>>“SARS is a new, virulent, highly contagious respiratory viral epidemic. Available evidence and well-documented historical precedent suggest that this disease has the potential of becoming the most catastrophic medical disaster ever to befall humanity. Only the Black Plague of the 14th century will likely prove worse on a percentage basis. No other event will have ever caused so many numbers of deaths. Only the Pandemic of 1918 provides a suitable comparison and precedent.” <<
From "SARS: What We All Need to Know" a highlight:
>> April 7, 2003
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SARS: What we all need to know
Steven T. Coulter, MD
Introduction
As I write this, a new epidemic is just starting to sweep the globe. Called SARS, it was first identified in early March, 2003 in Hong Kong. Later investigation proved it to be a spread of an ongoing epidemic in Guangdong province, China, that appears to have started in November 2002. From there, it has hit Hong Kong first and hardest, with Vietnam, Singapore, and now Canada being hit in sequence. Public schools have been closed in Hong Kong; Toronto has had to close at least two hospitals. As of April 5, the CDC is reporting 2416 cases globally to date, with 89 deaths. Of these the United States accounts for 115 cases and zero deaths. Of note, the US uses a different case definition than does WHO. It is not yet clear to me whether use of the WHO definition would yield a higher number of cases and deaths for the US. Various travel restrictions, and quarantines are in effect in various areas of the world. Tourism to affected countries has plummeted. Ten days earlier the numbers were 1323 cases and 49 deaths, yielding a case rate and death doubling time of just over 10 days, as well as a death rate of 3.7% for both points in time.
Biologically, the hunt for the causative organism has been a compelling story of its own, though already, most of that story is of historical interest only. We now know with fair certainty the causative organism is a new virus of the coronavirus family. This has been familiar to clinical virologists as primarily just a cause of the common cold. However, in various animal species, corona viruses cause very contagious and quite lethal infections. Partial genome analysis of the SARS virus has, by report, revealed a mix of human, mouse, and cow coronavirus DNA. There is still some talk that the clinical disease could be a result of co-infection with both this virus and a respiratory strain of chlamydia, or perhaps another virus, though this hypothesis seems to be generally in disfavor. I find it implausible as well, though not impossible.
I am a residency trained Family Physician. For the past 13 years, I have spent a good portion of every winter caring for patients with respiratory infections of varying severity. I’ve been fascinated by the illness of influenza. Every winter there is a flu season, and each season has different characteristics. Some winters, the nursing homes are hit hard and hearses are a frequent visitor there. One recent winter, I saw no cases in people older than 35. Children of ages 0 – 12 almost always make up a good portion of the total, though they tend to recover faster. Sometimes cases start showing up as early as October, not unfrequently, few cases arise before New Year’s Day. Generally, deaths are rare and limited to the quite elderly and infirm. Duration of illness can vary from about 3 days to 2 weeks. But after such a significant respiratory tract infection, many people continue to have ongoing trouble with cough or wheezing for weeks, even a few months.
Although there is a virus called “influenza” (of types A or B), the clinical illness “influenza” isn’t quite synonymous. Through history until now, doctors have relied on signs and symptoms to diagnose the disease. Although viral cultures (and now more rapid diagnostic tests) have been available, they’ve been infrequently used, mostly because the results haven’t been helpful in guiding treatment or predicting outcomes. Most clinical cases of the disease “influenza” are, indeed caused by the “influenza virus,” but the syndrome can be caused by many other agents, including parainfluenza virus, and many other myxoviruses.
The distinction between the virus and the disease (syndrome) of the same name is a bit confusing but important to understand. In terms of the clinical impact of the untreated disease, the precise virus responsible isn’t directly relevant. Any virus that causes the clinical disease can hit you the same way, regardless of what classification of virus it falls into. All of these respiratory viruses tend to be quite contagious. All these viruses both within and outside the “influenza” category can vary by strain in terms of contagiousness, typical symptoms, and severity of disease.
