UCSF pediatric infectious disease specialist, Prachi Singh, DO, provides an update on COVID-19 in California, followed by a briefing on what’s currently known about SARS-Co-V-2 in kids. Know the signs that may look like other diseases, when to test, and the value of PCR versus various types of serologic testing.
Good afternoon everybody. Thanks for joining. You have questions along the way. Please feel free to go ahead and type in the Q. And A. And we'll try to aggregate them and um um answer them. Uh at the end of my talk and we'll also be joined by Dr Shea and Dr Petru who are our division chiefs on the Oakland side. Um are Doctor Petra is also our infection control officer. So she's been dealing with a lot of in hospital stuff so but we'll get to that towards the end. Um First I wanted to talk to you guys a little bit about the temple presentation and diagnosis of covid 19 in pediatrics or in Children. A lot of this information is rapidly turning over. So I feel like as much as I try to keep up with data, I feel constantly behind. So now we have published reports from pediatric population from china europe including U. K. And Italy of course in the U. S. Um there's new emerging data about clinical manifestations most recently. There has been this Katie like an inflammatory response syndrome that we have all heard about in the last couple of weeks associated with covid 19. Um what we also know is the large majority of the pediatric population remains asymptomatic as john alluded to a little bit earlier in terms of the specific signs and symptoms really it hits all target organ systems and neurologic manifestations reported in young adults as like this ischemic injury or stroke like injury, Eyes with conjunctivitis. And you've probably heard a lot about the hypothermia or last of sense of taste or smell. My card itis ground glass capacities um And pulmonary findings and lungs associated with some G. I. Findings a spell. And then let's subpoena from versus. Um and then the systemic inflammatory response that we have been seeing. Um And some skin manifestations. So in terms of the range of symptoms there is quite a bit of wide range of symptoms that patients can present. Uh fever, cough and sore throat being the most common ones that predominant presented pediatrics. But you can also see that there's a range associated there with fever being anywhere from 6 to 65%. Um Other associated findings, fatigue neuralgia, diarrhea, gonorrhea, vomiting and then poor feeding and cyanosis associated in the younger population. In terms of lab findings you often see as you would see with many other viral emphasis. Some limp a pina neutropenia. Um More often than not you'll find normal pro calcitonin or elevated calcitonin. I'm sorry Crp. Um It's either neither here nor there. Crocodiles are known in much less than crp. And then liver enzymes can be elevated. You can also find more sicker patients with LDH quigley apathy and di di mar being elevated as well. So does it really all that differ from Children to adults. Um There's was from the mm. Wr article that general also mentioned from C. D. C. That came out almost a month and a half ago now and you can see the similar spectrum of disease in both adults and pediatrics. So fever cough shortness of breath predominated both pd african adults in terms of their signs and symptoms associated with some nostalgia, runny nose, sore throat, nausea, vomiting, abdominal pain and diarrhea. The proportion of asymptomatic Children is unclear, but at least in this study, a large majority of them had no symptoms at all listed. So we don't we don't know um and much as evolving in terms of what the presenting signs and symptoms are for for pediatrics in terms of imaging. Um they're pneumonia was found in asymptomatic Children. Um This was initially came out from china where when they initially started doing contact tracings and they admitted um pediatric patients for even if they were completely asymptomatic, if they were a known household contact of a covid positive person. So, and they did a chest x rays and cts sometimes even in these completely asymptomatic kids and they found that they had evidence of pneumonia and imaging And you can see patchy airspace disease. Ground glass opacity is in about 20-60% and oftentimes can be bilateral or unilateral. And then um other clinical findings that have been associated with covid 19 is the systemic inflammatory uh syndrome that we have heard about. Initially it came out of findings from. UK where the S the H. S. J. Put out this report as a national alert that coronavirus related syndrome could be emerging in Children and they'll talk about a little bit more about it in the following slides. Um the skin manifestations um and popular news media it was reported as covid toes or vascular phenomena. Other findings. Ocular environment kIM moses conducted by this initially reported in adults. But we've also seen pediatric reports now of having patients having conducted by this smell and taste. It was there was a study published from Italy that one third of the adults reported self reported at least a one old factory