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Rational Responses to CoVID-19

Notes for Week of April 6, 2020

The rapid transmission of SARS-CoV-2 was a shock to many people and the internet now has a plethora of videos and articles explaining exponential expansion. However, I haven't seen much about what this exponential expansion means for an individual person or for the long-term expectations for the virus and CoVID-19.

Currently, the cases of CoVID-19 in San Diego county look like this:

The number of new cases per day is holding steady, or even possibly going down. The total number of cases is doubling every 5-6 days (e.g., 3/30-4/5). This is substantially better than the previous doubling every 2-3 days at the beginning of the outbreak (e.g., 3/16-3/19). Together, this strongly suggests that sheltering in place and social distancing are having a positive effect. This is no longer exponential growth (1).

That is the good news. The bad news is that right now you are in much more danger of developing CoVID-19, because there are more infected people. Some assumptions and back-of-the-envelope calculations:

  1. About 3.4 million people live in San Diego county.
  2. At best, there is about 50% detection rate of SARS-CoV-2 infected people (2).
  3. Assume an even distribution of cases (not true).

On March 20th, when the shelter in place order was given, there were 118 CoVID-19 cases in the population of 3,400,000. That means that the probability of encountering an individual with CoVID-19 was about 0.01% (i.e., 118*2/3400000*100 = 0.0069).

As of April 5th, there are 1404 cases, changing this probability to 0.1%. Very roughly speaking, you are now 10X as likely to be exposed to someone with CoVID-19. This means that while the overall situation might be better, individually we are in more danger and need to be more careful.

Here’s more good news/bad news.

Good news: The CDC is recommending that everyone wear the mask. This is essential, especially given that we really don't know how well SARS-CoV-2 is being spread through aerosols.
Bad news: There is a serious shortage of the appropriate masks. The ones that we do have need to go to the hospitals and first responders.

Good news: The government has stopped its frankly insane policy of not importing masks into the USA from China.
Bad news: It will take months for overseas masks and domestic production to produce the number of masks we need.

Good news: The DIY community has a whole bunch of ways of making masks.
Bad news: Most of these DIY masks offer limited protection, but this is still better than no protection.

This is going to be a horrific week in some of the CoVID-19 hot spots. There are signs that if we remain vigilant in San Diego, we can keep the total number of cases below the level that overwhelms the hospitals. We desperately need Personal Protection Equipment (PPE) for civilians.

In addition to creating a whole bunch of viruses and sick people, exponential expansion is also the fodder for Natural Selection. There are currently over a million people (106) infected with SARS-CoV-2 and each one of those harbors at least 100,000,000 (108) viruses. This means that there are at least 100,000,000,000,000 (1014) SARS-CoV-2 viruses on the planet. Every time the virus replicates, different mutants are produced. Because SARS-CoV-2 is an RNA virus the mutation rate is even higher than most DNA viruses. Together, these large numbers mean that the virus is mutating and strains of SARS-CoV-2 are being selected at nearly unfathomable rates (much like exponential expansion is hard to grasp). So, what do we expect to happen?

  1. Some strains of SARS-CoV-2 will be selected to last longer in environmental reservoirs. The longer the virion can survive the more likely it is to be picked up and reproduce.
  2. Some strains of SARS-CoV-2 will be selected to be more easily aerosolized. Again, there will be a selection to be more easily transmitted. For example, mutations that produce more violent coughs.
  3. Other strains will no longer be detectable by current screens. After all, we are putting lots of pressure on SARS-CoV-2 to not be detected. Mutations that are not picked up by the RT-PCR tests will do better.
  4. Some strains of SARS-CoV-2 will be selected to be more resistant to disinfectants.
  5. Others will develop longer lag times to keep carriers asymptomatic.
  6. Still other strains will move to non-human reservoirs. There are already numerous reports about SARS-CoV-2 in cats, including a tiger.
  7. And still other SARS-CoV-2 strains will eventually mutate and be selected to resist drugs and antibodies that are being developed to keep the virus in check.

