratory versus perhaps more upper respiratory sampling as was suggested by the prior work greater viral load that shown on the y-axis was appreciated and endotracheal aspirate compared to a saliva sputum sample and I think one of the interesting findings from this study there were a number was that a viral load was really highest early during on symptom onset and this is in notable contrast to the original stars corona virus where viral load often peaked after symptom onset and this early high viral load in patients who may have mild symptoms or when their symptoms are just beginning potentially could be an important aspect contributing to the spread of this infection and people minimally symptomatic or asymptomatic individuals next slide please some insight into this question of asymptomatic individuals viral positivity and whether they're worth testing comes from work examining what happened on a number of cruise ships in particular the diamond Princess cruise ship so on this cruise ship nineteen point two percent of passengers and crew ultimately tested positive and notably forty six point five percent of these individuals were actually asymptomatic at the time of testing and I think that probably reflects what was demonstrated and the study on the previous slide is that patients are have you know very high viral loads early during their disease course next slide please so what are we doing at ucsf with respect to asymptomatic patients well right now we're testing on in just a select number of cases this may change as test availability further increases but patients are being tested who are asymptomatic for pre transplant screens for solid organ transplants or bone marrow transplants patients admitted from nursing homes given the potential public health and societal implications and in addition patients from whom a history is unobtainable next slide please so what about serologic testing this is certainly an emerging area of a lot of interest I think it's helpful to step back and ask ourselves what are the goals of serologic testing and what what is the added value here compared to the nucleic acid reverse transcriptase PCR testing well perhaps the most significant is simply determining the presence and duration of protective immunity which could really have important implications for triaging the ability of health care or other workers to safely return to work can also have a role in evaluating efficacy of vaccines and durability of those vaccines without a doubt serologic testing will be key for enabling population wide seroprevalence studies to be able to determine on precisely what the prevalence is and in addition better estimate mortality rates and then as I had shown on the slide comparing the different test characteristics based on sampling site serologic assays could help improve the sensitivity of diagnosis as right now with nucleic acid testing really a negative test and someone with a high pretest probability or high suspicion of koban 19 does not rule out infection next slide please within the past week a number of Rapids serologic essays have become available in the United States I'm showing a general diagram of how many of the laminar flow ones work this is an assay that's now on being marketed by Becton Dickinson and these assays use a use colloidal gold nanoparticles that are affixed to that are affixed to to part of the strip if a patient has antibodies against SARS coronavirus - these will bind to the gold nanoparticles containing antigens - SARS coronavirus - and depending on on whether there is IgM present or IgG present there will be binding at specific locations as a patient's blood sample is flowed on through this assay to areas where there's anti anti-human IgM or anti human IgG present and it gives a very similar readout to let's say a rapid strep test where there's a a banding pattern that can be interpreted the 15-minute turnaround and in initial reports of this general assay type reasonable sensitivity and specificity although this these tests have not been broadly validated yet on actual patient samples and so I think this still remains to be determined next slide please there was some nice work out of Mount Sinai recently on that further advanced our understanding of serologic testing I should mention that one of the issues with many of these rapid serologic Diagnostics is cross reactivity with common coronaviruses the group at Mount Sinai was able to build an Eliza that targeted the spike glycoprotein receptor binding domain that's shown here in red in this model structure and this Eliza was specific for SARS coronavirus - unlike the case for many of those Rapids rapid laminar flow assays and provided significant ability to differentiate between cero converters and control samples next slide please I think it's important to consider the role of serologic testing in broader context so I think it's important to recognize the time needed for someone to cero convert and recognize that serologic testing may not be the best choice for detecting acute infections this is a nice word from a paper that recently came out and final copy in nature and showed that serial conversion of 50% of patients in their small study of individuals with mild to moderate disease happen by day 7 and that all patients in this study Siro converted by day 14 so I think that's important to keep in mind they also had some interesting work and data that looked at the relationship between positive viral culture obtainable from specimens from patients over time compared to simply detecting presence of the virus and what they found is that in their patients viral PCRs remain positive for up to two weeks or longer yet after eight days no patients in the study had culturable live virus that could be obtained from their samples presumably that is a reflection of the presence of neutralizing antibodies in the sample that correlates with antibody response it's a nice paper I encourage everybody to review it tonight over zoom happy hour with friends take a deeper dive next slide please some of the most exciting developments on the diagnostic front have come online in just the past week these are rapid nucleic acid Diagnostics shown on the left is an Abbott instrument called the ID now it uses an isothermal amplification approach and can provide a yes/no answer and under 10 it's so this certainly could have potential utility in many settings in the emergency department one potential concern here is the aerosol generating potential of the instrument and that has raised some concerns so it's unclear if that will really be a good option in the eg as it stands without some type of containment then shown on the right is the Cepheid expert platform you know this is a PCR instrument sample the answer that is available in many labs in the United States and throughout the world most commonly used for a micro bacterium tuberculosis diagnostics and this provides an answer in 45 minutes so I think some you know important developments here that will really improve our workflow and ability to rapidly identify patients and then implement the necessary infection control precautions and triage resources next slide please I just like to wrap up with meta genomic next-generation sequencing which is a technology that's used by a number of research labs and clinical lab at at UCSF UCSF was actually the first in the nation to bring clinical next-generation sequencing online for diagnosis of meningitis and really the advantage here is that it can take on any samples such as a respiratory sample it can take nucleic acid isolated from that sample and detect all microbes present in that sample within an unbiased approach and it was in fact metagenomic next-generation sequencing that first allowed the world to recognize that this idiopathic pneumonia syndrome taking place in Wuhan was due to a novel coronavirus I think in the future we'll see meta genomic sequencing were widely available in hospital microbiology laboratory so by the time the next pandemic hits we'll be ready with a test that can identify what's causing the problem so I'll wrap up there and turn things back over to Bob thank you guys really appreciate it and a lot of brings up a lot of questions we will get to Jen Babic is next jen is associate professor in our division of infectious diseases at UCSF health also the xxx program director for internal medicine residency and the person we also always run into with clinical questions and we had a lot of them now on some of the clinical manifestations of code 19 so can take away thanks so much Bob so what we're going to talk about today are updates in the clinical manifestations of code 19 next slide please and just to give you a sense of what we're going to talk about in this section we'll start by talking about some updates in clinical manifestations and we'll focus on cardiac GI ent and ocular manifestations we'll spend a little time talking about koban 19 in patients with cancer as a special population and then we'll talk about an update in us data on co-infections and then we'll close with some discussion of the clinical course can I see patients next slide please we'll start with an update in cardiac manifestations and we'll start by talking in the tan box on the left about some of the clinical syndromes that have been recognized in cardiology there have been a number of case reports of myocarditis myocarditis in tamponade and some of these cases have been permanent presentations there's been a lot of discussion about the prevalence of cardiomyopathy and some of this came out of the Evergreen ICU study so this was a study of 21 ICU patients at Evergreen Hospital outside of Seattle and they found that seven out of 21 of their patients had cardiomyopathy in the multicenter ICU study out of Seattle they found actually that 0 of 9 patients had cardiomyopathy so I think that true incidents of cardiomyopathy in these critically ill patients is not yet totally known arrhythmias have been described in anywhere between 6 and 17 percent of patients although the exact type of arrhythmias is not always described turning to the Box on the right there have been two high-profile papers in the last week one in JAMA and one in JAMA cardiology talking about the association of cardiac injury with adverse outcomes so these are both clinical studies from China one was 187 patients the other 416 patients and they showed that there was cardiac injury in 20 to 28 percent of patients and cardiac injury was described was categorized