The classification of the precise virus responsible in an epidemic is important mostly for guiding treatment and for some prevention efforts. We have some antiviral medications against some viruses, but different ones work on different viruses. For influenza viruses, isolates are used to manufacture the annual vaccine. SARS, then, is a virus that causes severe “influenza syndrome” but is not in the “influenza virus” category. We can better understand what’s in store with the SARS epidemic by understanding the aspects of the syndrome that have no basis in virus classification, and aspects of this corona virus that are unique to the family of corona viruses.
Through my medical career, I’ve been also been fascinated by stories of the Spanish Flu, or Great Influenza Pandemic of 1918. It was a global epidemic of infection by a virus that was “just” influenza, but it struck with a fury and virulence that humanity had never witnessed before. In one winter, 20 to 40 million people died. The suffering and loss was enormous, but perhaps more alarming was the effect on society of being afflicted with an unfightable, invisible killer. You’ll find references to the episode here; be careful, some of the anecdotes are the stuff of nightmares.
Every year, I’ve scoured reports of the annual influenza epidemics, watching for signs of a repeat of what happened in 1918. In 1996, there was a scare of a new chicken-related influenza virus in China that killed upwards of 30% of those infected—ten times more lethal than the Spanish Flu. Fortunately for humanity, it proved not to be contagious, and only a handful of unfortunate souls lost their lives. It didn’t spread.
We need to understand that the virulence of an organism (its likelihood of killing) is not necessarily related to how contagious it is. Humanity has been incredibly blessed that almost all infections that are quite lethal are hardly at all contagious (with the exception of the mostly conquered diseases like smallpox, measles, rubella, polio, and dysentery- causing agents that can be controlled through sanitation). The highly lethal diseases (such as Ebola, various hemorrhagic fevers, and some bacterial ones like meningococcal meningitis) are only very slightly contagious.
But, there is absolutely no reason why a new, highly contagious respiratory virus could not also be quite lethal. That happened in 1918, and may be happening again with SARS. Respiratory viruses are not controlled by routine sanitation measures (clean water, clean food, and proper processing of human waste). Can modern science and technology help us here? Maybe, but there is NOTHING “off the shelf” we can use against SARS so far. The view from the animal world of respiratory coronavirus infections is not encouraging.
What worries me deeply is that the SARS epidemic is showing signs of being roughly as severe an epidemic as in 1918, maybe somewhat less severe, perhaps significantly worse. I believe the evidence points to this being more contagious than the 1918 epidemic, not less. Certainly the syndrome is not significantly different among affected individuals, and pretty clearly no less lethal now than the 1918 catastrophe. I think the possibility of social disruption is worse now than what happened in 1918. I believe every adult needs to be prepared.
The Historical Precent – The Great Influenza Pandemic of 1918
I’ve made some references to the Pandemic above. I believe we can’t begin to properly imagine what the SARS epidemic could be like in the coming months without understanding what happened in 1918. I’m mystified and fascinated by the fact that this second-greatest medical catastrophe in human history (after the Black Plague) so quickly dropped from world consciousness once the epidemic passed. Just about everyone has seen movies set in WW I, but few have any awareness of the concurrent epidemic that killed ten times as many Americans in a much shorter time – one winter.
The Pandemic could be subject of a massive multi-volume work and still be fascinating. In the interest of maintaining a focus on SARS, I’ll limit my comments and provide some references. The Pandemic killed 2.5% of cases (see second link below). The current global death toll from SARS so far is remarkably consistent over time at about 3.7% (see WHO web site for total cases and total deaths at various points in time). SARS is more lethal than the Spanish Flu.
The link below provides some chilling anecdotes, only a few shall I discuss. In the winter of 1918, deaths across the country were so overwhelming that there was a critical shortage of coffins. Funeral home owners hired armed guards to protect their supply. In Philadelphia, graves couldn’t be dug fast enough; they had to use steam shovels. Hospitals were overwhelmed and most people just died at home or on the street. Face masks were mandated in major cities, one citizen was shot by a police officer for refusing to don his. Various quarantines and travel restrictions were put into place. None of these public health measures had noticeable effect.
