US Pharm. 2006;1:28-37.

"Once again, nature has presented us with a daunting challenge: the possibility of an influenza pandemic."1 With these words on November 1, 2005, President George W. Bush introduced the National Strategy for Pandemic Influenza, published by the Homeland Security Council. The motivation for its development was the recent alarming events related to the avian influenza in Asia. In addition, the pandemic potential of avian influenza has generated a substantial amount of media publicity in recent months. Since pharmacists are highly accessible to the general public, they will likely encounter many questions regarding avian influenza. This article aims to provide a basic understanding of the current issues surrounding avian influenza to assist pharmacists' important role in public health education and vaccine administration.

Influenza Virus
The virus responsible for avian influenza is a subtype of the common influenza virus that causes disease outbreak on an annual basis. Therefore, to develop an understanding of avian influenza, it is helpful to begin with some background information on the influenza virus itself.

The influenza virus is a single-stranded RNA virus that belongs to the Orthomyxoviridae virus family 2 and is divided into three distinct types: influenza A, influenza B, and influenza C. Of these three, type A is most often implicated in human morbidity and mortality, followed by type B. The influenza C virus, however, is not associated with serious disease in humans. Type A is further divided into subtypes based on antigenic surface protein markers, whereas type B is not divided into subtypes. The influenza A virus infects many animals, including humans, cats, pigs, horses, sea mammals, and birds; the natural reservoir for all known strains of type A is waterfowl.3,4 Type A has a remarkable ability to undergo antigenic changes regularly, preventing lifetime immunity to influenza in host organisms by vaccination or immune response secondary to disease. This ability is largely due to a lack of proofreading during viral replication, leading to a high rate of small mutational errors. Overall, this may be viewed as an adaptive mechanism that allows the influenza A virus subtype to evade host immune system defenses. 5

The most important antigenic marker proteins on the surface of the influenza A virus are hemagglutinin (H) and neuraminidase (N). Hemagglutinin is important for virus attachment to the cells of the infected host, as well as for the release of viral genetic material into the host cell. Once released, the viral RNA is used as a genetic template for viral replication. If the animal host has immunity against hemagglutinin, the chances for infection are reduced and disease severity is decreased if disease develops. Neuraminidase is vital for the release of newly synthesized virus from the host cells, allowing proliferation of the infection. 6 It is from these two antigenic protein markers that the H and N designations of the influenza A virus subtypes are derived (e.g., H5N1). Yearly mutations in these antigenic markers, a process called antigenic drift, leads to modified strains of the type A subtypes that humans have reduced immunity to. Of the known influenza A virus subtypes (H1 to H16 and N1 to N9), only three currently circulate among humans: H1N1, H1N2, and H3N2. 3

Influenza infection is an important cause of morbidity and mortality in the United States during winter months. In a typical year, about 36,000 people die from complications due to influenza.7 The influenza virus is spread mostly by inhalation of aerosolized respiratory droplets that are generated usually by the coughing and sneezing of those infected.2,7

Human influenza that develops into disease causes a wide spectrum of illness, from uncomplicated to complicated influenza. Most patients with influenza experience an abrupt onset of symptoms, such as fever, myalgia, nonproductive cough, sore throat, headache, and malaise, that last about one to two weeks. Children, patients over age 65, and patients with certain underlying medical conditions (e.g., cardiac disease, diabetes, chronic respiratory diseases) are at risk for severe and possibly life-threatening complications from influenza Complicated influenza that causes serious illness and death commonly occurs by coinfection with other pathogens (viruses or bacteria), leading to pneumonia. Typical influenza is due to influenza viruses that generally do not have the ability to cause primary viral pneumonia but instead cause pneumonia indirectly by facilitating the infection of lower respiratory tissue with other pathogens. In stark contrast, avian influenza has a relatively high risk of causing primary viral pneumonia that is associated with significant mortality.