disorder. And from our local experience here we had a patient was 16 years old, her first symptom or the only symptom was a lack of smell for three days and she was tested positive for covid. Um We've also seen reports of micro status and now the mechanism is kind of unclear whether it is direct or indirect direct mechanism. And um there haven't been much in terms of pediatric literature based for myocarditis. Pleased. So what about the cutaneous manifestations of covid 19 and adults was reported. About 1 to 20% had these earth minutes. Arctic ariel, the secular after all lesions. Both the scheme make and economic and um in in younger patients you can see these after ischemic toe lesions Now. Is this associated with an immune response or an antigen antibody deposition. We really don't know. And honestly a lot of these reports, they even have patients who are negative testing for covid but in the context of a pandemic. Could it be an association? It's really hard to decipher and kind of sift through this data and try to associate truly what's associated with Covid versus what's not. Um in any case this has been reported and then much talked about this association between Katie like or Katie even now, between last week to this week, people are starting to think that we should really not call it Katie because it's kind of different from what Katie presents, like in some situations, in some scenarios um and starts Kobe too. So like I alluded to before april, there was a cluster of patients, eight Children that had this hyper inflammatory shock which had features similar to atypical Kawasaki disease um, Kawasaki disease shock syndrome or toxic shock syndrome. Their typical number is 1 to 2 kids per week. So when they have saw a spike of eight kids per week, they put out this report and subsequent to that, there have been multiple reports in europe and us now um there was a collaborative call on 27th of april that had talked about these cases from London Madrid. You can see that there are 2010 to 20 cases that are presenting with toxic shock like syndrome or Kawasaki features um that are associated with SARS COv two, but I would say that not all of these 10 or 20 cases were positive for PcR findings and we still don't know if they had a context that had known covid and that's why they were included in this cohort when they presented the TSS. So um, we know that this is like a final type of Katie like um sorry, in SARS Cov two, it peaks somewhere um two weeks after your peak. So in the community, when you see your peak two weeks later you'll have cases emerging with presentation of fever, diarrhea, abdominal pain, limb subpoena and this toxic shock, kitty like inflammatory response. You can have anywhere between the range of the factory beso directory shock with normal cardiac function. Or you can have cardiac dysfunction mainly left particular dysfunction. And you can also have Katie like unless without being admitted to the ICU. I know there are natural registries now that I believe it's out of boston, Children's that are collecting data for us patients, both covid pcR positive and negative and including serology testing. So I think much will come out in the next couple of weeks on this phenomena itself. I know their talks on list serves up and down about potential mechanisms and theories behind it and also people trying to separate what's Katie and what's not really Katie but more of a systemic inflammatory response. So we don't really have a clear answer on this. Uh, though. And then talking about like more uh what what can happen or co infections associated with cars are not really associated with co infections with SARS Cov two. They have been reported. So most recently histories from a 74 Children that was published in pediatrics as of last week had 51% had Co infection and out of that, 84% had Michael Plasma. They didn't report how they tested for mycoplasma, whether it was serology based or it was pcR based. So I can't really say if it was truly uh true mycoplasma infection because I G M for mycoplasma is notorious for being false positive. And 16% of them had RSV um subsequently K series from again from Wuhan China 20 Children, they had 40% reported with infection and then study from Stanford that looked at adults with 1200 specimen, about 20% of them were positive for one additional pathogen. The way I consider it or think about it is that there's going to be an overlap based on your relative province of a viral disease at that time. So if flu is prevalent, you will see, screw with SARS Kobe too and it kind of makes sense Janet talked about this a little bit earlier too with the severity of disease. We can see that most of the Children are asymptomatic and have or have mild disease. Um, this study that was published in um land set look at the range of symptoms and you can see the majority of the pie is taken up by either asymptomatic, mild or moderate and I would argue that even the moderate should be lumped in as mild but the study defined moderate as mild pneumonia with fever, fatigue and cough not necessarily meeting hospitalization and then us data so far support that