Major influenza epidemics have apparently occurred since at least the Middle Ages, if not since ancient times (24
). In addition to periodic, seasonal, and regional epidemics, there have also been occasional influenza pandemics (9
). When pandemics appear, 50% or more of an affected population can be infected in a single year, and the number of deaths caused by influenza can dramatically exceed what is normally expected (2
). Since 1500, there appear to have been 13 or more influenza pandemics (see ‘Past influenza pandemics’, below); in the past 120 years there were undoubted pandemics in 1889, 1918, 1957, 1968 and 1977 (47
). In 1918, the worst pandemic in recorded history caused approximately 546,000 excess deaths in the United States (675,000 total deaths) (67
) and killed up to 50 million people worldwide (26
Although most experts believe that we will face another influenza pandemic, it is impossible to predict when it will appear, where it will originate, or how severe it will be. Nor is there agreement about the subtype of influenza virus most likely to cause the next pandemic. The continuing spread of H5N1 highly pathogenic avian influenza (HPAI) viruses into poultry populations on several continents, associated with a growing number of human ‘spill-over’ infections, has heightened interest in pandemic prediction (21
). H5N1 HPAI viruses caused an epizootic in poultry in southern China in 1996, followed within a year by an epizootic in Hong Kong that produced 18 human ‘spill-over’ cases and six deaths. H5N1 strains continued to circulate thereafter in China, reappearing in epizootic form in 2003, and spreading widely thereafter. Geographical extension was accompanied by the appearance and spread of genetically and antigenically different strains of H5N1 HPAI (4
). Since 2003, dispersion of H5N1 viruses has led to epizootics in about 60 countries on three continents, and has caused 403 human cases and 254 deaths (as of 27 January 2009) (80
), millions of avian deaths, and infections and deaths in several other mammalian species (77
Despite uncertainties in the historical record of the previrology era, the study of previous pandemics may help to guide future pandemic planning and lead to a better understanding of the complex ecobiology that underlies the formation of pandemic strains of influenza A viruses. However, there has long been disagreement about which historical outbreaks were bona fide influenza pandemics and which were not. Before discussing past pandemics, we will present definitions and suggest criteria for categorising an historical event as an influenza pandemic.
The Merriam-Webster Online Dictionary defines a pandemic as an ‘outbreak of a disease ... occurring over a wide geographic area and affecting an exceptionally high proportion of the population’ (http://www.merriam-webster.com/
). In public health practice, it has become traditional to require at least that the pandemic disease in question spreads over a distinct geographical region of the world (e.g. the Caribbean), if not a continent, a hemisphere, or the entire globe. When speaking of animal diseases, the corresponding nouns/adjectives are ‘epizootic’ and ‘panzootic’. That the most highly explosive and highly fatal epidemics of influenza-like illnesses occurring over the past 500 years have usually featured global spread within a few years has led to the expectation that influenza pandemics must necessarily be deadly and spread explosively, which has in turn affected the conceptualisation of the term ‘pandemic’ when applied to influenza. In reality, widespread and even global dispersion of antigenically ‘drifted’ seasonal influenza strains can technically lead to pandemics, although they are not usually referred to as such because they produce neither the clinical nor the epidemiological picture associated with historically recognised influenza pandemics. Nor do they produce the modern picture of the introduction of antigenically ‘shifted’ viruses (i.e. human influenza viruses that have acquired a novel haemagglutinin [HA] gene segment, with or without other gene segments, by reassortment) into immunologically naïve populations. Thus ‘pandemic influenza’ has taken on a colloquial meaning derived from old notions about severe recognised pandemics of the past. Had ‘mild’ pandemics occurred in the distant past they may not have been so recognised or documented; thus our perception of influenza pandemic behaviour may be biased towards those that are most severe, most explosive, and most recent, a possibility that is important to bear in mind as we anticipate and plan for future pandemics.
Influenza pandemic history: approaches and problems
Although influenza pandemics have presumably been occurring for 500 years or more (see below; references 10
), their conceptualisation as pandemics is more recent, a fact that complicates historical determination of events occurring in the pre-virological era. While we can be reasonably certain of pandemic influenza events that occurred during the last 150 years or so, earlier outbreaks were largely (but not exclusively) documented without access to data on population vital statistics, pathology, or microbiology. Deciding what was or was not a pandemic before this time requires reliance upon non-standardised clinical, observational and anecdotal information evaluated with respect to criteria derived from the few modern pandemics that have been studied scientifically, an obviously subjective process dependent upon circular reasoning (see below).
It is nevertheless possible to make educated guesses about the appearance of influenza pandemics going back to the 1500s if we are willing to accept the unproven (and possibly incorrect) assumption that they would have appeared and ‘behaved’, epidemiologically and clinically, as they have in the modern scientific era. Many observers have attempted to construct such pandemic chronologies, with a disconcerting level of disagreement that increases the farther back in time one goes. The problem is particularly difficult before the late 1700s, at which time there was renewed interest in cataloguing and differentiating epidemics of all kinds using nosological, clinical and proto-epidemiological means, and at which time a specialised international medical literature began to appear. Before that era, observers had to rely upon often obscure and largely uncatalogued publications, including monastery chronicles, local newspapers, general histories, and accounts of travel and exploration, to collect, assemble, and make sense of anecdotal reports in various languages and from many different locales. Often working out of single libraries with limited collections, different observers found different sources, failed to find others, and arrived at substantially different conclusions.
A recent publication has examined many older sources to arrive at a speculative list of probable and possible pandemics (47
). Although the present authors strongly believe that much more scholarship is needed, this may be a helpful starting point from which to create a framework for understanding the historical occurrence of influenza pandemics.
