How did the Spanish Flu fade out? When/where did the it start?
The Course of an Influenza Infection
Influenza infections start to appear in flu season, typically late December or early January in the Northern Hemisphere. Symptoms may include some or all of the following: throat pain, runny nose, sneezing, coughing, headache, blocked sinus, muscle pain, aching joints, fever, lack of appetite, lack of energy. Patients may be bed bound for two or three days, full recovery taking anywhere from 10 to 20 days.
Humour: How do you know you've got the flu? If there is a 100 dollar bill lying on the ground and you can't be bothered to pick it up, you've got full blown influenza. If you pick it up you've got a cold.Innate protection: mucosa, inflammatory response, anti-bodies from mother's milk.
Acquired protection: anti-bodies produced by surviving previous infection, anti-bodies produced after vaccination.
Symptomatic treatments: anti-pyretics, pain killers, anti-histamine.
Speculative and experimental curative treatments: neuraminidase inhibitors, drugs targeting the matrix protein, drugs targeting viral RNA polymerase, drugs targeting viral haemagglutinin, drugs targeting stages in the viral lifecycle like the budding process or endocytosis.
Risks: viral resistance appears quickly, rendering some curative drugs useless.
Clearly, understanding the structure and lifecycle of the influenza virus will suggest approaches for developing targeted symptomatic, preventative (vaccine), and curative treatments.
Introduction - the Spanish Flu pandemic of 1918.
Influenza is a contagious disease of the respiratory system. The word 'influenza', from the Italian word for 'influence', was originally a generic turn for diseases that were associated or 'influenced' by the cold, swamps or damp. In 1901 the first influenza virus in poultry (Fowl Plague - 188) was isolated but it wasn't until 1931 that the respiratory disease we recognise as the flu was first identified as a viral infection (Richard Shope - 189). Human influenza was identified and isolated in 1933 and the first vaccine developed for a human influenza strain was created in 1944 (Thomas Francis, Jr.). N.B. there is however wide variation in vaccine effectiveness ranging from 70% to 3% effective from year to year.
"There have been four official pandemics - 1918 (Spanish H1N1), 1957 (Asian H2N2), 1968 (Hong Kong H3N2) and 2009 (Mexican H1N1). There has been one unofficial one in 1977 (Russian H1N1) and there is also an intriguing theory about a “missing pandemic” - another H1N1 that may have occurred in the 1920s. If true, it would help explain some of the anomalies molecular phylogeneticists find in their evolutionary trees. However, it must have been very mild not to be noticed at the time." Derek Gatherer
The use of the term virus to describe a nebulous class of infections of animal and human populations caused by a kind of fluid, poison or toxin introduced through wounds is first recorded in Aurelius Cornelius Celsus's fifth book on medicine. "de Medicina" [Celsus, 1938].
When were viruses first discovered? The tobacco mosaic virus (a disease of tobacco plants) was first isolated in 1892 by Dmitri Ivanoski who was continuing research into the tobacco mosaic disease reported by Adolf Mayer in 1886. Mayer had thought the infectious agent might be new bacteria but could not isolate the infectious agent, whereas Ivanoski showed that the infectious agent could pass through porcelain filters which hitherto had been known to block bacteria. Ivanoski had succeeded in isolating the infectious agent but was unsure of its cause; whether this isolate was a new class of bacteria or an infectious toxin produced by bacteria. It was Martinus Beijerinck, continuing Mayer's research into the tobacco mosaic disease, who in 1898 named the 'incitant' a virus after realising that the disease could not be caused by a bacterium but was in fact produced by a new class of much smaller infectious agents that could pass through bacterial blocking filters [Lecoq, 2001]. Aside from extreme differences in size the fundamental difference between cellular bacteria and non-cellular viruses was not understood until 1935 when Wendell Stanley demonstrated tobacco mosaic virus's crystalline form [Stanley, 1938].
The practice of variolation or innoculation against variola (smallpox) gradually grew in use over the fifteenth to eighteenth centuries. It as achieved by introducing pus from infected patients to uninfected healthy individuals. While variolation was known to be reasonably effective at conferring immunity, it was not known how the disease was produced nor how immunity was acquired. Furthermore, variolated individuals still contracted the disease, albeit a milder form, and some still died from the full blown infection.
Footnote: What was the impact of the Spanish Flue pandemic of 1918 on Australia? News about the epidemic was now widely known and it was associated with an increase in deaths due to influenza recorded in Victoria.
"Returns prepared by the Victorian statist Mr A M Laughton shows that influenza was responsible for 210 deaths in 1918, as against an average of 101 for the preceding five years". [The Argus, 1919]The arrival of influenza was attributed to returning service men and women who had been stationed in Europe during WWI. Those returning in 1919 were often subject to quarantine on their arrival in Australia (AWM exhibition). Indeed, the state of Victoria was effectively quarantined from New South Wales at this time due to the imposition of strict restrictions. The News South Wales government restricted travel from Victoria in an attempt to stop the influenza outbreak from spreading to Sydney. The Argus newspaper reported:
"Another urgent appeal was made yesterday by the Premier (Mr Lawson) to the Premier of New South Wales (Mr. Holman) for a relaxation of the quarantine" [The Argus, 1919]The photograph below shows people penned behind a makeshift fence at the Albury quarantine camp
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| MM 5545 Negative - Albury, New South Wales, 1919. source: [Museums Victoria Collections, 2017] |
Immunoassay, Epidemiology and Phylogenetics to Study Influenza Variants
Immunoassay is the detection of specific proteins (antigens) using other proteins called immunoglobins (antibodies) that bind specifically to antigens. Western Blotting and ELISA (Enzyme-Linked ImmunoSorbent Assay) are the basic tools of immunoassay.