basically by an increase in troponin irrespective of EKG changes and they found that cardiac injury was more common if patients had pre-existing cardiac disease cardiac injury was associated with an increased risk of complications and that included arrhythmia RDS intubation and Aki as well as increase in inflammatory markers including white blood cell count CRP and d-dimer as well as an increased risk of death anywhere from 6 to 10 fold and they postulate that cardiac injury may be due to either direct infection systemic inflammation or demand and I do want to mention that other respiratory viruses including influenza have been also shown to have an increased risk of MI and that is thought to be due to systemic inflammation next slide please I want to take a moment to talk about ACE inhibitors and angiotensin receptor blockers there's been a lot of attention paid to these drugs because the ACE 2 receptor is the Czar's COBE to sell entry receptor and it is unclear at the moment if these drugs would actually worsen Kovach disease or improve Kovach disease and both have been hypothesized and the idea is that these drugs could worsen kovat potentially by increasing these two receptors for the actual virus to gain cell entry or on the other hand they might improve Cova disease by decreasing pulmonary inflammation and there's some animal model data from SARS proving one that might support that but because of this unclear effect in kovat and because of the likely harm in stopping these drugs and patients who need them multiple European and American specialty societies have advocated that patients who are already taking these medicines should continue them and just to note that there are clinical trials underway of both a recombinant East 2 molecule as well as losartan next slide please so let's turn to an update in GI manifestations so as we talked about in the last Grand Rounds GI symptoms diarrhea nausea vomiting are relatively uncommon so about one to ten percent of patients in most of a large clinical case series to date there have been two other case series of 69 and 452 patients that did report a higher rate of diarrhea between 14 and 27 percent so this may be a bit more of a comment symptom but importantly what I wanted to talk about today was that there have been reports of atypical cases where patients have GI symptoms without other respiratory symptoms and this was reported in 2k series in the GI literature of 204 and over a thousand patients where they found this in three and 10% of those patients so that's just important to look out for and to consider testing in those types of patients next slide please there's been a lot of attention in the media with regards to the loss of smell as a potential clue to kovat and most of what's out there are media reports and some statements from some ENT societies there is one published paper on this that was published last week in Clinical infectious diseases it was a cross-sectional study of 59 hospitalized pruvit patients in Italy and they found that these patients had an olfactory and/or taste disorder in 20 patients or 34% there was an isolated taste disorder in 10% and dis museu was more common an olfactory disorder alone in 5% and those patients had high posny and all in all cases and then a mixed taste and olfactory disorder in 19% and many of those patients did have a NAS Nia or the loss of smell they found that these disorders were more common in women and younger patients interestingly and that all patients at the time of the survey had persistent symptoms and the survey was done on day 15 of symptoms anecdotally we have heard reports of people having improvement in these symptoms over time the mechanism is not entirely clear it might be due to direct infection we do know that stars poby one can infect the olfactory bulb versus an inflammatory effect we know that there are ace 2 receptors throughout nasal and oral cavity next slide please the last clinical update I want to give is with respect to ocular manifestations so this was a paper that was published two days ago in JAMA ophthalmology looking at ocular findings in patients with kovat this was a study out of China where they looked at 38 patients and found 12 32 percent had ocular manifestations all of which were types of conjunctivitis they found he Moses conjunctival hyperemia and Petra which is watery eyes for those not as well-versed in the literature and interestingly these were found mostly in patients with moderate severe or critical illness so it seemed that the sicker patients had and interestingly one patient had Petra as the first symptom of disease they looked in all patients to see if they had a positive conjunctival swab and only two of eleven had a positive rt-pcr for SARS pv2 so one of the accompanying editorials to this article pointed out that the potentially the main point here is that from an epidemiologic standpoint that there potentially could be transmission through the eyes next slices I wanted to talk a little bit about kovaydin patients with cancer there have been two papers in the last week discussing this so the first is a paper on the left from JAMA oncology where they looked at over 1,500 patients admitted to a cancer hospital in Wuhan and they found that 12 patients had proved it which was an incident rate of 0.7 9% which was twice the community incidents at the time 58% of the patients had non-small-cell lung cancer and 42% were on active chemo or xrt and they had a 25% mortality rate the other study was in annals of oncology where they looked at clinical features of 28 cancer patients with Kovac again lung cancer was the most common in this series as well about a third of patients had stage 4 cancer 21% had chemo or xrt within 14 days and those patients potentially not surprisingly had a higher risk of severe disease in this study 29% of patients actually acquired couvade while they were hospitalized for another reason and they found a 29% mortality so I think the two features that stand out to me from both of these cases are the high prominence of lung cancer in both of these studies and then the high mortality rate although these are small studies next slide please at the last Grand Rounds we talked about the co-infection data which at that time had mostly come out of China and Singapore and they had reported mostly a zero to six percent co-infection rate although it was not clear at the time how systematic the testing was there are now a number of studies in the u.s. that report some co-infection data the first is a study out of LA and USC where they look at seven Kovac patients who were all tested for flu and RSV and 0% or positive the Evergreen ICU study out of Seattle of 21 patients recorded one patient with Pseudomonas battery Mia and then three out of 21 or fourteen percent did have a viral co-infection - with influenza A and one with influenza the multi Center ICU study out of Seattle had system systemic testing they had zero patients out of twenty-three with a viral infection and 0 out of 15 with a positive sputum culture and 0 out of 20 with positive blood cultures so out of those three studies the co infection rate ranged from zero to fourteen percent I will mention the Stanford data because this is commonly cited and just to mention that this is reported online only not in a pure manner but they found that 11 out of 49 of their coded positive patients or 22% were positive for another respiratory virus although none with influenza so I think the trucco infection rate is still not entirely clear there haven't been any very large systemic studies to date but probably the true rate lies somewhere within this range next slide please so we wrap up with talking a little bit about the clinical course in the ICU and we'll start by considering some of the critically ill patients in terms of their mortality rates so in China there have been about three studies of critically ill patients with a d12 78% mortality and then a very high mortality rate 81 to 100% in intubated patients in some studies of ICU patients from the US and the UK the rates have been a little bit lower so in the Evergreen ICU study 21 patients in the ICU 71 percent were intubated and they had a 67 percent mortality in the multi Center ICU study from Seattle 24 patients 75% were intubated and they had a 50% mortality including 50% if they were intubated so that was a bit better than the Chinese data and their ICU length of stay was nine days and then there's a nice new report out of the UK of a hundred and ninety-six patients again 75% intubated so that's pretty consistent with a 48 percent mortality and their IC length of stay was a bit shorter so again pretty high mortality rates I'm out of the ICU although in the US and UK seems to be a little bit lower than the data from China and I'll wrap up with the question of cytokine storm so there have been a lot of anecdotal clinical observations about the question of cytokine storm and some of our critically ill patients a lot of this has been driven by several reports in the literature that severe disease and death seem to be associated with higher inflammatory markers including white count CRPD dimer ferritin aisle six and TNF alpha it's not totally clear though what the pathogenic role is of these cytokines and there's a lot of interest in whether we should be targeting these molecules as as a therapeutic strategy and I think we're going to learn a lot more in the coming weeks about both the pathophysiology and potential targets for therapy and I'll wrap up there thank you so much for your attention Thank You Jen that was terrific and actually a perfect bridge to our last of formal talk which is by any lucre Meyer who is a professor in the division of HIV infects diseases in global medicine at Zuckerberg tempo Cisco General Hospital where she directs the HIV clinical trials group which conducts both investigator-initiated and Industry HIV trials and she is helping to lead our therapy trials enterprise for kovat here at UCSF so any thank you thanks so much I'm really happy to give an update on koban 19 treatment as we talked about several weeks ago I think it's most helpful to divide this up into two buckets so in my introductory slide here I've included on the left hand side a schematic of a typical coronavirus life cycle which is where we typically think of antivirals being effective and we want to have effective antivirals to help stem the tide of the disease and then on the right hand side this is just a CT scan from a typical