Kiki’s Comments for TWiV 638

Kiki’s Comments                                                                                                        July 2020

                        TWiV 638: Do, there is no try

Key Points:

*there are two anecdotal incidences of reinfection of individuals with COVID-19 that went from outpatient first time around to more severe admission to the hospital. We will have to wait until there are more similar cases before we can conclude anything, but this is something to watch out for with implications on the vaccine and herd immunity

*schools should not reopen unless we ca do it safely and minimize transmission risks

*Ivermectin is being looked at for COVID-19 treatment, but is not yet proven and may not be feasible

*there are a range of neurological presentations of COVID-19; these are likely immune and thromboembolic complications

*it is most likely that COVID-19 was introduced to New York in early February

*You cannot use serology for immunity passports, no matter how good your assay is. This should just be used for epidemiological inferences and reasons only.

n.b. when TWiV members are speaking about countries and responses, this is based on the information they have at the time and is a comment on the governmental responses and not the people themselves. If you feel like they do not have the full picture of a situation, feel free to write in with constructive comments and additional literature. 

Clinical Update with Daniel: 

“The fishermen know that the sea is dangerous and the storm terrible, but they have never found these dangers sufficient reason for remaining ashore” -Vincent van Gogh

*to all the healthcare providers: stick in there. We know that this is tough and that this will be tough, but you went into medicine to make a difference, so stick with it.

*Why are the case numbers rising but not the deaths? We are seeing younger people infected at this point (mean age was 60 early on, but now the mean age of infection is 40, although the people being admitted to hospital tend to be older) and when younger people are infected, the death rate is lower. We are also better at managing and taking care of patients than we were, which may also be contributing to the lower death rate (delaying intubation, proning, steroids, avoiding kitchen sink of drug cocktails, etc have helped). A lot of the deaths in the New York area were in the nursing homes (around half of the deaths), so many States are learning from the mistakes made in the earlier hit cities by doing things like testing staff, waiting until people are not infectious before sending them back to nursing homes, and overall protecting the vulnerable populations. On the other hand, we will likely see an uptick in deaths in the coming weeks due to resulting delays and time to include the overall disease course.

*Does natural infection with coronaviruses cause herd immunity? We have had a patient that was COVID-positive in April who was recently feeling ill again and tested positive again for COVID-19 now (July). There is also a Washington DC case with a man who got sick early April with COVID-19, became PCR negative and went back to work before being re-infected by his son and tested positive again for COVID-19. In both of these cases, the patients were sicker upon reinfection (outpatient for the first infection and had to be admitted for the second). This means the virus may not give long lasting immunity, so herd immunity in society may be beyond us. This is something we will find out in time. It would be helpful to have a T-cell assay for these purposes, if researchers could start taking those from patients.

*Should schools reopen? None of us are saying “go back to school” until it is done safely. This will require testing because we are learning the large proportion of asymptomatic transmission and spread before symptoms appear. Without testing and surveillance, it wouldn’t go well. 

            Questions for Daniel:

*Thomas: What was the likelihood that COVID-19 was present in Pennsylvania in early February? Serology is an avenue that we can pursue to determine if early patients were in fact COVID-positive. We have been seeing evidence that COVID-19 was in the Tri-State area earlier than expected, so it is possible. We will know more with time.

*Ewa: do people with high serology titers become seronegative (referencing previous comments)? Just to clarify, 40% of the asymptomatic become seronegative. 60% of the asymptomatic are IgG positive, 40% negative, as some are losing their antibodies. Slope is going down for both asymptomatic and symptomatic groups.

*Richard: Ivermectin was mentioned in a previous TWiV, what do you think of the use of this medicine for COVID-19? The therapeutic level needed for effective COVID-19 treatment according to patients would theoretically be a very large number of pills (hundreds), but there does appear to be evidence from South America that they are having good results treating patients with Ivermectin. We will know more with clinical trials that are starting here for Ivermectin. It is important to note that while Ivermectin is currently FDA approved, it is not FDA approved for COVID-19 treatment. We will report when we know more. 

Papers:

*Brain Paper on Neurological Findings of COVID-19: We certainly saw neurological symptoms in many patients, particularly in week 3 with a robust antibody response. On top of this, we also saw delusions in patients, which we observed across a range of patients. We have seen delirium, psychosis, Guillain-Barre, all of this is similar to what we saw earlier on. We imagine many of the neurological presentations are likely immune and thromboembolic complications.

Viviana Simon: Mount Sinai Pathogen Surveillance Program

*serology & ELISA assays: we use a two-step ELISA that is specific and sensitive with emergency authorization by NY State and the FDA. First step is a screen against the RBD, the second against the entire spike protein. This is the only test of this type available from an academic institution at the moment.

*What is the correlation between ELISA positivity and neutralization? There are many assays that look at neutralization and there appears to be a good correlation between high antibody titers and neutralization in Vero cells. There is no correlation between disease severity and antibody type. Severity of disease does effect the amount of antibodies created. 

n.b. neutralization in Vero cells does not necessarily mean neutralization in a patient body will be similar, i.e. this is not synonymous 

*based on serology, it is most likely that COVID-19 was introduced to New York in early February

*positive and negative predictive values: these are measures to predict how often the test is wrong (negative) and right (positive). Very specific tests are more likely to miss some of the infections. Even if an assay is 98% specific, there can be hundreds of thousands with the wrong result if you have a large population with a low virus prevalence. You have to look at sensitivity and specificity of tests.

*saliva for tests: it looks like saliva is comparable if not better than nasopharyngeal swabs. The reason many labs are still using nasopharyngeal swabs is because there is already approval for the nasopharyngeal swabs and labs would need additional approvals to use saliva instead.

*what is the NYC-wide seropositivity? It is very regional and ZIP code based in New York, ranging from 60% to 0.5%.

*when do you think we will have a vaccine? If the antibodies prove protective, then it will take maybe a year from now (maybe June 2021).

Questions:

*Andres: Vitamin D for COVID risk mitigation? We do not see this as a major part of the response. Vitamin D is a fat-soluble vitamin, so you can overdose—do not take too much. Do not use this for risk compensation. Recommended normal dosage may be useful, but the studies have not yet shown this.

*Victoria: why might there be an association between coronaviruses and Kawasaki-like disease? People have been trying for many years to find out whether there is a biological agent associated with Kawasaki disease. The New Haven coronavirus (mentioned by Victoria) did note a correlation between the virus and Kawasaki-like manifestations. Kawasaki’s is associated with cytokine storm and inflammation, which we have noted separately in later stage COVID-19 infections in children and adults, but we are not yet sure why. We will update this when we know more.

*Julia: on the predictive value of tests and the immunity passport, is 98% predictive value good enough? That is not great at high levels. If used broadly, this could be a good indicator of seroprevelence, but this is not good at the individual level. You cannot use serology for immunity passports, no matter how good your assay is. This should just be used for epidemiological inferences and reasons only. 

*Brian: can you discuss aerosolized droplet transmission? There is evidence that some sorts of aerosol transmission can happen over longer distances than expected, given the virus is not inactivated in that time, as even larger droplets can travel and carry the virus for a sizeable distance. We will discuss this more on later podcasts.

*Juan: What role do weakly positive infections play in immunity? Small amounts of virus are probably dealt with by innate systems (NK cells, interferons, etc) with no adaptive response. This would not confer immunity. 

By Kiki Warren (https://www.linkedin.com/in/kikiwarren/)