Western Blot method is used to detect an on-going infection. ELISA (Enzyme-Linked ImmunoSorbent Assay) is used to detect past exposure. ELISA is useful for detecting past exposure to diseases we already have a library of sample antibodies for but it is not as useful for detecting new strains. Western Blot can be used to extract and isolate sample proteins from all viral infections whether previously encountered or not. Western blot allows us to highlight known infection types (using our library of sample antibodies), but also, to reveal - by not attaching to the antibody markers - new proteins from patients presenting with influenza symptoms.
There are a number of influenza types or variants, for example A, B, C, D. Type A is the avian strain and is designated by the surface protein antigen types e.g. haemagglutinin and neuraminidase (H1N1 etc.). Trivalent vaccines are aimed at type A, B & C viruses; quadrivalent vaccines target type A, B, C & D.
Pandemic and seasonal flu are infection occurrences. The distinction between the two categories is determined post ante, after the event. Ex ante, forecasts or prediction of how a flu variant will affect a population is problematic. Antigenic drift is the process of gradual genetic shifts (evolutionary) resulting in variation in the composition of virus surface protein.
Epidemiological models of infection within a population employ the concept of a 'patient zero' and the 'reproductive number - R'. Patient zero is the idea that an epidemic originates in an original infection. The R number represents the typical number of additional cases produced by each case. R0 is the reproduction number in a population in which everyone is susceptible. In real populations not all individuals are susceptible. Therefore R is the net reproduction number multiplied by the proportion of the population susceptible (the following notes and further reading from the London School of Hygiene & Tropical Medicine course "Ebola in Context").
R = R0 x proportion susceptible
Herd immunity threshold = (R0 – 1) / R0
Vaccine efficacy: VE = (rate of disease in unvaccinated – rate of disease in vaccinated) / rate of disease in unvaccinated
% population needed to be vaccinated to reach herd immunity = herd immunity threshold / vaccine efficacyBuilding a Phylogenetic Tree:
Tutorial part 1 - Compare 1977 Russian Flu with Roma 1949.
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| NCBI - Influenza virus database main form |
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| Blast result comparing Human Russia 1977 and Roma 1949 HA protein sequence for H1N1 |
Tutorial part 2 - Phylogenetic tree of HA protein of H1N1 over the period 1918 – 1980
The Lifecycle and Structure of Influenza Virus
The dormant or resting phase of the flu virus is an inert package containing just nine crucial proteins, encoded by 8 genomes. The outer surface of the virus presents two typical surface proteins, haemagglutinin (H) and neuraminidase (N). The H proteins are used by the virus to bind to the host cell surface and the N proteins are involved in the budding process. Variants of each protein are designated H1, H2, H3 & N1, N2 etc. These proteins offer an antigenic signature for the virus, thus H1N1 or H2N2, and they are also the antigens that our immune system targets when it produces antibodies against the virus. Three fast acting viral polymerases (acidic polymerase, polymerase 1 & polymerase 2) are crucial for the virus lifecycle as they replicate copies of the viral DNA. The viral polymerase is not very accurate and produces many mistakes; this process is the basis for antigenic drift that produces different variants of the flu from year to year. Host cells are coopted into producing viral proteins when viral mRNA (messenger RNA) is processed by the host cell's ribosomes.
The virus binds to target distinctive surface sugars (glycans) of host cells, this is called differential binding. Common influenza strains such as seasonal H1N1 preferentially target the Alpha-2, 6-sialylglycan on cells of the upper respiratory tract (sinus, nasal passages, throat). The most feared strain, H5N1, targets Alpha-2, 3-sialylglycan on cells deep in the lungs.
The virus introduces itself into the host cell through a process called endocytosis (the process of a cell engulfing or taking matter into the cell, as a vesicle within the cell). Budding is the reverse of this process.
Influenza is a budding virus; its reproduction in and by host cells results in a non-destructive budding or ejection of replicated virus bodies from the cell. The infected host cell stays alive and may recover as antibodies produced by the immune system may succeed in overwhelming the virus. This is in contrast to lytic viruses which totally subvert the host cell and destroy it in the final step of the process.
Pandemic Origins: Reassortment
H1N1 and H3N2 are the human subtypes of what is in essence an avian disease. Humans are "only temporary receptacles of the virus" (Derek Gatherer). Avian influenza surface proteins are antigen types from sixteen different haemagglutinin types (H1-H16) and nine different neuramidinases (N1-N9).
