Is a Global Flu Pandemic Imminent?

Is a Global Flu Pandemic Imminent?

By Kelly M. Pyrek

In the past several years, the infection control community has been on high alert, dealing with bioterrorism threats as well as emerging infectious diseases such as severe acute respiratory syndrome (SARS), the influenza vaccine shortage, and most recently, watching Asian countries cope with avian influenza virus. World health officials have been watching this growing threat, pondering the eventuality of an antigenic shift from animal to human, resulting in a recombinant strain of influenza to which no one is immune. This global disaster waiting to happen has many public health experts asking not if, but when.

When someone asks, Will it happen? the answer is almost certainly, yes, says David K. Henderson, MD, deputy director for clinical care at the Warren Grant Magnuson Clinical Center at the National Institutes of Health in Bethesda, Md. But the trick is to know when, of course. At some level, it is a quirk of nature as to when these viruses recombine.

When that happens, thats when antigenic shift occurs, and thats when we get into trouble. Antigenic shift is defined as a sudden shift in the antigenicity of a virus resulting from the recombination of the genomes of two viral strains.

Antigenic shift is seen only with influenza A viruses. It results usually from the replacement of the hemagglutinin (the viral attachment protein that also mediates the entry of the virus into the cell) with a novel subtype that has not been present in human influenza viruses for a long time. The source of these new genes is the large reservoir of influenza viruses in waterfowl. The consequences of the introduction of a new hemagglutinin into human viruses is usually a pandemic, or a worldwide epidemic.

Influenza viruses are composed of an icosahedral (20-sided) protein capsid surrounded by a lipid envelope. Imbedded in the envelope are spikes of two proteins: hemagglutinin (H) and neuraminidase (N). H and N are coded for by two separate pieces of viral RNA; influenza has eight pieces of RNA total. Antigenic shift occurs due to reassortment of RNA segments from two different viral strains infecting the same cell.

According to information from the World Health Organization (WHO), All type A influenza viruses, including those that regularly cause seasonal epidemics of influenza in humans, are genetically labile and well adapted to elude host defenses. Influenza viruses lack mechanisms for the repair of errors that occur during replication. As a result of these uncorrected errors, the genetic composition of the viruses changes as they replicate in humans and animals, and the existing strain is replaced with a new antigenic variant. These constant, permanent and usually small changes in the antigenic composition of influenza A viruses are known as antigenic drift.

Influenza A viruses, including subtypes from different species, can swap or reassort genetic materials and merge. This reassortment process, or antigenic shift, results in a novel subtype different from both parent viruses. As populations will have no immunity to the new subtype, and as no existing vaccines can confer protection, antigenic shift has historically resulted in highly lethal pandemics. For this to happen, the novel subtype needs to have genes from human influenza viruses that make it readily transmissible from person to person for a sustainable period.

According to WHO, Conditions favorable for the emergence of antigenic shift have long been thought to involve humans living in close proximity to domestic poultry and pigs. Because pigs are susceptible to infection with both avian and mammalian viruses, including human strains, they can serve as a mixing vessel for the scrambling of genetic material from human and avian viruses, resulting in the emergence of a novel subtype. Recent events, however, have identified a second possible mechanism. Evidence is mounting that, for at least some of the 15 avian influenza virus subtypes circulating in bird populations, humans themselves can serve as the mixing vessel.

The biology of influenza is very well understood by the scientific and medical communities, which is a good thing, Henderson says. That means we are in a position to really understand how the virus works. But, unfortunately, we cant always predict exactly how its going to work.

Avian Influenza Infection in Humans

Several instances of human infections and outbreaks of avian influenza have been reported since 1997, according to the Centers for Disease Control and Prevention (CDC). The agency says, Most cases of avian influenza infection in humans are thought to have resulted from contact with infected poultry or contaminated surfaces. However, there is still a lot to learn about how different subtypes and strains of avian influenza virus might affect humans. For example, it is not known how the distinction between low pathogenic and highly pathogenic strains might impact the health risk to humans. Of the documented cases of human infection with avian influenza viruses, illnesses caused by highly pathogenic viruses appear to be more severe.

