Symposium on Pandemic Influenza - October 2007
By Kevin A Swartz, MD, and James P. Luby, MD
Influenza is an acute illness caused by members of the Orthomyxoviridae family of viruses, which are negatively stranded RNA viruses. Influenza infection in humans is usually self-limited and is typically characterized by a distinct viral syndrome that may be associated with epidemic spread. However, pandemics of new forms of influenza A virus have occurred throughout recent human history and have caused much higher rates of morbidity and mortality. Recent epidemics of avian influenza and the availability of modern travel have heightened awareness as well as concern regarding the occurrence of a new human influenza pandemic.
Influenza epidemics have existed for at least 400 years as evidenced by records describing the classical nature of epidemic influenza by Sydenham in 1679. The greatest influenza pandemic occurred in 1918 and claimed the lives of more than 50 million people worldwide in just 25 weeks. 1 To give perspective, the AIDS epidemic has taken 25 years to produce similar numbers, and some think the estimates of death from the 1918 influenza may grossly underestimate the tragedy of that pandemic.
Two other pandemics occurred in 1957 and 1968 with new strains of influenza, and a virus similar to the 1918 strain saw a resurgence in 1977. The 1977 virus is particularly interesting because it was found to be nearly identical to a strain that circulated in the 1950s (which, itself, was a persisting 1918-related virus). This finding prompted consideration that this 1977 virus may have resulted from an accidental release from a laboratory back into the human population. Even outside of these periodic surges of disease, influenza is routinely a leading cause of death in the United States in the form of seasonal epidemics. 2
Influenza A viruses can be found in all kinds of animals; however, aquatic birds are considered the natural reservoir, with every known HA and NA type found in these animals. Furthermore, infection of aquatic birds is typically asymptomatic, and there appears to be a state of evolutionary adaptation with their avian hosts. 3 Conversely, these viruses may cause significant disease when introduced into land-based birds and mammals. However, because of the variation of host receptors, different mammals exhibit differing capacity to be infected with each subtype of avian virus. This difference in infectivity gives rise to the concept of "avian-like" viruses, which typically infect domestic land-based poultry, versus "human-like" viruses, which cause typical human influenza infection. Furthermore, certain species of mammals (such as the pig) can be infected by both "avian-like" and "human-like" influenza viruses because they possess receptors for both forms. Previously, avian influenza viruses were thought to require an intermediate host, such as the pig, to develop the capacity to infect humans, thus creating new pandemic forms. Although there is evidence for this process, recent investigations suggest that this is not necessary and that avian viruses have the capacity to jump directly from birds to humans without such an intermediate host. 4
Transmission of influenza is via contact (either directly with respiratory secretions or indirectly through fomites) and from aerosolized droplets. 5 A new host will become infected after the virus attaches to and enters the cells of the nasopharynx or the cells lining the respiratory tract. However, this process can be aborted and infection avoided if the host has preformed antibodies specifically able to neutralize the particular strain of influenza.
Typically, symptoms of influenza A infection begin within 24 to 48 hours after infection; 6 it is characterized initially by systemic findings such as high fever, myalgias, and malaise. Some patients can be completely incapacitated by the systemic symptoms alone. Respiratory symptoms such as a dry cough, pharyngeal pain, and shortness of breath may develop from the beginning of the illness, but are often surpassed by the systemic complaints. This dissociation is characteristic of influenza infection in contrast to other viral respiratory syndromes. Symptoms may persist for up to a week before beginning to subside, and infections with influenza B virus tend to be somewhat milder than those with influenza A. Death is usually associated with infection in extremes of age (children and elderly); however, a characteristic finding of the 1918 pandemic was an increased case-fatality rate in persons aged from 15 to 44 years.
The most significant complication of influenza infection is pneumonia, manifested either as a primary viral pneumonia from influenza itself or as a secondary bacterial pneumonia. Usually presenting early in a course, primary viral pneumonia is typified by a high mortality rate that may be due to a rapidly progressive hemorrhagic form of pneumonia with acute respiratory distress syndrome (ARDS). This was particularly true with the 1918 pandemic virus.
