Spanish flu

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The Spanish Flu Pandemic, also known as La Grippe Espagnole, La Pesadilla, or the 1918 flu, was a pandemic caused by an unusually severe and deadly strain of the subtype H1N1 of the species Influenza A virus (which apparently killed via cytokine storm, explaining the severe nature and unusual age distribution). In that pandemic, 50 million to 100 million people worldwide were killed during about a year in 1918 and 1919 [NAP].

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The Allies of World War I called it the "Spanish Flu". This was mainly because the pandemic received greater press attention in Spain than in the rest of the world, as Spain was not involved in the war and there was no wartime censorship in Spain.

Contents

1 Rapid and lethal spread of influenza

1.1 Patterns of fatality
1.2 Devastated communities
1.3 Attempts to curb the pandemic
1.4 Unaffected Locales

2 Spanish flu research
3 Sources and notes
4 Further reading

Rapid and lethal spread of influenza

The global mortality rate from the 1918/1919 pandemic is not known, but is estimated at 2.5% – 5% of the human population, with 20% of the world population suffering from the disease to some extent. Influenza may have killed as many as 25 million in its first 25 weeks; in contrast, AIDS killed 25 million in its first 25 years. Influenza spread across the world, killing more than 25 million in six months; some estimates put the total killed at over twice that number, possibly even 100 million.

In US, about 28% of the population suffered, and 500,000 to 675,000 died. In Britain 200,000 died; in France more than 400,000. Entire villages perished in Alaska and southern Africa. In Australia an estimated 10,000 people died and in the Fiji Islands, 14% of population died during only two weeks, and in Western Samoa 22%. An estimated 17 million died in India, about 5% of India's population at the time. In the Indian Army, almost 22% of troops who caught the disease died of it.

While World War I didn't cause the flu, the close quarters and mass movement of troops quickened its spread. It has been speculated that the soldiers' immune systems were weakened by the stresses of combat and chemical attacks, increasing their susceptibility to the disease.

Patterns of fatality

The strain was unusual for influenza in that this pandemic killed many young adults and otherwise healthy victims; common influenzas kill mostly newborns, the old and infirm.

People without symptoms could be struck suddenly and within hours be too feeble to walk; many died the next day. Symptoms included a blue tint to the face and coughing up blood caused by severe obstruction of the lungs. In later stages, the virus caused an uncontrollable hemorrhaging that filled the lungs, and patients drowned in their body fluids.

In fast-progressing cases, mortality was primarily from pneumonia, by virus-induced consolidation. Slower-progressing cases featured secondary bacterial pneumonias, and there may have been neural involvement that led to psychiatric disorders in a minority of cases. Some deaths resulted from malnourishment and even animal attacks in overwhelmed communities.

Devastated communities

While in most places less than one-third of the population was infected and a fraction of that died, in a number of towns in several countries the entire population was wiped out.

Even in areas where mortality was low, those incapacitated by the illness were often so numerous as to bring much of everyday life to a stop. Some communities closed all stores or required customers not to enter the store but place their orders outside the store for filling. There were many reports of places with no health care workers to tend the sick because of their own ill health and no able bodied grave diggers to bury the dead. Mass graves were dug by steam shovel and bodies buried without coffins in many places.

Street car conductor in Seattle not allowing passengers aboard without a mask in 1918.

Attempts to curb the pandemic

The social effects were intense due to the fast spread of the pandemic. Many cities, states, and countries enforced restrictions on public gatherings and travel to try to stop the pandemic. In many places theaters, dance halls, churches and other public gathering places were closed for over a year. Quarantines were enforced with little success. Some communities placed armed guards at the borders and turned back or quarantined any travellers. One U.S. town even outlawed shaking hands.

Unaffected Locales

In Japan, 257,363 deaths were attributed to influenza by July 1919, giving an estimated 0.425% mortality rate, much lower than nearly all other Asian countries for which data are available. The only sizeable inhabited place with no documented outbreak of the flu in 1918–1919 was the island of Marajó at the mouth of the Amazon River in Brazil.

Spanish flu research

One theory is that the virus strain originated at Fort Riley, Kansas, by two genetic mechanisms — genetic drift and antigenic shift — in viruses in poultry and swine which the fort bred for local consumption. But evidence from a recent reconstruction of the virus suggests that it jumped directly from birds to humans, without traveling through swine.

