Pandemic Influenza: A Catastrophe in Waiting?

“Bird Flu” has recently become a household word. Experts warn that the world is unprepared for an avian influenza pandemic. President Bush met recently with leaders of pharmaceutical companies to discuss vaccine-production issues. Officials from international organizations have been meeting to determine ways to fight a pandemic that at least some experts already believe is inevitable.  

Although many people still consider influenza, also called “the grippe,” more a nuisance than a serious illness, it can be deadly. More than 30,000 Americans die annually from this disease. The three great influenza pandemics of the 20th century (Spanish Influenza in 1918, Asian Influenza in 1957, and Hong Kong Influenza in 1968) affected up to one-third of the world’s population and produced staggering numbers of deaths. It is impossible to predict if the current strain of avian influenza will make the jump to the human population – and, if it does, how severe the consequences would be.  

Current U.S. government worst-case mortality figures are 1.9 million fatalities, with 200,000 dead a “best case” scenario. In any case, it is reasonable to assume that at some time not too far into the future another influenza pandemic will occur, and the results could very well be as catastrophic as any other disaster, natural or manmade, in modern history. Prudence dictates an organized approach to preparedness and response on the part of government at all levels, emergency managers, public health officials and medical professionals, and the general public as well.  

Epidemics occur all the time. An epidemic is a sudden increase, within a defined geographic area, in the incidence of a particular disease above the normal levels. Pandemics have three characteristics that distinguish them from epidemics. First, they are global in nature, affecting people over the entire world. Second, they spread rapidly in progressive “waves” – typically over a year or so, sometimes longer, sometimes less. Finally, they are caused by particularly virulent organisms that affect large segments of the population. Pandemics are rare events that result in widespread illness, death, and both social and economic disruption.  

Virology 101 and the Early Years of H5N1 

Of the three types of influenza viruses – A, B, and C – Influenza A viruses are of the greatest concern because they are capable of mutating at an alarming rate and they can infect many species of animals. Influenza A subtypes are identified and designated by protein markers on their coats – e.g., H1N1, H4N7, etc. All Influenza A viruses exist in aquatic migratory birds.  

Influenza A viruses mutate in two different ways. “Antigenic drift,” which is caused by small changes in their DNA structure during replication, occurs frequently and gives birth to a “new” virus. Prior immunity may not totally protect a human against infection from this changed virus. It is largely for that reason that annual influenza vaccinations are recommended – but effective vaccines can be developed only after the prevalent types of modified viruses have been identified, and this usually is not possible until at least a few months after an outbreak begins.  

“Antigenic shift,” a more worrisome type of mutation, occurs when a host is infected concurrently by different subtypes of the Influenza A virus. When that happens, whole segments of DNA may be exchanged. If the “new” virus contains significant genetic material to which the unwitting and unwilling “host” to the virus has never been exposed, the host species will have no immunity to the disease. If the new virus is particularly virulent, the disease may be fatal. Even worse is the fact that, if the new virus retains characteristics that facilitate transmission, the disease will spread easily and rapidly. When all of these occur, the result will be a pandemic.  

The Highly Pathogenic Avian Influenza or H5N1 virus, first identified in 1997 but not widespread throughout Southeast Asia until recently, is of significant concern to the medical community – and to governments all over the world – for several reasons. Highly Pathogenic Avian Influenza viruses produce a rapidly fatal disease in birds – but certain migratory waterfowl, such as geese and ducks, may harbor H5N1 infections without significant impairment, thus serving as relatively asymptomatic spreaders of the disease.   

Although once considered an exclusively avian virus, H5N1 has caused disease in other species, including humans (but not yet, so far as is known, through human-to-human transmission). For antigenic drift to occur, pigs usually have been the species that have been co-infected with human and avian influenza viruses. That does not seem to be the transmission chain for the H5N1 virus. The human disease caused by this virus is particularly lethal, and tends to more severely affect different segments of the population – e.g., children and young adults – than are affected by typical seasonal influenza. Moreover, unlike other “typical” cases of influenza, H5N1 viruses cause a primary viral pneumonia, and also seem to have developed a resistance to many antiviral drugs. Finally, so far as can be determined, the human population has never before been exposed to H5N1 influenza viruses, so it seems likely that the human vulnerability to infection following exposure to H5N1 will be almost universal.  