Secondary bacterial pneumonia typically presents after an initial improvement of the course of influenza infection and has classically been associated with Streptococcus pneumoniae or Haemophilus influenzae , which are two of the most common causes of typical community-acquired pneumonia (CAP). These organisms can usually be treated with standard antibiotics but can still be associated with significant mortality in elderly patients. Recently, a more disturbing finding is the increasing incidence of community-acquired methicillin-resistant Staphylococcus aureus (CAMRSA) as a cause of postinfluenza pneumonia. 7 This new manifestation is rapidly progressive and is associated with an extremely high mortality rate. Furthermore, MRSA is usually resistant to all first-line antibiotics that are routinely given for routine CAP per current treatment guidelines. 8
Influenza viruses can be divided into three types: A, B, and C. These types are grouped according to the most abundant protein found in the virus, the nucleocapsid protein. A standard method for describing influenza viruses further includes the influenza type, place of initial isolation, strain designation, and year of isolation. For example, a major strain of influenza A virus during the 2006-07 season was A/New Caledonia/20/1999-like.
Influenza A viruses are further divided into subtypes of the hemagglutinin (H or HA) and neuraminidase (N or NA) proteins, as these are essential for immunologic neutralization by the human host. For example, the previously mentioned strain is an H1N1 strain. Currently, 16 known subtypes of HA and nine subtypes of NA 9 and strains of influenza A virus exist in nature with every combination of these subtypes.
Influenza B viruses are not categorized into subtypes because HA and NA proteins of influenza B viruses remain fairly constant except for yearly drift.
Influenza C viruses, which cause a "common cold" sort of illness, are seen infrequently.
One of the unique and most remarkable features of influenza virus is the rapidity with which influenza is able to evolve to avoid immune detection within the human population. This is possible because of a high rate of viral replication, along with a virally encoded RNA-dependent RNA polymerase that lacks proofreading capability, allowing for frequent mutations to arise. These two factors work together to ensure that these viruses change over time.
Remarkably, we are still able to benefit from immunization to influenza viruses because we change the vaccine strains yearly. This has not been possible with other RNA viruses such as hepatitis C virus (HCV) and the human immunodeficiency virus (HIV), which also have a high rate of spontaneous mutation.
When subtle mutations occur in the genes that encode the hemagglutinin and neuraminidase (the main determinants of immune recognition), variants can develop in which there is little immune recognition in the current human population. 10 This process, called antigenic drift, is the basis for the seasonal epidemics of influenza. However, this does not account for the major shifts that can occur to form "new" viruses and to which the population has absolutely no immunity. In this process, very little or no serologic relationship exists between the HA or NA antigens of the "old" and "new" viruses, and incredible morbidity and mortality can result from the introduction into an immunologically naïve population; this is antigenic shift.
Antigenic shift is possible through at least two mechanisms. One likely process reflects the unique characteristic of the influenza virus containing a segmented genome. Influenza virus has eight separate segments of RNA that make up its genome; the immunologically important HA and NA genes are represented on different segments. One copy of each segment is packaged into a single viral particle. In intermediate hosts, such as the pig, it is postulated that coinfection with two separate influenza viruses, such as an H1N1 and an H2N2, can lead to reassortment events where viruses are packaged with any combination of these two subtypes (i.e., H1N1, H1N2, H2N1, and H2N2 viruses). 11
In the event that a novel subtype is then introduced into a naïve human population, an antigenic shift can occur in the predominant influenza type, leading to a devastating pandemic.
Influenza A H2N2 and H3N2 subtypes are believed to have been introduced, due to reassortment, in 1957 and 1968, respectively. In the H2N2 pandemic, it seems that the genome segments encoding H2 and N2, as well as a protein called PB1, were of avian origin, whereas the remaining five segments were of the circulating human H1N1 virus at that time. Subsequently, the H3N2 pandemic is believed to have arisen by the replacement of the H2 from this prior strain with a new avian H3 gene segment, along with the addition of a new PB1 gene segment. However, less is known regarding the role that reassortment may have played in origin of the H1N1 virus that caused the 1918 pandemic.
