[COVID-19.P4] The Path For Now and Forward

Bài viết đã được chuyển ngữ sang Tiếng Việt.

Other articles on COVID-19:

Part I: When Breath Becomes Air (published on Vietcetera), click here.

Part II: The Dichotomy of Hope and Complacency, click here.

Part III: The Point of No Turning Back, click here.

In my previous discussions on COVID-19, I have iterated again and again the importance of two concurrent strategies: (1) public access to testing and (2) strict quarantine in order to contain the spread of the outbreak. On that day, March 12th, we had ~2,200 confirmed cases in the US. Today, that number has reached 83,507, with ~3800% change within 2 weeks. The number of deaths in the US also doubles every 3 days. On par with the US on doubling time are France and Spain, which have recorded 1,331, and 3,434, respectively. Meanwhile, Italy, standing at global worst record of deaths, has an even lower doubling time of every 5 days.

The SARS-CoV-2 virus, which was not known to exist four months ago, has now infected over 510,000 people across 175 countries. While we look at this stark reality, let’s remind ourselves of one simple fact: the increase of new cases does not reflect the spread of the virus.

Instead, this number reflects our testing capacity, measured by the number of people getting tested and the number of administered tests. More indicative of the spread of the virus than the number of cases is the percentage of positives over the number of tests performed. As of March 19th, the US has performed roughly 103,945 total tests, about 9% of which has confirmed positive. Now, joining the US, Italy, and South Korea are Spain and the UK, countries with the highest rate of confirmed cases over the total tests administered.

In the hysteria of food, mask, and disinfectant scarcity, how would we see our near future? Below you would find the summary of many experimental drugs against SARS-CoV-2/2019-nCoV currently on clinical trials, followed by my analysis of how science is waging its own war against the pandemic of pseudoscience theories that I believe we should all review and discuss. At the moment, NO drugs have been proven effective to prevent or treat COVID-19.

Experimental Drugs for COVID-19

Remdesivir, Lopinavir/ritonavir, and other experimental antivirals

The first class is antiviral drugs, which essentially work by blocking the replication of the targeted virus. Their efficacy is evaluated based on potency, selectivity and bioavailability. These criteria assess the amount of drug needed to be effective, whether that amount is toxic to us, and if that drug can be absorbed, metabolized, and stabilized in the human body.

Remdesivir (GS-5734; trial ID: NCT04257656; NCT0428075, NCT04252664), is an analog of nucleotides, the bricks of our genetic code. Based on in vitro evaluations (here, and here), remdesivir might seem like one of the most promising candidates at the moment for COVID-19. However, in a recent preprint paper, the first 12 US patients with mild or moderate symptoms were evaluated, three of whom (25%) received remdesivir under compassionate use (a category of exemption for using unapproved drugs to treat patients where no other treatment exists). Following the study, with or without treatment, all patients recovered or were improving; there was no clear association in improvements in oxygen requirements, fever or viral load between patients untreated and treated with remdesivir. Side effects were noted, including nausea, vomiting, rectal bleeding and elevated liver enzymes.

The results of the current trial are expected next month. In the mean time, in case you are interested, Gilead is currently facing some heat for limiting drug access to patients, and its filing for a tax-exempt, rare disease status.

You might have heard of lopinavir floating around the news these days. In a randomized, controlled study, treatment with lopinavir/ritonavir (LPV/RTV) for severe COVID-19 patients did not show any benefit beyond standard care. Despite being antivirals, these drugs also did not reduce viral replication. A nice commentary on this trial could be found on NEJM.

Telling enough, in a recent MERS-CoV study published on Nat. Comm., remdesivir + interferon beta (IFNb, a compound used in management of MS) showed improved respiratory function and reduced viral load compared to LPV/RTV + IFNb.