Epidemiology of Influenza
In terms of epidemiology, influenza may be classified as either epidemic or pandemic. Influenza causes annual epidemics, where local geographic regions have increased rates of morbidity and mortality secondary to influenza. Fortunately, pandemics are far less common. Historically, pandemic influenza arises every 10 to 30 years and entails a worldwide increase in morbidity and mortality due to influenza that typically occurs in several waves.4 The pandemics of the previous century (table 1) have all been the result of the influenza A virus. The greatest pandemic was the infamous 1918–1919 Spanish influenza in which an estimated 40 million people died worldwide.




When a major antigenic change occurs in influenza type A, such that a new subtype is created to which an antibody is lacking, pandemic influenza results.4 This phenomenon is known as antigenic shift--a much more dramatic event in influenza epidemiology than the smaller annual changes known as antigenic drift. With the exception of the Russian influenza pandemic, past influenza pandemics have been due to a new influenza A virus subtype that was both highly pathogenic and readily spread by person-to-person transfer. The annual influenza vaccine is modified to reflect antigenic changes caused by antigenic drift. However, the emergence of a highly pathogenic influenza A subtype secondary to antigenic shift, such as the virus causing avian influenza, will likely require a considerable length of time for vaccine development. During this time period, it is likely that pandemic influenza will occur.

The ability of the influenza virus to infect and circulate in many types of animals allows high rates of mutational change, leading to an increased chance of transferring new viral subtypes to humans.8 Subtypes of the influenza A virus were not known to spread from birds to humans until 1997. Prior to this time, it was generally believed that the avian virus would initially spread to other mammals (e.g., swine) that could be coinfected with a human strain of influenza. In the swine, avian and human influenza strains could "swap" genes in a process known as reassortment, allowing a novel humanized strain to emerge. However, this assumption regarding influenza type A was altered by the first major human exposure to avian influenza. Recent evidence indicates two possible mechanisms by which avian influenza may acquire pathogenic potential: (1) coinfection of a human host with an avian and human influenza virus and subsequent gene reassortment, giving rise to a virus capable of human-to-human transfer and (2) direct mutation of avian influenza to a virus capable of human-to-human transfer.9 For example, the deadly H1N1 influenza virus that caused the 1918 influenza pandemic was likely developed by the latter mechanism, as recent research findings have shown that this virus arose from direct mutation of an avian influenza virus.10

Avian Influenza
Avian influenza ("bird flu") is a type of influenza virus carried in the intestines of wild birds, especially waterfowl.11 Wild birds infected with this virus do not typically get sick but can transmit it to domestic birds. Avian influenza viruses can be devastating to domesticated birds. Due to the conditions associated with the poultry industry, such as crowded bird populations and humans living in close contact with these birds, ample opportunity exists for people to interact with birds infected with avian influenza. The immune system of the host organism recognizes the hemagglutinin marker of influenza viruses to which it has been exposed by antibodies produced by natural infection or vaccination. Thus, avian influenza may be very devastating to humans if the viruses circulating among birds have hemagglutinin markers that are not recognized by the human immune system. If this virus is highly pathogenic to birds and could then attain the ability to be transmitted from human to human, instead of just bird to human, then the stage is set for a severe influenza pandemic.

In 1997, a strain of influenza A (H5N1) that was highly pathogenic to poultry emerged in Hong Kong, resulting in worldwide attention to avian influenza for the first time. Aside from the pathogenic nature of this virus to poultry, public health officials found the unprecedented ability of this virus to transfer from poultry to humans especially alarming.12 A subtype of influenza A that was highly pathogenic to poultry and previously unknown to infect humans had now developed the ability to cause disease and death in humans. The outbreak began with the discovery of avian influenza A (H5N1) in a 3-year-old boy who later died of pneumonia, which was directly caused by the virus and complications of Reye's syndrome. By the end of 1997, 18 individuals had been infected by the virus; of these, six died of complications due to the infection.4 The massive culling or killing of all poultry in Hong Kong during the outbreak has been credited as a potential reason that a pandemic was avoided.5 In the years since the initial outbreak, several additional subtypes of avian influenza have been found to transfer from birds to humans, such as H9N2, H7N3, and H7N7.4 Furthermore, several cases of probable person-to-person transfer of avian influenza have recently been documented. 8 The following section discusses the H5N1 subtype, currently the most important avian influenza subtype.

