Pediatric infectious disease specialist Manjiree Karandikar, MD, MBS, provides an update on COVID-19 to inform pediatric care, including a look at the variants and the level of concern they warrant. She lays out the signs that should raise suspicion of multisystem inflammatory syndrome in children (MIS-C).
My name is Mandrake Miranda Kerr. I'm a pediatric infectious disease Faculty member at UCSF. I predominantly practice in san Francisco and the Mission Bay campus. My primary kind of clinical interests are an immuno compromised patients. Um Solid organ transplant, bone marrow transplant patients. Um but I'm happy to don't usually give you an update on COVID-19 thus far. Um I do have some financial disclosures. I do serve as a medical consultant for educators say I am do you receive compensation for that? But I will I will not be kind of referring to any of that work in this talk. Um U. C. S. F. Is a participating site in several chemical trials in adult patients. Um We don't really have any pediatric uh therapeutic trials at the time but there are a number of other trials that patients are uh are open to. I received personally. No compensation have no conflict of interest considering that the material discuss in this presentation. Um The biggest caveat I think is that the COVID-19 pandemic is a rapidly involving incident. Um and so the CDC website really has the most up to date information and resources. Um I'll point out parts of my presentation in which the data might not be as up to date as we go through the go through the talk. Um And then idea is a very collaborative field. So I appreciate um doctor in a von and dr Manisha, Is there any jiang for providing some of the information that will be presenting in the slides as well? Um so the objectives of the talk today are to summarize the current understanding of epidemiology of COVID-19 to provide recent updates on clinical manifestations of acute covid 19 and M. I. S. C. In pediatric patients and then current evidence for therapeutic options in pediatric patients. Um So corona viruses in general are a very diverse group of respiratory viruses that are named for the crown like spikes on their surface. Um corona in latin means crown or a wreath. There are many different types of viruses, some infect humans, others in fact a variety of animals. Um and they have very diverse clinical syndromes as well. There are seven known types of human coronavirus is the first of which were discovered in the 1960s. Uh four of these viruses cause upper respiratory illness or the common cold. And these are Corona viruses are the ones that commonly infect people around the world. Um In general, they tend to be fairly self limited with mild symptoms. Um your eye symptoms of mild fever, acute otitis, um asthma exacerbations unless I'm in league And also colitis group or particularly in infants or immunocompromised hosts. Um peak onset of illness is usually around 8, 3 or four. Um there are some other coronavirus is um that are slightly different. Um these ones typically infects animals, but then they evolve and gain the ability to infect humans and thus become novel or new human coronavirus is um, examples of these include SARS or severe acute respiratory syndrome, coronavirus or MERS. Um SARS is the coronavirus that caused a global outbreak back in 2000-2003. Um, it has more severe symptoms than the other typical hearing coronavirus is. But again, there is a spectrum of illness, it disproportionately affected adults. Um, 20% of patients required intubation and ventilation, there is a 10% overall mortality. Um, but there are no inventor child desktop documented in this outbreak, there's a Middle Eastern respiratory syndrome also causes a spectrum of illness ranging from asymptomatic infection to mild to severe disease, primarily affecting male adults with coal morbidity, ease and Children were also infected, but they did present with milder symptoms. Um so now let's turn to the latest episode a to on the Kinetic. So these slides are a little outdated I prepared this top last week. So the numbers and the screenshots are from February 9th. Um but you can see that you know, um a lot of different dashboards exist tracking that the genealogy of covid 19. This has happened to be the W. H. O. Dashboard and you can see that coronavirus is um Coben has been kind of making the rounds. Um The majority of countries now are reporting cases to the W. H. O. With the exception of North Korea in turkmenistan um who are not reporting yet. Um This is a little bit more um different than in a different way. Looking at the new confirmed cases. Um as of February nine. Again, you can see that the America is consistent. Both north and South. America kind of our at the uh lead in the number of new confirmed cases followed closely by europe and Southeast Asia. Um, and then nationally can the C. D. C. Has its own dash for looking at coronavirus cases and deaths in the United States. Um, the sources in the bottom right corner there below and again, the state is from february 9th. But at that time we had about 26 million total cases. Um about 33.5 average daily cases per 100,000 people in the last seven days And about 460,000 deaths um total. Um and then the infographic shows the areas which are um a little bit harder than, than the rest. Um, California has its own dashboard as well. We're child number tricks in the Dallas is on the left for example, and deaths on the right. Um, and as you can see the cases have been dropping over the last couple of months or so. Um, and there's perhaps maybe a downward trend in the death rates as well. Um This dashboard also attracts testing as well as the positivity rate. Um and both of these rates have been decreasing in the last month or so. Yes. Um It also tracks hospitalizations um, and I. C. U. Beds which again has been decreasing since overall kind of a nice downward trend so far. Another cool part of the website looks at the distribution of cases and deaths by age. Um, So on the left side is a positive cases on the right side of the total deaths. You can see that our pediatric population accounts kind of for a smaller chunk of both cases and deaths by age and