Another antiviral agent, Rintatolimod, which acts on the toll-like receptor 3 (TLR-3), is being tested in Japan for COVID-19 (AIM Immunotech). TLR-3 is a receptor for double-stranded RNAs like those of viruses, that upon recognition of infection, triggers an immune response. Other antivirals being investigated for COVID-19 are azvudine, danoprevir, plitidepsin and favipiravir. Again, these drugs with complicated names are essentially inhibiting a necessary component of viral replication and thereby blocking infectibility. Moving forward, in order to improve efficacy, we might need to know the distribution of the drug to the tissues where SARS-CoV-2 is actively replicating.

Hydroxychloroquine and chloroquine

Sorry for making you scroll this far to find the only section you might care about! Yes, it is an anti-malaria drug, but it is also used to treat autoimmune diseases like lupus erythematosus and rheumatoid arthritis.

However, so far, the only studies showing that chloroquine could effectively inhibit SARS-CoV-2 are in vitro, meaning it has not been tested on animals (here and here). Yet, a dosage was still recommended, and in the urgent search for a cure under extreme conditions, chloroquine was given to 100 patients in China with COVID-19 pneumonia. We need to be cautious here that the amount used in these cases is 14 times higher than the weekly dosage for malaria prophylaxis, with potentials for serious cardiac toxicity. Even though chloroquine has been shown effective in vitro against numerous viruses, clinical trials for this drug have never come out productive.

A clinical trial on prevention of COVID-19 progression after exposure is ongoing here. If you have found this French study on hydroxychloroquine, please note the many caveats: (1) there is no data that viral clearance on day 6 is clinically meaningful, suggesting that this endpoint picked by the authors is arbitrary, and (2) patients who refused consent to the study were still included in the control, which makes us question the enrollment of the study.

Other investigational drugs are corticosteroids, which are not recommended for COVID-19, and nitric oxide (Trial ID: NCT04290871), whose use should be limited to mechanically ventilated patients with severe acute respiratory conditions. Nitric oxide also costs about $100/hour.

All vaccines and other drugs being considered for management of COVID-19 are included at the end of the page.

The Pandemic of Conspiracy Theories, SOLVED.

HIV-born? Bioweapon? Asymptomatic transmission?

1. SARS-CoV-2 is a laboratory-constructed or manipulated virus.

The theory started in the comment section of the first-ever-paper-on-COVID-19's-origin on Nature, and since then, it has been echoed over here and here. First, the gap between SARS-CoV-2 and other coronaviruses like SARS-CoV or MERS-CoV is wide, suggesting that this virus did not derive from its relatives. In addition, the first two infected cases were not linked to Wuhan animal market. Therefore, they argued that in order to prove natural selection of SARS-CoV-2, the virus needs to be detected in a third-party animal carrier (basically, bat - X – human, find animal X), which was never found.

On the other hand, the presence of polybasic cleavage site likely resulted from cell culture/in vivo adaptation. Last, based on the evidence of pShuttle-SN vector on SARS-CoV-2 sequence and the correlated Chinese patent here, they hypothesize that SARS-CoV-2 was intentionally made as a vaccine against SARS. (Science can be a double-edged machine).

In this Nature paper, Malayan pangolins, imported illegally to Guangdong, were suggested to be animal X. They contain coronaviruses strongly similar to SARS-CoV-2, especially at six key places termed residues. The study further suggested that SARS-CoV-2 has acquired an additional mutation (hint: polybasic cleavage site) that bestows the ability to jump from human to human. They also argued against lab-grown acquisition of these sites since those have been observed only in low-pathogenic avian influenza. I personally found this paper argued against part of the problem; it would be interesting to have the structures of isolated pangolin coronaviruses modeled recombined/mutated polybasic sites.

2. SARS-CoV-2 was engineered from HIV.

Since this theory is very premature, I am just going to give the link to the counter-study here. Thanks the Internet for giving me a good read.

3. SARS-CoV-2 can be infectious in asymptomatic patients: Mounting evidence

I have shown two preliminary studies in my previous article, suggesting that post-symptoms individuals need to get quantitatively tested for the level of viral load in their bodies to know that they are no longer infectious.

