Writing in 1750 seven years after a devastating European-wide outbreak of influenza, the English country doctor, surgeon and

medical historian John Huxham characterised flu as the morbus omnium maxime epidemicus.1 For the next 300 years or so Huxhams notion of influenza as an extensively diffused epidemic disease served as pretty good working definition. The only difference between an epidemic and a pandemic was that in the latter case the infection extended, as the German disease geographer August Hirsch put it writing in 1883, over the whole habitable globe.2 If only matters were so simple today. This week a distinguished committee of public health experts headed by Dr Harvey Fineberg, president of the Institute of Medicine in Washington, DC, admonished the World Health Organisation (WHO) for propagating widepsread confusion and suspicion about its handling of the 2009 swine flu pandemic by failing to adopt a sufficiently rigorous and transparent definition of precisely what constituted a pandemic.3 For many years, the WHO had insisted that in order for a new strain of influenza to be considered pandemic it had to cause enormous numbers of deaths and illness. However, on 29 April
1 2

John Huxham, An Essay On Fevers (London: S Austen, 1750), p. 11. August Hirsch, Handbook of Geographical and Historical Pathology, trans. by Charles Creighton, 3 vols., I (London: The New Sydenham Society, 1883), p. 7. 3 Report of the Review Committee on the Functioning of International Health Regulations in Relation to Pandemic H1N1 (2009). http://apps.who.int/gb/ebwha/pdf_files/WHA64/A64_10-en.pdf [accessed 17 May 2011]

2009, shortly after the unexpected emergence of the swine-origin H1N1 virus in Mexico, the WHO deleted the severity requirement from its pandemic guidance papers and reverted to something closer to Huxhams original defintion. The result that when in June 2009 WHO director-general Margaret Chan called a press conference in Geneva to announce that the world was now at the start of the 2009 pandemic all that was required was sustained human-to-human spread of the H1N1 virus in two countries in one WHO region plus community level outbreaks in a country in another region. That decision turned out to be something of an Eldorado for pharmaceutical companies, triggering sleeping contracts for the supply of billions of dollars worth of vaccines and anti-viral drugs to national health providers. It was also a decision that boomeranged badly on Chan when swine flu turned out to be far milder than WHO experts had feared, prompting allegations in the Council for Europe and the pages of the British Medical Journal that the WHO had somehow faked the pandemic for the benefit of drug manufacturers an allegation Chan strongly denies. It is not my intention to discuss the truth or otherwise of these allegations for that I direct you to Finebergs carefully considered report (for the record, he found no evidence of financial malfeasance but criticized the WHO for not doing enough to dispel suspicions that it had something to hide). Instead, I wish to examine where the present-day notion of a pandemic comes from and how it

has evolved over a time. In particular, I wish to explore the part played by historical epidemiologists in the emergence of what I will call the modern notion of a pandemic, before going on to consider the role of virology and new genomic technologies in the definition recently adopted by the WHO.

A pandemic has always been a slippery and malleable term. Writing in 1997, the esteemed American virologist Ed Kilbourne compared the process to pornography: We all know it when we see it, but the boundaries are a little blurred. 4 For Kilbourne, as for Hirsch, the difference between an epidemic and pandemic of influenza was simply the occurrence of many cases throughout the world in a short period. Certainly, in the earliest recorded English usage severity was not part of the definition. Thus, writing in 1666, the English physician Gideon Harvey uses Pandemick interchangeably with Epidemick to refer to a malignant disease which do generally haunt a Country.
5

Interestingly, the Victorian historical

epidemiologist Charles Creighton eschewed the term altogether, preferring to refer to epidemics of influenza even when they were extensively diffused over large parts of Europe and the word, as was the case with the epidemics, or pandemics, that visited England in

Edwin D. Kilbourne, Influenza Pandemics in Perspective, Journal of the American Medical Association, 237, 12, (1977): 1225-8, p. 1225. 5 REF. Interestingly, though he was writing in the year of the Great Plague, the malignant disease Harvey was referring to was consumption (tuberculosis).