In February 1998, The Molecular Pathology Division of the US Armed Forces Institute of Pathology (AFIP) recovered samples of the 1918 influenza from the frozen corpse of a Native Alaskan woman buried for nearly eight decades in permafrost near Brevig Mission, Alaska. Brevig Mission lost approximately 85% of its population to the Spanish flu in November 1918. One of the four recovered samples contained viable genetic material of the virus. This sample provided scientists a first-hand opportunity to study the virus, which was inactivated with guanidinium thiocyanate before transport. This sample and others found in AFIP archives allowed researchers to completely analyze the critical gene structures of the 1918 virus.

"We have now identified three cases: the Brevig Mission case and two archival cases that represent the only known sources of genetic material of the 1918 influenza virus", said Jeffery K.Taubenberger, MD, PhD, chief of the institute's molecular pathology division and principal investigator on the project.

In September 2000, Noymer and Garenne published a study that poses an etiological theory explaining the unusual W-shaped mortality age profile of the virus. This profile is characterized by a mode in the 25 – 34 year age group. Usually, influenza has a U-shaped profile, being most deadly to the young and the old. Additionally, after the pandemic the difference in life expectancy between men and women decreased (women had a historically longer life expectancy). Noymer and Garenne have causally linked these two anomalies to an interaction with tuberculosis, a predominantly male disease of young adulthood.

In October 2002, the AFIP together with a microbiologist from the Mount Sinai School of Medicine in New York started to reconstruct the Spanish Flu. In an experiment published in October 2002, they created a virus with two 1918 genes. This virus was much more deadly to mice than other constructs containing genes from contemporary influenza virus. The experiments were conducted under high biosafety conditions at a laboratory of the US Department of Agriculture in Athens, Georgia.

The February 6 2004 edition of Science magazine reported that two research teams, one led by Sir John Skehel, director of the National Institute for Medical Research in London, another by Professor Ian Wilson of The Scripps Research Institute in San Diego, had managed to synthesize the hemagglutinin protein responsible for the 1918 outbreak of Spanish Flu. They did this by piecing together DNA from a lung sample from an Inuit woman buried in the Alaskan tundra and a number of preserved samples from American soldiers of the First World War. The teams had analyzed the structure of the gene and discovered how subtle alterations to the shape of a protein molecule had allowed it to move from birds to humans with such devastating effects.

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On October 5, 2005, researchers announced that the genetic sequence of the 1918 flu strain had been reconstructed using historic tissue samples. Special report at Nature News: [The 1918 flu virus is resurrected], Published online: 5 October 2005; DOI:[10.1038/437794a] . See: "Characterization of the 1918 influenza virus polymerase genes" by Jeffery K. Taubenberger, Ann H. Reid, Raina M. Lourens, Ruixue Wang, Guozhong Jin and Thomas G. Fanning in Nature (2005) volume 437 pages 889–893 DOI:[10.1038/nature04230] . Also: "Characterization of the Reconstructed 1918 Spanish Influenza Pandemic Virus" by Terrence M. Tumpey, Christopher F. Basler, Patricia V. Aguilar, Hui Zeng, Alicia Solórzano, David E. Swayne, Nancy J. Cox, Jacqueline M. Katz, Jeffery K. Taubenberger, Peter Palese and Adolfo García-Sastre in Science (2005) volume 310 pages 77–80 DOI:[10.1126/science.1119392] .

Influenza viruses have a relatively high mutation rate that is characteristic of RNA viruses. The H5N1 virus has mutated into a variety of types with differing pathogenic profiles; some pathogenic to one species but not others, some pathogenic to multiple species. [New genotype of avian influenza H5N1 viruses isolated from tree sparrows in China] by Z. Kou, F. M. Lei, J. Yu, Z. J. Fan, Z. H. Yin, C. X. Jia, K. J. Xiong, Y. H. Sun, X. W. Zhang, X. M. Wu, X. B. Gao and T. X. Li in Journal of Virology (2005) volume 79, pages 15460-15466. The ability of various influenza strains to show species-selectivity is largely due to variation in the hemagglutinin genes. Genetic mutations in the hemagglutinin gene that cause single amino acid substitutions can significantly alter the ability of viral hemagglutinin proteins to bind to receptors on the surface of host cells. Such mutations in avian H5N1 viruses can change virus strains from being inefficient at infecting human cells to being as efficient in causing human infections as more common human influenza virus types. [Evolution of the receptor binding phenotype of influenza A (H5) viruses] by A. Gambaryan, A. Tuzikov, G. Pazynina, N. Bovin, A. Balish and A. Klimov in Virology (2005) electronic release on October 11 ahead of print publication. This doesn't mean one amino acid substitution can cause a pandemic but it does mean one amino acid substitution can cause an avian flu virus that is not pathogenic in humans to become pathogenic in humans.