I’ve been fascinated by the history of the Pandemic for perhaps twenty years. Some day, I’ll perhaps write my own book about it. But my understanding of what it was like for society in 1918 was most profoundly informed by a PBS documentary, “Influenza 1918,” produced by the series “The American Experience.” You can buy it for about $20 at: dde.liverpool.k12.ny.us
For a good on-line description of the epidemic you can check out:
stanford.edu
SARS – Clinical picture
Here, lifting from the CDC web site will serve to describe what the illness is like:
As of March 21, 2003, the majority of patients identified as having SARS have been adults aged 25--70 years who were previously healthy. Few suspected cases of SARS have been reported among children aged <15 years.
The incubation period for SARS is typically 2--7 days; however, isolated reports have suggested an incubation period as long as 10 days. The illness begins generally with a prodrome of fever (>100.4°F [>38.0°C]). Fever often is high, sometimes is associated with chills and rigors, and might be accompanied by other symptoms, including headache, malaise, and myalgia. At the onset of illness, some persons have mild respiratory symptoms. Typically, rash and neurologic or gastrointestinal findings are absent; however, some patients have reported diarrhea during the febrile prodrome.
After 3--7 days, a lower respiratory phase begins with the onset of a dry, nonproductive cough or dyspnea, which might be accompanied by or progress to hypoxemia. In 10%--20% of cases, the respiratory illness is severe enough to require intubation and mechanical ventilation. The case-fatality rate among persons with illness meeting the current WHO case definition of SARS is approximately 3%.
Chest radiographs might be normal during the febrile prodrome and throughout the course of illness. However, in a substantial proportion of patients, the respiratory phase is characterized by early focal interstitial infiltrates progressing to more generalized, patchy, interstitial infiltrates. Some chest radiographs from patients in the late stages of SARS also have shown areas of consolidation.
Early in the course of disease, the absolute lymphocyte count is often decreased. Overall white blood cell counts have generally been normal or decreased. At the peak of the respiratory illness, approximately 50% of patients have leukopenia and thrombocytopenia or low-normal platelet counts (50,000--150,000/µL). Early in the respiratory phase, elevated creatine phosphokinase levels (as high as 3,000 IU/L) and hepatic transaminases (two to six times the upper limits of normal) have been noted. In the majority of patients, renal function has remained normal.
The severity of illness might be highly variable, ranging from mild illness to death. Although a few close contacts of patients with SARS have developed a similar illness, the majority have remained well. Some close contacts have reported a mild, febrile illness without respiratory signs or symptoms, suggesting the illness might not always progress to the respiratory phase.
Treatment regimens have included several antibiotics to presumptively treat known bacterial agents of atypical pneumonia. In several locations, therapy also has included antiviral agents such as oseltamivir or ribavirin. Steroids have also been administered orally or intravenously to patients in combination with ribavirin and other antimicrobials. At present, the most efficacious treatment regimen, if any, is unknown.
In the United States, clinicians who suspect cases of SARS are requested to report such cases to their state health departments. CDC requests that reports of suspected cases from state health departments, international airlines, cruise ships, or cargo carriers be directed to the SARS Investigative Team at the CDC Emergency Operations Center, telephone 770-488-7100. Outside the United States, clinicians who suspect cases of SARS are requested to report such cases to their local public health authorities. Additional information about SARS (e.g., infection control guidance and procedures for reporting suspected cases) is available at cdc.gov. Global case counts are available at http:// www.who.int.
Forecasting the epidemic
As of early April 2003, predicting what will happen with this evolving epidemic is not entirely straightforward. But reasonable estimates can be arrived at with somewhat greater reliability than a mere wild guess. When an infectious agent first enters a susceptible population, sustained progressive spread is observed at an exponential rate, until a substantial proportion of the population becomes unavailable for new infection (via death, recovery, or new exposure control interventions). “Exponential” growth of the epidemic means that the numbers of infected patients doubles every so many days.
