Great thanks to our local expert for an excellent, power packed update this week on COVID-19. As I mentioned in my introduction to Grand Rounds on Wednesday, Dr. Green has been a tremendous resource to our hospital, our residency, and our community from the very start of this pandemic. Just six months ago, with our first two cases of COVID-19 having walked through our doors, he gave a great presentation. And how much we have learned in 6 months time!?!
Gary talks fast, changes slides even quicker than he talks, and packs his presentations from virology to epidemiology to pathophysiology, but here are my key takeaways for COVID-19, 6 months in.
Epidemiology:
As of this week, the US has recorded almost 7 million cases of COVID-19 and over 203,00 fatalities. California has 793,000 cases and 15,000 fatalities. Sonoma County has had 7225 cases and 120 deaths.
Dr. Green said he believes that Sonoma County's peak of Phase 1 of this pandemic was mid to late August, putting us slightly behind the rest of the Bay Area (which is why we also are "behind" in reopening). He credits this later peak to the work Dr. Mase and our Public Health Department has done in public health prevention methods.
Whereas hospitalization rates in some cities have been much higher (25% in NYC) local data shows in Sonoma County that 5% of those testing positive have been hospitalized (49% male, 51% female).
Virology:
Dr. Green reminded us that the Coronavirus is a single-stranded RNA virus, which is important because RNA viruses (e.g. seasonal influenza) replicate with continuous random mutations. Whereas DNA viruses are more stable and tend to remain conserved, ssRNA viruses are frequently changing. COVID-19 is no exception.
There are currently 6 major clades of COVID-19 (D614G, L845, L3606F, D448del and G392D) and 14 subclades circulating. The virus that seems to be dominating worldwide is now the D614G clade (color blue in images below), which does seem to be slightly more infectious than the original virus but does not appear to be more severe.
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| https://www.cell.com/cell/pdf/S0092-8674(20)30820-5.pdf |
There has been much discussion in the medical literature and lay press about whether or not COVID-19 is primarily spread through large respiratory droplets OR by smaller suspended particles that can travel farther. Dr. Green's answer is that COVID-19 is mostly droplet tranmission, but also probably a little bit airborne (e.g. more like influenza, which has features of both than measles or TB, which are primarily airborne).
This week, after the CDC revoked a statement warning about airborne COVID-19 transmission, the California Department of Public Health (CDPH) released a statement saying that "long range (>6ft) aerosol transmission such as with airborne transmitted viruses such as measles, is the area of controversy. CDC did signal that the updated guidelines would acknowledge opportunistic airborne SARS-COV 2 transmission in settings with poor ventilation." Key in this statement is that airborne is likely the exception (not the rule) and requires poor ventilation to be spread in this manner.
What does airline travel have to do with this?
Dr. Green cited a study from a spring evacuation flight from Milan, Italy to South Korea (11 hour flight), in which flight was conducted with strict infection control procedures by the Korean CDC and WHO. There were 299 asymptomatic passengers on board; several others were refused passage due to symptoms. After arrival in Korea passengers were quarantined for 2 weeks at a government facility. Ultimately from that flight, there were 6 asymptomatic + Covid patients and 1 who developed symptoms and tested positive on D14. A study of the airplane location and transmission patterns surmised that there was unlikely to have been airborne transmission, more likely transmission occured through contaminated high touch areas (e.g. that dang bathroom). The CDC link for more information is here.
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| https://wwwnc.cdc.gov/eid/article/26/11/20-3353-f1 |
When and how to test for COVID-19?
Dr. Green shared a virologic study testing for COVID-19 in different respiratory sites from July 2020 (link to that Lancet article here), which found viral load in oropharynx, nasopharynx and sputum at much higher levels in the first 0-7 days. Viral levels were detectable but decreasing markedly in the oropharynx by day 8, and decreasing in nasopharynx and sputum to a lesser extent, though lower load by over day 14. This study underscoring the need for earlier testing for better viral detection (no matter which site). Bottom line: earlier testing is likely more accurate.
What about blood type and COVID risk?
There were reports early in the pandemic about certain blood types being associated with increased risk of testing positive for COVID and/or possibly worse outcomes. That literature is still evolving (and is frankly a little messy). A very early study from Wuhan, China (available here) proposed a link between Blood type A and higher risk of acquiring COVID-19. A later study (available here) found no relationship to Blood type A but rather that Blood types B, AB and RH+ were all associated with higher odds of severe disease; in that study Blood type O seemed to have lower risk of testing positive for COVID. A more recently released genomic study from NEJM (found here) found a possible a genetic susceptibility locus in patients with COVID-19 with respiratory failure and a potential involvement of the ABO blood group system. Bottom line: for now, there is no clinical reason to risk stratify using ABO.
What about vitamins and minerals?
Jury is still out. Per Gary Green, there is no good evidence on Zinc as protective. Vitamin A is currently being studied at UCLA in children in COVID, Vitamin C is being studied in Richmond, VA. Vitamin D seems to have a correlation in several studies, but very unlikely causation. Dr. Green reminded us that some vitamin and supplements can be dangerous in high doses, namely Vitamins A, E, D, and K (fat soluble one) and a recent statement from BMJ states that "there is no strong scientific evidence that very high intakes (mega supplement) of vitamin D will be beneficial in preventing or treating COVID-19". Bottom line: stay tuned for forthcoming studies on vitamins.