only 0.6 to 2% of the pediatric patients are in the ICU. So um we really the way other way to think about it is the burden of the disease kind of lies in the outpatient or a pediatric population where I think pediatricians in the outpatient setting will be the ones that will be seeing a lot of these kids with stars with covid 19 or positive for SARS cov two. So why do kids have mild their disease? There are several ideas, No clear answer. One could argue that they're healthier lungs, so fear capabilities. Um different wild pathogens have different pathways. So other corona viruses such as SARS and MERS were also miles and kids. And then on the counter argument to that is that there are other respiratory pathogens such as RFC. They do cause more severe disease in infants and younger kids is their age related phenomena differences in Ace two receptors expression? So as you age out your ace two receptor expression decreases. Conversely speaking, ace two enzyme is an important regulator of immune response. So is there some theory behind like how kids express that enzyme where they're able to um not have this severe disease and then does prior exposure to coronavirus is all sort of the disease course. Um uh like you can confirm some partially non neutralizing antibodies for partial protection. Um, the converse argument to that is that you could enhance viral entry. So correlate to that is when people get dengue the first time around you get dengue, um you're not as sick, but the second time around you have this enhanced viral entry. So you get sicker from it. And is there a job related difference in immune and inflammatory responses? I think there's going to be a lot of literature that comes out subsequent, you know, months, two years ahead. That will look at several of these theories and trying to prove or validate what holds true and what holds water. So talking about covid 19 and high risk pediatric populations, there's still a lot of unknowns associated with high risk pediatric populations such as the on patients or patients who have IBD who are on high dose steroids and rheumatology patients perhaps. Um the general recommendations are don't stop during minister present. Prior to talking to your aunt oncologist, gastroenterologist or rheumatologist patients who have diagnosed with covid 19 or have disease from covid 19 SARS cov two interrupting cancer treatment is generally recommended. But again, it's such a blanket statement. It has to be specialized to your patient and the kind of immunosuppressant that they're receiving and where they are in their course of chemotherapy. I want to point out this document that was put together by one of the pediatric eye doctor over at mission Bay along with the immunologists and some input from myself as well. And are in the infection prevention ist or infection control officer over at Mission Bay site. And the link is down below at the bottom. So moving on to the next phase of the talk about diagnosis and testing. And I have to say that there's so much that is happened in terms of diagnostic testing. And each day I feel like there's probably 10 papers that come out talking about diagnostic testing. I will try to pass through some of it. Um but a lot of it um taken with a grain of salt in terms of what you see, what, what testing is coming out and what what you see on the market. So diagnostic testing you mostly break it down in several different categories. Initially there was whole genome sequencing when this novel virus was detected china came out and reveal the whole genome sequence. So laboratories around the world can then create their pcR tests and other things. Um so then came the real uh real time not real team. Just realize some reverse transcriptase. And almost all diagnostic testing is focused on this method right now. Much is now talked about the serology testing. Instead of coming tests, we are still trying to learn about the role of this type of testing. And then lastly, there are no now knew more novel approaches that people are adopting like nestor and sequencing or saliva testing. Mm hmm. This was from I believe land set. Um And it talks about sort of like the evolution of a symptom onset and how it correlates to your PC are being positive versus your antibody detection. So if you look and you point your eyes to the big minus two, this is where you're exposed to start Kobe to a big minus one is you have this rapid peak of detection or your PC are being positive. It correlates to how much virus you're shedding and and kind of speaks to what we talked about earlier is that a lot of there is a lot of shedding or viral shedding could be asymptomatic. It doesn't quite correlate to infectivity. So yes, people can have the virus and be asymptomatic. But if you're asymptomatic you're probably not coughing. And if the primary mode of transmission is droplet contact, you may not be as infective even if you are a symptomatically shutting. So there's nuances associated to that. Nonetheless, like PcR being positive is usually between the first couple of weeks and then after that it sort of varies and drops down. You start seeing