Is SARS showing such exponential growth? Yes, unequivocally. Consider that the very first case is considered to have been diagnosed on November 16, 2002. As of April 5, there were 2416 cases. At multiple points in time (as per the WHO web site who.int ) the growth of the epidemic follows a doubling time of 11 – 13 days quite consistently. The death rate is remarkably stable at about 3.7% Sustained epidemic behavior over more than four months is the best evidence that such exponential growth will continue for some time.
Since the epidemic is global, and since control methods have not changed substantially since early March (i.e., measures have shown no demonstrable effect in altering doubling time) we can reasonably predict continued exponential growth with cases and deaths doubling every 11 – 13 days until a significant fraction of the world’s population is exposed, or until new and effective interventions are instituted. Since deaths have been a fairly constant proportion of cases, we can expect numbers of deaths also to double every 11 – 13 days, as they have to date.
This relatively simple analysis (some might say “simplistic”) certainly is subject to modification by a host of factors not considered above. I believe the most important consideration is the observed behavior of respiratory virus epidemics in general. We can take a page from the annual influenza virus epidemics that cover the globe. We consistently see negligible growth in numbers of infections from late spring until autumn. Influenza infections are rare over this period of time, and identified cases don’t result in notable spread. But when winter arrives, that low level of smoldering infections starts to take on exponential growth until reaching a peak, typically somewhere around January each winter. The reason for this seasonality in contagiousness of respiratory virus is not known. Multiple hypotheses have been stated (and I have a few of my own), but regardless of the reason, we can expect that this will affect the dynamics of the SARS epidemic.
Indeed, looking again at the historical precedent of 1918, sporadic cases were observed from early March 1918 through the summer. The epidemic didn’t achieve explosive growth until the arrival of cold weather.
Applying these observations to the SARS epidemic, it is alarming that exponential growth has been sustained through March and into April. Nevertheless, if seasonal trends apply, we can probably anticipate some slowing through the summer, but likely acceleration again in the autumn and winter. Absent new kinds of interventions, we can anticipate something on the order of 100 million global deaths by January 2004. I certainly hope I’m wrong, but given that we have several months of good statistical data AND a well-documented historical precedent, I’m not optimistic.
Prospects for control of the SARS pandemic
We have lots of experience fighting a number of different viral infections. We should consider the potential for various approaches to have an impact on the dynamics of the SARS epidemic.
1. Public health interventions. For many viruses, sanitation, quarantine, and isolation of infectious individuals can have a major impact. The various agents that cause gastroenteritis (bacterial and viral) are excellent examples. Unfortunately, there is no precedent for successful control of highly contagious respiratory viruses through such measures. The annual influenza epidemic is the best example of repeated failure. Explosive spread every winter is the rule, despite annual admonitions about staying home if sick, washing hands, using tissues for coughing, etc. Fairly rigorous quarantines, travel restrictions, mandatory face masks, and hygiene laws were passed and enforced in the 1918 epidemic. They had no observable effect on spread.
Indeed, some small towns instituted strict self-quarantines in 1918 prior to arrival of the epidemic. The epidemic came anyway, perhaps via the postal service. Mandatory wearing of face masks had no effect.
That last point is worth expanding upon. Surgical masks have become widespread in China, Hong Kong, and Vietnam in response to the epidemic. Some are touting the use of high-efficiency filtration masks that might more effectively filter out the SARS virus. There is no evidence of efficacy. It is clear from basic research on respiratory viruses that although some individuals can be infected by direct inhalation of virus, most infections happen by our contaminated hands touching our face, with entry of virus through the eyes, nose, or mouth. Touch a contaminated elevator button, and then rub your eye, pick your nose, or pop a tic-tac in your mouth. Bingo, you’re infected. Touching our faces with hands that are not freshly washed is probably the most important common denominator with spread of respiratory viruses. From personal experience, I know that we touch our faces more, not less, when we wear surgical masks. They can be anticipated to be counter-productive.