patient with sort of the pathognomonic findings of of koba disease with a really robust inflammatory response that we see not only in the lungs but as Jen referred to really undef' Ekta other organs so this has led to a lot of interest in targeting the this robust immune response with immune modulators and these two approaches are occurring very quickly in the research and I'm going to highlight from the updates today next slide so REM desapear is a drug that we talked about several weeks ago that's gotten a lot of attention this is a nucleoside analog just as a reminder and it inhibited RNA dependent RNA polymerase and so in the schematic here you could I've highlighted where in the life cycle this is active in vitro REM desappear looks like it has some broad antiviral activity against the number of corona viruses and other viruses and it's given only as an IV medication so what do we know now about REM desapear and how it works why I would caution us first of all that there are a number of clinical case series that have been published that will include a handful of patients treated with REM desapeared through compassionate use and I think we can't draw any conclusions about those patients at this point in time and how effective REM death severe may have been because it's they were not controlled but the good news is is that we have five large randomized control trials that are underway and we anticipate the first results probably from the randomized control trials conducted in China to be coming out very very soon these are actively enrolling one of the studies is actively enrolling at UCSF in San Francisco general and a number of the other studies are actively enrolling around San Francisco and across the United States one other update about REM death veer is about the compassionate use program I think many had access to rib desapear through this route and as you may have seen in the news this has been closed with the transition to an expanded access or EAP program that's starting just as a reminder though that this is a limited access that really is for people who are intubated so quite ill but not on pressors and don't have multi organ failure but I think many medical centers including our own has moved towards getting expanded access REM desappear but it is not available to many including at UCSF yet so we're actively pursuing this so I think the take-home for REM desappear one of our exciting antivirals is stay tuned we need more data next slide so hydroxychloroquine boy who thought we would ever talk quite so much about hydroxychloroquine and i think it's become increasingly confusing to understand what hydroxychloroquine is actually doing hydroxychloroquine falls into the category of both an antiviral and anti-inflammatory and what are the updates that I have to share for you well they've been two randomised controlled trials that were reported out of China both of which were conducted in mild disease and I'll just remind you as a caveat as Chaz nicely referred to that in patients with mild to moderate disease as was summarized in the woeful paper out of Germany most patients get better and most patients have a steady decline of their detectable viral load by culture and by PCR so we really have to be careful when drugs are given and then they report that the viral load comes down and that patients get better because that's what we expected the majority of patients who are not critically ill so in this first randomized control trial on the left-hand panel it was 30 patients they got hydroxychloroquine 400 milligrams a day compared to standard therapy there's another caveat here that standard therapy in this study could be a wide variety of antivirals and many individuals received more than one treatment including inhaled medications and oral medications it was open-label 80% of the patients had mild disease and the primary endpoint was day 7 PCR 13 out of 15 of those on hydroxychloroquine had an undetectable Tsarskoe b2 PCR so 87% and 14 out of 15 had an undetectable of PCR or 93% in the control arm there was no difference in clinical outcomes or safety the second randomized control trial was slightly bigger 62 patients also got 400 milligrams daily of hydroxychloroquine versus again standard therapy which could include a whole variety of antiviral and those were not controlled it was unclear to me at least whether or not this was a blinded study this study proof specified that it was only for those with mild illness the primary endpoint was the clinical status at day six and there was no viral object data reported yet from this group what they found is that there looked like there was a trend towards a one-day reduction in fever and cost in those who were treated with hydroxychloroquine for individuals progressed on to severe illness in the control arm and two individuals had a drug interaction in the hydroxychloroquine a drug reaction in the hydroxychloroquine arm but it was not a QT prolongation so what can we conclude from these two studies I don't think we can say much given the B's also really mirror what the typical natural history would look like in terms of clinical recovery and biologic decline so it's reassuring to see limited safety signal here but I think we need more data another important point is what's the right dose of hydroxychloroquine these are data from rate of Saavik and colleagues here at UCSF that are have modeled the available data on hydroxychloroquine and its efficacy in Tsarskoe b2 and these data suggest that dosing at 400 milligrams a day is going to be really too low to get you above the extrapolated patient ec50 that the target is that we likely want to target that really higher doses like 600 milligrams twice a day maybe what we need to get us above that AC 50 but keep us below concerning levels for QTC prolongation next slide what about hydroxychloroquine and asia through Meissen there were some intriguing data out of a group from France that suggested that hydroxychloroquine given with a DES through Meissen reduce the viral loads more quickly than those who did not receive that combination in a follow-up study from the same group a single armed uncontrolled study of 80 individuals mostly this mild disease received hydroxychloroquine 600 milligrams a day and Industry Meissen and what this graph shows is that there was the black bars or those who had viral logic testing the brown bars or those who were undetectable at those time points that you could see there was a trend towards the viral load coming down I didn't show the data but the culture also there was a trend towards that becoming negative most of these patients did well three were transferred to the ICU one stopped and 65 had been discharged out of the 80 at the time of of this publication in preprint what can we say about this I think we can say that these are people who in general will be expected to do well this is what we expect to see with the viral load coming down so it's really difficult to say how much of a role hydroxychloroquine with a distro my son is having here there was a contradictory study then to this in Contra distinction from the French a different French group there was a small study single-arm uncontrolled eleven patient same regiment of hydroxychloroquine and a distro Meissen and they found slightly worse outcomes one patient died two and an ICU transfer for head QTC prolongation but only one had to stop drugs because of it excluding the person who died they found that most patients were still PCR positive at day five or six and their conclusion was there was no evidence for rapid viral clearance or clinical benefits so where do things stand right now with hydroxychloroquine we still don't know if it has efficacy in people living with kovat the dose may need to be higher I don't think we know if there's any role of additive at this room Ison and to really sort this out we're going to need robust clinical trial data and I think that we need to be careful about the safety of hydroxychloroquine with unmonitored use we've seen you know reports of people overdosing when taking this outside above the medical setting and certainly concerns about the impact on the drug supply next one what about convalescent plasma this is also an antiviral strategy it's been around for a very long time it's one of our oldest medical interventions you can see this this picture from 1918 we have data for reduction in mortality from the 1918 flu as well as more recent h1n1 outbreak convalescent plasma was used in stars and MERS and the suggestion is that was earlier treatment was more efficacious but there are anecdotal data to support use in critically ill patients in koban 19 patients I think we were all heartened to see this Jam of publication showing that five patients who are critically ill did well when they were treated with convalescent plasma we know from the data that Jen just showed us that in general when people go to the ICU and our intubated they can have poor outcomes but I think we need more data we now have an FDA emergency IND for severe or life-threatening disease which I think will help us get access to patients who may who may need this but we're really going to need to understand who is best served here the other area where convalescent plasma really may be quite useful and it's being explored is to provide post exposure prophylaxis for individuals who are high-risk and in healthcare workers who may be at high risk as well one really important point is we're all starting to see these patients and that they're as big as they get well and leave the hospital or leave our care encourage them to give blood many blood centers or getting their SOPs up and going to allow people to donate blood so that they can provide convalescent on plasma and this is a really important way that they can help in the efforts to understand how to treat far as Coby to next slide please so what about immune modulation this is the other bucket that I referred to and this schematic on the left hand side shows what happens to people with moderate disease as Jen referred to we know that the TNF alpha levels il-6 and I'll tend go up and that there's some immune dysregulation there and when people progress to severe Kovac 19 we can see what's been called a cytokine storm and a number of different flama Tory markers are elevated in this setting which are summarized below this has led to a lot of interest in using the immune modulators on the right hand side of the slide these include il-6 inhibitors