While all of this sounds bad, these evolutionary dynamics will almost assuredly attenuate the SARS-CoV-2 virus. Mutations that favor one trait, often come at a cost for another trait. Over the long term, we expect SARS-CoV-2 to become less virulent. Strains of SARS-CoV-2 that produce less severe disease and avoid detection should become dominant.

Annotations

  1. Note that the growth is no longer exponential but closer to linear now. Epidemiological models only predict exponential growth when the epidemic starts. At some point the curve bends because of herd immunity or things like social distancing. Exponential growth requires an INCREASE in the number of new cases daily. Linear growth requires an EQUAL number of new cases. We see a decrease (hopefully) so that is even less than linear growth. From Arlette Baljon, SDSU Physics.
  2. The early RT-PCR tests have an up to 40% false negative rate, so even when we test it's not that accurate. Probably the cause of the reinfection stories. From Rob Edwards, SDSU Biology.
  3. There is a hint of an attenuating deletion in some GISAID data from Singapore. There is a 382bp deletion from ORF8 which is the same ORF where mutations attenuated the last SARS but this data is not clear yet, because they are culturing in Vero cells and the deletion may have occurred there. From Rob Edwards, SDSU Biology.

Notes for Week Starting March 30, 2020

Bar graph of CoVID-19 cases in San Diego County as of March 29, 2020.

https://www.sandiegocounty.gov/content/sdc/hhsa/programs/phs/community_epidemiology/dc/2019-nCoV/status.html
  1. The doubling rate of Total Cases is about every 3 days, which is consistent with models predicting a major increase in CoVID-19 in San Diego sometime mid/late-April in the "limited action" scenario . There is a slowdown on March 28, 2020. Do not read too much into this yet; it is only one data point.
  2. The ray of hope is that fewer New Cases will continue to occur at this rate or slower. But it is still WAY TOO early to tell if this trend will continue. Remember that it takes about 5 days for most people to develop CoVID-19 symptoms.

    It is essential to maintain the quarantining/social-distancing to keep the number of new CoVID-19 cases low. Currently the quarantining/social-distancing are buying time for our manufacturers and scientists to produce the tools to fight SARS-CoV-2. Do not relax your vigilance against this virus.

  3. It may be helpful to draw analogies between the CoVID-19 and the AIDS pandemics. Quarantining/social-distancing is analogous to the abstinence phase. We will need to go through the personal protection phase (e.g., PPE versus condom; enhanced SARS-CoV-2 screening) and use these tools until the doctors and scientists come up with more effective treatments regimes, antiviral drugs, and/or vaccines.

    Manufacturing and distributing Personal Protection Equipment (PPE) must remain a top priority. Masks, eye protection, gloves, and gowns need to be in the hands of first responders and medical staff. As supplies of PPE increase, they need to be distributed and used by the delivery services and anyone involved in the food supply. Eventually, everyone will need to be using PPE to stop resurgence of SARS-CoV-2. This is going to be awhile, be patient, wash your hands, and use the hand sanitizers. Face masks means shaving off beards for many of us...

    In addition to PPE, rapid screening to identify active CoVID-19 cases is essential. The tools to do this are ramping up.

  4. Medical treatment for severe CoVID-19 is still mostly about keeping people alive with ventilators. However, best practices are evolving rapidly. The SARS-CoV-2 virus elicits a strong inflammatory response, also called a “cytokine storm”, and a number of anti-inflammatory treatments are being explored (1).

    The relatively long lag time for people to show CoVID-19 symptoms is probably due to SARS-CoV-2 delaying the type I IFN response.

  5. Like the HIV/AIDS pandemic, antivirals may be our best hope for controlling and treating CoVID-19 in the future. Chloroquine and hydroxychloroquine are the early hopefuls (2). Remdesivir (GS-5734) has shown prophylactic and therapeutic efficacy against MERS-CoV infection in the rhesus macaques. (3). Lopinavir–Ritonavir has not been effective in a human CoVID-19 trial (4). For all the serious math nerds, Stebbing et al. (2020) used an AI approach to suggest combining a specific anti-inflammatory and antiviral regime...who knew that stats/math could be useful? :) (5)
  6. Of antibodies and vaccines: Vaccines are the Holy Grail for controlling viruses, but they are often very hard to make. For example, we still don't have one for HIV. Another approach is to make blocking antibodies to viruses (either isolated from recovered patients or made in the lab). These antibodies are then injected into susceptible patients as a treatment or as a prophylactic. This is called Intravenous Immunoglobulin (IVIg) therapy.

