The year 2018 marks a grim anniversary: 100 years ago, the world was in the throes of an insidiously communicable affliction that, by some estimates, infected a third of the planet’s population, or upwards of 500 million people. Of those, at least 50 million perished before the outbreak suddenly abated.
The influenza pandemic of 1918-19 (sometimes referred to as the “Spanish flu”) ranks among history’s most devastating outbreaks. During that period, influenza – normally a seasonal ailment not considered widely dangerous in the general population – suddenly and chillingly upended the usual scenario, in which the flu’s worst effects fall upon the very young, the old, and the infirm. Instead, the novel virus strain displayed a brutal efficiency at killing healthy young adults between the ages of 20 and 40.
Although that specific strain of the virus receded seemingly as quickly as it appeared, the threat of another deadly influenza pandemic has echoed ever since – for example, in the “Asian flu” outbreak of 1957-58 (2 million deaths), the “Hong Kong flu” variant of 1968-69 (approximately 1 million deaths). More recently, a 2009 outbreak of a novel virus raised fears of a major pandemic, ultimate causing an estimated 60 million cases worldwide. Laboratory tests confirmed nearly 20,000 deaths from the new strain, although experts speculate that the true toll may have been on the order of 200,000, most under the age of 65.
Of course, the abiding fear for researchers and public-health experts is that, from the perpetual, constantly mutating reservoir of waterfowl, poultry, and swine, some new and deadly variant of influenza, for which most people possess little or no immunity, will emerge. Such an agent, if capable of airborne transmission between humans, might unleash a lethality not seen since the 1918 pandemic.
An abiding fear for researchers and public-health experts is that […] some new and deadly variant of influenza, for which most people possess little or no immunity, will emerge. Such an agent, if capable of airborne transmission between humans, might unleash a lethality not seen since the 1918 pandemic.
Influenza paper totals from 1900 On
With its available data files reaching back to the year 1900, Clarivate Analytics Web of Science Core Collection charts the course of influenza research in the modern era, as reflected by papers indexed from the world’s premier scientific literature.
Figure 1, showing the annual number of Web of Science-indexed papers that include “influenza” as a title word, demonstrates that influenza barely registered as a research topic at the beginning of the 20th century. After a minor peak of 29 papers indexed from journals in the year 1901, the total failed to exceed 20 for the next 16 years.
Figure 1. Web of Science-indexed papers on influenza by year, 1900 to 2017. Source: Web of Science, Clarivate Analytics
The 1918 outbreak, as the inset makes plain, prompted a nearly vertical spike in the quantity of research papers: from 9 recorded in the Web of Science for 1917, to 158 in 1918, with the latter total more than doubling to 336 in 1919.
The 1918 outbreak prompted a nearly vertical spike in the quantity of research papers: from 9 recorded in the Web of Science for 1917, to 158 in 1918, with the latter total more than doubling to 336 in 1919.
Just as precipitously, however, and seemingly matching the fleeting appearance of the deadly 1918-19 virus strain, research papers manifestly devoted to influenza dropped back to double-digit quantities for the next two and a half decades. Not until the mid-1940s do totals exceed 100. Upticks around the years 1957 and 1968 seem to correspond to major outbreaks, with a steady rise in papers thereafter. The late 1970s also brought a discernible rise, with totals thereafter holding steady for the better part of 20 years.
Another upswing is evident in the late 1990s, on the heels of a 1997 outbreak of a novel avian flu in Hong Kong – a strain evidently transmitted directly from poultry to humans.
In 2000, the total of Web of Science-indexed influenza papers exceeded 1,000 for the first time, rising thereafter as new strains, primarily in poultry, were detected throughout the decade, and work on vaccines continued.
The sharpest spike, as might be expected (and strikingly similar in profile to the 1918 increase), coincided with the 2009 outbreak of the novel strain of avian-origin flu which, as noted above, may have killed as many as 200,000. In subsequent years, from a high point exceeding 4,300 papers in 2013, the numbers have fallen off – at least for the present.
