Coronavirus: Therapy

The discussion of hydroxychloroquine and remdesivir as treatments for conronavirus infection understandably attract a lot of attention. Certainly, there will be extensive efforts to find interventions that shorten the duration of COVID and limit the severity of the disease. It is too early to tell if any reasonable therapeutic agents are on the near horizon, but some general observations can be made regarding the issue.

I. Vaccine. It certainly seems reasonable that a vaccine will be developed to mitigate the spread of coronavirus infection. It is not reasonable to assume that this is a foregone conclusion. Depending on the year, influenza vaccines have only limited efficacy. Some viruses for which vaccines are sought do not have them. While it is expected a vaccine would provide immunity, as for smallpox or measles, there is no guarantee that this will be the case for SARS Cov-2. It is not clear if people who displayed symptoms of COVID-19 have developed immunity, or if only some of them do. It is not known if a widely available vaccine would still leave large "vulnerable" populations, such that the social distancing practices currently in use would not still be required if a vaccine were available.

II. Choloroquine and hydroxychloroquine. The evidence of efficacy of these agents seems to a little more substantial than merely isolated anecdotes. This is particularly true of reports of efficacy against SARS Cov-1. There are plausible mechanisms, or perhaps constellations of mechanism by which to conclude that efficacy is at least plausible, but even if it were scientifically established that these medicines have a therapeutic benefit, we would not expect them to function as "cures." A reasonable way to look at choloroquine and hydroxychloroquine is that they improve the chances of resolution of symptoms without life-threatening crises. They improve odds; they will have more benefit for some people than others. One would expect that different study designs will reflect this fact in that some studies will show a discernible benefit while others will not. This will not mean that the drugs have no effect, but rather that the effects are not uniform and are contingent upon factors that may not seem obvious when the studies are designed.

III. Convalescent plasma, IL-6 inhibitors and monoclonal antibodies. These interventions are primarily intended for extremely ill individuals at high risk of death; i.e. those that have severe lung disease. Here we may contemplate a relevant possibility: that the risk factors for developing COVID-19 once infected with coronavirus are different than those associated with developing a life-threatening case. One way to look at this is that COVID-19 with viral pneumonia is a different disease than COVID-19 without viral pneumonia. This is true even though the causative organism is the same in both cases. It is the same type of distinction made between pneumonic and bubonic plague, or between ordinary, modified and malignant smallpox. The reason for making the distinction with regard to coronavirus is that therapy is likely to differ between the different disease manifestations. For example, early in the course of disease, fever may be beneficial, but may then become damaging to lung tissue once ARDS (acute respiratory distress syndrome) has developed. Immune modifying agents may be harmful if given early, and beneficial once mechanical ventilation is required. It should be expected that the course of disease is affected by multiple factors, some of which may not even have been guessed at, much less studied and understood.

IV. General principles. Returning to chloroquine and hydroxychloroquine for a moment, we may observe that many useful pharmacologic agents fall into two broad categories: blockers of one form or another, and enzyme inhibitors. Beta blockers and calcium channel blockers are obviously members of the former class while statin drugs, NSAIDs, and a great many antibiotics are examples of the latter. What these have in common is that they interfere with the metabolic pathways associated with biological processes, both physiologic and pathologic. The experience with choloroquine and hydroxycholoroquine is that they affect a large number of metabolic pathways, affecting for example the metabolism of heme, the regulation of inflammation and Toll-like receptors, as well as the acid-base balance within cells. It is certainly possible that some of these effects influence the course of infection in humans, through as yet unknown mechanisms. It is also useful to note that the beneficial effects of quinine, from which chloroquine and hydroxychloroquine are derived were discovered by happenstance, (the same with biguanides, penicillin, and nitrogen mustards for treatment of cancer) not rigorous or rational design and development. It may well be that they preferred management for COVID-19 is discovered the same way.