Of the avian influenza subtypes documented as causing infection in humans, avian influenza A (H5N1) is of greatest concern due to the high rates of infection in poultry and a disturbing rise in morbidity and mortality in humans. Following the 1997 outbreak of the H5N1 virus in poultry and subsequent infection in humans, the virus continued to circulate in animal reservoirs but was not reported to cause disease in humans.13 In February 2003, human infection by H5N1 was reported for the first time since 1997. From December 26, 2003, to November 17, 2005, the World Health Organization (WHO) reported 130 cases of human infection by the currently circulating H5N1 virus in five nations (table 2). Of these cases, over 50% of patients have died from influenza complications.14 In addition to causing infection in humans, the H5N1 infection continues to spread among birds, where it has been a cause of significant health and economic devastation. For example, during 2004, H5N1 was reported in the poultry of nine Asian nations: Cambodia, China, Indonesia, Japan, Laos, Malaysia, South Korea, Thailand, and Vietnam.15,16   In each of these outbreaks, culling around a certain radius of the affected flock was used to protect humans and other flocks. Although this was a necessary step, it created economic hardship on the affected farmers and, ultimately, the entire industry.




Most human cases of avian influenza A (H5N1) are believed to have been the result of contact with contaminated bird excretions. The first case of probable person-to-person transfer of H5N1 was reported from the 2004 outbreak, which occurred in eight Asian nations. 8 In this case, a child (the index patient) became ill three to four days after exposure to dying household chickens infected with the H5N1 virus. The index patient's mother and aunt were subsequently infected while caring for the child. Both the index patient and her mother died of pneumonia and progressive respiratory failure within three hours (index patient) to several days (patient's mother) after admission to the hospital. This case report represents two important points regarding avian influenza. First, the case may indicate the probable ability of the virus to transfer from infected poultry to humans and also to transfer from person to person; however, sustained human transmission has not been documented. Second, the virus' ability to cause primary viral pneumonia is alarming because influenza usually facilitates the development of pneumonia by other pathogens in patients at risk for complications, rather than being a direct cause of pneumonia.

The clinical features of the H5N1 infection in humans have similarities to and differences from those of typical human influenza. The incubation period of the virus in humans is likely two to five days, but some case reports indicate the incubation period may be up to eight days.17 Initial symptoms of H5N1 include high fever (>38ºC), cough, rhinorrhea, diarrhea, vomiting, abdominal pain, shortness of breath, myalgia, and headache. During physical examination and laboratory analysis, many patients present with pulmonary infiltrates, lymphopenia, increased aminotransferase levels, and thrombocytopenia. Several clinical features, such as lymphopenia and thrombocytopenia, are atypical of classic uncomplicated influenza, especially in terms of their frequency of occurrence in infected patients. The fact that nearly all patients present with symptoms of primary viral pneumonia (often hemorrhagic) is especially alarming, indicating that the influenza virus directly caused pneumonia--a characteristic of influenza that is generally only seen during pandemics. Thus, it is now clear that many deaths in the 1918–1919 outbreak were due to primary viral pneumonia. Progression to acute respiratory distress syndrome (ARDS), multiorgan failure, and sepsis syndrome is common and occurs within four to 13 days after the onset of symptoms. Although the mortality rate has been especially high among hospitalized patients, the mortality rate among all patients is likely much lower. The death rate among infected children is higher than it is in adults. For example, during a recent outbreak in Thailand, the fatality rate was 89% among patients younger than 15 years. 18 Overall, death occurs within about nine to 10 days after onset of symptoms, with most patients dying of progressive respiratory failure.

Interestingly, the response of the human immune system to H5N1 may contribute to disease pathogenesis.17 Several immune factors, such as interleukin-6, tumor necrosis factor-alpha, interferon-l, and soluble interleukin-2 receptor, were elevated in patients in both 2003 and 2004 disease outbreaks. In addition, these immune factors have been found in higher levels in patients who have died, compared to those who have lived. It is hypothesized that elevation of these immune factors may lead to the ARDS, sepsis, and multiorgan failure observed in victims.

