Influenza: a historical perspective.

Although pandemics of influenza seem to have occurred throughout history, the first well-recorded pandemic occurred in 1580. (1) This outbreak seems to have originated in Asia and subsequently spread to Africa, Europe, and America. Mortality estimates were staggering, and several European cities experienced huge losses in their citizenry.

In 1932, influenza virus was first identified in the laboratory as the causative agent responsible for these periodic outbreaks of respiratory illness. Three main influenza types were defined: A, B, and C. Types A and B are associated with disease epidemics nearly every year. Antigenic variation in the surface glyco-proteins (ie, hemagglutinin, neuraminidase) accounts for the long-term epidemiologic success of influenza viruses. (2) Pandemics can occur when influenza A shifts to new hemagglutinin (H) or neuraminidase (N) proteins, which yields a novel virus to which humans have little or no immunity.

These extraordinary events in medical history occur at unpredictable intervals, arise in defined geographic areas, and subsequently spread throughout the world with an associated high infection rate and excess mortality. (1) The virus is spread from person to person primarily by small aerosol droplets generated by coughing or sneezing. Interestingly, certain aspects of modern society, including an ever-expanding population, crowding in urban areas, and the ease of regional and international travel, have contributed to the global spread of influenza. The highest attack rates for both pandemic and interpandemic periods occur in schoolchildren, who are important vehicles for the spread of infection within a family or a community. (3) School absenteeism is seen early in an epidemic, and employee absenteeism and hospitalization as well as influenza- and pneumonia-related deaths usually occur among the elderly during the latter part of an epidemic. It also is critical to acknowledge the role of particular animal hosts (eg, birds, swine, horses) in influenza pandemics. (2) A recognized reservoir for influenza A is found in avian populations such as ducks and chickens. Although avian strains can occasionally cause outbreaks of disease in humans, a reassortment of human and avian influenza viruses usually occurs in intermediate hosts such as pigs. In this setting, virus is produced that contains determinants for human infection as well as avian characteristics to which a majority of the human population may not be immune. It is noteworthy that many of the pandemics described over the years were thought to originate in Asia, where large human populations live in close proximity to ducks, chickens, and pigs, thus facilitating the phenomenon of viral reassortment. (1)

Clearly, influenza has earned its reputation as a remarkably versatile microbe. Its record of adaption and survival over time as well as its ability to infect humans is both impressive and intimidating. Experience during the past century not only reinforced respect for the capabilities of the virus but also left the medical community with important lessons. In this regard, it is worthwhile to examine aspects of the 20th-century influenza pandemics.

The 1918 "Spanish flu" (influenza H1N1) may have originated in midwestern U.S. military camps. In this extraordinary event, approximately 20 to 40% of the worldwide population became ill, and it is estimated that the total human deaths associated with influenza was approximately 40 million. (1) Interestingly, deaths occurred mainly in the 20- to 40-year-old age group. There actually seemed to be negative excess mortality among the elderly, suggesting that this age group possessed a degree of immunity, perhaps reflecting previous infection with a similar influenza strain. (4) The clinical course described for many young adults with Spanish flu was aggressive and resulted in death within days of infection onset. (3)

The 1957 "Asian flu" (influenza A H2N2) began in southern China, and, with improved public health and diagnostic methods, the outbreak was identified more readily and the pandemic was anticipated. The highest infection rates occurred in children and young adults (ages 5-19 yr), and, as might be expected, the epidemic in the United States became energized when schools opened in fall 1957. A second wave of illness in early 1958 involved more elderly individuals, and mortality was highest among people at the age extremes (ie, a U-shaped distribution pattern).

The "Hong Kong flu" of 1968 (influenza A H3N2) was first isolated in Hong Kong during summer 1968 and caused infection in the United States by the fall and winter of 1968. Again, the highest attack rates occurred among 10- to 14-year-old children and young adults. The majority of deaths occurred in people ages 65 years and older, but the total number of deaths attributed to influenza infection was relatively limited, and the pandemic was characterized as mild compared with previous influenza epidemics. Perhaps similarities between the 1968 Hong Kong flu (H3N2) and the 1957 Asian flu (H2N2) resulted in a degree of immunity that may have moderated the disease. (2) Other noteworthy features that may have contributed to the lower mortality rate associated with the 1968 epidemic in the United States include that the outbreak of infection peaked in December 1968, at approximately time of school holidays, and that improvements in medical care (eg, new antibiotics) likely reduced death as a result of secondary bacterial infections.

In addition to the three major influenza pandemics (ie, Spanish flu, Asian flu, Hong Kong flu), several smaller influenza epidemics as well as flu "scares" occurred in the 20th century. In 1976, an influenza virus thought to be related to the Spanish flu virus of 1918 was identified at Fort Dix, NJ. The recovery of this "swine flu" raised concern about a worldwide pandemic, and a mass vaccination program was launched in the United States. The virus never extended beyond the Fort Dix area, however. The 1977 Russian flu epidemic (H1N1) seemed to have originated in China and subsequently was spread worldwide, mainly infecting children and young adults. Many older adults who failed to become ill with the virus likely had some immunity associated with previous H1N1 virus infection. In 1997, the Government Virus Unit in Hong Kong isolated an influenza A virus obtained from a sick child and characterized this entity as an H5N1 virus. When the virus was recovered from additional members of the Hong Kong community as well as from sick chickens in the area, it was determined that this avian flu virus was transmitted directly to humans without undergoing alteration by infecting pigs as an intermediate host. Large numbers of chickens in the live bird markets of Hong Kong were subsequently slaughtered, and the outbreak was halted. (2) In 1999, the Hong Kong Government Virus Unit isolated another avian flu virus (H9N2) that caused illness in children, but this virus did not result in widespread infection. Like the H5N1 avian influenza A virus, the H9N2 virus was recovered from the Hong Kong live bird markets, and it too infected humans without an intermediate host. (2) These episodes serve to remind clinicians of the presence of influenza A virus in the avian population and suggests that the virus is evolving in ways that affect its transmissibility.

This brief review of the history and epidemiology of influenza infection underscores the notion that this opponent is formidable and can potentially threaten the welfare of large populations and that its spread throughout societies has been facilitated by a variety of modern advances ranging from urbanization to international travel. Governments throughout the world need to cooperate and collaborate in efforts to identify emerging variants of influenza A so that appropriate influenza vaccines can be developed and overall preparedness can be optimized.

References

(1.) Potter CW. A history of influenza. J Appl Microbiol 2001;91:572-579.

(2.) Cox NJ, Subbarao K. Global epidemiology of influenza: Past and present. Annu Rev Med 2000;51:407-421.

(3.) Glezen WP. Emerging infections: Pandemic influenza. Epidemiol Rev 1996; 18:64-76.

(4.) Luk J, Gross P, Thompson WW. Observations on mortality during the 1918 influenza pandemic, Clin Infect Dis 2001;33:1375-1378.

From the James H. Quillen VA Medical Center and the Department of Internal Medicine, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN.

No financial support was obtained for this manuscript. The authors of this manuscript do not have any financial, commercial, or proprietary interest in any drug, device, or equipment mentioned in this article. The views contained in this article do not necessarily reflect those of the Department of Veterans Affairs of the United States.

Reprint requests to Felix A. Sarubbi, MD, Department of Internal Medicine, James H. Quillen College of Medicine, East Tennessee State University, Box 70622, Johnson City, TN 37614. Email: [e-mail]

Accepted June 19, 2003.