Unique COVID-19 manifestations include:
- Late onset ARDS (~8 days) and multiorgan dysfunction (MODS)
- Thrombotic events, including VTE (25-31%) and arterial thrombosis (CVA, acute limb ischemia)
- Cardiac events (STEMI w/non occlusive coronaries, LV failure, myocarditis, kawasaki like illness)
- Neurologic events (acute CVA in young patients), Guillain-Barre syndrome, encephalitis/opathy and seizures
- Dermatologic events (pernio/Chilblains "covid toes")
What do we know about the cytokine storm? Should it be also called the bradykinin storm?
Here, Dr. Green expounded on a bunch of virology and biochemical mechanisms that are hard for me to capture in words (partly because I had a hard time keeping up!). The links to the papers are here and here, and the images from each of those studies are below. The top one discussing the immunologic response and the bottom the bradykinin storm.
The gist of this part of the talk is that COVID-19 seems to elicit biphasic viral response that was also seen in virus causing the 2003 SARS virus outbreaks. In phase one (days 0-4), an acute infection stimulates an immune response. If that immune response is unsuccessful in clearing the virus, there is a second adaptive immunity response, which leads to a storm (see image below)
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| https://jvi.asm.org/content/jvi/84/3/1289.full.pdfAdd caption |
This immunology and pathophysiology is actually very clinically important because it informs our current treatment approach for severe COVID-19 illness; that is, antivirals early, anti-inflammatories/immunologics (e.g. dexamethasone, tociluzimab) later when that inflammatory cascade is occuring. Here is my very favorite image from Dr. Green's talk:
I use this image ALL the time when talking with residents about this illness. It also helps me ground myself in where we are in an individual patient's course (e.g. symptom day 12 is very different than symptom day 4)
At SSRRH and around the country, we are tracking specific labs (procalcitonin, D Dimer, LDH, CRP, PMN/lymph, ferritin and sometimes baseline IL-6) to assess where a patient is in their disease course and how likely it is that they will develop severe illness. Several publications suggest that some or all of these values may have predictive value for severe disease.
This includes "Simple Rule of 6" (Ferritin>600, LDH>600, CRP>60) as well as other markers for severe disease: D Dimer >2-6, IL6 >163, and PMN/Lymph ratio >3.5
Why are we doing Convalescent Plasma?
Plasma is very safe and may improve outcomes in COVID-19. May is the key word here. Plasma was used in the influenza epidemic of 1918, also during outbreaks of polio, mumps and measles in the 1940s, in 2003 in the SARS Coronavirus in Hong Kong. Its use and study was largely abandoned after the discovery of penicillin and other antibiotics. It was tried (and failed) in 3003 (West Nile VIrus), 2012 (MERS) and 2014 (Ebola) outbreaks.
SSRRH has been participating in a historic Extended Access Program via May Clinic, involving over 82,000 patients and 2700 sites. This is NOT an RCT. That program closed 8/31. Mayo is just beginning to study the potential benefit of convalescent plasma through this data set. It does appear in early papers that plasma given early that happened to contain high Antibody titers is associated with lower 30 day mortality. Preliminary results are available here.
Figure below from that paper compares 30 day mortality in low, medium, and high titer plasma given early <3 days vs. late >4 administration of plasma. As we currently have no clinical way to measure antibody titers in plasma, Dr. Green is occasionally giving more than one unit in very sick people. This is experimental.
What about Remdesivir?
Here at SSRRH, thanks to Carolyn Dam (pharmacy) and Dr. Green, we were part of the earliest compassionate use of Remdesivir for our very first COVID-19 patients. Since then, data has begun to emerge on the utility of this antiviral designed originally for treatment of Ebola. Preliminary reports suggested benefit, particularly on duration of disease.
The more recent ACTT-NIH study of 538 patients with severe disease found a reduce median recovery time (11 vs. 15 days for placebo, statistically significant) and a trend toward mortality benefit 7.1% vs. 11.9% (though not statistically significant). It appears that remdesivir is more effective the earlier it is administered (not unlike tamiflu) and most effective in patients who require oxygen but who are not ventilated.
Where are we today, September 2020, 6 months into our own pandemic experience?
In addition to working from home, wearing our masks, and helping our kids fumble through distance learning, our current standard of care at SSRRH for COVID-19 includes the following:
- Full PPE for clinical staff caring for suspected or confirmed cases of COVID-19
- Swab testing for COVID-19 for all admitted patients and preoperative patients
- Daily labs for patients including IL-6 (baseline), CRP, didmer, ferritin, procalcitonin, CBC (leukopenia) and thrombocytopenia
- Treatment:
- Early convalescent plasma for all hospitalized pts (even asymptomatic ones)
- Proning (for anyone needing O2)
- High flow oxygen before mechanical ventilation
- Early IV Remdesivir for severe illness
- Anticoagulation for everyone, double for our sickest
- Steroids/dexamethasone (later-- if/when cytokine storm)
- Other immunosuppressants only with care (taciluzimab), watch for secondary bacterial infections
- Blood sugar control (diabetics)
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