The 1957 H2N2 pandemic putatively arises when H2N2 avian strain infects a human who simultaneously has H1N1 seasonal flu (the descendant of the 1918 pandemic). Reassortment occurring in a mixed infection giving rise to a new strain of human H2N2.
The H3N2 strain likely came about through reassortment when someone with an infection of human H2N2 seasonal flu also have become infected with an avian H3Nx influenza. The combined infection, coexisting in infected cells, enabled both stains to mingle and produce a stable H3N2 strain. The H3N2 strain became pandemic in 1968 but now occurs as a seasonal flu.
The existence of bird flu in wild bird populations and its relative prevalence among different species remains an open issue. Field studies of wild bird populations are necessarily limited as we have no means of studying all members of any particular species in the wild, therefore an ascertainment bias is possible when conclusions drawn from population sample may not in fact represent the wider population or if findings for one species may not extend to others. However it is clear that a diverse pool of bird influenza strains is possible in the wild avian population as bird flu surface proteins may be comprised of up to 144 (16x9) different antigen pairs - i.e. haemagglutinin H1-H16 and neuramidinases N1-N9.
The virus is transmitted between wild birds, from wild to farmed birds and from farmed birds to workers on farms, in markets and abattoirs. Small scale, quasi-intensive poultry farming has been highlighted as a key location for cross-over events. Fomite and droplet transmission are indicated; in poor hygiene environments when direct physical contact through handling occurs with few precautionary protocols in place, measures which are in any case costly and infeasible for very low income poultry farmers. The point of 'transmission' is 'frequent and intimate contact with poultry'; when a person with seasonal flu becomes doubly infected with a pure avian strain. The reassortment mechanism then produces structural permutations of the virus some of which may become new viable types (see NHS advisory information).
How does influenza manifest in poultry (video - warning distressed animals) and how does transmission occur within a bird population? Does it happen through physical contact, through breath plumes, grooming, feeding, fouling? Do the same contamination paths occur in agricultural settings, particularly in poor and low tech environments? What if any passive methods could be effective to reduce fomite transmission among an animal population and from animal to human? For example, if brass fittings in buildings (e.g. door handles, push plates etc.) are actively anti-microbial then we should retrofit our buildings [Warnes et al., 2015]. This is relevant to primary health care but also applies to industries with less rigorous active hygiene standards. One suggestion is to reduce transmission occurring from the animal to human population by using brass fittings extensively in construction.
Hygiene and Prevention
Among the most effective means to avoid exposure to the flu virus is by limiting its infection transmission route. The flu virus spreads by both aerosol inhalation and fomite transmission, the name for infection acquired through physical contact with contaminated materials and surfaces. Hand hygiene is an important preventative measure both by sufferers of the flu and by uninfected people.
Ayliffe et al. [1978] is the main reference article and the standard text describing the technique (see paragraph 6). Interestingly the article was written to report the hand washing method as such but to report on experiments testing the effectiveness of different disinfection agents used for hand washing i.e.: antiseptic-detergents, alcoholic solutions, and unmedicated soap.
They found that
"70% alcohol, with or without chlorhexidine, was the most effective preparation. The two antiseptic detergents showed variable results, but against Gram-negative bacilli neither was significantly more effective than plain soap." [Ayliffe et al., 1978].Clearly the Ayliffe technique is the gold standard for hygienic hand washing. As it happens it is the method documented (and illustrated) in the World Health Organisation international guidelines for hand hygiene in healthcare and it has been adopted by health services around the world.
References and further reading:
[Ayliffe et al., 1978] Ayliffe, G. A. J., Babb, J. R., and Quoraishi, A. H. (1978). A test for ’hygienic’ hand disinfection. Journal of Clinical Pathology, 31:923–928.
[Celsus, 1938] Celsus, A. C. (1938). Celsus: De medicina. II. William Heinemann Ltd.
[Lecoq, 2001] Lecoq, H. (2001). Discovery of the first virus, the tobacco mosaic virus: 1892 or 1898? Comptes Rendus de l’Académie des Sciences - Series III - Sciences de la Vie, 324(10):929–933.
[Long Term Care and Community Services, 2014] Long Term Care and Community Services (2014). Hand hygiene for staff. Technical report, Health Service Executive.
[Museums Victoria Collections, 2017] Museums Victoria Collections (2017). Item mm 5545. negative - al- bury, new south wales, 1919. web page.
[Stanley, 1938] Stanley, W. M. (1938). Virus proteins - a new group of macromolecules. J. Phys. Chem., 42(1):55–70.
[The Argus, 1919] The Argus (1919). Statist’s figures.
[Warnes et al., 2015] Warnes, S. L., Little, Z. R., and Keevil, C. W. (2015). Human coronavirus 229e remains infectious on common touch surface materials. mBio, 6(6):1–10.
[World Alliance for Patient Safety, 2006] World Alliance for Patient Safety (2006). Who guidelines on hand hygiene in healthcare. Technical report, World Health Organization.
[Spanish flue: the killer that still stalks us] Mark Honingsbaum 2018
Websites:
The influenza course, hosted by Derek Gatherer from Lancaster University (on FutureLearn).
NHS advisory information
Infected poultry video - warning distressed animals
