Influenza historical perspective

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Historical Perspective

• The symptoms of human influenza were clearly described by Hippocrates roughly 2400 years ago.
• Since then, the virus has caused numerous pandemics.
• Historical data on influenza are difficult to interpret, because the symptoms can be similar to those of other diseases, such as diphtheria, pneumonic plague, typhoid fever, dengue, or typhus.
• The first convincing record of an influenza pandemic was of an outbreak in 1580, which began in Asia and spread to Europe via Africa.
• In Rome over 8,000 people were killed, and several Spanish cities were almost wiped out.
• Pandemics continued sporadically throughout the 17th and 18th centuries, with the pandemic of 1830–1833 being particularly widespread; it infected approximately a quarter of the people exposed.

The difference between the influenza mortality age-distributions of the 1918 epidemic and normal epidemics. Deaths per 100,000 persons in each age group, United States, for the interpandemic years 1911–1917 (dashed line) and the pandemic year 1918 (solid line).

Spanish Flu Pandemic

• The most famous and lethal outbreak was the so-called Spanish flu pandemic (type A influenza, H1N1 subtype), which lasted from 1918 to 1919.
• Older estimates say it killed 40–50 million people while current estimates say 50 million to 100 million people worldwide were killed.
• This pandemic has been described as "the greatest medical holocaust in history" and may have killed as many people as the Black Death.
• This huge death toll was caused by an extremely high infection rate of up to 50% and the extreme severity of the symptoms, suspected to be caused by cytokine storms.
• Indeed, symptoms in 1918 were so unusual that initially influenza was misdiagnosed as dengue, cholera, or typhoid.
• The majority of deaths were from bacterial pneumonia, a secondary infection caused by influenza, but the virus also killed people directly, causing massive hemorrhages and edema in the lung.
• The Spanish flu pandemic was truly global, spreading even to the Arctic and remote Pacific islands.
• The unusually severe disease killed between 2 and 20% of those infected, as opposed to the more usual flu epidemic mortality rate of 0.1%.
• Another unusual feature of this pandemic was that it mostly killed young adults, with 99% of pandemic influenza deaths occurring in people under 65, and more than half in young adults 20 to 40 years old.
• This is unusual since influenza is normally most deadly to the very young (under age 2) and the very old (over age 70).
• The total mortality of the 1918–1919 pandemic is not known, but it is estimated that 2.5% to 5% of the world's population was killed. As many as 25 million may have been killed in the first 25 weeks; in contrast, HIV/AIDS has killed 25 million in its first 25 years.

Known Flu Pandemics

Name of pandemic	Date	Deaths	Case fatality rate	Subtype involved	Pandemic Severity Index
1889–1890 Flu Pandemic (Asiatic or Russian Flu)	1889–1890	1 million	0.15%	possibly H3N8 or H2N2	N/A
1918 Flu Pandemic (Spanish flu)	1918–1920	20 to 100 million	2%	H1N1	5
Asian Flu	1957–1958	1 to 1.5 million	0.13%	H2N2	2
Hong Kong Flu	1968–1969	0.75 to 1 million	<0.1%	H3N2	2
Russian flu	1977–1978	no accurate count	N/A	H1N1	N/A
2009 Flu Pandemic	2009–2010	105,700-395,600	0.03%	H1N1	N/A

Other Flu Pandemics

• Later flu pandemics were not so devastating.
• They included the following:

• The 1957 Asian Flu (type A, H2N2 strain)
• The 1968 Hong Kong Flu (type A, H3N2 strain)

• Even these smaller outbreaks killed millions of people.
• In later pandemics antibiotics were available to control secondary infections and this may have helped reduce mortality compared to the Spanish Flu of 1918.
• Although there were scares in New Jersey in 1976 (with the Swine Flu), world wide in 1977 (with the Russian Flu), and in Hong Kong and other Asian countries in 1997 (with H5N1 avian influenza), there have been no major pandemics since the 1968 Hong Kong Flu.
• Immunity to previous pandemic influenza strains and vaccination may have limited the spread of the virus and may have helped prevent further pandemics.

Influenza Virus

• The etiology of influenza, the Orthomyxoviridae family of viruses, was first discovered in pigs by Richard Schope in 1931.
• This discovery was shortly followed by the isolation of the virus from humans by a group headed by Patrick Laidlaw at the Medical Research Council of the United Kingdom in 1933.
• However, it was not until Wendell Stanley first crystallized tobacco mosaic virus in 1935 that the non-cellular nature of viruses was appreciated.