this is for acute covid 19 not I M I S E. Um, so with that background some bunch of kind of another hot topic that's been in the press lately and that's the different variants that have been emerging. So I think it's important to note that all viruses evolve and mutate over time. Um, and stars Kobe too is no different. It requires about 1-2 limitations per month. Um, the stream that hit the U. S. Was already different than the original Wuhan strain and had a slightly higher infectivity as well. Um, corona viruses do mutate more slowly than other RNA viruses because I proofreading ends and the typically absent in the other irony viruses. Um, you know, there's a lot of talk about these variants and and it feels kind of like alphabet soup and argue with all these different names and letters and numbers. But you know, the crucial questions are do they matter? Are there any functional differences between the variants, for example, that perhaps make them more transmissible? Are they more very lynch like are they more likely to cause disease? And those are the questions that are truly kind of important. So um I wanted to um kind of introduces the concept and then we'll go through each of the variance. Um So there's three variants that we have been tracking. The CDC has been tracking the B 117 the B 1351 in the P one. Um The B 117 has had the most number of reported cases in the U. S. Um Compared to the other two so far. Um so this variant um was identified in the early December of 2020 where there was a surge of cases that were caused in about 62 countries. Now It has 23 mutations that are different from the original Wuhan strain and eight of those are within that spike protein. Um There are mutations in the receptor binding domain of the spike protein and and this is how it um it also is house Tightly that spike protein binds these two different human cells. And what this means is that statistical models suggest that the transmissibility of this variant is increased by about 56%. Um there's also some concern for neutralizing activity of monoclonal antibody products with this stream. Um And thus far as if I run in, there is no evidence to suggest that there's um but it can cause more severe illness or increased debt. Um and it's unlikely sufficient enough to decrease the efficacy of our vaccine induced immunity. The C. D. C. As I mentioned is tracking all these variants. And so this graph is taken from the CDC website. Um The references at the bottom of the slide um Looking at which states so far have reported this this variant. You can see there's a number of cases in florida in California as well as new york and then a smattering throughout the rest of the country. Um The next strain is the South African strain or the B 1351 This was identified in a fast growing epidemic in the Eastern Cape Problem in 2020. Um and then it spread subsequently across South Africa into 28 countries. There after this variant has nine mutations within the diamond domains of the spike protein. Um it is associated with increased transmissibility. Um There was a paper that was published this year by Whitmore at all that demonstrated various escape from three classes of the therapeutic monoclonal antibodies and some escaped from convalescent plasma neutralizing antibodies as well. Um There is some concern for reduced efficacy um a recurrence based based vaccines um but thus far no evidence of more severe illness or increased death. Um So far we have a couple of cases that have been reported in the US predominantly on the East Coast. So far, The next strain is the P one lineage and this was identified in the US at the end of June 21. It is a branch off the B. one went to eight lineage that was first reported um in Japan uh in four travelers who had come from Brazil. Um they're just sampled during routine screening at the airport. Um it has through mutations in the spike protein receptor binding domain. Um And it's thought that these mutations may affect its transmissibility and androgenic profile. Um which may then subsequently affect the ability of antibodies generated either through previous natural infection or vaccination to recognize and neutralize this virus. Um There haven't been too many cases of this report in the US thus far. Um I think uh only a couple. Um But this is another strange to watch up and then there's a couple more. There's a California Street. There's a couple of other strains that have been circulating as well. Um So where do we stand? Um You know people are really asking those quick those key questions. It's like well variants are more infectious or transmissible and whether the vaccines that we have will protect against them or not. And it's important to recognize that the vaccines were really generated towards that original strain from England. Um It certainly looks like the vaccines that we have right now. We're going to protect against the U. K. Variant because they're kind of similar um that immunization with one would would protect against disease caused by the other. Um There was one article that was that's non period would thus far that was an in vitro study In 20 patients who had participated in the Pfizer trial and they tested the this variant these two variants against their to see if there are antibodies neutralize it. And then they found that there was equivalent neutralization of the viruses um implying that there was no kind of difference in the effectiveness of those antibodies that were generated by the vaccine. With the limitations that you know those mutated viruses have have all of natural um strains and it was a small sample size. So as of now I don't think we have any strong conclusions regarding the effectiveness that can be made, but it seems hopeful. Um the one stream that may be a little bit more worrisome is the South African variant. Um and it seems like there's a data generated from a day and a trial um, that it may somewhat escaped recognition but not not entirely. Um, so I think it's it's still kind of remains to be seen. You know, if you've been giving the vaccine or your or if you've been naturally infected and then you're exposed to one of these variants. You know, whether um