In this essay I present a critical analysis of the currently available options for combating the coronavirus SARS-CoV-2 and the disease it causes, COVID-19. As in any pandemic disease, meeting the challenge is a matter of getting a test.
Fortunately, the word is out now on what is needed for rapid, locally conducted, unequivocal, and early-stage detection of coronavirus infection. The test is RT-qPCR, the reverse transcriptase quantitative polymerase chain reaction, also denoted as real time or rRT-PCR.1 After considerable delay, hospitals in the West are now slowly beginning to acquire the instruments, reagents, and expertise for in-house testing. Devices like Cepheid’s new GeneXpert Systems, which can give results in less than 45 minutes, represent the current state of the art.2 Cepheid, and other companies including Mammoth and Sherlock Biosciences, are now poised to ship a new generation of even more accurate tests that take advantage of the high sensitivity of CRISPR–Cas editing. These tests employ loop-mediated amplification, a simplified technique that uses various primers similar to PCR but does not require the extensive thermal cycling for nucleic acid amplification.3
For those with full-blown coronavirus, the most important medicine is oxygen. When breathing first becomes difficult, pure oxygen can be delivered from tanks or created on the fly from oxygen concentrators. Home concentrators based on the molecular sieve principle are now cheap, safe, and widely available. They pump air through a zeolite material where nitrogen is first absorbed and then cyclically vented. As a stopgap, this is probably better than trying to use oxygen from an oxy-acetylene welding rig or a MAPP gas torch. Yes, the oxygen is the same as the medical grade stuff, but the rusted tanks are not.
In the worst-case scenario, a person with a severe reaction to infection needs to be intubated. Some individuals are more susceptible than others to an exaggerated immune response known as cytokine storm. This causes acute respiratory distress syndrome (ARDS), which makes it nearly impossible to breathe. Tamping down the immune system with suppressive drugs may be one option here. Some success has been reported using colchicine to inhibit immune cell activity, or using other drugs to target cytokines such as interleukin-6 directly.4 When ARDS occurs, there is considerable swelling and fluid buildup in and around the alveoli of the lungs. This presents a hard barrier to gas exchange with the surrounding vasculature. Intubation at this point helps, but it has still been associated with a mortality rate of 45%.
Three things have been found that can bring this mortality rate down to roughly 30%. None of them are pretty. The first came with the realization that the traditional approach of trying to expand alveoli and compress out the fluid using large tidal volumes was actually making things worse. Tidal volume refers to the oscillatory component of the breathing cycle—how much air is forced into and out of the lungs. The idea was to use smaller tidal volumes while keeping some positive level of backpressure even during the exhalation phase. This is exactly analogous to the electrical situation where one has a small AC ripple voltage riding on top of a DC voltage. Essentially, this prevented the alveoli from completely collapsing on the downstroke. The result was far less inflammation.
The downside was that the CO2 buildup tends to induce quite a bit of panic in patients, causing them to try to breathe more on their own. Sedation could help with the discomfort to some extent, but runs the risk of further respiratory depression. The solution—the second advance—is to paralyze the patient. The third recommendation for reducing vent mortality is to turn the patient over, putting him or her facedown in the prone position.5
One major problem at the moment is getting good ventilators. Many nonmedical companies, including Tesla, are now pledging to dedicate assembly lines for production of these instruments. One place that could use them is New York. Hindsight may be 20/20, but New York just learned a painful lesson. It was reported that in 2015, the governor and the NYC mayor were advised to purchase 16,000 reserve ventilators at $36,000 apiece for just the kind of pandemic we now face. Instead they chose to put the $576 million toward climate change.6
For the sickest of the sick, one way to try to increase the odds at intubation would be to use a technique called extracorporeal membrane oxygenation (ECMO). The devices used in this technique are in principle similar to the heart-lung bypass machine. The lungs can be given a rest while gas exchange is done outside the body. A VA ECMO connects to both a vein and an artery and is used when the heart is involved. If just the lungs are involved, the more portable VV ECMO, which connects to veins only, can be used. Installing, monitoring, and removing these machines is not a trivial job, but they can get a patient past a tough spot. During the swine flu epidemic a decade ago, ECMO technology was still in its infancy and the devices were not readily available.
When the disease is detected early, there are now many other medicines that may be useful. The antimalarial and Lupus drug chloroquine, and its more potent form hydroxychloroquine (Plaquenil), have shown some efficacy. A significant number of patients that were given hydroxychloroquine, either alone or with a supplementary Z-Pak (azithromycin) to fight bacterial pneumonia, made a quick recovery. Because no sick patients were refused treatment as a control, an inhuman action by any standard, critics argue that the results were worthless. Those critics are in fact people who do not have the coronavirus. The truth is that the entire infected world of people who were not given this drug were the control. Their lengthy recovery times are the data.
Hydroxychloroquine is a pleiotropic drug, a fancy way of saying it works in many mysterious ways. One primary action is that it increases the pH of lysosomes inside cells from around 4 to 6. This inhibits acidic proteases and decreases intracellular processing, glycosylation, and protein secretions. In antigen-presenting cells, this leads to a decrease in inflammatory activities. Perhaps more importantly, in other cells infected with the coronavirus, this leads to a decrease in viral loads.
