Kiki’s Comments                                                                                                          May 2020

Episode 608: Daniel Griffin’s COVID-19 clinical report

            Key Points:

*be proactive at maintaining your mental health—this is for patients, medical workers, and the general populace. Do not wait to seek help.

*Remdesivir may not be clinically beneficial, particularly when currently administered, and may be not be recommended due to increase in adverse events

*the cases of re-infection in South Korea were identified as fragments of viral RNA (viral litter) and not active virus—no evidence yet that the virus can re-infect hosts

*hypercoagulability is driven by endothelial disfunction: the endothelial cells may be triggered in a dysfunctional manner that may be causing this increased clotting seen in COVID-19 patients

*do NOT stop taking prescribed anticoagulation medication if you have coagulation issues

*contact your health provider before starting to take anticoagulation medication (e.g. heparin, aspirin), as the potential benefit is measured on an individual basis

*recovery post-ventilator may be associated with pre-COVID health and demographic, but we need more evidence

*clean surgery hospitals are being prepared for non-COVID surgeries, but will likely need to be dynamic to respond to future demand, particularly if there is another outbreak spike in COVID-19 and require rapid COVID testing to maintain clear of the infection

*there is an interesting phenomenon where eosinophils are clearing from the peripheries and being found in the lung tissue—this may play a role in the not-so-helpful, over-exuberant immune response, but we do not yet know why

*there are concern about having a big wave of infection coming in the Fall and Winter, particularly as the virus will have been disseminated instead of found in pockets at that time

            Daniel’s View:

*Clinical Update:

Social Distancing: We are getting near to the point where many places are stepping back on social distancing, including the public that has been taking more liberties with or without regulatory permissions. We will likely see the consequences of this in time.

Mental Health: Mental health professionals and primary care doctors can do a lot of good here. A lot of healthcare workers are having a tough time and could benefit, alongside the general community. Do not wait to seek help. 

Clinical progression: Crummy first week, looking for decompensation event in the second week. The decompensation event can happen pretty quickly, even in young patients—do not underestimate shortness of breath. 

Seeing more and more arterial complications. Beginning to notice that even if you make it passed the respiratory period, you are at risk of the coagulation issues. Figuring out whether aspirin or more aggressive anticoagulants are useful to different patients.

The day or two before people get very ill is the highest level of virus in the mucosal airways, then the level of virus appears to drop quite low before the cytokine storm. This can be so low that the PCR tests are negative—patients can be past the point where they have detectable virus. Currently with PCR we are getting positives or negatives, but we would really like to get a more quantitative dataset.

Decompensation: The generic is someone goes from doing well to very poorly; in COVID-19 there is a special progression: a patient will go from a period of time where they are hypoxemic (the level of oxygen in their blood is getting below 90) to requiring 2-5 litres of oxygen to potentially being on a ventilator or a machine for high floor oxygen in a 24 hour period of time.

Treatment: Standard supportive care does work. Help them with their oxygen, try to keep them off the ventilator, and even as they leave the hospital we have to be aware of thromboembolic complications, and we have to keep an eye on our patients in the outpatient setting (should a leg start swelling up or a coagulation issue arise).

Breastfeeding: Possible that an infected and recovered mother is giving anti-CoV-2 IgG antibodies to the newborn. This is currently being looked at. The virus is not found in breastmilk.

*Patch Studies — recruiting healthcare workers and patients early on in the disease. We need more clinical studies and trials as we are returning to evidence and the ‘Do No Harm’ core value of physicians.

*Clean surgery hospitals: There are some hospitals in New York City and elsewhere that are shifting COVID-19 patients to other hospitals in order to create a place to perform surgeries COVID-free, for example for cancer patients or those with burst appendices, to meet that need. Potential negatives: Should we have another wave, instead of a few travelers bringing the virus in and there being pockets, we are worried the virus will be so widespread that when it erupts it will be more so—what do we  do when we have switched these hospitals to surgery centers? We may have to switch back as quick as possible. Another issue is that there are people who wish to come in for their surgeries who are COVID-infected and have to be sent away.

Biggest challenges: unless you have the ability to rapidly test people coming to the Emergency Room, it is very difficult to switch between facilities that are COVID positive and negative. We need highly sensitive, rapid information so that we can keep facilities COVID negative. We need to keep COVID-19 away from places with surgeries and people with the coagulation and inflammatory issues.

*Remdesivir: there may not be beneficial effect on survival and could increase negative clinical events in patients

1. Wuhan study: has all the hallmarks of what you would like in a multi-center study, with small exception that they did not meet pre-specified enrollment number. Patients were 12 days or less from symptom onset and oxygen below 94. 

Significance: found Remdesivir was not associated with shorter time to clinical improvement or more rapid drop in viral load. There were events leading to drug discontinuation: ARDS 5% higher in Remdesivir group, increased transaminitis, issues with kidney function, and other issues that required drug discontinuation—this could indicate that Remdesivir use could potentially be clinically harmful.

Administration is past virus peak where many of the issues are immune-driven. For this to be the most effective, the antiviral would have to be given day 1-2 of illness at peak of viral replication-ideally this would be given the day before onset of symptoms. Not seeing any benefit and there is concern about adverse events—7% of the patients in the study were having issues. 