whether you'll get really sick, severe symptoms and only hospitalization or go to the ICU. And so far it doesn't look like there's any evidence for that, but that's something that's kind of um that's on everyone's mind and will be closely observed as more and more people get vaccinated. Mm. So now here's a little bit um and talk about some recent updates on clinical manifestations of acute covid 19 and MSC and pediatric patients. Um We'll talk about the clinical spectrum first. I'm focusing on acute covid 19 and So I think most of us are probably familiar with these days already, but just to make sure we're on the same page, the incubation of COVID-19 usually is 2 to 14 days, median 4-5 days from exposure to symptom onset. Um And 95 7% of those who do develop symptoms will do so within the 1st 11.5 days or so of infection. The most common signs and symptoms include fever, chills, cough, shortness of breath or difficulty breathing. And this is found in about 73% of people, um less commonly, headaches or throughout my al, just I found the quarter of people diarrhea, nausea, vomiting, congestion in about 1/10 and then abdominal pain about 6%. Um There are some less common symptoms, such as fatigue, the news of travel and poor appetite or feeding. Um I think it's important to differentiate between asymptomatic and pre symptomatic infection. Um So asymptomatic are people that never develop symptoms versus presymptomatic that are not yet symptomatic, but then go on to develop it. Um And this is kind of incompletely understood, you know, for the most part, early on in the pandemic, we're really only testing people who were symptomatic um and people without symptoms are not and are still not, I think routinely tested everywhere. Um there was a meta analysis that was done that estimated about 16% of kids with stars, Kobe two are asymptomatic. Um but then there's another different study that showed that total cases was more likely underestimated for that. Um In terms of demographic center pediatric population. So 11% of lab lab confirmed cases are less than 18 years of age. There's a 51% predominance of males. Um and at least a quarter had at least one underlying condition. So things like a cardiovascular disease or immune suppression. Um and it felt that Children likely has several viral loads in the nasopharynx and similarly similar in secondary infection rates compared to adults as well. I mean, I've listed a couple of references there for that at the bottom. Um We've heard a lot about aerosols or aerosol transmission. Um And so I think when you're thinking about this, aerosol transmission is really kind of an umbrella term that encompasses both chocolate, which is short grain transmission, and airborne transmission, which is longer long range transmission. Um Droplet transmission, which is, you know, those larger respiratory secretions that tend to fall quickly to the floor um spread up to six ft. This has really been shown to be the most important means of transmission during this pandemic um Direct contact with infected individuals is also very important, and indirect contact is also possible, but this really accounts for a small Portrait of around 6% of so have been reported a secondary to to indirect transmission. There's also been talk of this, you know, asymptomatic versus presymptomatic transmission. Um and it's felt that transmission during the pre symptomatic incubation period increasingly is increasingly we've done on the street in every studies. Um and but the proportion of transmission between asymptomatic versus presymptomatic is a little unclear. Um in terms of illness severity and kids um it appears that Children are less likely than adults um to have severe disease, but they are at risk for developing it as well as complications associated with it. Um Hospitalization rates for kids are in general lower, but they have been increasing and there are there we have some limited evidence regarding the risk factors for severe illness and kids and these include um things like genetic neurologic, metabolic conditions, disease, obesity, diabetes, asthma or chronic lung disease, sickle cell suppression or age those less than when you're old. Um it is important to note that most will not develop severe COVID-19, but village vigilance is obviously warranted um in terms of hospitalizations um for in our pediatric population, the rates a little bit lower. It's about eight per 100,000. Um a little bit higher in those that are less than two years of age and one and three kids are admitted to the ICU. Um Non Hispanic, Black Hispanic and Latin. Next Children. Um do you do have a higher incidence in our population and at least 42% have one underlying medical condition um predominantly obesity, 38% or so. And then chronic lung disease. That 18% of the top two in that group. Um 42% of the patients that are hospitalized you have? Yeah. I symptoms interestingly nausea, vomiting, nine pin diaries is something unique, you know, pediatric cohort compared to compared to adults. Um and some have worsening illness within the second week, like a covid 19 associate hyper information state, which I will go into shortly. So, um let's switch gears to M. I. S. C. Or multi system inflammatory syndrome and Children. Um so this was first described in the UK in April 2020, where they noted that previously healthy Children were presenting with um you know, the severe inflammatory syndrome where Kawasaki disease like features. And they seem to have a current or recent Sars-Cov-2 or EPI linked to COVID-19 cases. Um their symptoms included persistent fevers, multi organ involvement and elevated inflammatory markers. This was also seen in New York around the same time. 15 patients aged 2 to 15 years are hospitalized with multi inflammatory syndrome. Um There are 100 cases reported in new york state and most of those were positive for stars Kobe to by pcR astrology. Um And so the CBC and may recommended um the healthcare providers report the suspected cases to the Department of Public Health to better characterize this newly recognized condition and that's how M. I. C. Was discovered and named. Um the case definition is a individual less than 