“It’s Déjà Vu all over again" - Yogi Berra
For those of us who have experienced and responded in some fashion to the H5N1 “Bird Flu,” H1N1, SARS, MERS, Zika, or Ebola, the immediate reactions of fear, exaggerated response, emotion-based public policies, and blame are, unfortunately, all too predictable. Just as inevitable are the plethora of lay and professional publications on all aspects of diagnosing, treating, and controlling the outbreak, more often based on anecdote and opinion rather than observation and knowledge. Much of what is published is duplicative and too often based on incomplete or misinformed information.
Rather than add one other piece that contributes nothing to what is available elsewhere, I feel it would be more useful to briefly cover the salient aspects of COVID-19, and try to better understand some of the dynamics that hold sway when we are dealing with a novel, emerging infectious disease with particular attention to the parameters used to define it.
Fear, paranoia, panic – however we describe it – why do we as individuals and nation states react that way? The simple explanation is that the risk is unknown; that does seem to be a necessary ingredient, but is it sufficient to explain the degree of overreaction? I, personally, do not believe so. I feel we need an accelerant and the traditional media is always eager and ready to fill that role through exaggeration and sensationalism. Our social media outlets aid and abet through an unfiltered internet and the echo chamber effect of self-validation. The result is an aroused public; one that necessitates political action, action aimed at primarily appeasing the public and not at taking the proper public health initiatives to limit and control the outbreak. And the voice of public health can do little to modify the reaction as they must, through necessity, plan for the worst case. I am not sure how to break this cycle, but if we do not, we will continue to do more harm than that which we are trying to prevent.
Blame is and has been a constant, from the earliest records of disasters up to the present. When something bad happens, we must have someone or something to blame outside ourselves. We thereby condone, individually and societally, whatever actions we take to supposedly better protect ourselves. When dealing with influenza and corona viruses we have our ready-made culprit in China, in that so many of these novel outbreaks seemingly originate there; notwithstanding that corona viruses are ubiquitous and have been with us for thousands of years. And the benchmark microbe for all modern pandemics, 1918 H1N1, probably originated in Kansas. But wherever the origin, a pandemic is a global problem, and is best addressed through open cooperation and transparency.
Unfortunately, this transparency comes at a price. Although debated, most observers feel that China was fairly transparent in its handling of COVID-19 once clearly identified and recognized for what it was; and what was its reward – the stigmatization of its citizens, disruption of international commerce, and yet to be tallied onerous economic impacts. Again, I am not sure how to disrupt this, but if transparency is an essential component of global prevention and response, we must.
Turning now to the parameters by which we define the epidemiology of COVID-19, much has been published to date on cases and deaths with an estimated 2.4 percent mortality. What has not been addressed or well-estimated is the number of sub-clinical cases that may go undetected, thus throwing into question the denominator of our mortality statistics as well as the number of other upper respiratory diseases (it is flu season) that may confound the numerator. What may be more ominous is the slowly increasing death rate among Chinese cases and the large percentage of critical cases (≈ 20 percent). In the screening to date of passengers classified as exposed or symptomatic on the cruise ship in Japan, approximately 174 have been positive, indicating some number of sub-clinical cases. A complete screening for the virus of all on board would have provided some evidence as to percentage of sub-clinical cases in this outbreak and would provide some rationale to end the confinement of the thousands of individuals forced to remain in a dangerous, closed environment, a reverse-parody of Porter’s “Ship of Fools.”
In a number of publications, however, the estimated 2 percent mortality rate has been compared to the 2 percent estimate given for 1918 H1N1 and sensational extrapolations made to predict millions of deaths. All well and good, except that the 1918 estimate is based on multiple other estimates, most of which have unacceptably large variances. Using a mortality figure from a time when H1N1 cases could not be confirmed, and the recording of causes of death quite variable and non-standardized, cannot help but lead to error. There are published numbers that attribute deaths due to H1N1 in 1918-1919 anywhere from 25 to 100 million -- an unacceptably large variance.
A second number we see constantly referred to is R0 (the basic reproduction number), which is poorly understood and frequently misused. R0 is meant to give the average number of new cases generated by a single case. However. the definition of R0 is the expected number generated by one case in a population where all are susceptible -- not where other individuals are infected or immune. Also, R0 is not a constant as it varies across populations and environments and is generated by mathematical models that are based on differing assumptions and variables. Most importantly, it is a non-dimensional number and is therefore not a rate. In general, what is usually referred to as R0 should be defined as R, the effective reproduction number which measures the number of cases generated in the current state of the population. The number of variables that affect R explains the wide range, from 1.5 to over 4, we have seen for COVID-19.
Another consideration that would indicate that the current outbreak is not replicative of the 1918 pandemic and does not have a high R0 is looking at the propagation of 2019-mCoV outside of China. The current strain was almost certainly circulating to some extent in early December of 2019. Wuhan is a city of over 11 million and by the time the quarantine was instituted, hundreds of thousands had travelled throughout China, Asia, and the world. Now, two months later, outside of China, we have some 518 cases across 27 countries, with two deaths as of this writing, a case mortality rate close to one half of one percent, with no explosive outbreaks that I have seen reported. Data from Africa, with over a million Chinese inhabitants and workers, are sparse to date.