The authors’ criteria for classifying a disease event occurring before 1889 as an influenza pandemic, are as follows:
- there must be documentation of a clinical disease characterised by fever and respiratory symptoms, with relatively low population mortality (to exclude more highly fatal epidemic diseases)
- there must be evidence of high attack rates across a broad age range
- the disease must have occurred in at least two geographical regions of the world
- there should be no clear evidence that exposed regions remained unaffected
- there must be evidence of explosivity and rapid geographical spread.
When available, supporting evidence includes:
- geographical directionality of spread
- short prevalence intervals (e.g. around six weeks) in major towns
- higher than expected mortality in the elderly, the young, in pregnant women, and in debilitated persons, and evidence of miscarriages or pre-term deliveries
- evidence of multiple deaths from pulmonary conditions indicative of, or consistent with, pneumonia.
Two particularly noteworthy problems with these criteria should be pointed out. First, the requirement for geographical spread is complicated by slower modes of transportation in historical times. For example, it is difficult to be certain that an influenza pandemic in Europe in the 1700s, when the fastest ships took weeks (many serial generation times for influenza) to sail across oceans, would be capable of spreading to the American colonies. Although pandemic influenza probably reached Fiji in 1838, measles – a much more highly contagious disease with a longer incubation period – did not reach Fiji until 1875 (46
). This paradox is consistent with the possibility that chance played a major role in the global spread of respiratory diseases in the eras before rapid travel. Even in the years before the first undisputed influenza pandemic (1889), in the era of clipper ships and extremely rapid sea travel, the example of Fiji suggests that highly communicable respiratory diseases had considerable difficulty spreading to every inhabited place. Secondly, we face the problem of ‘negative information’ in eras in which few observers noted the occurrence of epidemics and many major epidemics probably went unrecorded or poorly recorded. Before the late 1700s, the absence of information on the regional and even the national occurrence of a respiratory epidemic cannot be taken as evidence that an epidemic did not occur. Had an earlier pandemic been as ‘mild’ as that of 1968 (see below), which was associated with a virus that contained a novel HA, it may not have been detected in the early 1800s, let alone earlier. Such problems prevent definitive conclusions about historical pandemic occurrence; it is only with such cautions that we proceed.
Influenza pandemic history: a framework for examining past pandemics
Application of the criteria listed above to the available historical information suggests that there may have been at least 13 pandemics over the past 500 years (1509 to 2009), or approximately one pandemic every 38 years. These pandemics may not have occurred randomly. Whether or not there has been clustering of pandemics, there is evidence that some (but not all) pandemics have been followed by periods of high respiratory disease activity, which were associated with large outbreaks and high mortality, over a number of years. It may thus be helpful to think not only about pandemics as events that occur at specific points in time, but to consider also the occurrence of ‘pandemic eras’. For example, the 90 years since 1918 can be said to comprise a pandemic era, because all of the influenza A viruses circulating since that time, up to the present, are descendants of the 1918 virus, and because seasonal influenza activity has been detected continuously during that period. Yet clearly in that interval there have been three (depending on how one defines the H1N1 recurrence in 1977, see below) or four pandemics.
Whether influenza pandemics occurred before 1510 is speculative. Documentation of influenza-like illness beyond Europe in the pre-Renaissance era has to date been sparse, perhaps in part because scholars have not studied Chinese, Indian, Japanese and other non-Western sources as intensively as they have European sources. It has been said that influenza was described separately by Hippocrates or his followers and by Diodorus Siculus, but the clinical evidence is too sparse to make an identification, and in any case neither pandemics nor even large-scale epidemics were documented (79
The first conceivable candidate for an influenza pandemic was recognised in Italy in 876 AD (CE), from where it followed the army of Charlemagne and spread all over Europe. However, its identity with influenza, though probable, cannot be confirmed and there has as yet been no evidence of it spreading beyond Europe. One curious feature is that birds and dogs were said to have been affected. It has since been frequently observed, up to the time of the 1918 pandemic, that influenza epidemics and pandemics were often preceded (or in other cases followed) at a short interval by equine epizootics, and occasionally by influenza-like illnesses in dogs and other domestic animals. Avian epizootics were apparently not recognised until modern times. It is noteworthy that in ancient Greece avian deaths were believed to be harbingers of human epidemics in general, and could well have been introduced into human disease histories for literary or other non-factual purposes. Although this practice was clearly understood by the time of the Renaissance, the extent to which 9th Century chroniclers may have appreciated it is not known.
Many historians believe that a European-wide epidemic of ‘a certain evil and unheard of cough’ that appeared in December 1173 was pandemic influenza, but evidence of spread beyond Europe is again lacking (10
). Some historians believe the first ‘true’ pandemic of influenza began in either 1293 or 1323. The 14th and 15th Centuries featured repeated influenza-like illnesses and epidemics, including a major European-wide epidemic in 1386−1387 followed by other European-wide epidemics over the next 30 years, but without documentation of pandemic spread beyond Europe. Irish documents introduced the term creatan
to describe a specific epidemic chest disease in the 14th Century; the term influenza
was first used in Italy to describe a disease prevailing in 1357, and was again applied to the epidemic in 1386−1387 that preferentially killed elderly and debilitated persons. This is probably the first documentation of a key epidemiological feature of both pandemic and seasonal influenza (14
). The 15th Century brought increasing documentation of influenza-like epidemics, as well as features we now recognise as characteristic. For example, an epidemic of coughing disease associated with spontaneous abortions was noted in Paris in 1411, and increased mortality in young children and in the elderly was noted in epidemics of influenza-like disease in 1427, 1438, and 1482.