2. NIH Study: ACTT (Adaptive COVID-19 Treatment Trial); preliminary results showed 30% increased time-to-recovery on Remdesivir and an increased survival (not statistically significant) in multi-site trial. No data currently given for conclusions about timing, adverse effects, or general information (selection criteria, methods, how groups matched, administration timing, etc). No statistical significance on mortality benefit.

n.b. Remdesivir is given intravenously, if given in a pill form it is not absorbed properly

n.b.ii Remdesivir has been used for emergency use in the United States before

Summary: this may make sense to get into patients early in the disease course and to figure out who the high priority patients are (e.g. those in the ICU may not benefit as much as individuals early in the trial) to determine a benefit

*Re-infection (Korea Herold Article): the cases of presumed re-infection with SARS-CoV-2 turned out to be just pieces of RNA (viral litter) rather than infectious active virus, even with acute infections there are RNA bits that persist for a long time. Therefore, to date, we do not have cases of re-infection with SARS-CoV-2.

*Coagulation—hypercoagulability is driven by endothelial disfunction: the endothelial cells may be triggered in a dysfunctional manner that may be causing this increased clotting

Three ways people might be hypercoagulable: 

  1. activation of the clotting system (e.g. for some reason factors move down the pathways, get activated, and a clot forms)
  2. platelets being activated
  3. endothelium itself (dynamic cells that line the blood vessels with mechanism that, if there is a break, will trigger the clotting cascade) by attracting cells through expressing proteins (e.g. integrins) on their surface or by expressing pro-clotting factors—this is what is currently being investigated

There is no significant viremia in COVID-19—the virus replication is occurring on mucosal surfaces (e.g. upper airway, lung)—so this endothelial disfunction is downstream of the cytokine activation. This might in part account for the increased incidence of thromboembolic conditions in COVID-19 patients. 


*Debbie: for those who get off the ventilator, what is their quality of life and does it relate to whether their health is good or average? People who are young and healthier tend to bounce back, people who are older take a longer time to get better. Patients are generally coming off the oxygen after they leave. The hypothesis that general health pre-COVID-19 impacts outcomes post-COVID-19 is a good one, but time will tell. 

*Judith: should people who are COVID-positive immediately start taking aspirin because of noted clotting issues? Be in communication with your doctor, but recommendations will be different for different individuals: the young, healthy woman in her early 20s, she may need nothing and you would not put her, most likely, on high dose heparin (anti-coagulation medication), but we are still learning and we need trials to learn what to do with this large population that stay out of hospitals (hopefully the Patch studies will take more of these individuals that are not in the hospital into account). People who are ill enough to come to the hospital are eventually sent home with anticoagulant (sometimes heparin, sometimes aspirin, sometimes other anticoagulants). There are a number of patients that are at increased risk that are being put on anticoagulant medications preemptively. Reach out to your doctor and find out what is right for you.

*Stephanie: are those with existing blood clotting disorders at higher risk for blot clots during COVID-19? Definitely—we are seeing these in people without risk factors, but it is increased with patients who were coming in with coagulation issues. If you have a clotting disorder and you are on your medicine, do NOT stop, particularly as there is evidence of patients taking their appropriate medication having better outcomes. 

*Julia: what do you think about looking for smaller peripheral emboli (PE) with VQ scans, as well as CT-PE scans to get a better idea of the chronicity of some of these PEs? Some of my oncology patient with hypercoagulability would have hypoxia, especially with exertion, out of proportion to their CT findings, but with many smaller distal chronic appearing clots better visualized with VQ. Would having better idea of the timeline of clotting help prevent hospitalizations if it led us to consider, for example, prophylactic Apixaban (Eliquis) for patients with COVID or suspected COVID? Translation of the question: people are developing clots that then progress up into not-so-low parts of the lower extremities and sometimes small or not-so-small pieces of these can break off or ‘embolize’ and these emboli can end up in the pulmonary system and become pulmonary emboli. We see large central ones, but we also have seen smaller distal emboli. We have confirmation of these smaller distal emboli from autopsies where we see patients that have died of COVID-19 have these smaller distal emboli. We do these CT angiograms (CTAs) and can visualize these. We are also do these VQ mismatch scans, which is a nuclear medicine approach, and we are seeing evidence of the clots in those settings as well. A VQ scan allows you to go out a little further than a CTA before losing resolution to see issues.

n.b. VQ scan is a ventilation perfusion scan; PE is pulmonary emboli; CT is a cat scan

*Harrison: why are we seeing decreased eosinophils in the blood, but increased eosinophils in the lungs—are they migrating and, if so, why are they doing this if eosinophils are not typically associated with clearance of a virus? This is a good question that we do not have the answer to yet. Among the types of white blood cells (WBCs) we have lymphocytes, neutrophils, eosinophils, monocytes, basophils, etc, and the eosinophils are involved in parasitic diseases and other actions in the body, not generally viral clearance. When a person gets infected and are given steroids (not anabolic muscle-builders), the eosinophils will clear from the peripheral system (they do not die, just are going to other regions). What we are seeing is the eosinophils are clearing from the periphery, and we have recently found them in the lungs of COVID patients. We are seeing this as part of the not-so-helpful, over-exuberant immune response. We are trying to figure out what they are doing in those air spaces—they may be lost and we are figuring out why.*Torcuata: Fevers in mechanically ventilated patients must be treated to avoid additional demand for oxygenation—is the same logic possible to be applied to inducing hypothermia instead of preventing fever to reduce the demand for oxygen, to avoid intubation, or even to reduce risk associated with hypoxia? Interesting concept—we don’t know, but this is not something we are currently doing. Some patients are developing hypothermia during the 2-4 weeks while on the ventilators as part of the response to secondary infections.