2. Antiviral medication. It is certainly well-known that antibiotics have no effect on viruses, including corona viruses such as SARS. Less well-recognized is that there are a number of anti-viral medications with activity against a number of known viruses. There are a host of drugs in use against the AIDS virus, for example. There are even drugs available for influenza and a few other viruses, such as amantadine, rimantadine, and the broader-spectrum agent ribavirin. Alas, these have no effect on coronaviruses, and the CDC has reported that the SARS agent is not sensitive to any known anti-viral drug.
All is not lost, however. There is some very limited animal data that interferons can help protect against many viruses, including coronaviruses. Interferons are part of the body’s natural defense against viruses, and are produced by the body naturally. Levels can be boosted through injections, or by administering agents that boost interferon production. The use of such agents in battling respiratory viruses is unknown territory in humans. Yet, this is certainly one avenue worth vigorous expedited research.
3. Vaccine development. There is good and bad news here. Several contagious, lethal animal coronaviruses have plagued commercial animal production for decades. Perhaps the agent most analogous to SARS is the coronavirus that causes “Avian Infectious Bronchitis.” The veterinarians have done a fairly vast amount of research on this virus over the past few decades. No medications appear to be of help, but diagnostic tests have been developed and vaccines have been produced. There is therefore good reason to believe that a human vaccine can be developed.
Certainly there is precedent for being able to mass-produce vaccines against a respiratory virus on an expedited basis. Every year a new mix of influenza viruses is used to produce the annual influenza vaccine. It takes roughly 8 months from isolation of the next year’s vaccine viruses to delivery of millions of doses. It will likely be a bit longer to develop a SARS vaccine, however, since nobody has ever mass-produced a human coronavirus vaccine. I’ve been told that coronaviruses grow relatively slowly in culture. Yet, with adequate resources devoted to the project, I suspect this could be done in roughly 12 months. Unfortunately, given the doubling time of this epidemic, a vaccine becoming available in 12 months could be like closing the barn door after the cow has gone.
4. Antibodies/anti-serum. The use of immune globulin in treating acute infections has become rare in recent years. But there is a huge body of historical precedent for using antibodies to treat acutely infected individuals. The annual Alaskan Iditarod dog-sledding race commemorates a valiant attempt to deliver diptheria anti-serum to a remote settlement experiencing an outbreak of diptheria. The process of preparing anti-serum is simple: an individual who has recovered from an infection typically has a high level of inactivating antibody in his bloodstream. Serum is separated from cells, and treated to inactivate known viruses. Typically a dose of a few cc’s can dramatically affect the course of infection. Precedents include rabies anti-serum, diptheria as above, anti-Rho delivered to pregnant women, and some snake venom treatments.
The modern twist on anti-serum use is to genetically engineer mouse cells to produce human-type antibodies that are free from any possible contamination with human pathogens. This avenue of treatment could conceivably be brought to fruition within a few months. It deserves devotion of major resources.
Summary
SARS is a new, virulent, highly contagious respiratory viral epidemic. Available evidence and well-documented historical precedent suggest that this disease has the potential of becoming the most catastrophic medical disaster ever to befall humanity. Only the Black Plague of the 14th century will likely prove worse on a percentage basis. No other event will have ever caused so many numbers of deaths. Only the Pandemic of 1918 provides a suitable comparison and precedent.
Several approaches for control appear feasible. The least effective is likely to be standard public health exposure control interventions. They failed in 1918 and have shown no evidence of substantially affecting the current epidemic.
Other technologies show promise, including interferon therapy, vaccine development, and monoclonal antibody production. Development of these new technologies demands immediate substantial investment of resources if catastrope of biblical proportions is to be averted. Action by congress to enable such research and development is mandatory and urgent.
Steven T. Coulter, MD, ABFP
Bethesda, MD 20814
SteveMDFP2@aol.com
Fax 301-215-7162<<
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