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The author is the Health Resources and Services Administration Regional Bioterrorism Coordinator in Saginaw, Mich. He has indicated no relationships to disclose relating to the content of this article.

Influenza pandemics have struck repeatedly over the centuries. The 1918 flu caused the greatest morbidity and mortality to date; the fear now is that avian influenza may cause as great a pandemic. While there are numerous options for preventing and treating influenza, shortages of vaccines and antiviral drugs, as well as the apparent high dosages needed to treat avian flu, may require rationing of these drugs. The challenge to public health agencies and clinicians is to be prepared for the inevitable outbreak.

A potentially severe outbreak of influenza could easily impact the entire world population. According to Julie Gerberding, MD, Director of the CDC, “Today, many influenza experts, including those at CDC, consider the threat of a serious influenza pandemic to the United States to be high. Although the timing and impact of an influenza pandemic is unpredictable, the occurrence is inevitable and potentially devastating.”¹ The nature of the disease and the likelihood of this outbreak are the subjects of much discussion. This article provides a general overview of influenza and the history of flu pandemics; examines a particular influenza virus strain, which is the prime candidate to cause the next pandemic; and discusses current planning for the clinical response. While this subject can easily fill entire texts, this article is intended to give the clinician a basic foundation from which to approach the problem.

A pandemic is an outbreak of an infectious disease that affects people or animals over an extensive geographical area. A pandemic of influenza occurs when a new virus strain emerges that exhibits the following features:

• It is highly pathogenic for humans
• It is easily transmitted between humans
• It is genetically unique, evidenced by a broad lack of preexisting immunity in the human population.²

Influenza basics

Influenza is caused by spiky, globule-shaped viruses from the Orthomyxoviridae family; these viruses contain between six and eight chains of RNA that easily mix with other viral RNA, thus causing antigenic shifts. This variation causes differences in the form of the virus that can allow it to elude a host’s immunity to previous, similar types of flu. All strains of influenza virus that cause pandemics in humans are avian viruses that have mutated and crossed into mammals and then into humans or, sometimes, directly into humans.

Types There are three types of influenza virus.^2,3 Type A, the most common of the three, causes disease in humans and other mammals such as horses, pigs, cats, whales, and seals. Birds carry the greatest number and range of influenza strains, and it is believed that the type A virus was originally an avian (bird) virus that jumped to mammals. Type A virus often undergoes changes in its surface antigens, allowing the virus to sicken people who developed an immunity to previous strains. Because of these changes, type A influenza virus is the most common cause of pandemics.

Type B strains infect only humans and are less common than type A strains. Type B influenza undergoes relatively slow changes in its antigens and tends to cause milder illness. Type B virus has no known link to pandemics.

The third, type C virus, is rare, and its clinical manifestations are uncommon. It also differs from types A and B in the number of RNA chains it contains. It reportedly rarely causes clinical disease in humans; there have been fewer than 12 cases confirmed, and they were very mild. There is no indication that type C virus affects other animals at this time.4

Identification The influenza virus is identified by its surface antigens. Hemagglutinin (H) antigen has up to 16 major antigenic types. Neuraminidase (N) antigen has nine major antigenic types.

An influenza virus is fully identified by its type (A, B, or C), the location where it was first isolated, the number of isolates, the year of identification, and the major types of the H and N antigens (eg, A/Hong Kong/6/86 [H1N1]). Most commonly, the virus is referred to just by the type and antigens or just by the antigens. For example, the avian strain of influenza virus that currently is causing concern is referred to as A(H5N1) or H5N1.

Symptoms Influenza is spread by droplets, and the virus can be inhaled, entering the body through the pharynx and lower respiratory tract. It can also be passed via hand-to-mouth and human-to-human transmission. Influenza tends to be highly contagious, especially in crowded populations such as offices, factories, schools, and military bases. Incubation periods range from 1 to 3 days. Classic flu symptoms are cough, fever, headache, myalgias, pharyngitis, and usually no coryza. The effects on patients range from virtually none to very severe, depending on the viral strain and the patient’s age and physical condition prior to being infected. Influenza also makes patients susceptible to serious opportunistic infections such as bacterial pneumonia. It generally appears in seasons, lasting from late fall to early spring.