21 years of age who is presenting with fever, lab evidence of inflammation. Um and asters at the bottom note the specific lab findings um and evidence of clinically severe illness that requires hospitalization With multi system important. It's greater than two organs. Um And no plausible alternative diagnosis and who is positive for current or recent SARS COV two infection is diagnosed by pcr serology and engine test or who has exposure to a suspected or confirmed culminated team care to the onset of symptoms. Um This appears to um develop maybe 2 to 4 weeks after onset of infection or illness with covid 19. Um And there are overlapping clinical features with toxic shock and atypical kawasaki. Um But these patients tend to have really high inflammatory markers abdominal pain. Um And a lot of them do have evidence of cardiac inflammation as well. Um So the C. D. C. Has been tracking M. I. S. C. Um The source for these data at the bottom of the slide. Um There was about 1700 or so 1700 that that case definition. Um They tended to be Children median age of eight years but ranged from less than 1 to 20 predominantly hispanic latino or black non hispanic. 50% 7% were male and two out of three didn't have any their pre existing home or abilities. Um 99% of cases where positive for SARS cov two. The majority had antibodies that were positive compared to pcR. S. Or antigens and 1% had been exposed to confirmed covid 19 contact. Um The majority had four or more organ systems affected. Um G. Iving the most common followed by cardiovascular than german derm or michael cutaneous. The most common presenting signs and symptoms included abdominal pain, vomiting, rash, diarrhea, low blood pressure and can drink title injection. Um And there were severe complications in this part in this cohort, notably cardiac dysfunction, shock, myocarditis or coronary artery dilatation or aneurysm. And, okay, the majority were admitted to the ICU. And the mean length this day was five days ranging from 3 to 3 to seven. Um So now let's switch gears again to looking at evidence of therapeutic options in our pediatric patients. Um So we'll split this up into management of acute covid 19 as well as M. I. S. C. Um So again, most of us is probably reviewed and you all but um uh to evaluate for acute covid 19, the most common method that's currently being used as viral testing. And this can be either a PcR or a bandage and test know that the antigen tests have high specificity but low sensitivity. So if it's positive you can trust it but if it's negative, um we usually need a pcr to to confirm that negative test. Um And a body testing has also become more widely available and is employed. Um but you know a serological kind of test is one of the ways to evaluate for this diagnosis. That should be the only way. Um the specific city of our current antibiotic testing is not 100%. A positive test may reflect antibodies that were developed not to SARS cov two but any of the other corona viruses that cause the common cold. Um And I know that we do test for antibody and our neonatal. The serology may actually reflect maternal antibody um not the infants antibody. Um And the sense it's the sensitivity and specificity for I. G. M. In our neo nazis hasn't really been been saved as well yet. Um specimen types um There's a variety of ones that are being used. Upper respiratory specimens are the most common. So he needs to look for in jail or frank swab mid term and aspirate. Um An Np wash for example. And saliva is also being used in certain places now as well. Um Lower respiratory tract specimens of available. Sometimes we'll give you a higher positivity particularly if you're testing kind of later in the illness. Um products can be sent if the patient has a productive cough but know that induction is not recommended because of the concern for our civilization. Or B. A. L. Or lower respiratory tract. Aspirin can be used as well. Um Note that all of these tests for uh live or dead virus right? They can't differentiate. The gold standard would need to do a viral culture where you can actually culture the virus and then if it grows it's alive. But that's not um That requires moving very strict specific lab safety measures which is unavailable coming to the general public and it takes a while. Um Other lab findings include things like Olympus psychosis, to limbo pena, um mildly employment elevated inflammatory markers or liver enzymes. Um Radiographic findings are fairly non specific and you can have unilateral or bilateral infiltrates. Um We use CT scans kind of sparingly. Um Usually if if people are hospitalized or if we're looking for a specific clinical indications and uh ground glass opacity consolidation with the Hazan or two of the things that have been reported with Covid 19 and the American College of Radiology does have recommendations on the use of chest X ray and CT for suspected Covid 19 patients. Um And the link is provided there um in terms of management for acute Covid 19 is largely supportive um focusing on prevention and management of complications. Um for patients who have severe critical disease. Remdesivir is FDA approved for those who are 12 years and over or about and about 40 kg otherwise you can get it yet. You a dexamethasone is used in patients with severe disease, has shown to reduce mortality adults who require supplemental oxygen or ventilation. Um And we considered it we do considering kids who require respiratory support. Um and uh gentle kind of therapy for RDS adrenals sanctions a fictional And then convalescent class. Uh better if you're more early in the disease process or you have not improved on remdesivir in series. And this is also available under Eu a for those less than 18. Um The UCSF infectious Disease Management Program or I D. M. P. Does have all of these criteria on the website. And this is really accessible to anyone on the who has access to the internet and it lists out kind of what the lab criteria. Um If you don't have access to that, there was this multi center interim guidance on the use of antivirals and Children with Covid that was published in J. P. Is the journal of pediatric infectious disease um last