il-1 bee inhibition with tannic einem AB or colchicine which can affect the inflammasome jak-stat inhibitors which also have broadly anti-inflammatory activity even ccr5 antagonism or gm-csf inhibition as well as the great anti-inflammatory steroids for which I think the jury is still out I think the considerations for these wide variety of anti-inflammatories is that we need to understand is it worth targeting one single pathway is that going to be the highest yield approach or do we really need a combination approach not only with the antivirals but also with other anti-inflammatories what is the optimal timing if we is this should best reserved for people once they become critically ill or where we better serve by trying to avoid them to come and critically ill and then lastly might we hurt people by doing this we may be immunosuppressive more in contributing to disease exacerbation and already quite critically ill patients so we really need to understand that piece and again study these medications very carefully so we know if we're hurting or helping by using these strategies next slide what about the vaccine this is a brave individual Jennifer Haller who was the first person to receive a koban 19 vaccine questions about coronavirus immunity we know that immunity to cold causing corona viruses is limited but we also know that those are mostly upper airway disease diseases when we see in lower respiratory tract diseases like SARS and mer these are associated with more durable immune responses which suggests that coronavirus 19 may also elicit a more durable immune response there are a number of major approaches that are ongoing the w-h-o has a really nice vaccine landscapes website that is being updated and the platforms that are being studied are summarized here there are more than 47 candidates and Counting these seem to go up every day when I look here excitingly we already have two inhuman safety trials the moderna vaccine which we see in this picture here which is an mrna subunit vaccine and then Cansino which is looking at an adenovirus vector I think the unfortunate piece here is that it's really difficult to rush vaccine therapy I think people have really rushed to get these compounds into studies but we anticipate that it will be at least 12 months until widely available will be a very welcomed tool when we do have them next slide so I want to just end here by highlighting the current clinical trials that are available at a variety of the UCSF campuses this is evolving on a daily basis which is really terrific it means that we continue to have interventions that we're offering to our patients both on the hospitalized side and then increasingly as possibilities on the outpatient side if I am Co chairing a committee along with other ID pulmonary and critical care researchers looking at interventional studies for treatment and prevention and my contact information in my home assays are below and we welcome people reaching out if they have other strategies that they want to talk about so that these can be discussed and prioritized so that we're ensuring that we have a good flow of research opportunities and therapeutic interventions for our patients so I'll go ahead and stop there and just leave this as a reference for people down the road if they're looking for studies Thank You Annie my computer's making a strange noise so I will try to address it let me bring back all of the speakers from this session before we move on to about 10 to 12 minutes of Q&A okay so let's start with Diane so the general public start wearing masks my my own opinion on this is yes it makes sense we have no vaccine we have no treatment for this disease and it does offer it makes sense from what we know about transmission it's certainly homemade masar no value in the hospital but if we can Purdue in red I think it is a good idea to do and I think I right now it could make a difference when we think about when and how that we are going to be able to back out of the current state that were in okay thank you I think I figured out my problem next question for you Diane you you sort of hinted at a night maybe George will get into this too but the breakout idea so how do we know that we have reached that stage do different regions reach that stage at different times and just paint it let's assume that here in California we reach that stage in six weeks so what does life look like in San Francisco eight to ten weeks from now well I think about this but when you just think about kind of first of all we need the data to be able to make that assessment like we need to know we need testing we need lots of testing so we know how many infections are we having right now because once we get to that stage as infections start coming up we're going to have to contact trace them right so if there's a ton of infections happening that's just not bio so when we get to that phase we need to have manpower in place through our health department or other mechanisms so that we can contact trace all the new infections so the ember doesn't spark a new fire again I think that that's the first thing secondly just in terms of movement and movement restrictions the package that we know that's been used is that you loosen movement restrictions gradually and that has occurred in conjunction with the mass I think one of the unknowns is how can we effectively use antibody testing how can and should we what our performance of the antibody testings and how can they help us do that more effectively I also think that we can't be naive like one of the hard things about this particular diseases you heard is that people at asymptomatic can probably transmit the disease so that makes it a little bit more difficult and not only does this disease spread fast but we don't live in a vacuum where we have the bay area we have the whole country you know we're built on travel so we're really going to need to think about those things we know from public health interventions and we talked about this you know two weeks ago if you do these if you live the restrictions too fast you're going to fail but I hope over the coming weeks as we get more data we're gonna have a better sense of when that will be and I think it's going to be gradual introduction of movement with masks and very aggressive contact tracing and antibody measurement and maybe this is both for you entry as when we talk about sort of aggressive testing as we move to that stage is it is it viral testing or is it antibody testing what what do we actually need to understand the dynamics if we do reach a stage that the the case the new case rate has gone down to to a much lower level you wanna start with that Dan and then Chas can chime in we absolutely need testing and we need if we could better test completely accessible to the public people need to be able to go to get tested if they think they're ill and we need specific tests I think antibody testing would be extraordinarily helpful in terms of many things we can do to make predictions including modeling because it tells us the prevalence of the disease and tells us about epidemic dynamics great ok Chas what are you weighing on on that one you know we've we sort of talked about testing and I think people think about it okay there's testing and it used to take a day and now maybe it'll take an hour and that's terrific but sort of this layering of testing for virus versus testing for antibodies how do you think about the balance of those particularly move on to another stage yeah I think both have a role without doubt so testing for viral nucleic acid is unquestionably key for patients with acute symptoms on patients early during their disease course viral nucleic acid testing is going to be the test of choice I think antibody testing is really going to have a role as Diane mentioned and understanding prevalence in the population accurately estimating mortality and in understanding who might be immune and who might not be something that nucleic acid testing simply can't do so I think moving forward both are gonna be useful okay who might be immune if I have antibodies am i immune and for how long so this is a very good question and one that is still unanswered you know there was a compelling paper looking at rhesus macaques demonstrating they could not be reinfected however there are other data some anecdotal some more robust suggesting that patients may be able to be reinfected so I think globally there is probably some degree of immunity that happens it might be completely protective but I think understanding I think that those details are still not fully worked out so an area that definitely needs more research okay and there was a number of questions about this issue of asymptomatic patients and the the sensitivity which is neither of those are very reassuring I mean I think where we were several weeks ago the party lines seem to be more there's not much of an asymptomatic phase that most people will have symptoms of some sort and that sounds like from the cruise ship we now understand that there actually is a fairly significant asymptomatic phase and the test can be falsely negative in those those folks and maybe even some people have symptoms so how do we get our heads around this and how does this new knowledge shape what we do going forward yeah this is an important question and an important area that that also needs to be further explored you know I think several studies now demonstrating that viral load in various in various locations in the human body are is highest early during disease onset maybe provides the most significant indication of how important transmission might be early during the course of infection you know I think these data do play into our understanding of what might be needed to effectively protect people yeah maybe take us a layer deeper than that so you know a couple of weeks ago we were kind of walking around and saying you know if you didn't have any symptoms at all you were safe and being in contact with you was safe and now I guess I don't feel that based on the emerging data do you is that your on your feeling as well have you changed in your in your assessment of this and then what is the implications as that means that the reason we should all be wearing masks is that the reasons that we should or shouldn't be concerned if we go out to the store I think it's a complex situation and there are a lot of moving parts so we know with very good data that this corona virus is transmitted by droplet particles and