Another study on 565 Japanese evacuees from Wuhan showed that 4 out of 13 people were infected despite never developed symptoms. This study, published on NEJM last week, also showed one asymptomatic patient with as much viral shredding as patients with symptoms. A modeling study derived from 3,711 passengers on the Diamond Princess cruise ship suggested that about 18% of 700 infected cases never showed symptoms. The author also predicts that asymptomatic or mild cases represent about 40–50% of all infections. Even though there is still a lack of evidence on direct asymptomatic transmission, the presence of high viral load often correlates with an active replication, suggesting that the person could still be infectious. Low viral load, on the other hand, could likely warrant low risk against viral spread.

How to Protect Yourself Without Protection?

In the last part, I will discuss some at-home methods that would not require fighting blood-and-bone for Lysol, Clorox or other chlorine-based bleach in your local grocery store. While all of these options, including alcohol- or chlorine-based disinfectants, have not been tested directly on the SARS-CoV-2 virus, our working knowledge of other similar viruses would likely be relatable in times of limited resources and capacity.

1. HOME-BASED AUTOCLAVE / YOUR PRESSURE COOKER

Autoclave is a method for disinfection and sterilization by high temperature, pressure and time to kill microorganisms, including viruses and spores. This method, which might sound strange to you, is routinely used to decontaminate biological waste and sterilize media, surgical instruments and lab-ware. To be effective, the autoclave must reach and maintain a temperature of 121° C for at least 30 minutes with at least 15 psi of pressure. To disinfect, you can put some water at the bottom of the pot, and sterilize whichever equipment that can stand pressure and heat (i.e. glasses, plastic sprays…).

Instant Pot has a max working pressure of 15.23psi, however it normally operates at a much lower pressure of 11.6psi. Stove-top pressure cookers normally has a max pressure from 12psi to 21.7psi. Some high-end stove-top models have 16~21.7psi pressure range. So please check with your pressure cooker for details.

2. DISINFECTANTS AGAINST VIRUSES

While the best disinfectants are chlorine-based, like Lysol or Clorox, and ~70% diluted alcohol (vodka has 40%, so don’t bother), several studies have tested acidity on efficacy against pathogens. Even though vinegar and baking soda could eliminate some bacteria, natural home products are typically less effective as a sanitizer than chemical products. However, in desperate times of an ongoing pandemic with low resources, home products might provide us a last resort. In this study, 1% bleach, 10% malt vinegar, and 0.01% washing-up liquid were shown to inactive influenza virus. Hot water, unsurprisingly, does nothing.

Currently, recommended disinfectants against SARS-CoV-2 can be referred to this list published by Environmental Protection Agency.

3. DIY MASKS

Given the current shortage, you might wonder how to make your own masks from a variety of materials. Even though not as effective as surgical masks (89%) against 0.02-micron bacteriophage MS2 particles, the following materials have been tested and might suffice in times of shortage: vacuum cleaner bag (86%), dish towel (73%), cotton blend (70%), and antimicrobial pillowcase (68%).

Scarf, 100% cotton, silk and linen are less effective but can give you at least 50% efficacy. If you don’t have a sewing machine, you can make one using staplers and elastic bands here. Here is a video on how to make mask at home:

Final Words

I hope that this article would remedy us given the most updated research I could able to short and narrate. As you might be able to derive, our road to a vaccine and a treatment is still a long way to go, but the flux of hourly information should never monger fear or confuse us. At this moment, excess information is rushed towards us, but these pieces are not knowledge. They are discrete trunks of information.

In this critical time, we should be vigilant to distinguish facts from fictions. We should educate ourselves in order to protect others. Fear is a derivative of the unknowns, so we raise questions, write, and reflect. We hypothesize, argue against it, and defeat our own mind. OR we can choose another path of no reflection, no cultivation, or simply bliss and negligence.

Regardless of your choice, the path ahead is a long way to go.

P/S: In case you are an absolute, hopeless nerd, like moi, here is a review written by our dear Tony Fauci on vaccine strategy for 21st century. Have a good read, and practice protection!