various methods of uh PcR testing viral isolations and those are your different colors. So the blue being the nasal pharyngeal pcr that's the most commonly used viral isolation from the respiratory tract, your bronchial lavage fluid. The pink. It's sort of peaks on and then it stays positive for quite some time. And then still we know that it it kind of peaks. Um and then it also stays and you can shut in your soup for quite some time. The purple and the green are your astrology testing or your antibody detection which usually comes along about two weeks into your illness course. So talking about the most uh common way that we are detecting acute illness from stars Kobe too, is this genetic uh detection of the genetic material from the stars Kobe to R. N. A. And we usually target these RNA dependent RNA polymerase, R. D. R. P. Uh gene or envelope or nuclear caps like jeans. And these are basically like talking about like what you're targeting. There are two methods the pcR or loop mediated I so thermal amplification the lamp and just keep that in mind. I'm going to come back to it in a little bit. Um I know at UCSF and see DPH sometimes what happens is that the RNA testing method will detect the ideally. It's supposed to target all these three genes and if all all three of them are positive, that's when you'll have a positive results. But let's say it only picks up the envelope and R. D. R. P. And it doesn't pick up the N. Gene, it flags as indeterminate. So the test will say that I have interpreted this to us means um should be considered positive if it's clinically indicated. So um indeterminant doesn't always mean that it's a negative test. Um but it just means that the testing may not have picked up all three targets as it's supposed to. So Laura is talked about in terms of sensitivity and specificity of these tests. We don't have a gold standard so it's difficult to interpret that. Um but generally speaking, the PCR tests are highly specific. Um greater than 99%. There is no cross reactivity. The sensitivity is depends on where you collect it and when you collect it. Um we know the mp plus Opie swab increases your sensitivity and you can see from the right hand side, we know the sensitivity which is derived from the common coronavirus is so the OPC who are being the least sensitive and as you keep going down, you increase your sensitivity as as you go down the list. What we know about the stars Kobe to we don't know necessarily about the sensitivity but we know percent positive and percent positive from the wrong. Theo Ellie leverages the highest percent positive speed of being 72% np swab 63 Opie being released. Um Again this is percent positive, not necessarily the sensitivity and you can imagine like patients who are getting a bronchial Villanova, you're probably sicker. So they have a higher percentage of iron studying and that could contribute to the percent positive. We we also have some other techniques where they are now approved by the CDC and and we know they're fairly sensitive, both nasal washes and mid turbinate swab samples are considered approved uh sort of on the CDC website as approved methods and good methods of collection which gets away from the fact of whether or not some of these other methods are air site generating or not. So um on something smaller. But the Seattle children's have published their raw data or their preliminary data from mid turbinate swabs. And it was considered to be pretty good. Like I think their sensitivity with upwards of 70 or 80% or so. So um this is uh new and latest and greatest and like I was talking about there's new testing and methods coming up every single day. So I think this was just um maybe earlier this week or late last week that black or came out with this at home kit that's available um that you can send to your patients. I could not find any studies that talk about the sensitivity or specificity. Neither on the FDA website but it is FDA approved under the emergency use protocol. And um the website is very clean and neat and talks about how you can figure out eligibility criteria. You're not going to be charged up front and and how you have your specific collection sample um and you can send it back to loud for other ones that I talked about is this loop immediate amplification testing or lamp. And these are two machines that currently run the detection of RNA by that method. One is the soviet and the other one is the Abbott. Id. I know I know center is using the app ID idea now method of collection. And the advantage of these machines is that there's a rapid turnaround time but the limitation is that you can only run one sample at a time so you can't catch them like 50 or 20 at a time. So um like I love it too a little bit before shutting declines over the course of illness. So it matters when you collect your PcR test on the left hand side if you see that these are nasal swabs that were collected from several different patients. And majority of the up for the cT value is between the they they three and day nine of illness. As you go beyond day nine your your pcR becomes less and less um sensitive to being