1836-37 and 1847-48.6 So when did influenza begin to be seen not just as an extensively diffused world epidemic disease, but also as a pandemic killer and hence an object of legitimate medical and public health concern? For the answer, we have to return to the successive waves of influenza that swept Europe, Britain, and North America in the early 1890s. Termed the Russian infuenza because the first reported oubtreaks occurred in St Petersburg in the autumn of 1889, these were the first epidemics to be subject to close clinical and epidemiological surveillance and the first to be studied with the modern tools of laboratory. The result of these investigations was a critical aetiological shift that saw influenza move from a miasmatic disease whose prevelance was thought to be due to mysterious telluric and celestrial disturbances, to what the Medical Department of Britains Local Government Board called an eminently infectious complaint, one that seemed to be intimately connected to new global transportation and communication technologies. At the same time, retrospective analysis of the death returns during the Russian flu pandemic (usually dated to 1889-93) made the high mortality due to respiratory complications such as pneumonia increasingly visible to doctors and public health officials, underlying the threat that influenza presented to a wide range of social classes and age groups. The result was that when, in the winter of 1892, Queen Victorias 28-year-old grandson the Duke of Clarence and second-in6

See, for instance, Charles Creighton, A History of Epidemics in Britain, 2 vols., II (Cambridge University Press, 1894), pp. 306-433.

line to the throne died from pneumonia following an attack of influenza, there were demands for influenza to be made a notifiable disease just like cholera and smallpox. The crucial contribution, however, came from epidemiologists attempts to divine a pattern in the recurrent waves of the disease. The Russian influenza was the first to be seen to occur in three distinct waves, with the first wave causing widespread morbidity but relatively few deaths, and with the second and third waves proving highly mortal. However, it was the recurrence of this pattern in 1918-1919 a mild summer wave of influenza, followed by deadly autumn and winter waves that fixed the notion that a pandemic usually took the form of three or more successive waves of infection. Moreover, as retrospective analysis of the 1918-19 Spanish influenza proved, the death toll from these follow-on waves could be immense: 60 percent of the estimated 228,000 British casualties died in the second wave of the pandemic; worldwide the death toll from the Spanish flu has been estimated at 50m a truly Apocalyptic figure. One result of this focus on 1918 was to fix the notion that influenza pandemics result in enormous numbers of deaths. As a WHO pandemic preparedeness document put it in 2005 at the time of mounting concerns over bird flu, the 1918-19 pandemic was the most deadly disease event in the history of humanity hence the importance of pandemic planners doing everything they can to avoid a reoccurrence of Apocalypse.

But what if 1918-19 was a unique, never-to-be repeated event? What if influenza does not conform to any set biological pattern or epidemiological cycle? What if instead of the past behaviour of influenza providing a guide to the future, it destabilizes the present, showing pandemics to be nothing more than a series of historically contingent events. This is the continuing challenge that influenza presents both to medical historians and pandemic planners. To be fair, the WHO seems to have recognised the dangers of the historiographical bias towards 1918, acknowledging that while the 1918-19 pandemic resulted in 50m deaths worldwide the subsequent 1957 and 1968 each resulted in just one million deaths globally. Moreover, by the late 1990s new insights into the virology and ecology of influenza viruses were forcing WHO scientists to revise their notions of how pandemic viruses emerge from animal reservoirs. The result was that whereas previously pandemics had been defined largely according to clinical and epidemiological measures, by 2005 the WHOs expert advisors were urging that changes to the viruss genes and mutations to the surface proteins also be taken into account. As Fineberg points out in his report for the International Health Regulations (IHR) Review Committee, these debates came to a head around bird flu. When the H5N1 virus first emerged in 1997 and then re-emerged in 2005, it proved highly mortal with a case fatality rate in excess of 70 percent. However, unlike true pandemic viruses, it was sluggish: human infections tended to occur in

isolated family clusters and did not spread easily to other villages. On the other hand, from analysis of the genome of the 1918 virus the most avian-like of all pandemic viruses - scientists knew that H5N1 already had many of the characteristics of a pandemic virus and that with just a few mutations, that could occur spontaneously or, most likely, as a result of recombinantion with another influenza virus, it could easily become highly infectious. The result was that in 2007, with growing evidence that bird flu was being seeded worldwide and that early action could contain and prevent the virus before it mutated so as to cause enormous numbers of deaths and illness, WHO experts recommended lifting the severity requirement and replacing it with the present defintion. Far from the defintion change being made suddenly at the last moment, the consultations lasted seventeen months. According to Fineberg, it was simply unfortunate timing that the WHO deleted the phrase from its pandemic guidance documents in April 2009 just as the swine-origin H1N1 virus emerged from bird flus shadow, thereby fueling conspiracy theories that there was more to the definition change than met than eye. Once theyre up and running, conspiracy theories are very hard to put back in the box and judging by the initial response to Finebergs findings this one will be no different. According to Paul Flynn, the Labour MP for Newport who as a member of the Council of Europes socialist group brought the original complaint against