year or so. Um And it really it's a really nice paper to read if you haven't already. It breaks down management by disease category. So for example in patients with mild or moderate disease, the first two rows um supportive care is um is recommended however, in patients who severe critical these as defined oxygen requirement um With or without need for ventilation from discovery suggested in kids with severe COVID-19 unless unless there's contraindications. Um Another kind of modality that we have is monoclonal antibody. So in november, the FDA issued a emergency use authorization for the use of family and even for the treatment of higher is symptomatic out patients with mild to moderate covid 19. Um The drug class works by buying into domains on the SARS cov spike protein um and it blocks his ability to buy into the east to receptors on cells and then stop cellular um invasion. Uh So this was the paper that was published in any Jm in 2020 from the blaze trial which was a phase two double blind placebo controlled randomized control trial looking at neutralizing antibody. Um In symptomatic out patients who are within three days of positive SARS cov two, they randomized to either placebo or monoclonal antibody and they in this child because it's basically they had to several different doses that they were trying. Um their primary outcome was change from baseline viral load a day 11 and patients did have a decrease Um in viral load and their secondary outcome which was outstanding was that the rates of Edie visits or hospitalization after Monica. Monica and nobody used significantly decreased 1.6 versus 6.3. Um So um it was authorized for emergency used by the F. D. A. Um In people who have covid 19 infection that is confirmed by pcr not orientation testing. They are have to be outpatient um and symptomatic and less than 10 days from the onset of symptoms with mild to moderate disease. So no Disney a no hypoxia and more uh infiltrates on X ray. Um the infographic really nice is from the CBC that looks at kind of the clinical spectrum of COVID-19 disease um primarily in adults but we can extrapolate some of those two kids. Um sorry that that breaks out, you know, it's a very ranging from out patient asymptomatic in which management really focuses on supportive care. Um And we recommend against steroids all the way down too impatient with critical disease where um you know, remdesivir plus steroids is recommended. And this monoclonal antibody really fits in the box that I've outlined there, which is those outpatient symptoms with mild out patients with mild symptoms. Um So we really do want to preserve us and people who are considered high risk for progression of severe covid 19. Um so I have all of the criteria kind of listed here but focusing specifically on our pediatric population to the bottom. Um the criteria, you know, at least one of the following B. M. A. greater than 98%. House disease disease, your own developmental disorders, medical related technology dependent, such as patients who require a trick or as or other respiratory disease requiring daily medication. They're kind of non specific and open to interpretation. And so we can really tailor it to their patients. Um There are exclusion criteria for these monoclonal antibodies. So um hospitals patients those who have a new oxygen requirement or those who have a worsening oxygen requirement who in those people who normally have you know some sort of supplemental oxygen at baseline. Um I think it's important to know pediatric patients were not included in those studies. Um So we don't really have a ton of data on their use. So um are kind of I. d. group here at UCSF is recommending against routine use unless you know the risk of progression to COVID-19 disease would be exceptionally high. Um And then also to know when you're considering playing in patients who may be getting their vaccines again. Unfortunately not in our pediatric patients yet, but a covid positive patient after vaccine can receive monoclonal antibody And after that vaccine should be postponed for at least 90 days even if the first vaccines given. And this is per guidance from that is easy enough to you. Um So here at U. C. S. F. We are um giving monoclonal antibodies in our outpatient respiratory screening clinic. Um These slides again are courtesy of Dr Manisha. Um is Ronnie Jiang, who runs our respiratory screening clinic here at Mission Bay. Um So they have this really nice setup where you know, patients who are tested for SARS COv two within our UCSF health system. There's an apex report that automatically gets reviewed by their team um to evaluate people who may warrant consideration of uh monoclonal antibody treatment. Um Otherwise is if patients are just elsewhere, they can be referred over to us. There's also there's a way through my tribe or be an email and the covid outpatient treatment at UCSF dot edu you know listed there. Um If there's ever a question, you can always call the number listed here. There's also a COVID-19 hotline through three CSF as well. Um So in this process that the team will you know assess for symptoms, make sure that the patients are within the eligibility window, that there's comorbidities um go through the whole eu a including the risks and benefits. And then if everyone agrees schedule the patient for um for infusion. And this is all done via telehealth um for our pediatric patients who are being referred to this. We do require approval from a pedes I. D. Physician um as well. So the prison team reaches out to whoever is on service in our group to decide whether um It may be reasonable to give long home anybody for our patients to. Um And I'll just mention that kind of this is a really developing field because you know there there's a couple of other monoclonal antibodies that are now have now been granted Eu a and you say stuff is kind of evaluating whether to switch over to to those um uh polyclonal antibodies. So that's something that may change kind of um in the near future as well that this process will remain the same. Um Alright so to evaluate for M. I. S. C. Um the testing is really aimed at identifying information as a set of the case