Another possibility for the introduction of novel influenza virus into the human population involves the direct transmission of "avian" influenza viruses from birds to humans. Less is known about this process; however, evidence suggests that this occurs among individuals with close contact with birds. 4 Furthermore, this is the method that seems to explain the introduction of H5N1 avian influenza viruses to man, 12 which has led to 186 deaths out of 307 confirmed infections (60.5 percent) from 2003 through mid-2007. 13 Although this method of transmission results in a highly virulent virus, thus far it has not resulted in a virus that can be easily transmitted among humans (a hallmark of humanized influenza virus). However, good evidence suggests that this method was primarily responsible for the origin of the 1918 influenza pandemic, and some speculate that this virus was circulating as early as 1915. 8
The most effective method to control influenza in a population is through annual vaccination. This is commonly recommended for persons at high risk for complications from influenza (the elderly, young children aged 6 to 23 months, children requiring chronic aspirin use who might be at risk for developing Reye's syndrome after influenza virus infection, and persons with complicated health conditions regardless of age) or those who are in close contact with these persons (such as health care workers). 14
An inactivated influenza vaccine was first licensed in the United States in 1943, and early studies demonstrated a protective efficacy approximating 70 percent in healthy adults. Ensuring adequate vaccination in a population could possibly provide further benefits in protecting those who are not vaccinated or those who do not respond to vaccination through herd immunity. 15
The current vaccines contain three strains of influenza virus based on updated analysis of circulating strains: one representative from influenza A (H1N1) and from A (H3N2), and an influenza B strain that ought to be prevalent in a given season. An H5N1 avian influenza virus vaccine that produces an adequate immune response has been prepared but not manufactured on a large scale because any potential pandemic strain may differ significantly from this vaccine strain.
A live attenuated influenza vaccine (LAIV/FluMist) was approved in 2003 for human use in the United States. The LAIV is based on a genetically attenuated strain of influenza A. In addition, LAIV strains are grown in a serial process that selects for growth at lower temperatures (like those found in the upper respiratory tract) but is less adapted at body temperature. Instead of being injected intramuscularly, like the traditional triple valent influenza vaccine, the LAIV is administered intranasally. This form of administration is likely to be more acceptable to patients. In addition, this route of administration allows for replication of the cold-adapted virus in the mucosa of the upper respiratory tract and is generally more effective at inducing mucosal IgA at the initial site of natural infection, whereas parenteral administration (of inactivated vaccine) tends to induce higher levels of serum IgG antibodies. 16 A meta-analysis comparing these two vaccines showed these two forms of vaccination to be equally efficacious at preventing culture positive influenza illness. 17
Currently, two classes of antiviral drugs are approved for use against influenza viruses. 18 The first class of drugs to be used act as inhibitors of the M2 ion channel and include the drugs amantadine and rimantadine. After the entry of an influenza virus into a host cell, the function of the M2 ion channel is to acidify the interior of the virion, which subsequently causes a conformational change in the virus and allows intracellular uncoating of the virus. Amantadine and rimantadine are active against influenza A viruses only. Influenza B virus has a similar hydrogen ion channel but lacks the specific site of activity for amantadine or rimantadine. However, there is a conserved region between the M2 of both influenza A virus and B virus, which may be a target for future drugs. 19 Both of these agents are approved for treatment and for prophylaxis; however, drug resistance occurs rapidly due to a single mutation in the M2 gene being able to confer complete resistance to both amantadine and rimantadine. H5N1 avian influenza viruses are generally thought to be resistant to this class of drugs. Recently, H3N2 strains have also been shown to be resistant.
The second class of antiviral drugs to be developed inhibits the function of the influenza virus neuraminidase. The neuraminidase enzyme cleaves terminal sialic acid from sialic acid containing glycoproteins on host cells. These glycoproteins act as receptors for the attachment of influenza virus. Without the activity of neuraminidase, newly formed influenza virus is unable to be released from the host cell to continue the chain of infection. This class includes the drugs zanamivir (Relenza) and oseltamivir (Tamiflu), and unlike the M2 inhibitors, these agents have activity against both influenza A and B viruses at tolerable human dosages. Both of these agents are approved for treatment and prophylaxis of influenza A and B. Drug resistance to neuraminidase inhibitors occurs but seems to be infrequent due to their activity on a highly conserved protein. In addition, resistant viruses may be less virulent because of decreased function of the neuraminidase enzyme that is produced by this mutation. More information is needed on this point.