by contact with particles on surfaces what we do know is that someone without symptoms is going to be less likely to be producing these droplet particles and emitting them in the environment so while someone without symptoms might have very high levels of virus in in their in areas in their oropharynx on they are probably less likely to actually deposit that virus into the environment I think we're still in a incomplete data situation in terms of we don't actually know the relative infectivity of people during these different stages but I think the the global understanding has shifted from where we were not too long ago in patience without symptoms likely could be infectious at a level that we previously didn't appreciate I think that is a strong rationale for wearing masks and I also think like when we saw the choir outbreak you know when you're singing you're doing forced air and I think that there are situations where we've got more data now we know the virus is there and it might not be you know a day before but still it's transmissible so I mean compared to SARS where that doesn't happen until five or six days into the illness this is one of the most difficult things with this virus right now okay thank you Jen maybe you could unmute so issues around convalescence and when you know you're better and are you infectious and someone asked for outpatients with diagnosis cope with 19 diagnose code 19 but who have not been tested how long should they stay in isolation there's a bunch of different questions but a lot of it relates to sort of the end game of this isolation patient in the hospital who's getting better when can they leave when they when could they go to a skilled nursing facility all of those kinds of questions yeah I mean I think we do know from from the data out there that even when people no longer have symptoms they may still test positive and Chazz showed some really nice data that the PCR positivity may not correlate with culture positivity so what you may be finding is dead virus but what we don't know is as trans mentioned we don't know how infectious asymptomatic people are we also don't know how infectious people are at the end of their course our discharge criteria currently are based or at least in terms of isolation and return to work are based on symptoms rather than testing at least for our immuno competent patients and you know we all get calls all the time from friends and family I had what I think was Co vid but didn't get tested first of all how likely is it that they had it and second of all how long should they stay in strict and ice yeah I mean I think it depends on the situation rate in terms of how likely they are to have it I think if someone had a contact then that's going to increase their likelihood that it was coded rather than another respiratory disease remember we're still in flu season we're still seeing a lot of circulating winter viruses so a lot of people who are being tested do not have covin I think our testing positivity rate at UCSF right now is around the four to five percent mark so we're testing a lot of people and we're only finding you know positives in four to five percent now that's a very we're testing very broadly ages which is appropriate I guess it should be said we're only testing people with symptoms so even testing people only only with symptoms one out of twenty is positive right we're expanding and Sarah can certainly speak to this more in the next session but we expanded our testing a bit to a symptomatic patients in certain circumstances okay maybe last connect sample thanks so much Annie you had a slide at the end of the last time that sort of was the guidance about what to do in various subgroups if you're not if you don't have clinical trials available so you know real doctors have to make real decisions with real patients today so can you take us through what's your record and I recognize that pretty much everything you said was we don't know the right answer to to any of these things but still people have to make decision so what is your treatment recommendations today for someone with mild symptoms someone with significant symptoms enough to be in the hospital but not so bad and then someone who's sick enough to be in the ICU yeah and I'm assuming that clinical trials aren't an option from an intro and not an option so trials are not an option so I'll serve as a the easier part which is if people have mild symptoms I think that that too in general it doesn't make sense to treat them outside of a study there are a lot of studies going on we need to understand if we can sort of break disease transmission but most people with mild symptoms will do very very well and we don't have to worry about it they need to worry about not infecting others and and come in if they're one of the few who gets more ill if that is a person with a lot of comorbidities they're older they have diabetes hypertension and you're very concerned there could be a consideration for using something like hydroxychloroquine but I think the real caveat with that is that it needs to be in conjunction with a medical provider who can make sure that they don't have words drugged or an interaction they don't have a pre-existing QT prolongation and that we're not hurting them because we have to recognize that we don't know if this medicine works and so we have to make decisions in the do no harm rubric there once people come into the hospital we have a lot of people who are in our Hospital where they're you know they're not intubated but they're on oxygen and we don't really know we're only offering them supportive care I think you're still in the same discussion about whether or not an intervention like hydroxychloroquine makes sense I think that it should be considered on a case-by-case basis once you've really looked at what the potential downsides would be and I think it's reasonable to offer again fully recognizing and having a discussion with a patient that we don't know if if this works once people become critically ill I think it becomes very challenging and we don't have a lot of we don't have anything to offer that's targeted to 2co with 19 but this is the case where I think it's useful for medical systems to try to prepare with things like emergency inds to have access to convalescent plasma that may feel like a Hail Mary and it may be a Hail Mary and in many cases that's just not going to be possible if there's a super high volume but I think that there are cases in the literature where it looks like it may have been effective having EAP access to things like REM desappear I think that those will be helpful and then just going back to the basics of making sure that you're providing the best possible a RDS care because that's a very complex series of interventions much of which is data-driven so so that is what at the end of the day is what people become very ill from we need to provide very good ard the patient great I'm gonna let all of you go and bring on our next group of virtual applause from our 1500 people watching and thank you so much and let's bring on the next Republican tens the conversation to a different set of experts and cover a few other a few other areas that we haven't touched on quite as much so our next group is Matt Aldridge who's professor in our department anesthesia and medical director of critical care who's really been directing our ICU response Brad monash associate professor of medicine and pediatrics here and associate division chief in hospital medicine who's been helping direct with our response from hospital medicine Sara Doron Berg who's associate professor of infectious diseases runs a adult antimicrobial stewardship and has been helping to direct their ID and infection control efforts George Rutherford was a professor in our department of epi and biostatistics and his research focuses on epidemiology and prevention and modeling of infectious diseases which is something they're all very interested in and sireesha and Arianna is assistant professor in hospital medicine and is chair of our ethics committee and chief of the ethics consultation service and is up until our work in trying to think through some of the key ethical conundrums so let me let me start with maybe a combination of Matt and Brad and ask the questions or what you're seeing clinically and do either of you have a sense of which patients who are hospitalized and what are doing okay are likely to start doing poorly all the report seems to be the patient's can look sort of okay and an hour later look really bad so first of all is that what you're seeing and second of all do you have any clues who those people are both from the standpoint of the patient on the ward from Brad standpoint and format standpoint receiving them in the ICU Brad you want to start yeah sure I'll start with that I think we have a team of UCSF that's currently looking into this to try to identify predictive factors for patients who are not going to do well I think it's been recognized in the late press as well as in scientific literature that there are patients who seem to do very well for that first week of illness and then rapidly deteriorate in the second week of illness some of the data I've seen it suggested that the presence of dis Nia and respiratory distress early on pretends a worse prognosis for a certain subset of patients but beyond beyond that I we don't have great predictive analytics yet but I anticipate in in the not so distant future we'll be able to do a better job predicting which patients will deteriorate we've been handing some of these patients over to our ICU colleagues so I'm interested if matt has additional input here actually before you go out I'd be interested in that because one of the things that we have seen and I've been asked a lot about this is sort of this flipped ratio early on the ratio of the patients on the ward was much higher than those in the ICU that has flipped and I was wondering whether some of that is because we're not getting crushed just yet and we have some ICU capacity is your threshold this is actually for both of you your threshold to send a kind of marginal patient to unit lower than it would be in a place where the units were very busy with sicker patients so currently the answer is yes we have developed some expertise outside of the ICU for the management of this patient population we have developed respiratory isolation unit patterned off of endemic wards in Singapore where we have just local interprofessional expertise