On Aug. 12, 2004, the Vietnamese Ministry of Health officially reported to WHO three human deaths from confirmed avian influenza H5 infection. Tests were needed to determine whether the virus belonged to the same H5N1 strain that caused 22 cases and 15 deaths in Vietnam, and 12 cases plus eight deaths in Thailand earlier last year. Cambodia, China, Indonesia, Japan, Laos, South Korea, Thailand, and Vietnam were previously affected by widespread H5N1 outbreaks in poultry during early 2004. At that time, more than 100 million birds either died from the disease or were killed in efforts to contain the outbreaks. Thirty-four human cases were reported only in Thailand and Vietnam. Beginning in late June 2004, however, new lethal outbreaks of highly pathogenic avian influenza A (H5N1) among poultry were reported to the World Organization for Animal Health (OIE) by China, Indonesia, Thailand, and Vietnam. The deaths reported by Vietnam on Aug. 12, 2004 were the first reported human cases associated with this second wave of H5N1 infection among poultry.

Because of concerns about the potential for more widespread infection in the human population, public health authorities closely monitor outbreaks of human illness associated with avian influenza. To date, human infections with avian influenza viruses detected since 1997 have not resulted in sustained human-to-human transmission. However, because influenza viruses have the potential to change and gain the ability to spread easily between people, monitoring for human infection and person-toperson transmission is important.

Instances of Avian Influenza Infections in Humans

Confirmed instances of avian influenza viruses infecting humans since 1997 include:

  • H5N1, Hong Kong, 1997: Avian influenza A (H5N1) infections occurred in both poultry and humans, the first time an avian influenza virus had ever been found to transmit directly from birds to humans. During this outbreak, 18 people were hospitalized and six died. To control the outbreak, authorities killed about 1.5 million chickens to remove the source of the virus. Scientists determined that the virus spread primarily from birds to humans, though rare person-to-person infection was noted.
  • H9N2, China and Hong Kong, 1999: Avian influenza A H9N2 illness was confirmed in two children. Both patients recovered, and no additional cases were confirmed. The evidence suggested that poultry was the source of infection and the main mode of transmission was from bird to human; however, the possibility of person-to-person transmission could not be ruled out. Several additional human H9N2 infections were reported from mainland China in 1998-99.
  • H7N2, Virginia, 2002: Following an outbreak of H7N2 among poultry in the Shenandoah Valley poultry production area, one person was found to have serologic evidence of infection with H7N2.
  • H5N1, China and Hong Kong, 2003: Two cases of avian influenza A (H5N1) infection occurred among members of a Hong Kong family that had traveled to China. One person recovered, the other died. How or where these two family members were infected was not determined. Another family member died of a respiratory illness in China, but no testing was done.
  • H7N7, Netherlands, 2003: The Netherlands reported outbreaks of influenza A (H7N7) in poultry on several farms. Later, infections were reported among pigs and humans. In total, 89 people were confirmed to have H7N7 influenza virus infection associated with this poultry outbreak. These cases occurred mostly among poultry workers. There was one death among the 89 total cases. The majority of these cases occurred as a result of direct contact with infected poultry; however, Dutch authorities reported three possible instances of transmission from poultry workers to family members. Since that time, no other instances of H7N7 infection among humans have been reported.
  • H9N2, Hong Kong, 2003: H9N2 infection was confirmed in a child in Hong Kong. The child was hospitalized and recovered.
  • H7N2, New York, 2003: In November, a patient with serious underlying medical conditions was admitted to a hospital in New York with respiratory symptoms. One of the initial laboratory tests identified an influenza A virus that was thought to be H1N1. The patient recovered and went home after a few weeks. Subsequent confirmatory tests conducted in March 2004 showed that the patient had been infected with an H7N2 avian influenza virus. An investigation to determine the source of infection is ongoing.
  • H5N1, Thailand and Vietnam, 2004: In January 2003, outbreaks of highly pathogenic influenza A (H5N1) in Asia were first reported by WHO. From Dec. 30, 2003, to March 17, 2004, 12 confirmed human cases of avian influenza A (H5N1) were reported in Thailand and 23 in Vietnam, resulting in a total of 23 deaths.
  • H7N3 in Canada, 2004: In February 2004, human infections of H7N3 among poultry workers were associated with an H7N3 outbreak among poultry. The H7N3-associated illnesses consisted of eye infections.
  • H5N1, Thailand and Vietnam, 2004: Beginning in late June 2004, new lethal outbreaks of H5N1 among poultry were reported by several countries in Asia. The new outbreaks of H5N1 in poultry in Asia were followed by renewed sporadic reporting of human cases of H5N1 infection in Vietnam and Thailand beginning in August. Of particular note is one isolated instance of probable limited human-to-human transmission occurring in Thailand in September.