Influenza maintains a special position in human medicine as the cause of the greatest pandemic of disease in all of human history as well as a continuous and significant source of worldwide morbidity and mortality every year. The very nature of the influenza virus allows it to evade and adapt to the human population. We currently have useful tools such as vaccination and antiviral medications to limit this burden; however, appropriate vaccines take time to prepare, and antiviral drug resistance has emerged as a significant problem. Continued vigilance and pandemic planning are essential, given the continued threat of novel strains that can arise and rapidly cause disease across the world.
Dr. Swartz is a fellow in internal medicine and infectious diseases, and Dr. Luby is a professor of internal medicine in the Division of Infectious Disease at The University of Texas Southwestern Medical School at Dallas.
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- Leading causes of death. National Center for Health Statistics; 2007. http://www.cdc.gov/nchs/fastats/lcod.htm. Accessed May 29, 2007.
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- Myers KP, Setterquist SF, Capuano AW, Gray GC. Infection due to 3 Avian influenza subtypes in United States veterinarians. Clin Infect Dis . 2007;45(1):4-9.
- Brankston G, Gitterman L, Hirji Z, Lemieux C, Gardam M. Transmission of influenza A in human beings. Lancet Infect Dis . 2007;7(4):257-265.
- Treanor JJ. Influenza virus. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases . 6th ed. Elsevier; 2005:2060-2078.
- Severe methicillin-resistant Staphylococcus aureus community-acquired pneumonia associated with influenza - Louisiana and Georgia, December 2006-January 2007. MMWR Morb Mortal Wkly Rep . 2007;56(14):325-329.
- Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis . 2007;44(suppl 2):S27-S72.
- Palese P, Shaw ML. Fields virology. In: Fields, BN, Knipe DM, Howley PM, eds. Fields Virology . 5th ed. Philadelphia, Pa.: Lippincott Williams & Wilkins; 2007:1647-1690.
- Schweiger B, Zadow I, Heckler R. Antigenic drift and variability of influenza viruses. Med Microbiol Immunol . 2002;191(3-4):133-138.
- Hay AJ, Gregory V, Douglas AR, Lin YP. The evolution of human influenza viruses. Philos Trans R Soc Lond B Biol Sci . 2001;356(1416):1861-1870.
- Guan Y, Poon LLM, Cheung CY, et al. H5N1 influenza: a protean pandemic threat. Proc Natl Acad Sci U S A . 2004;101(21):8156-8161.
- Cumulative number of confirmed human cases of avian influenza A/(H5N1) reported to WHO. World Health Organization. http://www.who.int/csr/disease/avian_influenza/country/cases_table_2007_05_24/en/index.html . Accessed May 24, 2007.
- Smith NM, Bresee JS, Shay DK, Uyeki TM, Cox NJ, Strikas RA. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep . 2006;55(RR-10):1-42.
- Glezen WP. Herd protection against influenza. J Clin Virol . 2006;37(4):237-243.
- Sasaki S, Jaimes MC, Holmes TH, et al. Comparison of the influenza virus-specific effector and memory B-cell responses to immunization of children and adults with live attenuated or inactivated influenza virus vaccines. J Virol . 2007;81(1):215-228.
- Beyer WE, Palache AM, de Jong JC, Osterhaus AD. Cold-adapted live influenza vaccine versus inactivated vaccine: systemic vaccine reactions, local and systemic antibody response, and vaccine efficacy. A meta-analysis. Vaccine . 2002;20(9-10):1340-1353.
- Hayden FG, Pavia AT. Antiviral management of seasonal and pandemic influenza. J Infect Dis . 2006;194(suppl 2):S119-S126.
- Pinto LH, Lamb RA. The M2 proton channels of influenza A and B viruses. J Biol Chem . 2006;281(14):8997-9000.
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