The writing on the wall…

What follows is an OpEd I wrote 17 years ago…

SARS is a call to action. It is a call to get the world’s public health infrastructure in order. It is a call to realize that when it comes to infectious agents, natural or created through human artifice, the world is epidemiologically linked. It is a call to bolster the resources of the WHO, the Centers for Disease Control and Prevention (CDC), and other national public health services of other countries. And it is a call to create a well­ provisioned SWAT team that can be easily mobilized to control infectious threats.

The impact of SARS will be measured in terms of infection rates, severity of disease, mortality rates, and economic effects, as well as alterations in our individual psyche and societal sense of well-being and security. The impact will also be measured in terms of how we modify our future behavior in dealing with this epidemic and in vouchsafing the community against other infectious threats.

SARS is not the epidemic that anyone expected. Comparisons can be made and will be made with epidemics of HIV, Ebola, Hanta, and influenza. Because of the novelty of the SARS agent, however, such comparisons are limited in their predictive power.

At the end of April, the total number of SARS cases reported by the World Health Organization (WHO) stood at 5663 with 372 mortalities. While these numbers are surely underestimated, they do not even come close to the devastation that malaria, HIV, tuberculosis, or infantile diarrhea produce in a single day. For example, the WHO estimates that over 3000 children die every day of malaria. So why are we fixated on this disease? First of all, our attention is drawn to the novelty of this disease and the absence of a frame of reference. Secondly, we fear the manner and rapidity with which SARS is spreading-leaping countries and continents. No one knows for sure how pervasive SARS will become. As a society, Americans have become inappropriately accustomed to the ongoing impacts of influenza, cardiovascular disease, cancer, and motor vehicle “accidents”. We expect them to take their daily, though no less heart rending, toll. Our protestations are heard primarily when these killers directly touch us or those who are close to us. In contrast, SARS holds for many the psychological impact of an unexpected terrorist attack.

What’s in a name? SARS emerged in Guangdong, China in late 2002. However, it did not emerge into public consciousness until early in 2003. Giving SARS a name gave it a reality that it did not previously have. The name is inelegant and uncomfortably reminiscent of several other medical acronyms including AIDS. However, like AIDS, the term, if not the disease, may be here to stay. For the web aficionado and the scientist alike, the word SARS gave us something to search on, a new entry into the public lexicon, and an entity of which to keep abreast. Reliable web sites of the CDC, the WHO, the Program for Monitoring Emerging Infections (ProMED), and others posted daily updates and have gone far to keep the public informed. For the technically minded, rapid publication in scientific journals and electronic journals have allowed us to scrutinize the data behind the assertions. The press has done a remarkable job reporting on SARS even in the midst of the war in Iraq. They share a diversity of angles, a spectrum of opinions. Two cautionary inquiries should be asked regarding this ample reportage. First, is this coverage overly dramatic? In that regard, time alone will provide the most clear-sighted evaluation. Second, will this barrage of information blunt the public’s response to the dramatic series of events that is daily unfolding? Clearly, in our stroboscopic world of media blitz, this is already beginning to happen.

The evidence needed to conclusively establish the microbiological cause of a syndrome is often difficult to obtain. In the case of SARS, a variety of respiratory viruses including influenza, paramyxo, metapneumo, and corona provided a string of suspects. Most recently, the evidence indicting a coronavirus seems to be rather unassailable.

Nevertheless, other agents including those listed may be involved in some cases of SARS-like disease, either as co-conspirators or as independent agents. Even as evidence continues to mount, it is necessary to keep our eyes open to these possibilities. One complication is the nonspecific nature of the symptoms comprising the SARS syndrome. This ensures that symptomatic or syndromic surveillance will produce numerous false alarms. False alarms carry with them economic and psychological costs. On the other hand, there are individuals who slip below the radar screen. They are asymptomatically infected and are capable of spreading the virus and the disease without getting sick themselves.

