SARS-CoV-2 and the lessons we have to learn from it.

(SARS-CoV-2 is the virus. COVID-19 is the disease.)

At this moment the media is covering SARS-CoV-2 in breathless tones- and somehow, key points about this discussion are being missed. If you are looking at this pandemic and thinking that the possibility of you or someone you love getting SARS-CoV-2 itself is the biggest threat- you are egregiously mistaken. I am afraid the reality is not nearly so simple.

SARS-CoV-2: An Overview

Mortality distribution for COVID-19. Courtesy of: https://virologydownunder.com/so-you-think-youve-about-to-be-in-a-pandemic/

First I can offer some good news: if by some stroke of misfortune you get this disease, you are not very likely to die. Case-fatality ratios for the novel coronavirus at this time are hovering at about 1-2% (and make no mistake- that’s not a small number, but it is considerably better than the initially reported values which went as high as 33%)- which means that 98–99% of people who get it survive. It also tends to be more serious in those who are older and in those who have significant comorbidities, especially respiratory ones. At this time, the vast majority of cases appear to be mild. To be clear, this isn’t license to treat the disease as something trivial because even from the very virology of the disease, that is not the case. And furthermore, when you think about dismissing this as minor, I want you to remember this:

There are people for whom getting SARS-CoV-2 will represent a very serious health threat- and they have to get it from someone.

Figure 28.1 from Fields Virology 6th edition demonstrating the phylogeny of the Nidovirales order.

SARS-CoV-2 is a coronavirus, which is a group of viruses- something that evidently many people fail to realize given the conspiracies of various disinfectants claiming well in advance of the pandemic that they kill coronaviruses- specifically in the Betacoronavirus genus, like its namesake SARS. The viruses are characterized by their spiky projections which give them a crownlike appearance, hence “corona” (at least that’s what the virologists tell me- I don’t really see it), their unsegmented, positive-strand RNA genome, helically symmetric nucleocapsid (the swirly thing in the picture below), and spherical shape.

Mouse hepatitis virus, a coronavirus that has been experimentally important because of its help in understanding the virology of the coronaviruses, especially with respect to viral replication. Figure 28.2 from Fields Virology 6th Edition.

As a pathogen, coronaviruses are quite important in both human and animal medicine. Coronaviruses are the cause of approximately 10–30% of colds, for instance, and are importance causes of disease in livestock. Most are not huge public health threats, though there are 3 notable exceptions: SARS CoV, MERS CoV, and SARS-CoV-2, which are notable for their significant mortality rates. The viruses commonly originate from bats and seem to make their way to humans via some intermediate species.

A detailed discussion of the pathogenesis of SARS-2-CoV is beyond the scope of this post, but I will present an overview. SARS-CoV-2 uses the ACE2 receptor to be able to get into cells via its S protein. The binding strength has been estimated to be about 10–20 times greater than what SARS-CoV’s S protein is capable of. However, ACE2 is an enzyme present on the surface of type I and II pneumocytes (particularly type II pneumocytes), which is a problem- because that means the natural tendency of the virus is towards a lower respiratory tract infection (LRTI). Additionally, the SARS-CoV-2’s S protein seems to have limited structural homology to that of SARS because monoclonal antibodies that are effective against SARS’s S protein do not seem to be effective at neutralizing SARS-CoV-2’s S protein. There are thoughts that a bias in the expression of ACE2 can affect the severity of COVID-19, as both men and Asians tend to have it at higher levels and tend to suffer the most severe disease. However, an epidemiological explanation is no less valid in that this demographic also tends to have poorer pulmonary health owing to smoking and is therefore more vulnerable.

In general, patients with SARS-CoV-2 present with several nonspecific symptoms that might sound familiar to you: fever, dry cough, fatigue, myalgias, sore throat, runny nose, nasal congestion and more rarely, diarrhea. A portion of patients may also have shortness of breath and hypoxemia (low blood oxygen) and this can progress into more serious complications.

It is well known at this point that the virus can cause pneumonia which is on its face quite serious. However, particularly dangerous is the complication acute respiratory distress syndrome (ARDS), which I want to discuss a bit.

ARDS is a condition in which there is widespread pulmonary inflammation culminating in pulmonary edema owing to the potent activation of the innate immune system that results in respiratory failure. This occurs in the alveoli, which are the terminal endpoints of the bronchial trees and sites especially critical for gas exchange, and being filled with exudative fluid is not conducive to their function. Additionally, this also has the unfortunate property of compromising lung barrier function which renders the host vulnerable to sepsis and coagulation derangements like consumption coagulopathy.

