Kiki’s Comments                                                                                                        May 2020

                                    TWiV 614: COVID Tetris — Test, trace, isolate

            Key Points:

*newly recognized hyperinflammatory phase four or more weeks post exposure has been noted, particularly in children, manifesting in vascularities and secondary symptoms

*Remdesivir may be useful for treatment in patients early in the infection course (7-10 days post exposure)

*the furin site is needed for cleavage of the spike and for infectivity in the human lung cells

*there are issues with serological antibody tests between tests and facilities—you may need two tests to try to reduce the false negative possibility and remember that results do not mean that you are immune; immune is not binary

*CoV-2 has not mutated into a more virulent virus

*Far UV-C lights may be helpful for killing the virus, regular broad UV-C lights are harmful to humans and are not to be used; UV lights can be used in hospitals to help sanitize rooms while no people are present

*if proper precautions are taken, sports like tennis may be viable to be played

*the virus can enter your body through your eye ducts, so be sure to not touch your face or eyes—goggles, face shields, and maybe even onion cutting glasses can be used to mitigate this risk

*herd immunity by infecting people with CoV-2 is not likely to be the ideal strategy for containment of the disease, as shown by the high mortality rate in Sweden; sheltering in place will not aid development of herd immunity, but will help to decrease mortality and not overwhelm hospitals

*There is no cross-protection between the common cold coronaviruses and CoV-2, but they can cause false positives in testing

            Clinical Update from Daniel:

*the number of cases of COVID-19 in New York has gone down—all the numbers are looking better

*We are returning to Do No Harm and priming patients for clinical trials

*COVID-free facilities for surgery have been made

*continue to use personal protective equipment and sanitize

*Leadership: a lot of getting through this pandemic were the people who stood up and took initiative

*Summer camp and school re-openings: we do not know

*Stages: 1) pre-symptomatic phase (people are shedding virus), 2) viral phase, 3) cytokine storm phase (this is usually when people go to the hospital with trouble breathing), 4) coagulation phase (e.g. veinous clots, arterial clots; patients may not have had a strong enough cytokine storm phase to have ended up in the hospital, but they come in with a stroke or ischemic toe), 5) late, multi-system hyperinflammatory phase (mainly described in children, e.g. an Italian study that showed a 30% increase in these vascularities in children with 80% having COVID-19-positive serologies; children are presenting with fever, abdominal pain, red tongue (strawberry tongue), Kawasaki-like syndromes that are related to IgG targeting) 

*Hyperinflammatory phase and vascularities: we have now seen several deaths in children from this late hyperinflammatory process and they are not just vasculitis that we are use to, but also a septic shock-type reaction where the children become hypotensive, which has caused several deaths. There is a small-vessel vasculitis being seen in adults reported by some nephrologists

n.b.i. worry with a vaccine is that if we trigger the wrong immune response, could this create vasculitis in some people receiving this, particularly worrying as we do not know how long this can last for (rheumatological, post-viral manifestations)

n.b.ii. we do not know if Kawasaki disease in parents will make kids more susceptible; it is possible that Kawasaki’s was always caused by a coronavirus and this may help to elucidate that idea

*Remdesivir: we have begun using this through the Limited Access program—we are using this earlier in the disease course (patients who have been sick 7-10 days). We are not seeing anything dramatic, but there has been a noted shortening of hospital stay

*Plasma: there are a lot of coagulation factors in plasma, so we want to be careful, particularly in the second and third weeks of heightened coagulability, when administering this to patients

*Vitamins: we are seeing fewer litres of vitamins being pumped into people—this is good, as no positive effect from hyper-dosing vitamins has been seen

*UV light: these are being used to clean the rooms. We are NOT using UV light on patients.