    Currently we don't understand the immune response to SARS-CoV-2 well enough to predict how well vaccines and IVIg will work. Remember that viruses are always engaged in a fight with the immune system and viruses often have mechanisms that circumvent or manipulate our immune system against us. For example, sometimes viruses use our own antibodies to hide from our immune system and even make the disease worse (e.g., antibody dependent enhancement (ADE)).

    It will take time to understand how SARS-CoV-2 interacts with the immune system so that effective IVIg and vaccines can be developed.

  7. Let's touch a touchy subject. The current mantra is that you can't get infected if you stay 6 feet away from each other because the virus containing droplets will fall to the ground. In theory, this is true. However, the real world is not theoretical. The truth is that air movements can easily transport droplets much further and/or keep them suspended in the air for much longer times. These sorts of dynamics are impossible to predict for someone walking down the street. This means that you really need to stay in your domicile as much as possible until the current exponential expansion of the disease ends and masks are available for everyone. And since the virus survives so well on surfaces, use hand sanitizer after handling packages from outside the house (6).

Stay Safe,
Forest Rohwer

P.S. There is a chronological release of these CoVID-19 related notes at

Annotations

  1. Prompetchara, Eakachai, Chutitorn Ketloy, and Tanapat Palaga. "Immune responses in COVID-19 and potential vaccines: Lessons learned from SARS and MERS epidemic." Asian Pac J Allergy Immunol (2020). & Conti, P., et al. "Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by COVID-19: anti-inflammatory strategies." Journal of biological regulators and homeostatic agents 34.2 (2020).
  2. Summary in Touret, Franck, and Xavier de Lamballerie. "Of chloroquine and COVID-19." Antiviral research (2020): 104762.
  3. de Wit, Emmie, et al. "Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection." Proceedings of the National Academy of Sciences 117.12 (2020): 6771-6776.
  4. Cao, Bin, et al. "A trial of lopinavir–ritonavir in adults hospitalized with severe Covid-19." New England Journal of Medicine (2020).
  5. Stebbing, Justin, et al. "COVID-19: combining antiviral and anti-inflammatory treatments." The Lancet Infectious Diseases (2020).
  6. van Doremalen, Neeltje, et al. "Aerosol and Surface Stability of SARS-CoV-2 as Compared with SARS-CoV-1." New England Journal of Medicine (2020)

Notes for Week Starting March 23, 2020

I hope you are all doing well. I'm writing you as a virologist and immunologist who isn't an alarmist. With the knowledge that we currently have, I really want to stress that nearly total quarantining/social-distancing is needed in San Diego at this time:

The important points are:

  1. There are almost assuredly a large number of asymptomatic SARS-CoV-2 spreaders. These people don't feel sick and do not have symptoms like fever, but they can spread the virus. Because we don't have enough testing to look at allegedly healthy people, we don't know how many of these people are out there in San Diego at this moment (1). But we do have data from other places and models.
  2. The models say that this week (March 23-29) is really important for controlling the exponential expansion of CoVID-19. This means that your probability of being exposed to SARS-CoV-2 has been relatively low up to this point. That is going to change within the next couple of days. There are going to be a lot more people carrying and shedding the virus sometime this week (2, 3).
  3. The immunological response to the virus is worrisome. First, it is an immune response that is leading to the severest symptoms of the disease (i.e., Acute Respiratory Failure Syndrome; ARFS). Second, it is not clear how to treat this immune response. This means that doctors are effectively using trauma treatment techniques because they don't have any other tools. This is bad because the only treatments are effectively oxygen and ventilators. And there aren't very many ventilators and fewer people to run them (<1,000 in San Diego). Third, there are reasons to believe that the immune response may not be exceptionally protective with the milder forms of the disease. This means building herd immunity may not be happening as fast as expected (4). Fourth, there is something weird about the older patients. It is almost like they have previously been exposed to a SARS-like virus that is pre-disposing them to a hyper-immune response that isn’t protective but makes ARFS worse (5; Nat Geo, March 25, 2020). Fifth, despite the preferential mortality rates in older people, about 1% of all age groups are dying from CoVID-19. This makes it a very dangerous virus for whoever you are.