Symptoms of Avian Influenza in Humans and Antiviral Agents

The reported symptoms of avian influenza in humans have ranged from typical influenza-like symptoms (e.g., fever, cough, sore throat, and muscle aches) to eye infections (conjunctivitis), pneumonia, acute respiratory distress, viral pneumonia, and other severe and life-threatening complications.

Four different influenza antiviral drugs (amantadine, rimantadine, oseltamivir, and zanamivir) are approved by the Food and Drug Administration (FDA) for the treatment and/or prophylaxis of influenza. All four have activity against influenza A viruses; however, sometimes influenza strains can become resistant to these drugs, and therefore the drugs may not always be effective. For example, analyses of some of the 2004 H5N1 viruses isolated from poultry and humans in Asia have shown that the viruses are resistant to two of the medications (amantadine and rimantadine). Monitoring of avian viruses for resistance to influenza antiviral medications is ongoing.

Influenza Pandemics: Can They be Averted?

Based on historical patterns, influenza pandemics can be expected to occur, on average, three to four times each century when new virus subtypes emerge and are readily transmitted from person to person; however, the occurrence of influenza pandemics is unpredictable. In the 20th century, the great influenza pandemic of 19181919, which caused an estimated 40 to 50 million deaths worldwide, was followed by pandemics in 19571958 and 19681969. Experts agree that another influenza pandemic is inevitable and possibly imminent, which was part of the reason why the temporary influenza vaccine shortage may have caused such a furor late last year.

Theres nothing new about people only wanting the flu vaccine when they couldnt get it, Henderson says. Those of us whose hair has had the opportunity to turn gray remember pandemics from the past. Pandemic influenza is a significant event for mankind. One only needs to look at the data about the impact of the 1918 influenza epidemic on lifespan in the United States, where I think it dropped from nearly 50 years of age down to about 37 or 38 in 1918, simply because of the flu. The country will need to get ready for the possibility of another pandemic, and society, I suspect might not react in the will react in the most optimal way. I think it will be a great challenge.

Henderson continues, The pandemics of Asian flu in 1957 and the Hong Kong flu in 1968 were minor pandemics, but they were in fact pandemic flu. They werent of the same magnitude as the pandemic of 1918. And Swine flu in the mid-1970s was a pandemic that just didnt happen. That was a recombinant virus from ducks through swine that killed a soldier at Fort Dix, New Jersey and created a lot of angst among the public health community, if not in the community at large, about the potential for a large pandemic of influenza.

Presentation of Influenza

So, how do clinicians and public health officials know when a potential pandemic is knocking at the front door? Signs and symptoms are really not terribly helpful, although mortality rates are a big tip-off, as is unusually severe illness, Henserson says. The real tip is the change in the virus that is being isolated from patients with the disease. So when you have an instance where the virus changes dramatically, recombines with a swine or fowl isolate, then the whole society is unprotected against that particular isolate, and thats when you get a pandemic.

Henderson explains further, There are similar signs and symptoms that have presented in pandemics of the past. Generally, a population has a fair amount of immunity against the strains of influenza we are dealing with. When both the hemagglutinin and neuraminidase are changing dramatically, then you find yourselves in a set of circumstances where no one has that kind of protection, and youre at risk for severe disease, morbidity and mortality. Not just in the classic pandemic model, with the very young, the very old and the immuno-compromised being at the highest risk, but otherwise healthy people being at substantial risk for severe complications.

WHO suggests several measures can help minimize the global public health risks that could arise from large outbreaks of highly pathogenic H5N1 avian influenza in birds. An immediate priority is to halt further spread of epidemics in poultry populations, which also works to reduce opportunities for human exposure to the virus. When cases of avian influenza in humans occur, information on the extent of influenza infection in animals as well as humans and on circulating influenza viruses is urgently needed to aid the assessment of risks to public health and to guide the best protective measures. The successful containment of public-health risks also depends on the epidemiological and laboratory capacity and the adequacy of surveillance systems already in place in affected areas.

