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 hasbeen on high alert, dealing with bioterrorism threats as well as emerginginfectious diseases such as severe acute respiratory syndrome (SARS), theinfluenza vaccine shortage, and most recently, watching Asian countries copewith avian influenza virus. World health officials have been watching thisgrowing threat, pondering the eventuality of an antigenic shift from animal tohuman, 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 notif, but when.

When someone asks, Will it happen? the answer isalmost certainly, yes, says David K. Henderson, MD, deputy director forclinical care at the Warren Grant Magnuson Clinical Center at the NationalInstitutes of Health in Bethesda, Md. But the trick is to know when, ofcourse. At some level, it is a quirk of nature as to when these virusesrecombine.

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

Antigenic shift is seen only with influenza A viruses. Itresults usually from the replacement of the hemagglutinin (the viral attachmentprotein that also mediates the entry of the virus into the cell) with a novelsubtype 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 inwaterfowl. The consequences of the introduction of a new hemagglutinin intohuman 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 arespikes of two proteins: hemagglutinin (H) and neuraminidase (N). H and N arecoded for by two separate pieces of viral RNA; influenza has eight pieces of RNAtotal. Antigenic shift occurs due to reassortment of RNA segments from twodifferent viral strains infecting the same cell.

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

Influenza A viruses, including subtypes from differentspecies, can swap or reassort genetic materials and merge. Thisreassortment process, or antigenic shift, results in a novel subtype differentfrom both parent viruses. As populations will have no immunity to the newsubtype, and as no existing vaccines can confer protection, antigenic shift hashistorically resulted in highly lethal pandemics. For this to happen, the novelsubtype needs to have genes from human influenza viruses that make it readilytransmissible from person to person for a sustainable period.

According to WHO, Conditions favorable for the emergence ofantigenic shift have long been thought to involve humans living in closeproximity to domestic poultry and pigs. Because pigs are susceptible toinfection with both avian and mammalian viruses, including human strains, theycan serve as a mixing vessel for the scrambling of genetic material fromhuman and avian viruses, resulting in the emergence of a novel subtype. Recentevents, however, have identified a second possible mechanism. Evidence ismounting that, for at least some of the 15 avian influenza virus subtypescirculating in bird populations, humans themselves can serve as the mixingvessel.

The biology of influenza is very well understood by thescientific 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 avianinfluenza have been reported since 1997, according to the Centers for DiseaseControl and Prevention (CDC). The agency says, Most cases of avian influenzainfection in humans are thought to have resulted from contact with infectedpoultry or contaminated surfaces. However, there is still a lot to learn abouthow different subtypes and strains of avian influenza virus might affect humans.For example, it is not known how the distinction between low pathogenic andhighly pathogenic strains might impact the health risk to humans. Of thedocumented cases of human infection with avian influenza viruses, illnessescaused by highly pathogenic viruses appear to be more severe.

On Aug. 12, 2004, the Vietnamese Ministry of Health officiallyreported to WHO three human deaths from confirmed avian influenza H5 infection. Tests were needed to determine whether the virus belonged tothe same H5N1 strain that caused 22 cases and 15 deaths in Vietnam, and 12 casesplus eight deaths in Thailand earlier last year. Cambodia, China, Indonesia,Japan, Laos, South Korea, Thailand, and Vietnam were previously affected bywidespread H5N1 outbreaks in poultry during early 2004. At that time, more than100 million birds either died from the disease or were killed in efforts tocontain the outbreaks. Thirty-four human cases were reported only in Thailand and Vietnam. Beginning in lateJune 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 Vietnamon Aug. 12, 2004 were the first reported human cases associated with this secondwave of H5N1 infection among poultry.

Because of concerns about the potential for more widespreadinfection in the human population, public health authorities closely monitoroutbreaks of human illness associated with avian influenza. To date, humaninfections with avian influenza viruses detected since 1997 have not resulted insustained human-to-human transmission. However, because influenza viruses havethe 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 infectinghumans since 1997 include:

  • H5N1, Hong Kong, 1997: Avian influenza A (H5N1)infections occurred in both poultry and humans, the first time an avianinfluenza virus had ever been found to transmit directly from birds to humans.During this outbreak, 18 people were hospitalized and six died. To control theoutbreak, authorities killed about 1.5 million chickens to remove the source ofthe virus. Scientists determined that the virus spread primarily from birds tohumans, 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 evidencesuggested that poultry was the source of infection and the main mode oftransmission was from bird to human; however, the possibility ofperson-to-person transmission could not be ruled out. Several additional humanH9N2 infections were reported from mainland China in 1998-99.

  • H7N2, Virginia, 2002: Following an outbreak of H7N2among poultry in the Shenandoah Valley poultry production area, one person wasfound to have serologic evidence of infection with H7N2.

  • H5N1, China and Hong Kong, 2003: Two cases of avianinfluenza A (H5N1) infection occurred among members of a Hong Kong family thathad traveled to China. One person recovered, the other died. How or where thesetwo family members were infected was not determined. Another family member diedof a respiratory illness in China, but no testing was done.