Historic pandemics

The first recorded influenza pandemic occurred in 1580 in Europe and spread to Asia and Africa. During the 17th century, localized epidemics were reported, and in the 18th century, there were at least three pandemics between 1729 and 1782. Three influenza pandemics were recorded during the 19th century (1830-1831, 1833-1834, 1889-1890).² The 1889 pandemic, which began in Russia, involved what is commonly known as the Russian flu. It spread rapidly throughout Europe, North America, Latin America, and Asia, resulting in approximately 1 million deaths.²sup>

Spanish flu In the 20th century, there were numerous influenza pandemics that caused millions of deaths globally.⁵ The first was the great flu pandemic of 1918: the Spanish flu, La Grippe, or the French flu. Caused by a type A(H1N1) virus, it first appeared in a US Army training camp in Kansas. It quickly spread to Europe as soldiers were sent to the front during World War I. Believed to have originated in sick farm animals and then mutated into a virus that infected the soldiers, this highly virulent virus killed more than 650,000 people in the United States and 30 to 40 million worldwide.

Influenza is usually most dangerous to the elderly, the infirm, and the very young; however, the 1918 pandemic was notable in that it caused the most deaths in otherwise healthy adults aged 20 to 50 years. This was an alarming disease in that a person who contracted it could be healthy at breakfast and dead before dinner. As with other influenzas, those who survived the disease were immune to reinfection with that strain.

Asian flu The next influenza pandemic was in 1957 when a strain of type A(H2N2) influenza known as the Asian flu appeared. It lasted through three flu seasons, and approximately 70,000 people in the United States died from it. The highest mortality rates were among the elderly, except in the first season when approximately 40% of the deaths occurred in persons younger than 65 years. Globally, this flu killed approximately 1 million people.

Hong Kong flu In 1968, the influenza virus type A(H3N2), or Hong Kong flu, led to another pandemic. This pandemic killed about 39,000 in the United States and was the mildest influenza pandemic in the 20th century. While the Hong Kong flu affected people of all ages, it was similar to one many elderly patients had been exposed to at younger ages. Their residual immunity resulted in a lower-than-normal morbidity rate in that age group.²

Swine flu In 1976, a localized outbreak in and around Fort Dix, NJ, raised the fear of a return of the 1918 strain in what became known as the swine flu. Also called the killer flu, it was found to be the same strain as the virus that caused the 1918 pandemic and was believed to have originated in pigs and then jumped to humans. Only one soldier died, but fear of another outbreak with death rates similar to those in 1918 resulted in immediate and aggressive action by the federal government. In an effort to vaccinate the entire US population, the National Influenza Immunization Program (NIIP) was created. While only one person died from the swine flu itself, hundreds of Americans became seriously ill or died after receiving the vaccine. The NIIP was suspended following reports of more than 500 cases of Guillain-Barré syndrome that were attributed to the vaccine, which resulted in 25 deaths.⁶

Avian flu The outbreak currently causing the most concern was first identified in 1997 in Southern China and Hong Kong. This is the Asian strain of avian influenza virus (type A[H5N1]). To date more than 130 people have died; more than 250 people have been infected, and countless pigs and other mammals and domestic and wild fowl have been infected. The virus has been steadily spreading throughout Southeast Asia and now has been identified in Eastern Russia, Southwest Asia, the Middle East, and Europe.⁷ It has made interspecies jumps from domestic chickens and ducks to wild fowl, which have migrated to other areas and spread the virus even farther, to swine and to humans.

Interspecies jumps occur when an animal is simultaneously infected with the H5N1 virus and another influenza virus strain. The different viruses swap RNA during their replication process, creating a new, mutated virus that can be a threat to another species. The World Health Organization (WHO) warns that the potential for the H5N1 virus to cause a global pandemic is extremely high. It projects a potential mortality rate of 50% or higher, with up to 7.4 million deaths globally.⁸ In the United States, it is estimated that more than 2 million people will be hospitalized and 500,000 will die.⁸ Such a pandemic could be a serious blow to the already strained health care system in the United States and would have a much more devastating effect on poor and underdeveloped countries.

Evolution of treatment

At the time of the 1918 pandemic, aside from quarantine, there was little that could be done to prevent infection from spreading; only supportive and symptomatic care was available for sick patients. Today, much of the advice for patients infected with influenza viruses is the same: rest, drink plenty of fluids, take OTC medications for fever and pain, and avoid groups to prevent spreading the disease.