*Viremia and bacteremia: we are seeing viremia and bacteremia in patients that never came in for treatment. COVID-19 has a similar late stage bacteremia (particularly Staph. aureus) as seen with some people that have had influenza

*Lancet Triple Therapy: this is a combination of 1) interferon beta-1b (antiviral arm of the immune system that stimulates innate immunity and will simulate flu-like symptoms), 2) lopinavir/ritonavir (lopinavir is a protease inhibitors from HIV therapy; ritonavir interferes with the breakdown of lopinavir and allows more specific dosing), 3) ribavirin (nucleoside analog that gets incorporated during replication in other viruses, but this might not be effective in CoV-2 because of proofreading). We would like more information about benefit before readily prescribing this to people as it will likely make people feel even worse for a while, which might not be worth it depending on the benefit

*Non-COVID update: there is still a large Telehealth presence in the medical system, although doctors are seeing more non-COVID patients in person as well

            Questions for Daniel:  

*Rachel: for a patient with positive PCR-test for two months after the start of the symptoms, can they still be shedding virus? We don’t know. We use a double negative way to measure usually instead, i.e. we need two negative PCR tests before we conclude that a patient is no longer infectious. For a positive testing patient after that long, we do not know yet, but it would be unlikely that viral machinery would stay around.

*Noreen: do contraceptive pills, thalassemia, and thalassemia traits increase clotting problems in COVID-19 patients? We are concerned about contraceptive pills because of the thromboembolic phase that happens after the second and into the third week, although if you are on contraception, we are not telling you to stop. If you on a contraceptive pill and have any symptoms for COVID-19, be in tough with your physician and coordinate with them for plans for what to do if you get infected. Work with your provider to address this. I would not think that thalassemia would have an effect on the coagulation issues, but we do not know.

*Maurice: faint ground-glass shadow found on a CT scan that was not present in the X-ray of this patient—why is this here? A lot of times people have a standard chest X-ray and then light up on the CT scan, this is seen in some other diseases as well. It is something to be aware of that a chest X-ray might not show everything.

*Multiple people: is loss of smell acute enough to be used as a screening procedure for COVID-19 that employs a universally detectable odor? No, currently only around 30% of people who test positive for COVID-19 are showing the anosmia (depressed or loss of smell). It would be interesting if there is a particular odor that people with COVID-19 can’t smell rather than a broad loss of smell. There are patient who have anosmia that do not have any of the respiratory symptoms of COVID-19 that have a high antibody titer. There is not necessarily a nasal congestion causing this loss of smell; it looks like the virus directly alters the epithelium of the nose.


*Molecular Cell—multi-basic furin cleavage site in the spike protein of SARS-CoV-2 is essential for infection of human lung cells: shows that the furin site is needed for cleavage of the spike and for infectivity in the human lung cells. Likely that the virus acquired this furin site in nature, as shown in a bat species from an abandoned mine.

*USFDA Point of Care Tests: this is the rapid PCR test (15 minutes), but a negative is not really a negative. People will need two tests to be more safely negative. There is a high proportion of false negatives.

n.b.i. Quest diagnostics has not released which test they are using for serology/antibody testing, so take all results with a degree of uncertainty and know that all tests are not necessarily the accurate and reliable

n.b.ii. you are not “immune” or “not immune,” there are many levels and layers of immunity and these are not directly correlated with risk


*David: once a certain virus vector has been used (e.g. the chimp adenovirus described in TWiV 613) for a vaccine base, will this make it harder to be used a second time for a different virus because of the innate immune response? This depends on the way the vaccine is made. Some of the parts of the vector may produce responses that may be overwhelming. This could be a problem with some vaccine immune approaches. There are many ways to counter this, but one way is by varying the viral vector. 

*Dji: what is the importance of small speech droplets in transmission of CoV-2? Speaking producing a whole range of droplets that will travel different distances. The tiny droplets go a long way, but we don’t believe that most of the time they are transmitting CoV-2.

*Vinny: the SARS-CoV-2 virus has mutated, but not into something more virulent—can you comment on this? We have mentioned this before, but CoV-2 has not mutated into a more virulent virus. 

*Talia: how different is SARS-CoV-2 from other viruses and could CoV-2 result in a long-term condition? Answering the second part first, we do not doubt that CoV-2 could cause a long-term condition. There are a lot of coronaviruses that we have found, but there are very many more that we have not; it is possible that there are many viruses like this, but not that we have found yet. 

*Rodrigo: Far UV-C light versus broad UV-C lights? Far UV-C lights are theoretically not harmful to people as the wavelength cannot traverse the skin or eye outer cell layers, but theoretically can traverse and kill microbes due to their micron size. Broad UV-C lights on the other hand are harmful to humans and should not be used. The two differ in wavelength and thus effect.

