In this episode, Dr. Paul Grewal, M.D. joins Peter to discuss what they have learned in the past week in the midst of the rapid changes surrounding the COVID-19 pandemic. Their conversation touches on both optimism and uncertainty: actionable steps we can take to improve the situation with the understanding that it is too late for viral containment. Specifically, Peter and Paul discuss some promising drug treatments, reasons for isolating-behavior adoption, and what they are personally instituting in their own lives.

Disclaimer: This is information accurate as of March 13, 2020, when it was recorded.

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We discuss:

When the gravity of Coronavirus (COVID-19) hit home [04:30];

Hospitalization and ICU bed space as an issue [8:15];

Natural history and pathology of COVID-19 [12:00];

Potential drug therapies [22:00];

How thinking has changed from containment to management [30:00];

What Paul and Peter are doing [49:00];

What we know about viral transmission [57:00]; and

more

Show Notes

When the gravity of Coronavirus hit home [04:30]

Mid-January a patient started asking questions about travel and later that month a team analyst was assigned to collect information on coronavirus

Was not until mid-February that Peter realized coronavirus was not going to be contained and the world was not prepared

On March 6, Peter became more pessimistic – testing had not been rolled out and no large Federal management action in the U.S. had been taken

Figure 1. COVID-19 U.S. Cases. Image credit (The New York Times)

Hospitalization and ICU bed space as an issue [8:15]

R o is on par with or higher than the flu but many cases have gone and remain to be undiagnosed

Italy taught us that it was the morbidity not the mortality rate of the disease that is grave

Morbidity is the percent of patients that have a serious illness requiring hospitalization and then from those patients who required elevated level of care

In South Korea with a young population and a quick response time, mortality was about 0.68%

Outside of Wuhan, with preparedness, mortality was 1%

Italy, by comparison, was as high as 6%

A back of the envelope calculation assuming …

New York state has 3,000 ICU beds at full capacity (and assuming no one else needs ICU bed that is not a coronavirus patient; a generous assumption)

Taking a reported 421 diagnosed cases in the state, a 1.3x growth rate, 20% hospitalization (assuming all ICU bedspace)…

X= 13.6 days to ICU bed failure (critical capacity)

Assuming 5% of hospitalized people need ICU beds…

X=18.8 days to ICU bed failure (critical capacity)

Natural history and pathology of COVID-19 [12:00]

What we know is that the immune response does not seem to be the critical part here. The critical part is the cell that gets damaged SARS-CoV-2 uses the angiotensin-converting enzyme 2 receptor, ACE2, for entry.



What system gets attacked first?

The receptor that SARS-CoV-2 uses to infect lung cells is most likely ACE2, a cell-surface protein on cells in the kidney, blood vessels, heart, and, importantly, lung AT2 alveolar epithelial cells These AT2 cells are particularly prone to viral infection due to high ACE2 expression Virus infects cells in the lungs called pneumocytes and in the process of replicating, damages that cell Acute respiratory distress syndrome (ARDS) occurs from profuse alveoli damage such that the lung fills with fluid or collapses

People that contract COVID-19 and need to be on respirators sometimes need mechanical ventilation for upwards of 5 weeks

Cardiovascular disease seems to be a better predictor of complication rather than a lung or respiratory pre-existing disease

Some patients showed atypical symptoms, such as diarrhea and vomiting

The GI manifestations are consistent with the distribution of ACE2 receptors, which serve as entry points for SARS-CoV-2, as well as SARS-CoV-1, which causes SARS. The receptors are most abundant in the cell membranes of lung AT2 cells, as well as in enterocytes in the ileum and colon

Potential drug therapies [22:00]

Angiotensin II receptor blocker

Originally, it was though that Angiotensin II receptor blockers could be an effective treatment ARBs block the receptor to which the virus binds But now it seems that individuals on hypertensive medication are actually more susceptible to the virus Current thinking is that those already on ARBs should remain on the medication Research team is continuing to look at case-control reports looking at hypertensive cohorts



Kaletra and Chloroquine

Studies didn’t show clinical endpoints but did show a decrease in viral load Mechanistically virus may be susceptible to chloroquine (changes lysosomal PH) Viral proteases is similar to HIV replication so HIV medications may be avenues in conjunction with Chloroquine with no obvious harm



Remdesivir

Repurposed from Ebola clinical trial

Used in treatment and as IV only

How thinking has changed from containment to management [30:00]

Virus cannot grow exponentially forever

Ro or replicative number – at some point cannot be maintained; when there are enough people infective

Not an intrinsic property of virus – reflects transmissibility and ability to access new hosts

Exponential growth moves to exponential slowing

Figure 2. When early intervention does not happen, transmission accelerates and peaks prior to management and/or independent decrease in Ro. Image credit: Vox.com

Ro or replicative number – at some point cannot be maintained; when there are enough people infective

Not an intrinsic property of virus – reflects transmissibility and ability to access new hosts

Exponential growth moves to exponential slowing

Cases outside of China still have exponential curves without passing inflection point

Some model estimates like that in a UCSF press release , reported that 1.23 million Americans will die from the virus over the next 12-18 months

To put it in perspective: 2.8M Americans died last year in total from various illness

Some unanswered questions …

What are some things that need to happen in order for the Ro to become manageable?

Objective: to reduce the number of lives lost and reduce economic damage

Strategy: reduce the rate of spread which decreases R o ; reduces lethality Reduce rate of spread by decreasing social interaction People taking the maximum amount of distance and isolation that is feasible A triage system with a test that is sensitive A false-negative test is a big problem (does not limit the rate of spread from that individual) We need a test that does not give a high false-negative Polymerase chain reaction (PCR) tests are accurate but we don’t know where the virus is in the body



From a lethality point of view …

By reducing the rate of spread, the lethality will naturally decrease

We may have some effective treatment or vaccine The drawback of convalescent serum requires infrastructure support for apheresis 1:1 donor to sick recipient ratio



Peter thinks that the best option to reduce lethality is to:

Repurpose existing drugs Flatten the curve Make sure healthcare workers and first responders are not getting infected

Buy time for the system to build capacity (e.g., ICU beds)

The goal of containment is to “flatten the curve”, to lower the peak of the surge of demand that will hit healthcare providers. And to buy time, in hopes a drug can be developed

What Paul and Peter are doing [49:00]

Peter instructed his parents to go into as much of quarantine as possible

Will be able to learn from other countries like China who will be able to reverse restrictions

Will see if R o re-increases or if it can remain under control

Peter is self-quarantined Optimizes his sleep Relies on his supplements Exercises every day: zone 2, lifting, time-restricted feeding

They both feel more optimistic than they were a week ago

What we know about viral transmission [57:00]

A paper about the mode of transmission looking at droplet, aerosol, surfaces

CoV-19 (SARS-2) could be detected in: aerosols, up to 3 hours post aerosolization up to 4 hours on copper up to 24 hours cardboard up to 2-3 days on plastic and stainless steel (13hr median half-life on steel; 16hr median half-life on plastic)

Cov-19 can survive better outside of the body compared to HIV

Given what the paper suggests, hospitals may consider closed-loop ventilation if a patient needs ventilation assistance and perhaps explains why mortality among healthcare workers is so high

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