The exudative phase of ARDS. The phenomenon seems to be largely orchestrated by alveolar macrophages which upon detecting inflammatory insult go on to release numerous pro-inflammatory cytokines resulting in the recruitment of neutrophils and CD4 T cells, which go on to amplify inflammation, a hallmark of which is vascular leakage to facilitate invasion by leukocytes and clear the threat to the host. This however, causes severe difficulties with gas exchange at affected alveoli resulting in hypoxemia and respiratory failure. Source: Figure 2 from Thompson, B. T., Chambers, R. C., & Liu, K. D. (2017). Acute Respiratory Distress Syndrome. New England Journal of Medicine, 377(6), 562–572. doi:10.1056/nejmra1608077

ARDS progresses in a series of stages. After the initial exudative phase, there is a proliferative and fibrotic stage. First, during the proliferative stage, attempts are made to repair the damage caused by the exudative stage. This largely involves a change of macrophage phenotype to become less inflammatory, with the aid of helper T cells, both of which produce mediators of inflammation resolution like lipoxins and resolvins (macrophages) and TGF-beta (T cells). Additionally, the alveolar epithelial cells begin to proliferate (hence the name) and generate tight and adherens junctions to preserve alveolar integrity. Macrophages also begin to release proteases that degrade chemotactic factors that would drive further inflammation by directing leukocytes to the site of injury.

Proliferative and fibrotic phases in ARDS. Figure 3 from Thompson, B. T., Chambers, R. C., & Liu, K. D. (2017). Acute Respiratory Distress Syndrome. New England Journal of Medicine, 377(6), 562–572. doi:10.1056/nejmra1608077

Following the proliferative phase, there is sometimes (but not always) a fibrotic phase. This is associated with ventilator use which may become necessary to manage respiratory failure. The mechanisms underlying its development are not very well understood but most fibrosis involves TGF-beta on some level and this cytokine is implicated as well in fibrotic ARDS.

As far as transmission goes, the information is still evolving. Most estimates of the virus’s R0 fall in the range of 2–3 and it is believed to be transmitted by respiratory droplets. Presumably large droplets as opposed to fine ones given that value. It is not clear at this time whether fecal-oral transmission is possible (though some coronaviruses are known to shed in stool) and this may become important for infection control and prevention. The incubation period of the virus as far as we can tell right now appears to be up to 14 days with a median of 5–6, though there are a few reports of values as high as 27 days (I highly doubt it). Patients who have recovered appear to be capable of shedding the virus for several days afterwards. It is not known exactly how long the virus can survive outside the body but based on other coronaviruses, several hours is a reasonable estimate. Whether or not the virus will exhibit a seasonality is unclear at this time, as MERS does not, for example. Estimates suggest that within a year we may see as many as 40–70% of people infected with the disease. I would caution these remarks however: as a novel virus arises and people recover, we generally observe some existing level of herd immunity exerting protection (though notably this is quite a bit slower than what could be accomplished by vaccination). What is concerning however is that a recent report from Washington state’s department of health suggests that the virus may have been in the US for as long as 6 weeks, meaning that community transmission in the US has likely been occurring.

As for what happens if you get the virus- therapeutic options are limited. There is no specific antiviral therapy for this disease. There are currently over 100 clinical trials in place to attempt to identify a viable candidate. Remdesivir may hold promise based on preclinical data, and liponavir/ritonavir showed efficacy against MERS in preclinical studies. China is also using favilavir on patients hoping for some efficacy. The trials using HIV antiretroviral (ritonavir/lopinavit) therapy leave me skeptical, as HIV is a fundamentally different kind of virus and the therapy is fairly specific.

You can observe updates to the case numbers in real time here:

The REAL Problems

I am sure that the vast majority of people who become infected with SARS-CoV-2 will be fine. That’s what the data show. In that regard, my concern is minimal. Of course, we should still continue to aggressively explore treatment options for those who develop serious disease and preventive measures, especially vaccination (stay tuned for a future post on why this has been so hard to do). So what’s the problem?

The real issue is what having this pandemic does to healthcare systems globally. Look at the most common symptoms for this disease: fever, cough, myalgias. Sound familiar? That’s because it’s a very nonspecific set of complaints that can apply to virtually any respiratory infection, though I admit the myalgias make it sounds quite a bit like flu. Now imagine every single person with these symptoms being sent to their nearest emergency room. That’s basically flu season and as it is I watched firsthand as my hospital struggled to ensure that all the patients who needed to be admitted had beds ready and could get treatment. Now imagine we have a flu season plus a coronavirus epidemic. And then, add measles on top of that because our vaccination rates have so dipped that it’s a very real risk that once the weather gets colder again, we could see resurgences. How is the healthcare system expected to cope with that?