To summarize, the avian influenza A (H5N1) virus is a highly pathogenic subtype of influenza A that causes extensive disease and death in domesticated birds. Outbreaks of H5N1 have occurred throughout Asia and, in rare cases, have resulted in transmission to humans, causing infection and high rates of death. Whether true person-to-person transfer of H5N1 has occurred remains uncertain, but it is clear from previous bird flu pandemics (e.g., 1918 pandemic) that this can occur.

Management of Avian Influenza
Given the lack of treatment options, the best methods to manage avian influenza are monitoring and prevention. Several national and international health organizations, such as the CDC and WHO, have emphasized the importance of continued efforts in monitoring circulating avian influenza viruses and disease outbreaks in birds. The prevailing opinion among experts is simple: If an outbreak is detected that can efficiently spread from person-to-person before it has spread from the region of origin, then a pandemic may be prevented by isolation of infected individuals.1 Accordingly, several nations have initiated strong collaborative support of the WHO global surveillance network. The CDC is one of four WHO collaborating centers that provides support to the WHO global surveillance network.19 Domestically, the National Influenza Pandemic Preparedness Task Force, an interagency organized by the U.S. Secretary for Health and Human Services, has been established to prepare the nation for a possible influenza pandemic.

At this point, there is little definitive information regarding effective management of patients with avian influenza. No clearly effective medical treatment, other than supportive care, has emerged during the management of infected persons during recent outbreaks in Asia. Antiviral medications and corticosteroids are examples of medications intuitive to the management of influenza; however, more evidence is needed to support their use in a pandemic situation.14

Avian influenza A (H5N1) remains highly sensitive in vitro to the neuraminidase inhibitors oseltamivir (Tamiflu) and zanamivir (Relenza). However, the strains of H5N1 implicated in recent human infection are uniformly resistant to amantadine and rimantadine--influenza drugs that work by a different mechanism. Based on this in vitro data, the WHO recommends that all persons with suspected avian influenza A (H5N1) receive a neuraminidase inhibitor pending the results of diagnostic testing. Specifically, the WHO recommends 75 mg of oseltamivir twice daily for five days in adults and weight-adjusted twice-daily doses for five days in children.17 For treatment of severe infection, the WHO recommends higher doses of oseltamivir (150 mg twice daily for seven to 10 days in adults). Although the recent WHO recommendations do not include zanamivir dosing in avian influenza, it should be noted that this neuraminidase inhibitor has comparable activity against avian influenza (H5N1), which may result in the use of zanamivir at doses equivalent to oseltamivir in the event of an H5N1 outbreak.

Thus far, no currently marketed vaccine provides immunity against any avian influenza A subtype that has caused disease in humans. However, the current influenza vaccine may provide indirect protection against the emergence of an avian influenza virus with pathogenic potential. Theoretically, the current influenza vaccine would decrease the chance of coinfection by avian and human influenza viruses by preventing proliferation of human influenza viruses in hosts. This, in turn, would decrease the chances of genetic reassortment that occurs between avian and human influenza viruses and leads to an avian influenza virus with pandemic potential. Accordingly, the CDC and WHO recommend that individuals in possible contact with avian influenza, such as health care workers and certain international travelers, receive the current influenza vaccine.20 In addition to the indirect protection provided by the current human influenza vaccine, the National Institute of Allergy and Infectious Disease awarded contracts to Sanofi-Pasteur and Chiron in 2004 for the development of avian influenza vaccines.21 As a result, several vaccines against avian influenza A (H5N1) are in progress. In one case, a vaccine based on H5N1 strains isolated during a 2004 outbreak in humans has been reported to be immunogenic at high doses of hemagglutinin.17 The National Institutes of Health expects to receive official reports from these trials in 2006.