In July 2004, researchers led by H. Deng of the Harbin Veterinary Research Institute, Harbin, China and Professor Robert Webster of the St Jude Children's Research Hospital, Memphis, Tennessee, reported results of experiments in which mice had been exposed to 21 isolates of confirmed H5N1 strains obtained from ducks in China between 1999 and 2002. They found "a clear temporal pattern of progressively increasing pathogenicity". [The evolution of H5N1 influenza viruses in ducks in southern China] by H. Chen, G. Deng, Z. Li, G. Tian, Y. Li, P. Jiao, L. Zhang, Z. Liu, R. G. Webster and K. Yu in Proceedings of the National Academy of Sciences of the United States of America (2004) volume 101, pages 10452-10457. Results reported by Dr. Webster in July 2005 reveal further progression toward pathogenicity in mice and longer virus shedding by ducks.

Recent research of Taubenberger et al has suggested that the 1918 virus, like H5N1, could have arisen directly from an avian influenza virus. Taubenberger JK, Reid AH, Lourens RM, Wang R, Jin G, Fanning TG. Characterization of the 1918 influenza virus polymerase genes. Nature. October 6, 2005;437(7060):889-893 However, researchers at University of Virginia and Australian National University have indicated problems in the Taubenberger et al. research Gibbs and Gibbs. [Was the 1918 pandemic caused by a bird flu?] Nature. April 27, 2006;440:E8Antonovics et al. [Was the 1918 flu avian in origin?] Nature. April 27, 2006;440:E9. Their work shows there is not enough phylogenetic evidence to suggest 1918 virus could have arisen directly from an avian influenza virus. It should also be noted that earlier research by Fanning et al. suggests that the 1918 virus did not acquire its HA gene from an avian source Thomas G. Fanning, Richard D. Slemons, Ann H. Reid,Thomas A. Janczewski, James Dean, and Jeffery K. Taubenberger. 1917 Avian Influenza Virus Sequences Suggest that the 1918 Pandemic Virus Did Not Acquire Its Hemagglutinin Directly from Birds. Journal of Virology. August, 2002;76:15 pages 7860-7862 . Other research by Tumpey and colleagues who reconstructed the H1N1 virus of 1918 came to the conclusion that it is was most notably the polymerase genes and the HA and NA genes that caused the extreme virulence of this virus. Tumpey TM, Basler CF, Aguilar PV, Zeng H, Solorzano A, Swayne DE, Cox NJ, Katz JM, Taubenberger JK, Palese P, Garcia-Sastre A. Characterization of the reconstructed 1918 Spanish influenza pandemic virus. Science. October 7, 2005;310(5745):77-80 The sequences of the polymerase proteins (PA, PB1, and PB2) of the 1918 virus and subsequent human viruses differ by only 10 amino acids from the avian influenza viruses. Viruses with seven of the ten amino acids in the human influenza locations have already been identified in currently circulating H5N1. This has led some researchers to suggest that other mutations may surface and make the H5N1 virus capable of human-to-human transmission. Another important factor is the change of the HA protein to a binding preference for alpha 2,6 sialic acid (the major form in the human respiratory tract). In avian virus the HA protein preferentially binds to alpha 2,3 sialic acid, which is the major form in the avian enteric tract. It has been shown that only a single amino acid change can result in the change of this binding preference. Altogether, only a handful of mutations may need to take place in order for H5N1 avian flu to become a pandemic virus like the one of 1918. However it is important to note that likelihood of mutation does not indicate the likelihood for the evolution of such a strain; since some of the necessary mutations may be constrained by stabilizing selection.