Hydroxychloroquine also binds to specific zinc transporters, or zinc ionophores, and keeps them open. If excess zinc is available, this presumably lets more zinc enter the cell. Zinc appears to alter the membrane permeability of lysosomes,7 but it has another important function. It can block the unique RNA-dependent RNA polymerase (RdRP) of the coronavirus.8 Although the literature calls hydroxychloroquine itself an ionophore, it only binds to the real zinc ionophores in the cell. This term is at best awkward and at worst misapplied.
With the viral RdRP polymerase activity halted, the coronavirus cannot replicate. Perhaps an even more direct way to block RdRP is by delivering the drug Remdesivir. Because Remdesivir looks like adenosine to the RdRP, it gets incorporated into the growing RNA chain when a uracil base is encountered on the RNA currently being copied. But Remdesivir is different enough from adenosine because it has an unusual triple-bonded nitrogen side chain. These features make it even more attractive to RdRP than adenosine itself, and when it binds, it causes the polymerase to halt. Demand is quite high at the moment and supply is getting scarce as trials of Remdesivir unfold.9
Anecdotal observations have recently led to some critical considerations for treating and understanding COVID-19. One is that using ibuprofen for pain actually suppresses the immune system in a way that could be detrimental in the early stages of infection when immune function is needed. Some children with coronavirus who were given ibuprofen were found to decline at a rapid rate. All else considered, substitutes such as acetaminophen have been suggested as a wiser alternative at this point.
Because the novel coronavirus uses the ACE2 receptor as an entry point into cells in the lungs and gut, medications that increase the number of ACE2 receptors may not necessarily be a good thing. Coronavirus-infected people on blood pressure medicine seem to have a rapid decline. These medicines are generally either ACEIs or ARBs (ACE inhibitors or angiotensin receptor blockers). In general, the ACEIs often end in “-pril” while the ARBs end in “-tan.” The problem is that animal models made using mice that have the ACE2 gene knocked out suggest that more ACE2 receptors could have some beneficial effects under infection. This situation therefore needs more clarification before any prudent recommendations can be universally given.
One seemingly powerful approach for dealing with coronavirus is using antibodies. Many of these options fall under the rubric of human convalescent sera. Because we already have a substantial number of people infected and recovered from the coronavirus, the ability to donate valuable immunoglobulin-containing serum looks like a better option than trying to produce massive amounts of monoclonal antibody in the lab.10 There are several significant problems with using antibodies. Some studies indicate that anti-spike protein antibodies can make the coronavirus worse by switching the macrophage profile toward an inflammatory phenotype.
This is bad news for the billion-dollar vaccine efforts now underway. Anti-spike IgG is correlated with severe diffuse alveolar damage and death. Instead of preventing viral entry, it binds to the virus and facilitates uptake by FcR-expressing macrophages, whereupon cytokine storms can occur.11 Other types of vaccines based on mRNA or DNA, targeting nucleocapsid protein, or even complex nanoparticle antigen display vaccines, also seem to have many potentially adverse effects.
To better illustrate the wider situation we now deal with, consider the flu vaccine. While the normal entry pathway of the flu is the lungs, vaccines generate an antibody response based on an artificial subcutaneous or intramuscular point of exposure. As we now know, this is a different animal altogether. The data show that to the body, this can look more like exposure to a dengue virus. The result is a dengue-like IgE response: a man-made influenza shock syndrome.12
In the face of these failures what else can be tried?
One recent proposal is a relatively new technique known as mitotherapy. The rationale is based on numerous observations indicating that mitochondria transfer through various intercellular circuits involving macrophages, mesenchymal stem cells, T cells, bronchoalveolar cells, and even the nervous system directly to control many specific metabolic processes. The most significant result is the direct reduction of inflammation, particularly of that seen in the lungs during ARDS. Although the best method of introducing restorative mitochondria has not yet been fully defined, both intratracheal administration of mitochondria-donating cells, as well as introduction of raw mitochondria directly into the general circulation have shown dramatic results.13
In finding useful treatments, it is important also to take stock of things currently being tried which do not seem to work. A case in point is the recent failure of efforts to repurpose the HIV protease inhibitors lopinavir and ritonavir for the coronavirus. Although it made sense to try to inhibit the coronavirus protease using protease inhibitors that worked against HIV, the drugs did not stop viral replication as measured by testing for RNA.14
Valuable information is contained in all failed studies. Another source of underutilized information is how the positive cases have been reported. Many places have been fearful of releasing names. This includes many hospitals where infected doctors have exposed many patients. An example of what good reporting looks like includes not just a regional breakdown, but crucially, age, sex, travel history, and where available, identity.15
I would like to make one more point in summary. A lot of far-fetched and perhaps a few even not so far-fetched conspiracy theories about the origins of the virus are floating around. While most are completely wrong if for no reason but the fact that they can’t all be simultaneously correct, many contain at least some small kernel of truth, or at least a lesson that helps us understand the full possibilities of what we could be dealing with in this unusual virus. Despite claims by researchers that any engineered component to the virus has been completely ruled out, the fact is we cannot know this right now.
For example, the authors of one recent and quite popular paper used computational modeling to show that the six amino acids present within the highly variably receptor ring region of the spike protein are not completely optimal for binding to the human ACE2 receptor. From this they conclude that the virus could not have been engineered, and therefore must be the result of natural selection, presumably because if it was engineered then surely its engineers would have found and used the optimal sequence.16 Faulty logic and inappropriate inferences will bring us no closer to understanding the virus.
