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.

Past Flu Seasons Adapted from CDC

2006-2007

• During October 1, 2006--May 19, 2007, the WHO and the National Respiratory and Enteric Virus Surveillance System (NREVSS) collaborating laboratories in the United States tested 179,268 respiratory specimens for influenza viruses; 23,753 (13.2%) were positive.
• Of these, 18,817 (79.2%) were influenza A viruses and 4,936 (20.8%) were influenza B viruses.
• Among the influenza A viruses, 6,280 (33.4%) were subtyped; 3,912 (62.3%) were influenza A (H1) viruses and 2,368 (37.7%) were influenza A (H3) viruses.
• The proportion of specimens testing positive for influenza first exceeded 10% during the week ending December 23, 2006 (week 51), peaked at 28.0% during the week ending February 10, 2007 (week 6), and declined to less than 10% during the week ending April 28, 2007 (week 17).
• The proportion was above 10% positive for 14 consecutive weeks.
• The peak percentage of specimens testing positive for influenza during the previous three seasons ranged from 22.6% to 34.7%, and the peak occurred during early December to early March.
• During the previous three influenza seasons, the number of consecutive weeks during which more than 10% of specimens tested positive for influenza ranged from 13 to 17 weeks.

2007-2008

• During September 30, 2007--May 17, 2008, the WHO and the National Respiratory and Enteric Virus Surveillance System collaborating laboratories in the United States tested 225,329 specimens for influenza viruses; 39,827 (18%) were positive.
• Of the positive specimens, 28,263 (71%) were influenza A viruses, and 11,564 (29%) were influenza B viruses.
• Among the influenza A viruses, 8,290 (29%) were subtyped; 2,175 (26%) were influenza A (H1N1), and 6,115 (74%) were influenza A (H3N2) viruses.
• The proportion of specimens testing positive for influenza first exceeded 10% during the week ending January 12, 2008 (week 2), peaked at 32% during the week ending February 9, 2008 (week 6), and declined to <10% during the week ending April 19, 2008 (week 16).
• The proportion positive was above 10% for 14 consecutive weeks.
• The peak percentage of specimens testing positive for influenza during the previous three seasons ranged from 22% to 34% and the peak occurred during mid-February to early March.
• During the previous three influenza seasons, the number of consecutive weeks during which more than 10% of specimens tested positive for influenza ranged from 13 to 17 weeks