That is unfortunately only half the problem. When infectious diseases become widespread in this fashion it is an inevitability that healthcare workers become infected. Which means that the proportion of qualified professionals available to tend to these patients, the really sick ones who actually need their attention, drops. And the number of patients increases.

If you have the time, I strongly encourage you to watch this interview of National Treasure, Peter Hotez MD PhD who is himself pursuing a vaccine against SARS-CoV-2 who has explained it far far better than I ever could conducted by Zubin Damania MD, better known as ZDoggMD:

If we end up in the position that we have healthcare workers out sick because of measles, flu, and coronavirus all in the middle of a triple epidemic- that is the actual potential for disaster here. Add to this the fact that China is in the middle of a number of supply chains for critical pharmaceuticals which means we are going to have drug shortages and price hikes (and this extends well beyond the pharmaceutical industry), that is a perfect storm of disaster. For record, the mortality rates in the epicenters of COVID-19 (Wuhan and Hubei) tend to be quite a bit higher than outside them. Why? Probably because the healthcare system’s resources are so strained.

I also really hope that this makes people see that political borders are an illusion and not respected by infectious diseases. There is no such thing as a disease that’s just “over there.” Public health does not exist in a vacuum. Maybe think about that the next time you hesitate to vaccinate your child against polio.

What Can I Do?

Everyone should heed Phoebe’s advice. Even when we aren’t in a pandemic. Seriously guys, it’s embarrassing.

First of all, observe good infection control measures. Wash your hands frequently, and correctly. This is a very helpful instructional video and no, I am not joking:

You should take the time to prepare now. At this time, the risk of any given person in the US getting the virus is low- but that can change. Make sure you are prepared in case of an emergency. For a guide on how to go about it, this is a solid one:

But here’s the thing that I haven’t seen mentioned enough: please, please, please make sure you and everyone you care about is up to date on influenza and measles vaccinations ESPECIALLY IF YOU WORK IN HEALTHCARE. There is quite literally nothing that drives me crazier than healthcare workers who refuse vaccines. This is not going to help protect you against COVID-19 necessarily. However, both measles and influenza are known to be devastating to the lungs and render them vulnerable to bacterial superinfection. This damage and weakening of the immunological defenses of the lungs could make you a more susceptible host to SARS-CoV-2. But, most importantly: it is going to help make sure that instead of having to deal with 3 epidemics at the same time, we have just 1 to worry about. I cannot implore you enough- get up to date on these things. This also applies to pneumoccocal vaccines- pneumococci are components of the commensal microbiome and can become virulent under certain conditions, which can happen when damage occurs to the respiratory tract, especially the lower respiratory tract. Prevent the things we can prevent. Minimize the burden to the healthcare system. Minimize the risks to yourself. Minimize the risks to the most vulnerable people who very well might die from any of these diseases and cannot be vaccinated. It is not just about you.

DO NOT BUY MASKS. Seriously. Stop it right now. The Surgeon General literally tweeted this:

You do not need one. I am not kidding. If you are infected or at high risk of complications, then yes, it may be appropriate for you. Why shouldn’t you get a mask?

For one thing, you’re probably not going to order the right ones. Simple surgical masks are not going to be effective long-term because they become moist from people’s breath which ruins their barrier function. In this case, the appropriate kind of mask is a respirator, probably an N95 or equivalent. Trouble is that these respirators aren’t just things you can don and doff no problem. To be effective, they have to form a seal on your face, meaning that they have to be fit tested. Oh and if you’ve got facial hair, that’s going to be a problem. No, seriously:

As long as the hair is under the respirator, it’s fine. But if it is on the boundaries where it forms a seal on your face, that’s unacceptable. There’s more though. Infectious disease experts have raised concerns that wearing masks will actually lull people into a false sense of security on the matter because people might inadvertently not wash their hands when handling it to put it on or take it off. Wash your hands. Additionally, experts are recommending that you avoid touching the T-zone of your face, as these are common entry points for the virus:

And honestly the ones who actually need these are the healthcare workers. The hysteria is causing shortages and that means that healthcare workers who are going to be dealing with actual patients who have SARS-CoV-2 could be left vulnerable.

For another guide, my pal Dr. Tara C. Smith PhD has an awesome one right here (also go follow her on Twitter! @aetiology):

Also this goes without saying, but I’ll mention it anyway. Do not panic. It never helps anything and we aren’t at the stage where panicking would be warranted and we might never get to that stage. It would be a lot of wasted energy. Concentrate on the things you can control and make sure you are prepared to handle an emergency.

References

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8. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, Wang B, Xiang H, Cheng Z, Xiong Y et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected Pneumonia in Wuhan, China. JAMA. 2020.

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