Needed: An All-Options Preparedness and Response Plan

It is clear that the necessary ingredients for an influenza pandemic already exist. The primary wild cards in the equation are the timing and resultant magnitude of the catastrophe. Moreover, there is an important piece of the puzzle missing – namely, that public health officials are uncertain why H5N1 has not yet undergone antigenic shift. If a shift occurs in the future, there probably will be no way to quickly predict the resultant transmissibility or virulence of the hybrid virus, compared to what is now known or likely to be known about either of the original viruses. This lack of certainty is the principal cause of the wide variability in predictive models – on rate of spread, for example, and overall lethality – of any pandemic that might occur.  

Several facts already seem obvious: First, not planning for a pandemic cannot be an option – the potential consequences are too great. Second, the likelihood of a pandemic affecting all the peoples of the world is a truly international issue of the highest magnitude that requires international – as well as, within the United States itself, federal, state, and local – cooperation and, it is hoped, solutions or at least partial solutions. Third, whatever preparedness and response requirements are developed to protect humans from this potential catastrophe are likely to be adaptable to other disasters or public-health emergencies, and thus provide an incentive for dual-benefits solutions. Fourth, there is no “magic bullet” that will with absolute certainty prevent a pandemic. Finally, all medical and other options must be considered, because it probably will take combinations of varying options to mitigate and respond if a pandemic does evolve.  

The logical question that now arises is a simple one: What can be done? In fact, a lot is being done, at all levels of government – international, federal, state, and local. Still, many public health experts warn that many of the actions taken thus far are too little, and may be too late as well. Following is a composite list – not necessarily in order of importance – of what most if not all of these same experts consider to be among the most effective initiatives, within the parameters indicated, that might be undertaken to improve national and international preparedness and response capabilities.  

1. Public information and education. The public must be much better educated about the manifestations and risks of influenza epidemics and pandemics as well as the measures that can and should be taken to reduce risk. The information provided should include advice on basic hygienic behavior, personal protective actions recommended, and forewarnings of the government actions likely should an outbreak be detected.  

2. The prevention of disease in domestic bird populations. Various truly heroic measures that already have been taken in Southeast Asia to prevent H5N1 disease in domestic birds have had only limited success thus far, and it may be impossible to eliminate disease in the wild bird population. There are, though, a number of “holding” strategies – e.g., the wholesale vaccination of domestic chickens that is being instituted in Vietnam – to delay subsequent waves of outbreaks. A similar strategy may not be needed globally at this time, but should be included in the armamentarium of those responsible for disease control within the poultry industry. Farms and other sites – poultry manufacturing and processing chokepoints are perhaps the most important example – where there are significant numbers of domestic fowl must be required to create and be ready to implement a graded response plan geared to current national and global H5N1 conditions.  

3. Animal disease surveillance. A close review of previous pandemics indicates that even the most draconian containment measures will at best only slow the progression of a pandemic. Migratory fowl infected with avian influenza have already been found in Russia, Turkey, and other countries outside Southeast Asia. It is unlikely in any case that any containment measures that might be implemented would prevent the spread of H5N1 to North America. Because H5N1 can infect, and already has infected, many animal species, the surveillance and immediate investigation of unusual disease patterns in domestic or wild animals may offer some limited or temporal protection against further spread. That surveillance must be conducted at all international ports of entry as well as within a country’s own borders.   

4. The rapid containment of animal outbreaks. An outbreak of H5N1 in a domestic flock would be devastating economically and in a number of other ways. Millions of domestic fowl already have been destroyed in Southeast Asian in an attempt to control the spread to unaffected flocks. Similar slaughters would be a likely mainstay of containment in other countries. In the United States, the poultry industries have developed a number of graduated plans that include the culling of vulnerable flocks. Inadequately addressed, however, are the large numbers of farms and households that maintain small flocks for personal consumption and are not part of the national poultry industry per se. Government oversight agencies must develop programs to prospectively identify these farms and households – prior to an outbreak, of course – and include them in the educational, surveillance, and potential culling operations that are or might be required. In addition, because H5N1 may affect other animals, those devising and refining the containment programs would be well advised to ensure that the actions recommended (or possibly mandated) are adaptable to other domestic species of animals as well. Finally, even those communities that are not considered part of the nation’s major agrarian industries should have their own parallel programs in place.  

5. Medical surveillance. All states as well as the federal Centers for Disease Control and Prevention (CDC) already have medical surveillance systems in place. However, the historic record shows, unfortunately, that accurate and timely disease reporting has been less than ideal. Many communities are now evaluating the value of so-called “syndromic surveillance” systems, in which data is provided not by final diagnosis but by the symptoms of patients cared for in doctors’ offices and/or emergency departments. A few communities are evaluating the possibility of instituting more sophisticated systems that might include, for example, the accumulation of data from such diverse sources as pharmacies, workplaces, and schools. These newer systems probably would not detect initial human cases, but may have value by helping to rapidly identify the leading edge of an outbreak, thereby facilitating the earlier institution of response measures. For these and other systems to work, providers and healthcare systems must use interoperable systems that possess many and diverse data-collection points. To be as effective as possible, however, the data accumulated must be reviewed, collated, and analyzed on a real-time basis.  