in managing this population not to say we can't manage these patients very well outside of this unit but based on this sort of culture we've developed in the unit and the concern for rapid deterioration of patients who are not appropriately monitored at this point as we are building our capacity outside of the ICU we are maintaining a low threshold for patients with coronavirus who have respiratory distress the respiratory symptom ecology who are having escalating action requirements right now we're maintaining a very low threshold to manage those patients in the intensive care unit yeah well I spot for you then I'll hand it to Matt when I see the report every day of we have X number of patients on the ward who actually have I have tested positive for virus and then there's a clicking and again I'm sorry and then we have a number of other patients who are under investigation first of all what percentage of those are turning out to be positive and second of all do you then move them off the ward when they turn out negative so right now the last numbers I heard was about a 4% positivity rate of our testing about 4% of patients we are testing our current of error is positive and our plan right now is to move whatever patients we can who are sort of acute care level to this respiratory isolation unit and so we are developing protocols with our nursing colleagues to manage patients who perhaps historically they have not been managing including potentially bringing nurses into that unit with expertise if needed and as well as developing the expertise in ICU which is existent there to manage patients of PC or ICU level care so we have been fortunate and a population level not to not to belittle the the terrible realities of our patients who have been affected by this disease but on a population level as do people have heard we have been incredibly fortunate locally and perhaps related to our early physical distancing measures that we are not overwhelmed our volumes are very manageable and while we have the capacity we are intending to cohort patients as much as possible into our care respiratory isolation unit and into our eyes views okay so Matt let's turn to you and just tell us a little about what you're seeing and kind of the decision-making about who goes who goes into the ICU and and and and also I'd love to your thoughts on this sort of flipped ratio why is it that the ratio now is so ICU heavy compared to the rest of the hospital well I think part of it is just has to do with the volume of faces they're coming into the hospital and I agree with Brad we have at a lower threshold in terms of who we will bring into the ICU so we've mainly been using an acute care ICU approach as opposed to a tcu approach and we have that because of our capacity we're able to do that now what we're seeing in the ICU and we've had 12 total patients requiring critical care at some points that we have some experience although I'm very cautious to interpret too much from that site I will say I think there's a lot of well-intentioned desire to gain experience from what other institutions have have gone through in over the last several weeks I think we all need to be cautious about what we see in anecdotal reports and and rely on what is now a growing literature of peer-reviewed studies so what we're seeing is is more consistent I would say with what I have seen reported in the literature from from China from Italy and now we have two small studies one from the Seattle area hospitals the other directive 13 from Evergreen Hospital we're seeing largely what what's being described in literature and perhaps less though than what I think many of us have seen in and email threads and anecdotal reports oh and by that I mean we are seeing generally speaking our patients are are in fact older or they have significant comorbidities we are not seeing a significant number of young otherwise healthy patients and and we are seeing patients with long I see you like this day which is consistent with what Jen Babic described certainly for patients who progress to era TS the course is long and they require lengthy mechanical ventilation and that's you know we're still relatively we're not early in our process as an institution we've been taking care of patients for many weeks now although I think certainly this this increased volume not a markedly increased volume with this increased value that we've seen has has given us more experience in the last few weeks so I think we really are seeing something that's consistent with what's been reported in the literature and when you read the literature now with some variations of whether the mortality rate is 50% for a patient who's been intubated or 80 or 90 and it seems like literature isn't quite sure what the right answer is imagine we'll get to serration a little bit but that matters in terms of decision making particularly if it turns out the ventilators or scares you and clearly we haven't seen enough patients to no for sure here but as you read the literature do you have a feeling about that well we're certainly aware of the literature and we're aware of the literature of what's reported in terms of outcomes for patients who who require ICU level care and then even the other subset of patients who require mechanical ventilation I think it's too early for us to tell I think it is a as I said I mean it is a long it is a long course and so I think our main approach now is just recognizing that we incent expectations for ourselves for the staff we work with for for families that certainly once we get to the point of respiratory mechanical ventilation we are not expecting rapid rapid recovery we're expecting patients who may require one to three weeks or more of support with mechanical ventilation so we're we're still hopeful that we can that we can continue that we can improve outcomes and that we can provide the kind of evidence-based critical care that we've done for four years and that's going to be our approach going forward have we seen anyone come off a ventilator who's been intubated for areas we have we've had we have and and but I still think I mean perhaps we've only seen one at this point just because of the time course of where we are with our are somewhat higher volume of ICU patients okay a surrey sir maybe I'll turn to you and it's sort of a natural segue as we talk about intubated and ventilated patients and what their outcomes are and too much time going through the process I know we're going through all sorts of reading what others have done and seeing there are algorithms out there and all sorts of white paper is just practically how are you and your colleagues approaching this matter of preparing for a day which we hope we will never see here but they are seeing in New York where you have to make decisions about two patients that need a ventilator and we only have one thanks Bob definitely something that is key on everyone's mind given what we're seeing in New York and so I think one thing that can guide us and thinking about the process and how we would make this decision or is general public health ethics mantra which is the idea of creating the greatest medical benefit for the greatest number of patients it's a little different from how we might think about our individual role and it comes to a unique patient that we're caring for we were looking at the population as a poll that said even when thinking about the greatest good for the greatest number of people we're also trying to balance the intrinsic worth of each person and the moral equality of all people and really trying to identify in the situation of a scarce resource we can take ventilators as an example who is going to actually benefit from that resource the most such that we are actually promoting the greatest health for the population as a whole so if we take that into consideration and/or we take that as our foundation then the next steps are really trying to say how can we be as objective about this as possible and that's where we get into scores and those we've read protocols or some the press there are various ways that you might try to make predictions about who might benefit the most from these scarce resources so there are some scores out there sofa scores frailty scores and then it's the context of well how critically ill is this patient how as Matt was alluding to a lot of our patients in the unit do you have other comorbidities how likely is it that giving of investing in a ventilator for that particular patient going to actually help them survive until discharge which is honestly probably well in the grand scheme of things is a very short term marker for the purposes of triage maybe our most effective marker to make sure there's equity and objectivity and what we think about is it is survival until discharge the main issue or is it also then expected years if you make it to discharge and if so how do we be sure we're not discriminating against older people yeah so this is definitely a challenge here you know I think the survival until discharge allows for us to really focus on triage and minimizes the tendency to then make broader as that's where we get into we get into difficulty in making assessments on quality of life for example or how many more years or less for example and that's where I think it helps us try to be as objective as possible again as Matt was alluding to we may this is an evolving disease process and there are a lot of elements that we need to continue incorporating as we learn more about the disease process overall the one of the other challenges and doing this kind of work is really this is quite theoretical right where we're trying to create documents that and create protocols that we can functionally execute at an Operations level but there may be a lot of nuances that we figure out only as we're actually executing them that we then go back and address and iterate on and have you been in touch with anybody in New York who is actually it's no longer theoretical or it maybe it is today but it might not be tomorrow yeah and there are you know New York State actually created ventilator protocols back in 2015 that's been pretty widely circulated and I've seen documents out at Sinai and I the the situation is sometimes despite having a guideline or a marker you're having to make very quick decisions in real time when you have five of the you know five to 20 of the same patients coming in at you and so I think it's still a work in progress to figure out how can we take