  • H7N7, Netherlands, 2003: The Netherlands reportedoutbreaks of influenza A (H7N7) in poultry on several farms. Later, infectionswere reported among pigs and humans. In total, 89 people were confirmed to have H7N7 influenzavirus infection associated with this poultry outbreak. These cases occurredmostly among poultry workers. There was one death among the 89 total cases. The majority of these cases occurred as a result of directcontact with infected poultry; however, Dutch authorities reported three possible instancesof transmission from poultry workers to family members. Since that time, noother instances of H7N7 infection among humans have been reported.

  • H9N2, Hong Kong, 2003: H9N2 infection was confirmedin a child in Hong Kong. The child was hospitalized and recovered.

  • H7N2, New York, 2003: In November, a patient withserious underlying medical conditions was admitted to a hospital in New Yorkwith respiratory symptoms. One of the initial laboratory tests identified aninfluenza A virus that was thought to be H1N1. The patient recovered and went home after a few weeks. Subsequent confirmatorytests conducted in March 2004 showed that the patient had been infected with anH7N2 avian influenza virus. An investigation to determine the source ofinfection is ongoing.

  • H5N1, Thailand and Vietnam, 2004: In January 2003,outbreaks of highly pathogenic influenza A (H5N1) in Asia were first reported byWHO. From Dec. 30, 2003, to March 17, 2004, 12 confirmed human cases of avianinfluenza A (H5N1) were reported in Thailand and 23 in Vietnam, resulting in atotal of 23 deaths.

  • H7N3 in Canada, 2004: In February 2004, humaninfections of H7N3 among poultry workers were associated with an H7N3 outbreakamong poultry. The H7N3-associated illnesses consisted of eye infections.

  • H5N1, Thailand and Vietnam, 2004: Beginning in lateJune 2004, new lethal outbreaks of H5N1 among poultry were reported by severalcountries in Asia. The new outbreaks of H5N1 in poultry in Asia were followed byrenewed sporadic reporting of human cases of H5N1 infection in Vietnam andThailand beginning in August. Of particular note is one isolated instance ofprobable 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 rangedfrom typical influenza-like symptoms (e.g., fever, cough, sore throat, andmuscle aches) to eye infections (conjunctivitis), pneumonia, acute respiratorydistress, 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 DrugAdministration (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 thereforethe drugs may not always be effective. For example, analyses of some of the 2004H5N1 viruses isolated from poultry and humans in Asia have shown that theviruses are resistant to two of the medications (amantadine and rimantadine).Monitoring of avian viruses for resistance to influenza antiviral medications isongoing.

Influenza Pandemics: Can They be Averted?

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

Theres nothing new about people only wanting the fluvaccine when they couldnt get it, Henderson says. Those of us whosehair 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 atthe data about the impact of the 1918 influenza epidemic on lifespan in theUnited States, where I think it dropped from nearly 50 years of age down toabout 37 or 38 in 1918, simply because of the flu. The country will need to getready for the possibility of another pandemic, and society, I suspect might notreact in the will react in the most optimal way. I think it will be a greatchallenge.

Henderson continues, The pandemics of Asian flu in 1957 andthe Hong Kong flu in 1968 were minor pandemics, but they were in fact pandemicflu. They werent of the same magnitude as the pandemic of 1918. And Swine fluin the mid-1970s was a pandemic that just didnt happen. That was arecombinant 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 notin the community at large, about the potential for a large pandemic ofinfluenza.

Presentation of Influenza

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

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

WHO suggests several measures can help minimize the globalpublic health risks that could arise from large outbreaks of highly pathogenicH5N1 avian influenza in birds. An immediate priority is to halt further spreadof epidemics in poultry populations, which also works to reduce opportunitiesfor 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 humansand on circulating influenza viruses is urgently needed to aid the assessment ofrisks to public health and to guide the best protective measures. The successfulcontainment of public-health risks also depends on the epidemiological andlaboratory capacity and the adequacy of surveillance systems already in place inaffected areas.

Clinical Treatment of Human Cases of H5N1 Avian Influenza

What clinicians know about treating avian influenza in humansis restricted to data published pertaining to cases in the 1997 Hong Kongoutbreak. 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 healthyadults and children, and some with chronic medical conditions, were affected.

Antiviral drugs, some of which can be used for both treatmentand prevention, are clinically effective against influenza A virus strains inotherwise healthy adults and children, but have some limitations. Some of thesedrugs are also expensive and supplies are limited. Experience in the productionof influenza vaccines is also considerable, particularly as vaccine compositionchanges 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, insignificant quantities, capable of conferring protection against a new virussubtype. WHO officials said in December 2004 that a vaccine might be viable inmid-2005.