Paramount in everyone’s mind is the question of where SARS is heading. Here again precedent offers limited guidance. I have often shown my students pictures of people taken during the 1918–1919 influenza epidemic. These photos depict individuals carrying out the activities of daily life wearing gauze masks to protect them from the ravages of the dread epidemic. There is always the sense of a bygone time and a sense of helplessness that modem science would never again permit such a situation. How ironic that such images now adorn the papers every single day. Do we know whether such masks are effective against such tiny agents of disease? Some well-fitted masks such as the N95 have been shown to be effective in preventing infection by bacteria such as tuberculosis. However, the role of other masks in blocking much smaller virus particles is much less clear.

The possibility exists that SARS will bum itself out or simply curtail its activities in the weeks to come. Many viruses are highly seasonal with respiratory viruses predominating in the winter months. Unfortunately, the basis for seasonality is ill-understood and SARS shows little evidence of abatement, the successes seen in Vietnam and more recently in Canada notwithstanding. The ability of these countries to contain their nascent epidemic illustrates the possibility that a combination of vigilance and luck may curb the tide of infection. Luck, whatever that may be, seems to have played a crucial role in the U.S. epidemic as well. The relatively small number of cases and the lack of mortality may simply be a prelude to the events to come. The experiences in Toronto and Hong Kong suggest that technological sophistication does not guarantee against the ravages of SARS. Moreover, as people continue to travel from place to place, viruses will accompany them. In terms of transmission, airline travel is the pathogen’s greatest ally. High tech screening for elevated temperature or respiratory systems is of limited use. During most of its estimated ten days of incubation, the SARS virus is completely asymptomatic and invisible, moving stealthily with its host. The fact that viruses are not transmissible through most of their incubation gives rise to both the promise and specter of quarantine as a mechanism of containing the epidemic. The existence of asymptomatic shedders makes this situation even more difficult.

Even if the epidemic were to be contained, there is the possibility that it could reemerge in the future. And what about other viruses? The number of viruses that commonly infect humans is low — a few hundred depending on how one does the accounting.

Unfortunately, every creature has its own cadre of viruses. Among this myriad microbiological zoo, there are surely many more that are capable of making the biological leap from nonhuman host to humans. Current scientific sophistication is not equipped to prevent this process, but we may possess the tools to detect these events and contain them as quickly as possible.

Like the situation in Iraq, SARS is a high-tech war being fought in a way that could not have been imagined a decade or two ago. The speed of sequencing of the SARS virus has been compared to the speed of sequencing HIV 20 years ago. This is an unfair comparison given the differences in technology. In fact, this discrepancy poignantly attests to how remarkably far molecular biology has come in two decades. (This is not meant to minimize the kudos for the UCSF and Toronto teams on their expeditious work.)

For viruses, like the one that has been associated with SARS, variation is generated when numerous mistakes are made as the virus copies its biological information. Such changes have the potential to alter virulence, modulate transmission rates, and overcome the effects of antiviral drugs, and even vaccines. Such promiscuous change is constrained, however, by the need to retain the essential viral abilities to infect, reproduce, and transmit from one individual to another. Analysis of sequence information may provide insights into how the SARS virus made its way into the human population.

The question of where SARS came from is of more than academic importance. Sophisticated molecular techniques have quickly revealed some of the virus’ inner secrets. Researchers at the University of California, San Francisco were able to pull a minute biological needle out of a haystack of pathogens producing the first evidence that SARS was caused by a member of the corona or crown virus family. These viruses take their name from the appearance in highly magnifies images taken in the electric microscope. In humans, the known coronaviruses cause a large fraction of colds, second only to the human rhino (or nose) viruses. Other coronaviruses have been more tentatively linked to instances of human diarrheal disease. Further analysis of the virus’ genetic information revealed that it is not a mutation of a known human virus. Situating the SARS virus within the coronavirus family suggests that it originated as a virus of another, as yet to be determined, host. Discovering the host would provide clues as to how and why the virus emerged and whether or not it is likely to reemerge. Ecological investigations in the Guangdong Province are most likely to provide the relevant clues.

The genetic sequences of the SARS virus also suggest that is unlikely to be the product of deliberate manipulation or bioterrorism. Moreover, molecular sequence information is generating interesting hypotheses as to why certain individuals, so called “superspreaders”, are more likely to spread the disease than others. Another molecular mystery that has yet to be solved is the question of why this corona virus is so severe and even deadly compared to its rather benign relatives. One interesting possibility is that our immune systems overreact to this novel pathogen so that our own bodies may paradoxically contribute to the development of severe disease.