A major improvement today is the availability and use of vaccines and antiviral medications.⁹ Because of frequent antigenic shifts among the various influenza strains, the annual flu vaccine is different each year. WHO recommends the formula for each season. Since the typing of the avian flu is already known, a vaccine has been developed and tested in healthy adults aged 20 to 35 years. In August 2005, initial study results indicated the vaccine was partially effective against the H5N1 virus.^10,11 However, the dosage required to produce a protective response is massive—roughly 12 times the normal vaccine concentration, divided into two injections. Further studies on the vaccine’s effectiveness and safety in the elderly and in children are needed.

There are four antiviral drugs approved for the prevention and/or treatment of influenza in the United States: amantadine, oseltamivir, rimantadine, and zanamavir. Oseltamivir, a neuraminidase inhibitor, is the recommended antiviral drug for treating the H5N1 virus. Although the effective dosage has not yet been determined, it would be significantly higher than that used for other strains of type A influenza.¹²

Federal agencies, including the CDC, have determined that oseltamivir should be the drug of choice. Zanamivir, also a neuraminidase inhibitor, is being recommended for use in those who are infected with an oseltamivir-resistant strain and in pregnant woman;¹³ oseltamivir is not recommended for use during pregnancy. Some early studies indicate that statins may increase the survival rates in patients infected with H5N1 virus with septic shock. Statins, unlike neuraminidase inhibitors, are relatively easily produced and can be stockpiled.¹⁴

In anticipation of limited supplies of vaccine and drugs, the National Vaccine Advisory Committee and the Advisory Committee on Immunization Practices recommended a schedule of priority by group for distribution of these medications (see Table 1).¹⁵

Preventive measures

CDC recommendations for preventive measures in the event of an influenza outbreak—including one of the H5N1 virus—are the same as for any type A influenza.¹⁶

Vaccination Health care workers should be familiar with the priority levels of their patient populations. Because of a potentially limited supply of vaccine, patients should be advised when to receive the vaccine according to the priority group they belong to.

Antiviral medications Use of recommended antiviral medications after exposure or if influenza is diagnosed is essential to reduce morbidity and mortality. A major challenge for public health agencies will be the timely, widespread distribution of these drugs. Availability of the antivirals may be further limited by the dosage needed and the potential number of infected patients.

Disease containment During previous flu pandemics, many people wore surgical masks. Because H5N1 virus is spread through droplets expelled while coughing or sneezing, this may be an effective means of containing the spread of disease. Regular surgical masks prevent only large-droplet spread. The N-95 masks used when caring for patients with tuberculosis and other infectious diseases are better for preventing the spread of type A flu.

Equipment Acquiring a stockpile of portable ventilators and other support materials is of great importance. Most facilities use just-in-time supply plans to maintain their inventory. This is fine for regular day-to-day practice; however, the increased demand for medical supplies during a pandemic event can result in scattered, widespread shortages of IV fluids, administration sets, gloves, gowns, and other supplies.

Facilities Preplanning of surge capacity can prepare facilities to quickly expand the number of available beds for ill patients. Increasing available beds will be of little use, however, without the skilled staff needed to provide care. Plans to secure adequate staffing levels should include certification and credentialing of volunteer staff.

Despite all preventive measures, an influenza pandemic can cause a large number of deaths. Fatality management must be addressed during facility planning.

Hygiene The basics of good hygiene and antibacterial practices are the backbone of effective disease management. All clinicians should maintain and encourage good health habits, including avoiding close contact with people who are sick; staying home during illness; covering the mouth and nose when coughing or sneezing; frequent handwashing; and avoiding touching the eyes, nose, or mouth.

Conclusion

Laboratory viral typing is highly valuable in identifying and tracking influenza virus during an outbreak, but diagnosis of type A influenza is generally based on the patient’s symptoms. For proper laboratory evaluation of viral specimens from a patient suspected to be infected with H5N1 virus, the preferred collection method is by pharyngeal swab. Polymerase chain reaction assays return preliminary results within 4 hours.^17,18

The incubation period for H5N1 influenza is similar to that for other type A influenzas; the onset of symptoms starts about 1 to 3 days after exposure to the virus. No current data indicate how many people who have been exposed to the H5N1 virus will experience flu symptoms, nor is there any indication that the disease lasts longer than annual flu strains have traditionally lasted. But there are strong concerns that the H5N1 virus will be much more devastating to the population than the routine annual flu outbreak.¹⁹

An outbreak of pandemic influenza is only a matter of time, and the Asian strain of avian influenza virus type A(H5N1) is recognized as the most likely current threat. Diligent public health and medical planning and preparation can minimize the impact of this impending cataclysm on humanity.