Clinical Treatment of Human Cases of H5N1 Avian Influenza

What clinicians know about treating avian influenza in humans is restricted to data published pertaining to cases in the 1997 Hong Kong outbreak. In that outbreak, patients developed symptoms of fever, sore throat, cough and, in several of the fatal cases, severe respiratory distress secondary to viral pneumonia. Previously healthy adults and children, and some with chronic medical conditions, were affected.

Antiviral drugs, some of which can be used for both treatment and prevention, are clinically effective against influenza A virus strains in otherwise healthy adults and children, but have some limitations. Some of these drugs are also expensive and supplies are limited. Experience in the production of influenza vaccines is also considerable, particularly as vaccine composition changes each year to match changes in circulating virus due to antigenic drift. However, at least four months would be needed to produce a new vaccine, in significant quantities, capable of conferring protection against a new virus subtype. WHO officials said in December 2004 that a vaccine might be viable in mid-2005.

Flu vaccines are a challenge to make, but we have technology now that we didnt have before, says Henderson. So, its another way we can perhaps be better prepared than we have been in the past, simply because we have the technology to help us get that work done. Once the virus is known, we have recombinant technology and things we didnt have in the past to help us make a vaccine quickly. That will be a big advantage if and when the pandemic comes. Short of a pharmaceutical silver bullet, conscientious infection control practices will have to suffice, experts say.

Respiratory etiquette is a great concept that we probably should have been focusing on long before now, Henderson adds. Its a great strategy, coupled with vigilant hand hygiene. Its pretty much a common- sense approach, but after all, infection control is based on commonsense practices. But healthcare has not always done a terrific job with implementation.

As an industrialized nation with a fetish for antimicrobial products and a somewhat high level of hygiene and sanitation standards, is the United States being lulled into a false sense of security about immunity from a pandemic?

Absolutely, Henderson says. It happened here with a vengeance in 1957 and 1968. To assume that just because were an industrialized country that we wont get pandemic influenza would be setting ourselves up for disaster. Hygiene will matter, certainly. Its like any other infectious disease; anything you do to break the chain of transmission is a good thing. Hand hygiene will make a difference, and the use of alcohol handrubs will make a significant difference, but people have to actually do it.

A State of Heightened Alert

If an influenza pandemic was a color on the national security threat advisory, it would be blazing red. Thats the opinion of public-health experts who are constantly urging hospitals to boost their ability to respond to a health crisis such as a pandemic.

The secret to preparedness is maintaining a high index of suspicion, Henderson emphasizes. Its having an index of suspicion for the diagnosis and rapidly implementing administrative controls and standard infection control procedures and isolation principles to keep from transmitting disease. If we do that well, well be able to manage an influenza pandemic far better than we have in the past.

He continues, Experts dont always agree about the best preparedness strategy, and what may be the best strategy in one set of circumstance may not be as good in another. Certainly, aspects of whatever disease we get will make a difference as to how well these strategies will work.

A great example is SARS. It was probably very fortunate for us that with respect to SARS, the viral burden of the illness unlike influenza where you get a big viral load right at the start and theres a lot of transmission early in the infection SARS had a relatively low viral burden and the burden increased up to day six or seven; by that time the patient got sick and had been sick for several days, and so we had a better chance to understand what was going on and manage the problem. With influenza, we may not be that lucky. But weve also had the opportunity to practice with SARS, and I think SARS preparedness has been a huge asset; having hospitals have to get ready for SARS has helped the medical community be better prepared for this kind of problem should it arise on U.S. soil in the future.

Henderson adds, You simply have to prepare. You have to know your hospital inside and out; you have to know what your infrastructure is, you have to understand what you can do with patients who present with signs and symptoms. If an epidemic threat comes to your city, you have to understand the hospital well enough to say with confidence, We can put these patients in this location because we know how the air is handled, we know which way the air flows, we know about the infrastructure, and hopefully you will have practiced enough with your employees that they will be comfortable providing care and following isolation guidelines with a degree of rigor that we ordinarily use. That comes down to practice, practice, practice there is no other way. You have to get totally comfortable providing care under duress so that you are not paralyzed with fear.