definition um and then starts Kobe testing as you mentioned below either by viral detection um and neurology um cardiac evaluation is done which can include an echo e K G B M. P for example. And then um additional evaluation for multi system involvement. Um Are PDF we have a pediatric covid working group here at UCSF Prize of um you know ted ruler division chief and Rachel, water stewardship antimicrobial stewardship lead as well as members in our cardiology and rheumatology department as well. I mean this is a cross made collaborative between the hospital that mission Bay and over at Oakland. Um So we have this kind of nice guideline that's that's kind of in the works. Um So one should consider MSC in a patient who has fever is critically ill or is fabric persistently for three or more days and has lab or clinical features that M. I. S. C. And is ill appearing or is persistent unexplained fever for more than five days. Um And then um suspected M. I. S. C. Versus confirmed. MSC is really the presence or absence of covid positive PcR or I. G. Or known exposure. Um To dive in a little bit deeper into the clinical features of my see. Um There has to be, you know, evidence of current or recent SARS COV infection as you mentioned. Plus exposure plus two organ system involvement and the organ systems are kind of listed here for consideration. These are the ones that have been reported in the literature. So anywhere from diarrhea shock, um we have some lab findings um on the white count less than for anemia and leukemia. Um and then kind of additional symptoms as well as I will list here. Um I think one of the important things to note that we kind of get involved with a lot is that there is a differential diagnosis for MSC that's not all related to SARS COV two. So when you're evaluating patients in your clinical setting it's important to keep these things in mind as well. Um So Kawasaki disease for example um It's more common in younger Children um than M. I. S. C. And these patients will have negative covid testing without any epic exposures. Um And also less likely to have Jack or cardiac dissension although not unheard of. Um drug hypersensitivity reactions for example consider stevens, johnson address or a serum sickness like reaction particularly if there's a history of recent exposure to a medication or drug. Um These patients tend to have you know more of our three ologists and diffuse mucus itis um than the patients that um classically presented or diagnosed with M. S. C. Myocarditis may have some overlap with MSC or an alternative cause um staph or strep toxin. Media diseases can also present you know what is a diffuse rash or hypertension. Um So you know doing cultures and a good physical exam including a gynecologic exam is often important to roll this out. Um bacterial infections like sepsis can obviously present like this and particularly if a patient has you know meningitis symptoms or um you go prodigy that's not classic given my city as well. Um Sir skin syndrome um typically has more you know bully um and erythema affects younger kids but obtaining cultures can help rule this in or out um with the right at the demon logic risk factor. Link tick borne illnesses can sometimes present this way with fever and rash. So consider things like Rocky Mountain spotted fever, electrodes, viruses of the patients travel to those areas or has lived in um an endemic area in the past, maybe less likely now with all the travel restrictions but important to the mind. Um And then there's other viral infections such as acute covid infection uh measles, adenovirus enterovirus that can also present similar. Um I think the take home message for this is just keep the differential diagnosis in mind in terms of management for MSC. And it's really a multidisciplinary approach between you know cardiology, neurology, rheumatology. Our group um and the human biology um hospitals. Our ICU group as well as far has really been driven by our rheumatology colleagues comprised of I. B. A. G. Steroids and human immuno modulators. Um Our I. D. Group is often involved to make sure that there isn't any alternative diagnosis they may also fit um In general, you know for those patients that present with shock. We generally have been giving antibiotics kind of upfront pending cultures but the de escalating as quickly as possible once the diagnosis of M. I. C. Is established. Um And then the evaluation of clot risks or treatment prophylaxis really lean on are hematology um colleagues to help uh with aspirin or not preparing for thrombosis and then when you do send these patients to cardiology um along discharge to obtain that goes um I'm moving on quickly to prevention updates um in the last couple minutes here. So um there's a number of public health mitigation strategies, you know that I think most people are familiar with but have really um kind of help decrease the transmission with the covid 18 I think. You know it's it's hard to keep telling people to do this obviously. Um But I think it's one of you know the best tools that we do have in our toolkit while we wait for, you know vaccines um are people to be immunized more completely and things like that. So that's important to kind of reinforce these things. Um there was a recent uh news uh press press briefing from the CDC that talked about, you know, double masking. And I think the concept that like the take home message from that is that you really want to mask that fits well. So whether it's, you need to wear two masks to ensure the tight fit or whether um you can, there's like a tuck and loop or something or um basically create a better seal with their mass. That that's really the most important part about it. Um The COVID-19 vaccine development has been rather exciting. Um both live in terms that have been um they've come out. So the ones that are currently bowl right now are the Pfizer Moderna uh as well as a, there is also an estrogenic and J. And J, which has not received approval yet in the US. And then there's a Novavax. There's also a number of other vaccines that have been developed around the world as well. Um The M. R. N. A. All the vaccines so far I'll target the spike