Taking everything together, this is a terrible week to be around other people. Stay home and eat those cans of food that have been sitting there for years. If you must absolutely go out, then use Personal Protective Equipment (PPE; gloves and masks) and use handwashing and isopropanol hand sanitizers (>70%; 6).

Sincerely,
Forest Rohwer

Annotations

  1. . Screening from Iceland suggests that at least 50% of the SARS-CoV-2 positive people are asymptomatic. Other estimates run from about 20% to 80%. These estimates are dependent on how good the test is working.
  2. . Models: If you are not in Southern California, then the timing may be different. Check out the models for your area at (https://www.covidactnow.org/about). These models have lots of assumptions that can greatly change their predictions. The main point is all of the models predict a massive, exponential increase that is predicated on a deceivingly slow ramp up. The of actual data from San Diego is consistent with a 3-day doubling in number of cases.
  3. . A great summary of what is known about CoVID-19 is the Department of Homeland Securities (DHS) Master Question List for COVID-19 (caused by SARS-CoV-2). Most of the parameter values for the models are derived from the sources listed in this document.
  4. . Okba, Nisreen MA, et al. "SARS-CoV-2 specific antibody responses in COVID-19 patients." medRxiv (2020). On the positive side, most of the evidence is pointing towards immune protection in the recovered populations.
  5. . Tetro, Jason A. "Is COVID-19 receiving ADE from other coronaviruses?." Microbes and Infection 22.2 (2020): 72-73. & Nat Geo (March 25, 2020) "The coronavirus spares most kids. These theories may help explain why." These experts hypothesize almost the opposite explanation as mine for the different mortality rates in young and elderly populations...this illustrates how little we know about this virus.
  6. . Government agencies are advising against PPE for citizens because they need PPE for the first responders.

Pre-March 23rd Notes

Slowing Down the Virus

COVID-19 exponential mod no grid

Figure. Exponential phase of COVID-19. The exponential model is projected from one initial infected case. The three scenarios correspond to the initial projection at Wuhan (yellow), the exponential dynamics observed on cruise ships (pink), and a controllable expansion with precautionary measures, like hand washing and quarantine. The reproduction number, R0, used was 3.05 (initial average in Wuhan), 15 (Diamond Princess cruise ship), and 1.5 (precautionary case). The average latent infection used was 8 days. Source data: Hellewell et al, 2020; Rocklov et al, 2020; Cao et al, 2020, Li et al 2020, and Riou and Althaus 2020.

References
  1. J. Hellewell, S. Abbott, A. Gimma, N.I. Bosse, C.I. Jarvis et al, The Lancet, March 5, 2020.
  2. Rockloöv, H. Sjödin, and A. Wilder-Smith, Journal of Travel Medicine, taaa030, 2020.
  3. Z. Cao, Q. Zhang, X. Lu, D. Pfeiffer, Z. Jia, et al, medRxiv, 2020.
  4. Q. Li, X. Guan, P. Wu, X. Wang, L. Zhou et al, N. engl. J. Med., January 29, 2020.
  5. J. Riou and C.L. Althaus, Eurosurveillance, 25, 2000058, 2020.

In much of the world, the CoVID-19 pandemic is in the early exponential increase phase. If the epidemic goes into full exponential phase, then basic medical and societal services will be severely impacted. SARS-CoV-2 is the virus that causes CoVID-19.

There is a great video explaining the different phases of exponential growth, in context of CoVID-19, here: https://youtu.be/Kas0tIxDvrg.

The goal of measures such as increased hygiene, quarantine (both official & self), and decreased human interactions (e.g., working from home and reducing travel) is to contain/slow down the exponential phase.

What can you do? Monitor your temperature. Fever is the single best indicator of a viral infection. If you have a fever, do not go into public and take precautions to protect your family/house mates.

If you develop a cough, then you need to contact your hospital/doctor. If SARS-CoV-2 invades your lungs, then it has become a serious disease.