Flu vaccines are a challenge to make, but we havetechnology now that we didnt have before, says Henderson. So, itsanother 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 thevirus is known, we have recombinant technology and things we didnt have inthe past to help us make a vaccine quickly. That will be a big advantage if andwhen the pandemic comes. Short of a pharmaceutical silver bullet, conscientiousinfection control practices will have to suffice, experts say.

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

As an industrialized nation with a fetish for antimicrobialproducts and a somewhat high level of hygiene and sanitation standards, is theUnited States being lulled into a false sense of security about immunity from apandemic?

Absolutely, Henderson says. It happened here with avengeance in 1957 and 1968. To assume that just because were anindustrialized country that we wont get pandemic influenza would be settingourselves up for disaster. Hygiene will matter, certainly. Its like any otherinfectious disease; anything you do to break the chain of transmission is a goodthing. Hand hygiene will make a difference, and the use of alcoholhandrubs 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 securitythreat advisory, it would be blazing red. Thats the opinion of public-healthexperts who are constantly urging hospitals to boost their ability to respond toa health crisis such as a pandemic.

The secret to preparedness is maintaining a high index ofsuspicion, Henderson emphasizes. Its having an index of suspicionfor the diagnosis and rapidly implementing administrative controls and standardinfection control procedures and isolation principles to keep from transmittingdisease. If we do that well, well be able to manage an influenza pandemic farbetter than we have in the past.

He continues, Experts dont always agree about the bestpreparedness strategy, and what may be the best strategy in one set ofcircumstance may not be as good in another. Certainly, aspects of whateverdisease 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 usthat with respect to SARS, the viral burden of the illness unlike influenzawhere you get a big viral load right at the start and theres a lot oftransmission early in the infection SARS had a relatively low viral burdenand the burden increased up to day six or seven; by that time the patient gotsick and had been sick for several days, and so we had a better chance tounderstand what was going on and manage the problem. With influenza, we may notbe that lucky. But weve also had the opportunity to practice with SARS, and Ithink SARS preparedness has been a huge asset; having hospitals have to getready for SARS has helped the medical community be better prepared for this kindof problem should it arise on U.S. soil in the future.

Henderson adds, You simply have to prepare. You have toknow 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 andsymptoms. If an epidemic threat comes to your city, you have to understand thehospital well enough to say with confidence, We can put these patients inthis location because we know how the air is handled, we know which way the airflows, we know about the infrastructure, and hopefully you will havepracticed enough with your employees that they will be comfortable providingcare and following isolation guidelines with a degree of rigor that weordinarily use. That comes down to practice, practice, practice there is noother way. You have to get totally comfortable providing care under duress sothat you are not paralyzed with fear.

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

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

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

Recommendations for Avian Influenza

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

Standard Precautions

  • Pay careful attention to hand hygiene before and after allpatient contact or contact with items potentially contaminated with respiratorysecretions.

Contact Precautions

  • Use gloves and gown for all patient contact.

  • Use dedicated equipment such as stethoscopes, disposableblood 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 orhave recirculated air filtered by a high efficiency particulate air (HEPA)filter.

  • Use a fit-tested respirator, at least as protective as aNational Institute of Occupational Safety and Health (NIOSH)-approved N-95filtering facepiece respirator, when entering the room. Respirators should beused in the context of a complete respiratory protection program as required bythe Occupational Safety and Health Administration (OSHA). This includestraining, fit-testing, and fit-checking to ensure appropriate respiratorselection and use.

Vaccination of Healthcare Workers Against Human Influenza

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

Surveillance and Monitoring of Healthcare Workers

Instruct healthcare workers to be vigilant for the developmentof fever, respiratory symptoms, and/or conjunctivitis for one week after lastexposure to avian influenza-infected patients. Healthcare workers who become illshould seek medical care and, prior to arrival, notify their healthcare providerthat they may have been exposed to avian influenza. In addition, employees should notify occupational health andinfection 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 aninfluenza pandemic. In particular, the plan provides guidance to national,state, and local policy makers and health departments for public healthpreparation and response in the event of pandemic influenza outbreak.

According to the draft, Characteristics of an influenzapandemic that must be considered in preparedness and response planning include:1) simultaneous impacts in communities across the U.S., limiting the ability ofany jurisdiction to provide support and assistance to other areas; 2) anoverwhelming burden of ill persons requiring hospitalization or outpatientmedical care; 3) likely shortages and delays in the availability of vaccines andantiviral drugs; 4) disruption of national and community infrastructuresincluding transportation, commerce, utilities and public safety; and 5) globalspread of infection with outbreaks throughout the world.

HHS-directed efforts to effectively respond to an influenzapandemic or other health threat have included allocating substantial resourcesto assure and expand influenza vaccine production capacity; increasing influenzavaccination use; stockpiling influenza antiviral drugs in the Strategic NationalStockpile (SNS); enhancing U.S. and global disease detection and surveillanceinfrastructures; expanding influenza-related research; supporting public-healthplanning and laboratory services; and improving healthcare system readiness atthe community level.

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