Surveillance, Diagnostic Evaluation, and Infection Control Precautions for Avian Influenza A (H5N1)

The CDC recommends maintaining enhanced surveillance efforts by state and local health departments, hospitals, and clinicians to identify patients at increased risk for avian influenza A (H5N1) that were issued on Feb. 3, 2004 (

The CDCs Interim Recommendations for Infection Control in Healthcare Facilities Caring for Patients with Known or Suspected Avian Influenza are based on what are deemed optimal precautions for protecting individuals involved in the care of patients with highly pathogenic avian influenza from illness and for reducing the risk of viral reassortment. Since human influenza is thought to transmit primarily via large respiratory droplets, Standard Precautions plus Droplet Precautions are recommended for the care of patients infected with human influenza. The CDC says, however, given the uncertainty about the exact modes by which avian influenza may first transmit between humans, additional precautions for healthcare workers involved in the care of patients with documented or suspected avian influenza may be prudent.

Recommendations for Avian Influenza

All patients who present to a healthcare setting with fever and respiratory symptoms should be managed according to recommendations for Respiratory Hygiene and Cough Etiquette and questioned regarding their recent travel history. Patients with a history of travel within 10 days to a country with avian influenza activity and are hospitalized with a severe febrile respiratory illness, or are otherwise under evaluation for avian influenza, should be managed using isolation precautions identical to those recommended for patients with known SARS. These include:

Standard Precautions

  • Pay careful attention to hand hygiene before and after all patient contact or contact with items potentially contaminated with respiratory secretions.

Contact Precautions

  • Use gloves and gown for all patient contact.
  • Use dedicated equipment such as stethoscopes, disposable blood pressure cuffs, disposable thermometers, etc.
  • Eye protection (i.e., goggles or face shields)
  • Wear when within 3 feet of the patient.

Airborne Precautions

  • Place the patient in an airborne isolation room (AIR). Such rooms should have monitored negative air pressure in relation to corridor, with 6 to 12 air changes per hour (ACH), and exhaust air directly outside or have recirculated air filtered by a high efficiency particulate air (HEPA) filter.
  • Use a fit-tested respirator, at least as protective as a National Institute of Occupational Safety and Health (NIOSH)-approved N-95 filtering facepiece respirator, when entering the room. Respirators should be used in the context of a complete respiratory protection program as required by the Occupational Safety and Health Administration (OSHA). This includes training, fit-testing, and fit-checking to ensure appropriate respirator selection and use.

Vaccination of Healthcare Workers Against Human Influenza

Healthcare workers involved in the care of patients with documented or suspected avian influenza should be vaccinated with the most recent seasonal human influenza vaccine.

Surveillance and Monitoring of Healthcare Workers

Instruct healthcare workers to be vigilant for the development of fever, respiratory symptoms, and/or conjunctivitis for one week after last exposure to avian influenza-infected patients. Healthcare workers who become ill should seek medical care and, prior to arrival, notify their healthcare provider that they may have been exposed to avian influenza. In addition, employees should notify occupational health and infection control personnel at their facility.

HHS Issues National Pandemic Influenza Preparedness Plan

On Aug. 26, 2004, the Department of Health and Human Services (HHS) unveiled its draft Pandemic Influenza Response and Preparedness Plan, which outlines a coordinated national strategy to prepare for and respond to an influenza pandemic. In particular, the plan provides guidance to national, state, and local policy makers and health departments for public health preparation and response in the event of pandemic influenza outbreak.

According to the draft, Characteristics of an influenza pandemic that must be considered in preparedness and response planning include: 1) simultaneous impacts in communities across the U.S., limiting the ability of any jurisdiction to provide support and assistance to other areas; 2) an overwhelming burden of ill persons requiring hospitalization or outpatient medical care; 3) likely shortages and delays in the availability of vaccines and antiviral drugs; 4) disruption of national and community infrastructures including transportation, commerce, utilities and public safety; and 5) global spread of infection with outbreaks throughout the world.

HHS-directed efforts to effectively respond to an influenza pandemic or other health threat have included allocating substantial resources to assure and expand influenza vaccine production capacity; increasing influenza vaccination use; stockpiling influenza antiviral drugs in the Strategic National Stockpile (SNS); enhancing U.S. and global disease detection and surveillance infrastructures; expanding influenza-related research; supporting public-health planning and laboratory services; and improving healthcare system readiness at the community level.

The draft addresses the role of infection control in a global or domestic health crisis: Implementing infection control strategies to decrease the global and community spread of infection, while not changing the overall magnitude of a pandemic, may reduce the number of people infected early in the course of the outbreak, before vaccines are available for prevention.

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