Role of the Pharmacist
Given the number and frequency of avian influenza–related news in the media, pharmacists will undoubtedly face questions from their patients regarding this disease. Several excellent sources of online information about avian influenza are updated regularly. Much of the information in this article will quickly become outdated. Accordingly, the pharmacist seeking information regarding avian influenza is encouraged to access relevant Web sites (table 3), which include recommendations of health care agencies about the preparation for, and management of, a possible influenza pandemic.




Pharmacists have a vital role in public health by facilitating the safe and effective distribution of medications. In the event of an outbreak of pandemic influenza, this role will be even more important. Accordingly, several national pharmacy organizations have collaborated with the federal government to create the Pharmacy National Response Team (PNRT). If an outbreak of pandemic influenza occurs, it is likely that services of the PNRT would be called upon. Pharmacists interested in pursuing a direct role in the PNRT should consult the PNRT Web page at the U.S. Department of Homeland Security National Disaster Medical System Web site (ndms.fema.gov/nprt.html).

In recent years, the pharmacist's role as a vaccine advocate has become increasingly important. In addition to providing vaccine education to patients and promoting the use of vaccines in patients who need them, pharmacists may now legally administer several vaccines (including the influenza vaccine) in many states. Given the potential for the current human influenza vaccine to protect against the emergence of pandemic influenza, this role is now particularly significant. The lack of an available vaccine for avian influenza may cause some patients to believe that they have no reason to receive this year's influenza vaccine. However, as in previous years, the total of vaccine-preventable human influenza deaths in the U.S. this winter will most likely exceed all deaths in humans from avian influenza to date. For these reasons, pharmacists should encourage all candidates eligible for the influenza vaccine to be immunized. (See www.cdc.gov/flu/professionals/vaccination for a complete list of persons recommended to receive the influenza vaccine.) Also, pharmacists may wish to consider becoming vaccine providers. (See www.immunize.org/laws/pharm.htm for a list of states in which pharmacists are currently allowed to administer vaccines.)

The absence of a vaccine and proven treatment methods for avian influenza serves to heighten tensions in the medical community and the general public regarding the threat of a pandemic. Unfortunately, this anxiety has led to irrational behavior, like the hoarding of antiviral medications. The news of oseltamivir activity against avian influenza A (H5N1) in vitro, and the subsequent WHO recommendation for use of oseltamivir in patients with suspected infection, has led to reports of hoarding of this drug. However, the assumption that oseltamivir will be efficacious against a potential avian influenza pandemic is dubious at this point for several reasons. First, as already noted, there is no sound clinical evidence of benefit derived from the use of oseltamivir in victims infected with avian influenza. Second, influenza A viruses may become resistant to neuraminidase inhibitors by a single point mutation in their viral RNA. Considering the ability of the influenza virus to mutate, it is possible that a future strain of a pandemic-causing avian influenza virus may be resistant to this class of drugs.15 Indeed, the current strain of avian influenza A (H5N1) implicated in recent human disease outbreaks is already resistant to the older antiviral medications amantadine and rimantadine. (Human influenza A in the U.S. remains generally sensitive to these medications.) Also, in limited case reports, the virus has shown resistance to oseltamivir.15 Third, hoarding of antiviral medications diverts supply from public health agencies that need to create stockpiles so that medication may be effectively distributed if an influenza pandemic occurs. Finally, the unnecessary exposure of patients to drug therapy only serves to increase their risk of unnecessary adverse effects. Thus, pharmacists can also help discourage and prevent the hoarding of influenza antiviral medications.

Summary
If a new subtype of the influenza virus to which we have no antibodies emerges, and it can infect and spread in humans, then an influenza pandemic will ensue. Avian influenza viruses that are highly pathogenic to domesticated birds are currently circulating in Asia. Furthermore, several outbreaks of avian influenza in humans have occurred secondary to the transmission of these viruses to humans. Although it is uncertain, person-to-person transfer of avian influenza virus may have occurred in isolated cases. Alarmingly, the mortality rate in humans infected with avian influenza A (H5N1) is extraordinarily high, mostly due to the virus' ability to cause primary viral pneumonia. These events are of great concern, as humans do not have immunologic protection against these types of viruses; therefore, the potential of a devastating pandemic is more likely now than in the past. However, national and international efforts are under way to prevent such a pandemic through coordinated surveillance, vaccine and antiviral production, and public policy. Pharmacists are encouraged to remain updated on this dynamic issue, as they may serve as a useful source of information and provider of vaccination and medications to their patients.