By contrast, in one of the documented outbreaks, a single probable case of 1918 H1N1 reporting to an Army base in Kansas resulted in 522 new cases within a week. All of this is not to question the potential seriousness of the current outbreak nor to downplay legitimate concerns, but to put it in perspective. The majority of cases are relatively mild. The more serious and lethal complications occur in the elderly (≈85% of deaths occur in those over 65), and predominantly in men (≈ 2/3 of cases).
Interventions and Countermeasures
In order to identify effective countermeasures, we must first achieve better understanding of the modes of infection. Obtaining this clarity, we can address the more common recommended public health interventions.
Masks – The ongoing discussion of whether an N-95 or a surgical mask gives superior protection continues without definitive resolution. Theoretically, for several reasons, the N-95 should be superior and there are certainly many studies to support this. There are also studies in clinical environments that show no significant differences. A more basic question, does either reduce the risk for the user, is itself debatable. What is not debatable is that for patients with respiratory infections, a mask provides a barrier to block or at least partially block and absorb the expulsion of droplets which are the primary transport vehicle for micro-organisms. Given conditions where masks are in short supply, as in China today, their distribution should be directed at those individuals with clinical symptoms.
Social Distancing – Theoretically, and obviously, this should work; if additional individuals are not exposed, the epidemic will die out. Actually, preventing this exposure in whole or in part is fraught with difficulty and such controls as isolation, quarantine, border closure, and other restrictions on movement have historically proven inadequate as they are imposed too late, lifted too early, and are predictably porous. Moreover, restrictions on movement can impede the flow of medical staff and supplies into an impacted area, as was the case in the 2014 West Africa Ebola outbreak, exacerbating an already dire situation. What has proven effective is targeting the at-risk population for a specific infection. A proven example is school closures for influenza. Given the increased mortality for the elderly of COVID-19 with comorbidities, steps should be taken to shield this group from exposure and, where appropriate, keep them away from healthcare facilities. The same precautions should apply to pregnant women given reported negative outcomes for this group with SARS and MERS. Also of note, at the individual level, the latest research shows that droplet nuclei can be propelled up to distances of over 20 feet and remain suspended for extended periods making this intervention difficult if not impossible, in the home environment.
Hand washing – With the dramatic demonstration by Semmelweis of the profound effect of antiseptic procedure on puerperal fever outcomes, handwashing has rightly become a first line defense against the spread of infectious diseases. The magnitude of the effect is, of course, related to the particular microbe and the mechanisms through which it is transmitted. Given the epidemiological characteristics of influenza, which is spread primarily and essentially as an airborne pathogen, hand washing in itself, although advisable at the individual level, may not have the hoped-for public health effect. This, however, is not the case with the coronavirus. Although most likely transmitted primarily as an aerosol, there are probable other mechanisms such as fecal-oral and contact with other body fluids. Given the increased hardiness of the enveloped coronavirus, its enhanced viability in the environment increases the likelihood of fomite transmission. This is further strengthened by early observation of potential ocular infection being of concern and by the fact that it can attach to multiple cell types. The utilization of hand washing as a primary defense is thus strongly indicated.
Anti-virals — Although there have been great advances in this field overall in the treatment of influenza and HIV, there are, to date, no specific anti-coronavirus compounds available. One drug targeted to coronaviruses, Remdesivir, will be tested in China on 270 COVID-19 patients. In addition, repurposing anti-influenza and HIV drugs is being evaluated in China as well. Other potential therapies aimed at mitigating the immunopathology associated with Corona to include interferon, mono-clonal antibodies, and targeted anti-viral peptides should also be considered.
Vaccines – Infectious disease has been the scourge of man for thousands of years. There are, of course, two principal interventions, treatment and preventions and, when possible, the latter is preferable. This is especially true with viral diseases where treatment options are extremely limited and where vaccine success for host of infections has been amply demonstrated. The greatest challenges arise with the de novo agents, whether newly expressed or a variant of a known pathogen such as is common with influenza. The greatest problem is time – the length of time traditional methods take to first isolate and identify and then grow the agent. With COVID-19, we are told it will take a full year. Placing that in the context of 1918, the pandemic peaked globally at ten months following the initial recognition; we remain as vulnerable today to a major pandemic as we were in 1918. The tools are available to do better, but a global commitment to establishing and funding vaccinology enterprise is imperative to preparing for the Andromeda-like strain we all dread. And this cannot be left to private industry, which has amply demonstrated an unwillingness to pursue such a course due to very legitimate concerns surrounding business models and liability. WHO is organizing a global research and innovation forum during the week of 16 February to develop a global research agenda in response to COVID-19, which could be a necessary first step.
As historian John Barry, a recognized authority on the 1918 pandemic, noted in his seminal work The Great Influenza, “in the next influenza pandemic… the single most important weapon against the disease will be a vaccine. The second most important will be communication.” Unfortunately, we have repeatedly seen sensationalized and fear-inducing communications prevail over sound risk communication, leaving us with but one true weapon – a vaccine. It greatly behooves us to establish the necessary systems to expeditiously identify disease agents and build vaccines using advanced tools and methodologies at our disposal before we are again facing a 1918-like pandemic.
Closing note: The body of this paper was prepared February 12th. Over the intervening 24 hours, a significant spike in confirmed cases has been reported and, predictably, the media responded immediately with alarmist broadcasts and headlines. What was not well covered was the fact that the reported numbers were primarily due to a change in diagnostic classification and that now the estimated mortality is 1.85 percent.
The cycle continues.
James James, MD, DrPH, MHA