6. The continuation of vaccine and antiviral medication research and development, the streamlining of approval processes, and the improvement of production and distribution. The cornerstone of disease prevention, and of pandemic eradication as well, will most likely be widespread vaccination – assuming that a vaccine can and will be developed, approved, mass produced, distributed, and administered in time to a sufficiently large segment of the population, a long but necessary series of actions that could not be carried out during previous pandemics. The development of a vaccine against human-variant H5N1 will have to await the detection of initial cases, of course. However, the machinery and processes most likely to be required can be in place well ahead of time, enabling governments to rapidly ramp up production once the vaccines needed are developed. Currently, European countries are the source of about 70 percent of the world’s vaccine production. If all of the U.S. vaccine manufacturing resources were devoted to a single pandemic vaccine, only enough vaccine for about five percent of the American people could be produced. The enactment of federal laws providing reasonable liability protection to vaccination manufacturers is one potential way to alleviate this unsatisfactory situation. In addition, more widespread acceptance by the American people of annual vaccinations would justify the cost of building larger production facilities.   

The required approval by the Food and Drug Administration (FDA) of new vaccines can and frequently does take considerable time. There already has been some streamlining of FDA processes, though, and the president can use an Executive Order to bypass various safeguards in a declared public health emergency. Here it should be noted that the government’s well publicized smallpox-vaccination initiative met with only limited success, so it is far from certain that the general public would quickly accept an investigational new drug, even in the face of a pandemic. In any event, there must be a continuing effort to ensure safety while expediting the development, production, and distribution of effective new antiviral medications. In addition, researchers must continue to look for novel vaccines that work against multiple strains of influenza and/or target different viral processes at the cellular level. 

Antiviral medication research must receive much greater emphasis for years to come. Viruses are remarkably adaptive, and the possibility that the hybrid H5N1 will develop resistance to all existing antivirals is real. The two primary antiviral medications showing promise against H5N1 are zanamivir and oseltamivir. Most attention has been focused on the latter, both because it is taken orally (zanamivir is inhaled), and because it already has been widely used against seasonal influenza outbreaks. Here, a footnote on two important developments: (a) the welcome decision by the Swiss-based manufacturer of oseltamivir that it may soon release its patent rights; and (b) a recent announcement in Hong Kong that, although animal studies indicate that oseltamivir is effective against H5N1, the strain that produced human disease in Vietnam earlier this year is apparently resistant to that drug. (In any event, the United States currently has only enough oseltamivir to treat approximately two percent of the population if that drug is needed on short or no notice.) 

7. Implementing a prioritized vaccination campaign against anticipated annual influenza virus subtypes and the development of stratified protective measures for high-risk populations. Humans co-infected with typical influenza viruses and avian H5N1 may serve as the mixing bowl for antigenic drift. People protected (by vaccination) from developing the more usual seasonal influenzas will of course reduce the likelihood that such mixing will occur. In addition to those segments of the population – the elderly, for example – at risk for developing severe disease and those who live and/or work in exposure-prone locales (college campuses, schools, healthcare facilities, and military installations), individuals who work around domestic birds, or who may be exposed, even episodically, to wild waterfowl should seriously consider being vaccinated against the identified seasonal influenza variants. 

There are other segments of the population that may require additional physical protection. The atypical animal-to-human transmission pattern that has occurred in Southeast Asia probably does not represent the pattern that would be most likely in the United States. People who are immunocompromised, are very old or very young, are afflicted by concurrent chronic diseases, and/or work in certain occupational sectors all will be at an increased risk for contracting H5N1 or of developing the most severe cases of the disease. Should a pandemic emerge, programs that go beyond prioritized vaccinations against H5N1 and the provision of personal protective equipment (e.g., masks and gloves) must be in place well ahead of time to provide enhanced protective measures to these segments of the population. 

8. The establishment and maintenance of regional countermeasure caches. The federal Strategic National Stockpile Program has proven itself, at the national level, to be highly effective. However, many states and cities are still struggling with a number of difficult issues – involving storage and security, for example, and the distribution and dispensing of medicines and medical supplies to the local citizenry and to healthcare sites – that must be resolved before the start of a pandemic. Recently, an adjunctive program, referred to as Chempak, has been instituted to regionally pre-position certain chemical-agent antidotes. All states should consider the purchase and storing of limited caches of antiviral medications, personal protective equipment, and other critical supplies. Even if such caches could not meet all needs of the general public, rapid access to these supplies for personnel involved in critical-infrastructure operations – as well as firemen, policemen, and other emergency-services professionals – might ensure the availability of more of these individuals during the outbreak. 