that burden of responsibility out of the individual bedside clinician into a larger objective body that can work very quickly as objectively as possible so no one group is discriminated against let me turn to Sarah and I don't know if you thought you'd be spending as much of your life on PPE as you have but we went a few days ago to Universal masking in the in the clinical setting as you heard in the discussion previously discussion about whether we should have Universal masking out in the real world where are you on all of that and how was your thinking evolved in the last couple of weeks I'm a little bit agnostic about the masking in the outside I am a little concerned that people who put on a mask might feel falsely safe and be tempted to go outside more often than they are currently so I think we really need to stress that social distancing capital s capital D is the most important thing now I think there are situations where wearing a mask in public may be appropriate so for instance if you're going to a grocery store you need food and you're going to be in close contact with people that might be a time where you might consider it I'm not sure that you know if you're going on a walk for some fresh air around the block that it's going to provide much protection and in the hospital you and your colleagues were part of a decision several days ago to move from recommendation not to wear masks in patients that were it deemed to be a blow risk to one one where the student was made to require masks all clinicians wear masks all the time how did that happen was just did we have the availability of mass or was that because of this emerging understanding about asymptomatic carriers what went into that yeah it was it was a convergence of several different factors one was the recognition that this is just a really difficult place to socially distance I think medicine is a social thing teams are rounding we're seeing patients and keeping a distance is very challenging so the combination of that recognition as well as some increased availability of masks in in concert with our increasing recognition though much needs to be figured out still about the asymptomatic spread of that piece and as you have come to understand this a somatic spread at least a little bit better than we did when we spoke a couple weeks ago how is it changing your overall approach to all the policy issues that you have to weigh in on well I think it's um it's definitely making you want to test more people though there are many caveats to this because we still don't understand the performance characteristics of the test in this asymptomatic population we're still learning exactly how best to test these people there's going to be operational issues with test turnaround time and and needing to know the answer for some for some of these tests but I think the more we can test individuals both with PCR testing for four patients and then eventually getting broad epidemiologic studies of serologic status the more we'll understand and so I'm very supportive of doing studies to figure figure out this issue and I think Jen might have mentioned that we have now kind of a Dorst as symptom a symptomatic testing and in three different patient populations that sounded like organ transplant someone who coming or going to a nursing home and then patients in whom you can't get a history is that a matter of not having enough tests and if we had unlimited testing would we expand the number of categories of asymptomatic patients who we would test yes this is our I think our first foray into starting to test some of these asymptomatic populations the the supply chain kind of the bottleneck of the supply chain has been swab test swab availability and we haven't wanted to expand testing until we're sure we're going to have swabs to test our symptomatic patients coming in reliably week after week and so we're doing some work to figure out if some of the non-traditional swabs that we do have more ready supply of would be useful and informative to use for testing and and if we had them I noticed that I believe Columbia New York Presbyterian went to universal testing of hospitalized patients a couple of days ago if our supply chain was more secure do you think if we had it today tomorrow would we be endorsing broader a systematic testing strategies it would be very seriously considered you know there's up operational pieces that would need to be put in place for instance right now whenever someone new comes into the hospital and gets tested we're using full PPE for a presumed patient with coronavirus and so there's concerns about burning PPE as we expand testing that I think need to be figured out but definitely something that that would need to be a strongly concern Jana thank you let's turn to George so George you've become a very popular man in the last couple of weeks because you do not only hey alright and epidemiology and and I think you know the most common question to you is probably please tell us when this will end and what the end looks like so go ahead you're it's all yours tell us when this will end and what the end looks like it depends on what this is are you talking about coronavirus as a medical issue it's good and I think it's probably here for the rest of talking about certainly take us to the next phase of ok it's gone down some and then take us to the phase after that maybe it's gone down because it's somewhat seasonal and it we're worried about it resurging and everybody's forgotten how to be citizens ok so you can't forget what you've learned okay this is uh this is gonna my prediction it which the only doctor Walker voices out loud but my prediction is that we're in a very flat phase we're gonna we're looking at something close to the apex right now in terms of bits bed space and ICU utilization will be out the other end by May early May I would guess then we'd enter a very long tail with handfuls of cases every day this is assuming there's no giant outbreak at the you know at the Laguna Honda or their big big long-term care facilities where among the homeless would we avoid those things there would be a long tail which will go well into the summer there'll be transmission during the summer when kids come back to school we will probably see a bump and that will you know and we're gonna have to work on that when when that comes out meanwhile we're gonna have very aggressive contact tracing in place we're probably going to have supervised isolation we're gonna have supervised quarantine we're gonna have aggressive case-finding we're gonna have a lot more testing and we're gonna be able to corral people who are infectious I think better than we are now you'd ask where the resources are my whole group is being retasked to do contact tracing for San Francisco that's like a hundred people okay so that's the kind of resources you need to to do this we say widespread testing I'm just struck by the whole asymptomatic thing I mean it would be one thing to say okay we're gonna now be more aggressive about testing people with mild symptoms but it sounds like there are people who may have this and who never have symptoms so is there some random testing that one does and how to even think about that did I mean the prevalence is way too low to do random testing I would think this is all a function of contact tracing and we're doctors just going to do household contacting tracing but we're gonna have to do community contact tracing you know everybody carry around a cell phone we can get their cell phones with their permission and find out where they were at five o'clock on the Thursday afternoon they were most infectious and we find out it's the marina safe way well that gives us a point of you know point to start looking for people that people who show up at the marina Safeway at five o'clock on Thursdays or you know or whatever it is I mean but those are these are geologic Geological these are geographical questions about where people are you know are intersecting with potential susceptibles so we're gonna have to learn how we're gonna learn by doing we're in contact with the South Koreans to make sure we understand exactly how they are doing all this every every app developer in the world has contacted me over the last three days with a new app to make this magically go away and so we have resorted or any of those promising I are a couple I like but you know there's a lot of sorting to go on to get to that but the whole this I you know I like the the digital thermometer that all the temperatures go up to some place in Corvallis and come back as a nice tight data set I like that but you know I mean I can tell you that people in San Francisco have to have temperatures yeah duh okay but it's like what block is it in and which house is it you know that's the sort of geographical stuff we need which then starts to make everybody very very very nervous so let's go let's go to the fall and we had it went down and in the middle of May and everybody sort of got back to normal are we doing widespread antibody testing so we can give people the Good Housekeeping Seal of Approval that you're immune and are we telling a 70 year old person with a little COPD well life even though everybody else is doing because you're at super high risk are we sort of parsing the population in different ways I think I think we will be parsing the time I mean understand it by September the population prevalence is gonna be a few percent right you know I unless we have something disastrously goes what goes wrong that's the core that's the that's the tack we're on so you know this sort of magical cohort effect we're gonna have all these people immune it's going to be like you know whatever 20% of a whatever two or three percent of 880,000 is um it's not they're not gonna be gigantic numbers and yeah we can we can cohort people together I'm thinking mostly of people who care for the frail elderly you probably want them immune or we can use people who are immune to take care of Kovach patients but it's you know they're not gonna be massive numbers and we're not gonna be able to like set schools up by like Ovid antibody status they're just not they're not gonna be enough people so there probably will be a bump in the fall and we're gonna have to get on it and make make sure what's gonna be backed us the most yeah go ahead sorry what's gonna protect us the most as other cities doing the right thing and and moving to shelter in place so we're not constantly reseeded by people from