positive. And um this is another study that looked at percent positive by clinical standard. Um if you had NP swab majority of them were positive within the first week. Similarly Opie swaps, majority of them were positive for the first week. Um so your viral burden gets less and less and this is one thing that people have generally talked about and how this is starting Kobe too is different from other viral viruses. The peak viral shedding seems to occur right before you become symptomatic and then declines over time. So when when you have a patient who is now day 10 days 11 of illness. And people kind of question your sensitivity of your PCR methods. And is that that's when we start talking about serology testing and I call it the promise and the peril of antibody testing because FADA has allowed some easing restrictions to these neurologic tests. And floodgates have essentially opened to all kinds of um companies coming up with their own serology tests. Um One thing I would say is that you usually see a serology testing being positive later in the disease. Um And one other thing to highlight as Jenna had highlighted earlier too in a low prevalence setting you really want to test that has high specificity. So um We're still learning a lot about this neurological responses. Um anybody response to spike protein which is what the study looked at and if you look% 100 of the patients turn zero positive. So really it doesn't occur in the first week of your illness. And then um this is another study that came out very recently. It's in the pre print uh met archive right now and it's a group out of san Francisco that looked at 10 different lateral flow assays and to Eliza. So down below you can see the lateral flow assays read like a pregnancy test script like GM being positive I. G. T. Being positive and all of them positive versus Eliza is sort of like the antibody antigen test. So out of the The 12 that they looked at only four of them had greater than 80% sensitivity at different time intervals. And the highest time interval that they were positive for is the greater than 20 days and they all uh the four of them had greater than 95% specificity. So the key points that I took away from that study was that sensitivity increased over time. So if you close to 81 200% at 20 days plus of symptoms and the specificity of these test scores around 83-84-100%. So this is another way of just looking at it. If you look at all the colors these are different tests that they ran and most of the high bars are around the great greater than day 20. Um if you look at 1-5% positive is between 0 to 50% and that percent goes up as you go up higher in your disease course. So my takeaway from it is that you should not consider positive serology testing as uh one thing is but we we shouldn't confer immunity based on your serology testing, we still don't know what that means like that. Confer immunity or not. We do know that serology testing will probably be helpful in diagnosis later in presentation population wide, zero prevalence and then immunity like I said, we don't know if it confers community or not and then potential lord in the convalescent plasma. We definitely need more testing to be done. And um in the last few flights I just want to leave you with other methods of collection. So PcR of saliva testing. This is a recent study that came out that looked at 44 in patients and they collected both Mp and saliva and their collection basically they have patients spit in a sterile in early morning and uh they found that saliva was just as good as their mp swap. And in fact some of them even had higher via loads and there was less variability in positivity. So that kind of opens up a potential south collection or stop swap conservation idea. So I will leave you with some conclusions. Children in general have milder disease and adults other infections do not rule out covid 19 and testing is primarily right now. PcR based with np swab being acceptable but also empty wash and mid turbinate swabs as well and false negatives are possible depending on the timing and the site of what you do And in terms of remaining questions we still don't know why Children get don't get severe disease and then outcomes in covid 19 and special populations. And then how will pcr and serological testing inform our decision making earlier. These are some of the good references because there's such rapidly changing dynamics in terms of what is out there. Department UCSF Department of Medicine. This is just general, not pediatric specific has been rounds every week on Thursdays and they have their collection posted up on Youtube. I found that I find them highly informative. They're about an hour and a half. Um Singapore. Department of Health also has a collection of various integrated uh resources that they have put together as a PcR. And this is on the right hand side as an example of all the tests. And then the kinds of uh talks about sensitivity specificity and other things. And then you can find um if you click on this link there's about 600 tests that are out there right now. Talking about diagnostic testing for covid 19.