protein. Um The M. RNA. Products done by Pfizer and Moderna um code to make the S protein locally and then it induces the immune response. This is kind of a new approach to to vaccine development which is kind of exciting um the astrazeneca and J. And J. R. Adenovirus factory vaccine. So they use viruses infect cells that then code for that's protein. Um And then that induces immune response. And then the Novavax um is a synthetic s protein that's injected and then that induces an immune response. Um And kind of F. D. I think one thing you know worked in our favor is that we had to jump start to vaccine development going to prior outbreaks of related coronavirus is so like stars in 2002 and murders. Um more recently, um you know, and even though no M. RNA vaccine had previously been licensed, um there had been research that was ongoing for decades um using this technology for things like flu, zika virus, rabies and CMB. Um It's quite remarkable, you know, to demonstrate this kind of efficacy against mild, moderate severe disease. Um you may remember that the FDA, you know, said its efficacy bar at 50% for a vaccine to be considered effective back in june. Um and the Pfizer biontech and the Moderna vaccines, you know, kind of blew that out of the water. So um the Pfizer study had 44,000 volunteers ranging from 12 to 85 years old. Um They had 100 and 70 cases of covid 19 I mean um and 95% efficacy rate 94%. And that's greater than 65. Madonna had kind of a similar African see efficacy rate. Um basically I um 30,000 volunteers. 196 cases of COVID 19. Um their group. Um So this is actually quite quite exciting. Um The New York Times has a coronavirus vaccine tracker which is kind of cool to look at if you're interested. Um they go through all the vaccines that are currently in Phase 123 clinical trials. Um those that are approved and those that have been abandoned. So if you have some free time is just checking that out um in terms of safety um I think the C. D. C. And the FDA has done a really good job at um you know acknowledging that these viruses are our new technology and have a active kind of surveillance for vaccine associated um safety concerns. Um It's a very robust recruitment numbers and diversity in the population and the data is reviewed by the FDA and the C. S. Um It's uh they also have active and passive surveillance um as well as individual case consults in a very large database to continue ongoing monitoring. Um So far there haven't really been major safety concerns. They've recruited about tens of thousands of volunteers so that should be a reasonable size to detect common side effects. Um and even some uncommon reactions I can show up when you administer vaccines. 40,000 people for example. Um The NIH group helped design the child's and purposely outlined a diverse group of volunteers that needed to be included in the child that spanned a variety of ages, genders, races, ethnicity um to provide kind of another level of assurance of safety. Um, the data was reviewed by the FDA and their advisory group, as well as the CBC advisory Committee on immunization practices. Um, and there's continual, you know, safety monitoring post you a approval and vaccine licensure. There's no next question, sudden data bases that are um as well. And you may have heard of the safe. I personally have used that. It was very easy to use this. Send a text message to your phone and you just um, type in what you're you click what your symptoms are. Um, and that data gets fed back to this, you see, um, and then as opposed to the safety profile. Um, and that was that refers to all adverse events that could potentially because triggered or worsened at any time following vaccination. Um, there's a concept of reactive ethnicity, which is the subset of reactions that occur soon after vaccination, and these are felt to be the physical manifestations of the inflammatory response to vaccines. Um, there's some information on, you know what the expected signs and symptoms are following vaccination. Um and those including a local things such as pain, redness, swelling in duration at the injection site, as well as suspect stomach, um symptoms of fever, algebra, headache, a rash. Um The city are the um the groups that are kind of closely monitoring this and it seems like most of the systemic symptoms are more common after the second dose. Um and they tend to be lower among adult populations. And I have a couple of references there and that go through this a little bit more. Um with regards to pregnancy and breastfeeding, you know, this is important. 75% of our health care workforce are women. Um And we know that there is you know an increased risk of severe material, no illness and preterm birth due to COVID-19s are pregnant, pregnant people are in that kind of high risk group to severe severe to develop severe infections. Um There is limited data on using MRNA vaccines from annual development and reproductive toxicity studies. Um for what it's worth. There were no safety signals in rats who were um pregnant who received the Moderna vaccine. But there you know it's hard to extrapolate that to people. So there are cities and pregnant women that are plans. Um And Modern Advisor are monitoring the clinical child participants who became pregnant while they were in the trial as well. And so the C. D. C. And the american College of Obstetricians are a cog is also involved in these studies too. Um So um this is kind of where we stand again these data as are as um from february 9th. Um so overall um we've delivered 62 million doses administered 43 million. About 32 million have received one dose. And about 9.8 million or so have completed their Tudo series. Um predominantly I think the majority of the doses are from the Pfizer biontech vaccine. Modern is not not far behind. Um babies have very nice to get popular once it but updated more updated information. Um So who should not get vaccinated? Anyone with an allergy to one of the components of the COVID-19 vaccine should not receive it. Um nor should anyone who received who had an allergic reaction to the first dose of the COVID-19 vaccine. Um Others who have a history of allergies to