the WHO, the issue was never malfeasance but whether there was a conflict of interest between the membership of the WHOs 15strong emergency committee that advised Chan on the pandemic, five of whom had previously declared financial ties to the pharmaceutical industry. Though Fineberg found no evidence of attempted or actual influence by commerical interests, because of the way the definition of a pandemic was altered so as to remove the severity test the suspicion remains. As Flynn put it to me in an email: Is it sensible to scare the world witless without any consideration to the severity of H1N1? Also, why did Poland have half the number of H1N1 deaths per million than the UK when they spent about seven zlotys and we spent 1.2 billion? In fact, as Fineberg points out, it is only with the benefit of hindsight that we can be say that swine flu, which to date has resulted in just 251 deaths in Britain and 18,448 deaths worldwide (or about half the number who die from seasonal flu in the US every winter), was not particular deadly. However, in June 2010 when Chan pushed the pandemic alert button, the mortality rate among critically ill patients hospitalized in Mexico City was running at 41 percent, and experts did not have that luxury. Though fears about the potential severity of the pandemic was not part of the official definiton, Fineberg also argues that in practice it was a major factor in the emergency committees deliberations. So what definiton should be adopted in future? The first thing to say is that it is no use looking for patterns in the past. Yes, the

1918-19 was severe, but based on the recent run of mild epidemics in 1957, 1968 and now 2009, 1918 looks increasingly like the exception. On the other hand, as Fineberg points out, it would be rash to assume on the basis of just four observations that pandemics are declining in severity. What about research into the genetic markers of influenza virus and other host factors? Are these likely to increase the accuracy of predictions? Again, for the moment, the answer appears to be no. As Jeffery Taubenberger and David Morens, two of the worlds leading experts on, respectively, influenza virology and epidemiology, argue, despite the tremendous progress made in virology, microbiology, immunology, pharmacology, epidemiology, vaccinology, and preventive medicine over the last century, influenza researchers are still no closer to being able to predict when new pandemic strains will emerge or how they will impact human populations when they do. As our understanding of influenza viruses has increased dramatically in recent decades, we have moved ever further from certainty about the determinants of, and possibilities for, pandemic emergence, they write.7 Indeed, for all that Chan once boasted that the 2009 pandemic was the first to have been observed right from the beginning, Taubenberger and Morens point out that in fact: No one predicted the emergence of the 2009 H1N1 swine-origin pandemic virus; [and that] with current
7

Taubenberger and Morens, Influenza: The Once and Future Pandemic, Public Health Reports 125, 3 (April 2010): 16-26, p.24.

knowledge, we doubt anyone will be able to accurately predict any future pandemic either.8 While we may be no closer to be able to predict pandemics, however, we are surely far better equipped to track their progress and marshall an effective public health response. In 1890, the world had no way of monitoring obscure outbreaks in the Yucatan, Mongolia or other silent spaces on the map. Today, for all its faults, the WHO has an uparalleled ability to keep tabs on novel pathogens thanks to its extensive Global Outreach and Response Network engaging 300 technical partners worldwide. Moreover, in 1890 and in 1918, there were no influenza vacccines, antiviral medications or antibiotics. Nor could doctors count on the NHS to care for the elderly and vulnerable. The best you could hope for if you got the flu was to wrap up warm, stay in bed, and pray. The problem with medical progress is that advances in prevention and treatment present governments and taxpayers with difficult financial choices, especially when the drugs and vaccines must be ordered ahead of time and in sufficient quantities to be of any use. It is this not differences over how best to define pandemics that lie at the root of the current dispute. Given that pandemics are likely, at least for the forseeable future, to remain very much in the eye of the beholder, surely what is required is a little less pedantry coupled with a health measure commonsense. Certainly, most experts, including Fineberg,
8

Ibid. p. 23

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recognise that in future the WHO should apply a severity test so that it can better assess the threat and likely health impacts of a pandemic. However, as Ed Kilbourne might have pointed out were he still alive, while such tests should surely be incorporated into the decision-making process, making them part of the definition makes about as much sense as trying to decide whether Lady Gagas lastest outfit merits an X-rating.

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