REFERENCES
1. National Strategy for Pandemic Influenza. Available at: www.whitehouse. gov/homeland/pandemic-influenza.html. Accessed November 17, 2005.
2. Treanor JJ. Mandell, Douglas and Bennett's Principles and Practice of Infectious Diseases . 5th ed. Philadelphia, PA: Churchill Livingstone; 2000.
3. Hien TT, Liem NT, Dung NT, et al. Avian Influenza A (H5N1) in 10 patients in Vietnam. N Engl J Med. 2004;350(12):1179-1188.
4. Horimoto T, Kawaoka Y. Influenza: Lessons from past epidemics, warnings from current incidents. Nat Rev Micro. 2005;3(8):591-600.
5. Weir E. The changing ecology of avian flu. CMAJ. 2005;173(8):869-870.
6. Moscona A. Neuraminidase inhibitors for influenza. N Engl J Med. 2005;353(13):1363-1373.
7. Diagnosis of Influenza. Available at: www.cdc.gov/flu/professionals/diagnosis. Accessed November 21, 2005.
8. Ungchusak K, Auewarakul P, Dowell SF, et al. Probable person-to-person transmission of avian influenza A (H5N1). N Engl J Med. 2005;352(4):333-340.
9. Russell CJ, Webster RG. The genesis of a pandemic influenza virus. Cell. 2005;123(3):368-371.
10. Taubenberger JK, Reid AH, Lourens RM, et al. Characterization of the 1918 influenza virus polymerase genes. Nature. 2005;6(437):889-893.
11. Avian influenza: General information. Available at: www.cdc.gov/flu/avian/gen-info/facts.htm. Accessed November 21, 2005.
12. Claas EC, Osterhaus AD, van Beek R, et al. Human influenza A H5N1 virus related to a highly pathogenic avian influenza virus. Lancet. 1998;351:472-477.
13. Li K, Wang J, Smith G, et al. Genesis of a highly pathogenic and potentially pandemic H5N1 influenza virus in eastern Asia. Nature. 2004;430:209-213.
14. Cumulative number of confirmed human cases of avian influenza A/(H5N1) reported to WHO. Available at: www.who.int/csr/disease/
avian_influenza/country/cases_table_2005_11_17/en/index.html. Accessed November 21, 2005.
15. The World Health Organization Global Influenza Program Surveillance Network. Evolution of H5N1 avian influenza viruses in Asia. Emerg Infect Dis. 2005;11(10):1515-1521.
16. Tiensin T, Chaitaweesub P, Thaweesak S, et al. Highly pathogenic avian influenza H5N1, Thailand, 2004. Emerg Infect Dis. 2005;11(11):1664-1672.
17. The Writing Committee of the World Health Organization (WHO) Consultation on Human Influenza A/H5. Avian influenza A (H5N1) infection in humans. N Engl J Med . 2005;353(13):1374-1385.
18. Chotpitayasunondh T, Ungchusak K, Wanna H, et al. Human disease from influenza A (H5N1), Thailand, 2004. Emerg Infect Dis. 2005;11(2):201-209.
19. Avian Influenza Outbreaks in Asia. Available at: www.cdc.gov/flu/avian/outbreaks/asia.htm. Accessed November 21, 2005.
20. Centers for Disease Control and Prevention. Interim Recommendations for Infection Control in Health-Care Facilities Caring for Patients with Known or Suspected Avian Influenza. Available at: www.cdc.gov/flu/avian/ professional/infect-control.htm. Accessed December 15, 2005.
21. National Institute of Allergy and Infectious Diseases. Questions and Answers H5N1 Avian Flu Vaccine Trials. Available at: www3.niaid.nih. gov/news/newsreleases/2005/H5N1QandA.htm. Accessed December 15, 2005.

To comment on this article, contact editor@uspharmacist.com.