*Philip: is there any benefit to the practice of elbow bumps or using elbows to do manual tasks instead of hands—how does a virus travel around on the skin? A virus doesn’t travel very well across the skin, it generally stays in and around places that are directly in contact with each other. The elbow method can be helpful because people are less likely to touch their elbow to their face, although if you touch your elbow with your hands and then your face, it can still transfer the virus. 

*Chirag: what is the likelihood of making an attenuated virus for CoV-2 and using this to challenge individuals while testing upcoming vaccines? This is what we do for flu challenges—they use an influenza virus that is not that virulent. Using an attenuated virus for a challenge in the vaccine trials could be an interesting idea. Attenuating a virus can take a while to do in a lab. There is a lab in China that is attempting to code an attenuated CoV-2 virus, but we will have to wait to see if it can be made.

*Joe: tennis and CoV-2—is this safe to be played by people from different household (singles tennis, specifically)? There are ways to mitigate risk and exposure with tennis. This is a sport where the players can be fairly distant most of the time. New regulations are recommendations are helping to decrease risk (only touch your own racket, don’t touch your face if you can help it, keep social distancing where possible). The surface of the tennis ball is unlikely to be good as a fomite for viral transfer for CoV-2, as smooth surfaces were shown to be more effective at transmitting the virus and materials like clothing less so. This may be a sport that can reopen with restrictions or considerations to safety—make sure to not touch your face and wash your hands thoroughly after playing. 

*Kathy: we see a lot of information about face masks covering both nose and mouth, but not much about goggles or eye coverings—is there something that can be done to mitigate this? If you were to get virus in your eye, there is a potential for the virus to get into the tear ducts that could then have access to respiratory epithelium and start an infection. Many places are having people wear face shields so that they don’t touch their eyes, and no doubt that goggles would help decrease risk. Onion cutting goggles could also be useful for the same effect.

*Chris: why not do a controlled herd immunity strategy that is stratified by risk, having the young and healthy be exposed to try to increase herd immunity? First, not all the young and healthy people have a good disease course. There is no zero risk. Lessons from Sweden would presume that this is not that effective. As we learn more about the disease and outcomes, optimal strategies may be elucidated.

*Aaron: how can we get to herd immunity if we are all sheltering in place? We cannot get to herd immunity if we are sheltering in place, but if we do not shelter, many more people will die and hospitals will not be able to handle it—we are biding our time until we have effective therapeutics or a vaccine. If we want people to go back to work we need to test, trace, and isolate as we go ahead. Once part of the outbreak is more under control, we can start opening things that we think are low risk and modify as data comes back. 

*Anne: what will destroy the S protein of this virus instead of a vaccine—is this a better or worse option? If we had a chemical that was noxious enough to destroy a protein on the virus, it would likely kill many more things in the environment and could be harmful to humans too. Vaccines are going to be the better option for humans as a small amount of the organic vaccine material can be more protective and much more helpful to humans and the environment. Vaccines are not filled with harmful chemicals that are causing other diseases. In fact, diseases were the first homeopathic remedy. A chemical for use on humans would be worse than a vaccine. That said, still disinfect items brought into your home and wash your hands with soap. 

*Michael: could an infection by one of the four common cold viruses confer a degree of immunity, even temporarily, against CoV-2 and could this explain some of the false positives? We have not seen great cross-immunity between the other coronaviruses and CoV-2, but we have seen cross-reactivity of tests (this would have a particularly pronounced effect on IgG), which could lead to false positives—these are being taken into account. There is no cross-protection between the common cold coronaviruses and CoV-2. 

*Worried about Sweden: Thoughts on Sweden? There are different opinions about the success of the Swedish approach during this pandemic. Death rates in Sweden are much, much higher than neighboring countries (one of the highest deaths per million). ICUs in some parts of Sweden are getting overwhelmed. Test, trace, and isolate may no longer be possible for Sweden as the virus has disseminated already. Time will tell us more of the repercussions of the Swedish disease control strategy.

*Beth: how long do antibodies remain in the system? Some antibodies can remain in the system for a long time, likely for months, as well as B cells that will continue to make those antibodies possibly for life. This varies a lot from antigen to antigen and person to person, which is why some vaccines have to be given more than once.

*Christina: dose-dependence in disease outcomes—are route and dose important to disease outcomes for CoV-2? Route and dose can play an important role for some disease manifestation, but not for all. There were some studies that showed that more shallow entrance of an infectious agent causes less severe infection, but this will not be the case for all microbes.