Dallas or Houston or wherever we're all of a sudden the population prevalence is 50% there's ongoing transmission all the time someone asked me the other day is the endgame here let's say vaccine takes a couple of years as the endgame here a hundred percent of people have gotten it or or not gotten the vaccine no let's say takes couple years to get the vaccine someone asked like why wouldn't we all eventually get it and I think your answer is that we're gonna do we're gonna stomp out these embers through recive testing contact tracing and yeah no need to get a herd immunity at 70 percent herd immunity of 70 percent which by the way isn't herd immunity you have to measles it's 96 percent that will come at a tremendous cost of life and I think there are other ways to do it that won't result in ten or ten or fifteen thousand excess deaths and you know that's those are the stakes we're playing with now yeah all right we're running out of time let's go around to everybody and I think I asked last time sort of one lesson that you have learned in and doing this now for I guess a month I mean it I think of like ovid years like dog years now it certainly does not feel like a month it feels like a year but and if you were on last time talk about something else something that you you have learned that you didn't understand about the disease about the way we're responding to it and whatever you want to talk about so Matt you want to start sure so I can't recall exactly what I said at this point last time but I'll say it but I'll say certainly the last few weeks have reinforced my belief that we can Nate we need to practice evidence-based critical care that that's core to this there's a lot of push to try new things to do different things to view this is fundamentally different from other Byerly mediator a RTS let's say and I think that's I think that's a mistake I think our focus really needs to be to do to do things we know or are proven in the literature to offer benefit and to follow the practices that were comfortable with I'm I remain concerned by the desire to treat this fundamentally differently I mean obviously there's some aspects of care we need to be very different about certainly the way we protect our staff protect ourselves PPE but I still think you know is Andy mentioned earlier I mean there we have a lot of evidence about how to manage a RTS now how to do it to offer the most benefit and I think we need to continue to do that and not get not get distracted by by our concerns and by the hope that there's something else out there that will make this make this different I think we need to really stay the course of that what's the most common anecdotal non evidence-based thing that you are push to do well I think this is said I will say this got some discussion in our group I mean I think there's a lot of discussion for instance about what the use of non-invasive ventilation strategies are in management of these patients and people see videos of you know of helmet CPAP and BiPAP being done in other parts of the country in Italy and in China I think there there's a role just I agree with the w-h-o guidelines on this there's a role for non-invasive ventilation and for - nasal canula and selected patients and I think we need to take the same approach to other patients with respirator and identify those patients for whom it's appropriate and so if you have a COPD patient of COPD who has an exacerbation we believe to be caused by cope at 19 and I think that's the patient we should look at for use of non-invasive ventilation I don't think we should suddenly because we've heard of reports from other places to decide that we're going to put everybody in helmet CPAP and hope that that's gonna work for Aaron yes when we have evidence that would suggest that that's probably not the best approach so I that's that's just an example and I'd say the same thing pharmacologically right now as Annie said there's limits on what we know and I think we need to stay focused on on on getting patients into trials and but not exposing patients to the potential for harm with a hope that somehow or another some medication will be beneficial I think that that's going to lead us down a path we shouldn't take got it all right bread yeah so I won't repeat last time I focused on slowing down on human connectivity and empathy and for human connectivity the one piece that has rung true for me is the w-h-o has shifted away from social distancing the physical distancing and the concept of the importance of social connectivity while maintaining physical separation I think I'll highlight just two things one is what I've learned operationally from our development of the respiratory isolation unit since I'm getting a lot of emails from around the country about this I'd say there's five aspects that I've taken away from this enterprise one is the importance of shared goals and vision the other one is adequate training and preparation of everybody who is involved in the unit three is making sure that there's consensus for all policies procedures and protocols on the unit four is the importance of seamless communication among peers and also bi-directionally between unit leadership and the folks on the unit and then five is just all efforts to build a culture a culture that's grounded on that shared vision as well as a culture of love and mutual support the other thing I'll just quickly reference is just three three papers that have really stuck out in my mind that I just would call attention to the first for those of our colleagues who are on the front lines really in battle a paper was just published by journal hospital medicine called 10 tips for a crisis lessons from a soldier that was put out by a retired lieutenant general Mark Hertling which I think is a very powerful look at how we in medicine can learn from our our friends in the me the second article of three that I'd like to highlight is a paper called that discomfort you're feeling is grief put out in Harvard Business Review by Arenado and it draws from learnings from david kessler who co-authored the grief work with Elisabeth kubler-ross and essentially discussing the notion of anticipatory grief that many of us are feeling before and during the waves of patients with prone a virus and the final piece that I'll highlight which was brought originally my attention by a friend and colleague Cindy Fenton was a piece in The New York Times called the moral meaning of the plague by David Brooks which is just a powerful reflection on how to try to find a semblance of meaning through all of this human suffering so those three pieces I keep on my desktop and I'd highly recommend them great Thank You Sara yeah I think I'll just highlight two things one is medicine is very very humbling and practicing medicine during a time when we know very little about what were what we're doing spending most of our time on is is humbling and I think it's very important that we continue to learn and study what we're seeing so that we can better understand how to safely care for patients and prevent further infections and then the other thing I'll say is I have a huge amount of respect for our Department of Public Health and the leadership in the city and the state for having me to call it that seemed premature to many and I think is saving life thank you thank you for highlighting that I think that's that's there's no question that's right sireesha and I'll I'll highlight two things I think doing a lot of the ethics work and thinking about triage and allocation which nobody wants to do and no one wants to think about or even address the realities of I've learned so much from colleagues about the importance of thinking very very critically and thoughtfully about every decision and that - especially when you're making really tough calls from a potentially value-based calls then making sure that there aren't groups that are unfortunately discriminated against and I'm very reassured by the conversations especially across the UCS about the with the thoughtfulness and ensuring that our vulnerable populations are protected and there's a lot out there about the disproportionate impact on certain groups of people and I think that is something that we all need to pay attention to and also count our own blessings in that context so the equity lens has been great now I'll echo Matt's comment we need to stay focused and just keep going and stick with what we're doing right now and hopefully we'll never have to get to a place where talking about ventilators we will hope that we stay their last word George we need to be really careful really understand what we're doing in the population since both art Reingold my equivalent at Berkeley and I brought up the same lowest experience in the 1918 influenza which it was very instrumental in driving a lot of these decisions and Sarah's totally right the health department the mayor's office the other county stepped up to this in a way that was unexpected unexpectedly unexpected you know in the broader state and certainly is saving I I would say well beyond thousands of lives and into the tens of thousands of lives and then the other thing just for your trivia books next time you play hospital trivia I think I'm the first pediatrician in the history of the world who's done both surgery and medicine Grand Rounds in the same week so that award let's let me sign off and thank you all for the five of you and the four before for an incredibly informative discussion and it's fascinating I think it's really important I think we'll probably do a version of this in a couple of weeks it feels like life is changing so quickly that there will be more to say as I mentioned before where we will put this on YouTube hopefully later today I will tweet that out later and then it will go out through more traditional channels in other ways I hope we can put up a slide that has the some thank yous to the folks that have that have had helped produce this and put it together ELISA ELISA Sarina John and Kyle thank you this is it turns out that producing something like this on YouTube is a little bit harder than doing it in person but thank you for all of that and so thank you for joining us and until then please do what you can to stay safe and thank you for all all you're doing taking care of our patients and we'll talk to you soon thank you

Channel: UCSF School of Medicine

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Length: 118min 19sec (7099 seconds)

Published: Thu Apr 02 2020