9. The rapid containment of human disease outbreaks. Viral pandemics almost always progress in waves, with later waves affecting larger segments of the population with usually less (although sometimes more) virulent forms of the virus. Examination of the three twentieth-century pandemics previously mentioned indicates that even the most severe imposition of isolation (sequestration of the ill from the healthy) and quarantine (separation of people who are well but might possibly have been exposed – as opposed to those known positively not to have been exposed) has been unable to prevent progression of the outbreak. What isolation and quarantine have been able to do – most successfully in Australia during the 1968 pandemic – was to slow the progression of the later waves, creating the time needed to institute other defensive measures, including the dissemination of more and/or later and more effective vaccines. The Model State Emergency Health Powers Act, prepared for the CDC by the Center for Law and the Public’s Health at Georgetown University, has been used by many states to revise their own public health laws, including some requiring the imposition of mandatory quarantines. Here, another footnote: A panel of public health and legal experts that reviewed the success of quarantines in previous outbreaks concluded that a mandatory enforced quarantine is probably not only impossible to implement, but also creates a number of administrative, legal, and logistical problems. Nonetheless, quarantine probably should be included in the toolkits of emergency planners as at least a potential line of defense against further spread of the disease. A well educated public will most likely take certain “shielding” actions on its own initiative. Among a number of other containment measures recommended are voluntary home confinement, the mass distribution of protective masks and gloves, business “holidays,” the issuance of advisories on travel restrictions, and the temporary cancellation of mass-gathering situations – including but not limited to school functions and sports events of various types. 

10. The creation of prospectively developed plans and policies on medical surge capacities and decremental standards of care. The cornerstone of federal medical response to disasters is the National Disaster Medical System, consisting of nearly 100 general and specialty medical-response teams, a patient medical evacuation system, and cooperative agreements with approximately 2,000 hospitals that have pledged access to 100,000 acute-care beds. Unfortunately, this system was designed primarily to provide an overflow capability to augment military healthcare systems during wartime – or to provide services for large-scale regional disasters – and might be totally ineffective in a pandemic. The contractual requirements of the Metropolitan Medical Response System Program, operated by the Department of Homeland Security, would be totally inadequate in the face of a pandemic that authorities say could affect half the population and necessitate acute care, in an inpatient setting, for up to 80 percent of those afflicted with the disease. Moreover, containment measures may slow but would probably not prevent a pandemic. 

A related Medical Reserve Corps initiative has thus far received limited funding and has had only limited success. The nation’s overall healthcare surge capabilities must be greatly enhanced in any case. To do this, though, would require, among other things: the enactment of legal liability protection for volunteers; interstate medical personnel licensing and certification reciprocity; and the creation of prospectively developed registers of physicians, nurses, emergency medical technicians, and other healthcare professionals (including those who have either retired, left the active workforce, or are in training). Methods to use non-professional volunteers, after providing them just-in-time training, also must be sought. Job-action sheets and standardized protocols must be prepared in advance. Even if all these steps are taken, the surge capability available is still likely to be inadequate and the extremely difficult problems of medical triage and the stratification and provision of decremental healthcare by “routine” standards would have to be addressed well beforehand so that policymakers and providers would not have to face the same issues during a pandemic. 

To many experts, the threat of an influenza pandemic is as great as, if not greater than, the threat of a terrorist attack involving nuclear or even biological weapons. As recent hurricanes and earthquakes have demonstrated, the history of mankind is replete with natural disasters and public health emergencies of various types that dwarf the effects of manmade catastrophes, accidental or intentional. Modern science and the nature of the current H5N1 Avian Influenza have given the world the opportunity of being better prepared than was possible before or during any previous pandemic. Some positive strides forward have been and are being taken. Whether they are sufficient remains to be seen. 

Jerry Mothershead

Dr. Jerry Mothershead is the Physician Advisor to the Medical Readiness and Response Group of Battelle Memorial Institute. An emergency medicine physician, he also is adjunct faculty at the Uniformed Services University of the Health Sciences in Bethesda, Md. A graduate of the U. S. Naval Academy, Dr. Mothershead served on active duty in the U.S. Navy in a broad spectrum of clinical, operational, and management positions for over 28 years, and has served in an advisory capacity to numerous local, state, and federal agencies in the fields of antiterrorism, disaster preparedness, and consequence management.

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