The increased hygiene methods, like washing your hands, stopping shaking hands, covering your mouth when you sneeze or cough, etc., are essential. Don't make this pandemic worse by going into public if you think you are sick! Even if you are coughing from something other than CoVID-19, people are already stressed out and you are making it worse. You are also more susceptible to a serious SARS-CoV-2 infection if you are sick with another microbe. Stay home.

It is important to differentiate between water droplet versus airborne containment. SARS-CoV-2 is contained by "water droplet" methods. Water droplet containment is much easier. This means that the virus is not staying suspended in the air for long time periods. Direct coughing can spread the virus over 6 feet, but you are very unlikely to catch the virus simply by breathing the air. This is why trying to reduce touching your face is also important: you may be bringing the virus more directly to your respiratory tract, increasing the chance of establishing an infection.

Treatment

Most SARS-CoV-2 infections will start and end in the sinuses and/or oropharynx. Basic supportive care, hydration and rest, will be the only necessary treatment for the majority of people. If you are self-quarantining, then protect your family using the methods outlined on the CDC website.

The disease becomes serious when the virus enters the lungs. Diabetes, hypertension, lung disease, and the elderly are at heightened risk levels. If you have a fever and you start coughing, then you need medical intervention. Because of limited medical resources, the first step will be determining if you have SARS-CoV-2 through a nucleic acid screen. This screening will help the doctors make a decision about where to put treatment resources (see below).

Treatment when SARS-CoV-2 gets to the lungs are hydration, oxygen, assisted breathing, and treatment for secondary infections.

  1. Hydration is important because fevers drain the body of water and electrolytes. Treatment is electrolyte drinks and, in severe cases, IV fluids.
  2. More oxygen can be delivered by using a nasal catheter (either an oxygen tank or oxygen maker). This can be done at home.
  3. The next level is assisted breathing using a ventilator with oxygen followed by endotracheal intubation with oxygen. This would occur as part of a hospital stay. These treatment protocols are changing rapidly as the medical community figures out the best responses to CoVID-19.
  4. Treatment for secondary infections. A lot of the most serious problems are due to secondary infections, that is bacteria that try to kill you when you are weakened by CoVID-19.
  5. Future: Clinical trials of Remdesivir (a new drug that works against SARS and MERS that is also likely to work against CoVID-19 and other similar viral diseases) are starting. Some other drugs have activity when tested in the lab. Vaccine development will most probably work well with this virus but development and testing of the vaccine may take more than 1 year to become available for human use.

What can you do? Be reasonably prepared to self-quarantine but also use your common sense; this disease is not going to shut down the supply lines all over the world and you don't need to hoard toilet paper. The most worrisome aspect of self-quarantining is getting family members sick. Be extremely cautious about coughing on and touching surfaces that family members might touch. Keep yourself in a separate room and don't let pets move between people.

This video provides a nice summary of what we currently know about CoVID-19: https://youtu.be/JKpVMivbTfg.

Scientific Response

If we enter the serious exponential phase, then more screening will be needed.

What can you do? If you are molecularly inclined, then set up PCR and/or sequencing tests for the virus. This could range from setting up the simplest, gel-based PCR to real-time PCR to nanopore sequencing. The primers are listed on the CDC website (CDC 2019-nCoV Real-Time RT-PCR Primer and Probe Information). This data will be useful, because right now we have no idea about what the actual infection rate really is, and the screening kits are being used to confirm clinical cases.

The best way to process the samples is to collect with a swab and immediately get the sample into something like TRIzol to inactivate the virus. You must use BSL2 procedures for the inactivated virus. Active SARS-CoV-2 is a BSL3 pathogen. If you have to look up any of the words in this section, then you should not be trying to set up a SARS-CoV-2 test!

Animal Trafficking and CoVID-19

Pangolin drawing by Ben Darby Many of us were involved in determining the virus in the SARS outbreak and other diseases of unknown origins. These spillovers into human populations are mostly associated with bushmeat and illegal trade in animals. SARS-CoV-2 almost certainly originated in pangolins, which were being trafficked for food and traditional medicine.

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