Adherents of coronavirus biology have suddenly found themselves in great demand. Even among the viruses, coronaviruses employ ‘some rather unusual means of expressing their genes. It is likely that a deep appreciation of these strategies will be confined to a relatively small group of aficionados and students of virology. As in the case of HIV, however, it is possible that the unique nature of its strategies may be the virus’ Achilles heel. Ultimately, such molecular insights will provide information vital to the development of new antiviral agents aimed at coronaviruses in general and the SARS virus in particular. This information may even be instructive in the construction of vaccines aimed at preventing infection. In any event, there is likely to be a flood of funding aimed at coronavirus research in the years to come.

Unfortunately, vaccines hold no promise for the near future. Vaccine candidates may be generated with great facility. For instance, one may emulate Jonah Salk and simply inactivate the virus with any of a number of techniques. The inactivated virus could be given to recipients to prime their immune system. That is the job of a vaccine- to trick the immune system into generating a protective response, the kind that is usually only found in individuals who have been exposed to the virus and survived an infection with that particular pathogen. Another strategy entails generating a weakened, though still replication-competent, form of the virus. A third strategy involves removing part of the virus’ genetic information, cloning it in a microorganism, such as bacteria, or yeast and using them as tiny factories to generate industrial quantities of the viral proteins to be used in the vaccine. However, the testing and regulatory hurdles to developing a vaccine are manifold. For those rare candidate vaccines that make it through this arduous process, the lag time between development and licensure is often ten years or more. Despite its menacing nature the current incidence of SARS infection worldwide is low. Given these numbers and a very uncertain future, will there really be a market for such a vaccine? Where and who would use it? The Rotashield vaccine against rotavirus is the only viral vaccine to be licensed in the last five years and it was quickly pulled from the market due to a rare complication known as intussusception.

Similarly, the use of medicines is no short-term panacea. The growing armamentarium of antiviral agents does not include any that are specifically designed to combat coronaviruses. Existing agents hold no hope in terms of stemming the tide of the epidemic. A few of the existing agents such as ribavirin should be tested for the possibility that they may limit mortality in the most severe cases. Innovative delivery methods may increase the effectiveness of these existing agents. Newly developed agents, even ones with great potential would need to go through a battery of tests before they would be available for routine use in humans.

Another frequent inquiry has to do with the stability of the virus in the environment. Similar concerns have been ubiquitous in the HIV field. Most viruses are not particularly hardy and do not persist outside the body. Recent studies on corona viruses suggest they may be able to persist for several hours. Even newer studies on the SARS virus suggest that it may be able to persist for up to a day. However, these studies have a number of shortcomings. First the studies are few in number and surely need further validation. Second, they look at the ability of the viruses to grow in a laboratory dish and do not address the likelihood that such viruses could initiate infection. Third, the actual results depend on the particular conditions chosen for the experiment. Important variables may include as the amount of virus used, whether or not the sample is wet or dried, the temperature, and the humidity.

Regions associated with SARS have experienced significant alienation. The economic impact has been devastating. Canada alone has been estimated to be losing more than 30 million dollars a day. And the impact on Hong Kong has been even more dramatic. It is little wonder that this situation has led to epidemiological obfuscation by the Chinese. As a consequence, resources for containing the spread of disease are more slowly brought to bear. It is important to minimize these barriers to information flow and to more rapidly deploy containment efforts — for the benefit of everyone.

In the words of Nobel laureate Baruch Blumberg, “When public health works, nothing happens.” That is, no epidemics. This adage goes far in explaining why public health spending lacks cache. In the lulls between the infectious storms, public health infrastructure may be left to atrophy.

The emergence of SARS is a clarion call to bolster the public health system, to be vigilant concerning infectious disease, and to promote international cooperation and communication. It is also an opportunity to fortify the existing tools against infectious disease and to motivate us to make inroads against those diseases toward which we have become complacent.

Robert David Siegel, M.D., Ph.D.
Associate Professor (Teaching)
Department of Microbiology and Immunology and
Program in Human Biology
Stanford University

May 1, 2003