Flu Vaccine

• The first significant step towards preventing influenza was the development in 1944 of a killed-virus vaccine for influenza by Thomas Francis, Jr.. This built on work by Frank Macfarlane Burnet, who showed that the virus lost virulence when it was cultured in fertilized hen's eggs.
• Application of this observation by Francis allowed his group of researchers at the University of Michigan to develop the first flu vaccine, with support from the U.S. Army.
• The Army was deeply involved in this research due to its experience of influenza in World War I, when thousands of troops were killed by the virus in a matter of months.

Year	Area	Affected Species	Subtype
1959	Scotland	chicken	H5N1
1963	England	turkey	H7N3
1966	Ontario (Canada)	turkey	H5N9
1976	Victoria (Australia)	chicken	H7N7
1979	Germany	chicken	H7N7
1979	England	turkey	H7N7
1983	Pennsylvania (USA)*	chicken,turkey	H5N2
1983	Ireland	turkey	H5N8
1985	Victoria (Australia)	chicken	H7N7
1991	England	turkey	H5N1
1992	Victoria (Australia)	chicken	H7N3
1994	Queensland (Australia)	chicken	H7N3
1994	Mexico*	chicken	H5N2
1994	Pakistan*	chicken	H7N3
1997	New South Wales (Australia)	chicken	H7N4
1997	Hong Kong (China)*	chicken	H5N1
1997	Italy	chicken	H5N2
1999	Italy*	turkey	H7N1
2002	Hong Kong (China)	chicken	H5N1
2002	Chile	chicken	H7N3
2003	Netherlands*	chicken	H7N7
*Outbreaks with significant spread to numerous farms, resulting in great economic losses. Most other outbreaks involved little or no spread from the initially infected farms.

1979: "More than 400 harbor seals, most of them immature, died along the New England coast between December 1979 and October 1980 of acute pneumonia associated with influenza virus, A/Seal/Mass/1/180 (H7N7)."

1995: "[V]accinated birds can develop asymptomatic infections that allow virus to spread, mutate, and recombine (ProMED-mail, 2004j). Intensive surveillance is required to detect these “silent epidemics” in time to curtail them. In Mexico, for example, mass vaccination of chickens against epidemic H5N2 influenza in 1995 has had to continue in order to control a persistent and evolving virus (Lee et al., 2004)."

1997: "Influenza A viruses normally seen in one species sometimes can cross over and cause illness in another species. For example, until 1997, only H1N1 viruses circulated widely in the U.S. pig population. However, in 1997, H3N2 viruses from humans were introduced into the pig population and caused widespread disease among pigs. Most recently, H3N8 viruses from horses have crossed over and caused outbreaks in dogs."

2000: "In California, poultry producers kept their knowledge of a recent H6N2 avian influenza outbreak to themselves due to their fear of public rejection of poultry products; meanwhile, the disease spread across the western United States and has since become endemic."

2003: In Netherlands H7N7 influenza virus infection broke out in poultry on several farms.

2004: In North America, the presence of avian influenza strain H7N3 was confirmed at several poultry farms in British Columbia in February 2004. As of April 2004, 18 farms had been quarantined to halt the spread of the virus.

2005: Tens of millions of birds died of H5N1 influenza and hundreds of millions of birds were culled to protect humans from H5N1. H5N1 is endemic in birds in southeast Asia and represents a long term pandemic threat.

2006: H5N1 spreads across the globe killing hundreds of millions of birds and over 100 people causing a significant H5N1 impact from both actual deaths and predicted possible deaths.

Evolution

See also: Punctuated equilibrium

Taubenberger says:

"All influenza A pandemics since [the Spanish flu pandemic], and indeed almost all cases of influenza A worldwide (excepting human infections from avian viruses such as H5N1 and H7N7), have been caused by descendants of the 1918 virus, including "drifted" H1N1 viruses and reassorted H2N2 and H3N2 viruses. The latter are composed of key genes from the 1918 virus, updated by subsequently incorporated avian influenza genes that code for novel surface proteins, making the 1918 virus indeed the "mother" of all pandemics.

Researchers from the National Institutes of Health used data from the Influenza Genome Sequencing Project and concluded that during the ten-year period examined most of the time the hemagglutinin gene in H3N2 showed no significant excess of mutations in the antigenic regions while an increasing variety of strains accumulated. This resulted in one of the variants eventually achieving higher fitness, becoming dominant, and in a brief interval of rapid Darwinian evolution rapidly sweeping through the human population and eliminating most other variants.