Most-cited papers from each decade
|A Century of Influenza Research|
|The most-cited paper of each decade, 1900 to 2018|
Listed in reverse chronological order, with Web of Science citations tallied through April 2018
|1||R.B. Gao, et al., “Human infection with a novel avian-origin influenza A (H7N9) virus,” New England Journal of Medicine, 368 (20): 1888-97, 2013.||1,209|
|2||Novel Swine-Origin Influenza A (H1N1) Virus Investigation Team, “Emergence of a novel swine-origin influenza A (H1N1) virus in humans,” New England Journal of Medicine, 360 (25): 2605-15, 2009.||1,946|
|3||R.G. Webster, et al., “Evolution and ecology of influenza A viruses,” Microbiological Reviews, 561 (1): 152-79, 1992.||2,728|
|4||I.A. Wilson, et al., “Structure of the hemagglutinin membrane glycoprotein of influenza virus A at 3-Å resolution,” Nature, 289 (5796): 366, 1981.||2,033|
|5||H.D. Klenk, et al., “Activation of influenza A viruses by trypsin treatment,” Virology, 68 (2): 426-39, 1975.||663|
|6||E.D. Kilbourn, “Future influenza vaccines and use of genetic recombinants,” Bulletin of the World Health Organization, 41 (3): 643, 1969.||355|
|7||I. Archetti, F.L, Horsfall, “Persistent antigenic variation of influenza A viruses after incomplete neutralization in ovo with heterologous immune serum,” Journal of Experimental Medicine, 92 (5): 441-62, 1950.||420|
|8||J.E. Salk, “A simplified procedure for titrating hemagglutinatting capacity of influenza virus and the corresponding antibody,” Journal of Immunology, 49 (2): 87-98, 1944.||649|
|9||W. Smith, C.H. Andrewes, P.P Laidlaw., “A virus obtained from influenza patients,” Lancet, 2: 66-8, 1933.||605|
|10||P.K. Olitsky, P.K. Gates, “Experimental studies of the nasopharyngeal secretions from influenza patients. IV. Anaerobic cultivation,” Journal of Experimental Medicine, 33 (6): 713, 1921.||58|
|11||E.W. Goodpasture, “The significance of certain pulmonary lesions in relation to the etiology of influenza,” American Journal of the Medical Sciences, 158: 863-70, 1919.||403|
|12||M. Neisser, “The symbiosis of the influenza bacillus,” Deutsche Medizinische Wochenschrift, 29: 462-4, 1903.||15|
Figure 2. A Century of Influenza Research. Source: Web of Science, Clarivate Analytics
Figure 2 provides another vantage point on influenza research. In reverse chronological order, the table lists the most-cited paper influenza paper (again, based on occurrence in the title) for each decade since 1900.
At the top of the list, the recent past produced reports on two outbreaks of human infection from novel variants. Paper #1, from 2013, describes an avian-origin strain from poultry in China and Vietnam that ultimately killed 127 people. The #2-listed paper, from 2009, recounted an early encounter with the swine-origin virus which, as noted above, sparked fears of a possible pandemic.
The paper at #3, the most cited of those collected here, is a 1992 review that examined the possibility that aquatic birds are the primordial source of all influenza viruses in other species. The next few entries, proceeding farther back in time, investigated various characteristics of influenza viruses and discuss the workings of vaccines.
Notable at #8 is a 1944 paper by Jonas Salk, describing a method for mixing a virus suspension with a suspension of chick red cells in order to gauge the relative concentration of virus in the sample. Six years earlier, in 1938, working with Thomas Francis at the University of Michigan, Salk helped develop the first modern flu vaccine. His experience with influenza was instrumental in his later work on the world’s first safe and effective polio vaccine.
Paper #9 recorded a milestone in 1933: the isolation of a virus from influenza patients by the British virologists Wilson Smith, Christopher Andrewes, and Patrick Laidlaw. Their discovery derived from the methods and findings of American Richard Shope, who in 1931 reported the isolation of influenza virus from swine.
The work in the 1930s by those four scientists and their colleagues marked the culmination of a major shift in the understanding of influenza – confirmation that, contrary to what researchers had initially believed, the cause was not bacterial, but viral.
Work in the 1930s by those four scientists and their colleagues marked the culmination of a major shift in the understanding of influenza – confirmation that, contrary to what researchers had initially believed, the cause was not bacterial, but viral.
In 1892, the German bacteriologist Richard Pfeiffer isolated a rod-shaped bacterium from the nasal secretions of flu patients. Dubbing his find Bacillus influenzae, Pfeiffer proposed the agent as the cause of influenza. The B influenzae bacterium underwent further study – for example, in paper #12, a 1903 German report by M. Neisser. (Note: B bacillus is now known as Haemophilus influenzae.) Meanwhile, as researchers continued to study influenza infection (as in paper #11, a 1919 report by the American pathologist Ernest Goodpasture), the hunt for the causative agent continued.
During 1920 and 1921, Americans Peter Olitsky and Frederick Gates reported their studies on filtering secretions from influenza patients (exemplified here by paper #10). The infectious agent passed through filters designed to capture bacteria, thereby eliminating B influenza as the cause. With the subsequent work by Shope and the others, the true picture emerged – of influenza caused by a viral agent, which then facilitates subsequent bacterial infections.
Despite the advances over the last century – more detailed knowledge of the virus and its varieties, improved capacity for vaccination and treatment, better surveillance and communication all around – the specter of another influenza pandemic continues to loom.
This analysis was developed with data from Web of Science. Learn more.
Photo credit: Otis Historical Archives Nat’l Museum of Health & Medicine (NCP 1603) [CC BY 2.0 (https://creativecommons.org/licenses/by/2.0)], via Wikimedia Commons.