References

1. Hearings before the Subcommittee on Labor, Health and Human Services, and Education House of Representatives Committee on Appropriations, 108th Cong, 1st Sess (2004) (testimony of Julie Geberding, director, CDC). Available at: www.hhs.gov/asl/testify/t041005c.html. Accessed December 3, 2006.

2. Center for Infectious Disease Research & Policy, University of Minnesota. Pandemic influenza. Available at: www.cidrap.umn.edu/cidrap/content/influenza/panflu/biofacts/panflu.html. Accessed December 3, 2006.

3. Centers for Disease Control and Prevention. Influenza viruses. Available at: www.cdc.gov/flu/avian/gen-info/flu-viruses.htm. Accessed December 3, 2006.

4. Katagiri S, Ohizumi A, Ohyama S, Homma M. Follow-up study of type C influenza outbreak in a children’s home. Microbiol Immunol. 1987;31(4):337-343.

5. Department of Health and Human Services. Pandemics and pandemic scares in the 20th century. Available at www.hhs.gov/nvpo/pandemics/flu3.htm. Accessed December 3, 2006.

6. Laitin EA, Pelletier EM. The influenza A/New Jersey (swine flu) vaccine and Guillain-Barré syndrome: the arguments for a causal association. Available at www.hsph.harvard.edu/Organizations/DDIL/swineflu.html. Accessed December 3, 2006.

7. Toner E. Further spread of H5N1 across Central Asia. Clinicians’ Biosecurity Network, Center for Biosecurity of University of Pittsburgh Medical Center. CBN Weekly Bull. August 30, 2005.

8. Fox M. Pandemic could kill half million in US—report. Reuters. June 24, 2005. Available at: www.infowars.com/articles/science/bird_flu_pandemic_could_kill_half_million_in_us.htm. Accessed December 3, 2006.

9. Centers for Disease Control and Prevention. Key facts: information about avian influenza (bird flu) and avian influenza A (H5N1) virus. Available at: www.cdc.gov/flu/avian/gen-info/facts.htm. Accessed December 3, 2006.

10. Altman LK. Avian flu vaccine called effective in human testing. New York Times. August 7, 2005.

11. Borio LL, Bartlett J. Initial results of avian flu vaccine trial reported: there’s no reason to celebrate yet. Clinicians’ Biosecurity Network, Center for Biosecurity of University of Pittsburgh Medical Center. CBN Weekly Bull. August 16, 2005.

12. Toner E. Efficacy of oseltamivir against H5N1. Clinicians’ Biosecurity Network, Center for Biosecurity of University of Pittsburgh Medical Center. CBN Weekly Bull. July 26, 2005.

13. Centers for Disease Control and Prevention. Antiviral drugs and influenza. Available at: www.cdc.gov/flu/protect/antiviral/index.htm. Accessed December 3, 2006.

14. Enserink M. Infectious disease. Old drugs losing effectiveness against flu; could statins fill gap? Science. 2005;309:1976-1977.

15. Nuzzo J. Federal advisory groups recommend priorities for vaccination and antivirals during a pandemic. Clinicians’ Biosecurity Network, Center for Biosecurity of University of Pittsburgh Medical Center. CBN Weekly Bull. August 2, 2005.

16. Centers for Disease Control and Prevention. Preventing the flu. Available at: www.cdc.gov/flu/protect/preventing.htm. Accessed December 3, 2006.

17. Beigel JH, Farrar J, Han AM, et al. Avian influenza A (H5N1) infection in humans. [Published correction appears in N Engl J Med. 2006;354(8):884.] N Engl J Med. 2005;353(13):1374-1385.

18. Hinesly D. Disease management: preparing for the avian flu. Clin Lab Products. 2006; 35(7):28-29. Available at: www.clpmag.com/article.php?s=CLP/2006/07&p=5. Accessed December 3, 2006.

19. Trust for America’s Health. A killer flu? ‘Inevitable’ epidemic could kill millions. Available at: www.healthyamericans.org/reports/flu. Accessed December 4, 2006.

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