other vaccines, medications, Who is our other allergens um currently should receive the vaccine. Um But with the caveat that these things are, these made these recommendations, they continue to change as we vaccinate more and more people. Um People with a history of anaphylaxis in the past are recommend to be observed a little bit more closely after the first dose. Um So how is it going? Um the CbC reported, you know about 4000 or so adverse events following receipt of the Pfizer vaccine, which is about 40000.2% of people we received it. Um 100 and 75 people reports were identified for further review uh due to possible cause cases of severe allergic reaction. There were 21 cases of anaphylaxis identified after administering the 1st 1.9 doses, which is about 11.1 cases per million, 75 or 71% occurred within 15 minutes of administration and 17 had documented allergies are allergic reactions. Um, There's 86 non an epileptic allergic reactions, 61 non allergic reactions in seven where your investigation, um, the influx is kind of reactions to the Covid vaccine were 10 times out of the flu vaccine, but the events were rare and non fatal. And so it's kind of a risk benefit decision where um, to have a conversation to have. Um, we continue to, you know, there's still ongoing effort required. This battle is not yet. One vaccination is not the end of the road just quite yet. Um, we know that efficacy against the development of disease, but we don't know, you know what, other people, We don't know yet whether people who are vaccinated, um, still continue to a symptomatically shed. And we don't have all the data yet regarding duration of effectiveness. So that's something to look for in the next coming months. So in the interim, masking social distancing and their public measures are still needed and should be enforced. Um, and kind of, you know, it's hard to say what the trajectory of the pandemic is going to be. It's really contingent on the contagiousness of the viruses used barbarians and vaccine efficacy. Um, it's estimated that seven out of 10 of every time people will need to be immune to control to control covid. So hopefully we'll get there. Um What about the survivor? So relying on infection alone to stop the spread, you need to have one million to 5.4 million people die en route to reaching the 250 million people needed to become immune. So that's not um, maybe something that uh we want to do um to we do not me for any viruses of immunity by natural infection. Um So something to keep in mind and I probably a little quickly because we're also at a time um You know, so when you're talking to your patients, it's not unreasonable to be skeptical of something new. Um But I can't say that there has been a tremendous amount of effort that's put into um into vaccine development to bring vaccines that are that are um effective that have a low kind of safety profile risk. Um you know, 95% is 100%. So there will still be some who can get infected and develop the disease even after immunization. Um and we need to get more epi studies from the get go to um um to see what vaccine will what, sorry to get more insight into what will happen with um new cases as vaccine rollout kind of continues. Um And there is also the sphere of vaccine and use indian pathology. Um It occurs rarely. So this is when you get a vaccine you get exposed to the virus and then you get more severe disease if you hadn't gotten the vaccine. So this happened, for example in the RSV vaccine that didn't make it to market Um back in the 1960s and can happen with it has been with the dengue vaccine as well and this has not been thus far demonstrated animal models. Um And so far not in human trials as well, but there's another thing to keep an eye out for. Um And then really briefly to touch on schools. Um The California DPH website does have a safe schools for all plan. The link is there below this excerpt is taken directly from that website. Um And I think the C. D. C. Last week um earlier this week also published kind of guidelines in a toolkit for safe school opening as well. Um So the successful approach preventing transmission in schools, I really leverages a couple of different layers of safety strategies, right? So the core strategy is simply masking physical distancing small stable groups, hand hygiene ventilation, screening for symptoms and asymptomatic testing. Um And each layer provides additional protection When used together. It has been associated with low or zero transmission even in communities when there's a high rate of COVID-19 prevalence. If you go to that website, there is a link to a paper where um that reference comes from. Um So in the interest of time. Thank you again. Um I have on my slide deck a list of references um that I used to generate this talk. The C. D. C. Has a covid 19 science update, which is a fantastic reference if you haven't seen it yet. Um Where about every week or every two weeks or so? They published kind of the latest data um on kind of all things. Covid they break it down into the resources or the studies that have been period. We read those habits. So if you haven't subscribed to get that as an email um the infectious disease society of America ideas, he has a covid 19 real time learning network. The link is there um And this again goes through all the different topics of code that they have a specific section for pediatric patients um with links to the ap guidance on vaccines and things like that. So I'm definitely look at that. Um the pediatric infectious disease society or Pitt's does have COVID-19 resources as well. And the paper on antibiotic use was published in that journal. And then you CSF has a number of COVID-19 resources, including the coronavirus website, the infection control website, as well as the infectious disease management website, which is um those references are there, there's also a hotline to call for patients and providers as well. Mhm. You know, you're having these are different members of our division on the San Francisco and Oakland side who have been working pretty relentlessly over the last couple of months. Um kind of combating COVID-19. Um, and with them, I will end my talk.