Elsevier

Vaccine

Volume 21, Issue 16, 1 May 2003, Pages 1762-1768
Vaccine

The epidemiology and clinical impact of pandemic influenza

https://doi.org/10.1016/S0264-410X(03)00069-0Get rights and content

Abstract

It is impossible to predict when the next pandemic of influenza will occur; however, it is almost 35 years since the last pandemic, and the longest inter-pandemic interval recorded with certainty is 39 years. The next pandemic virus is likely to emerge in southeast Asia, as have two of the last three pandemic viruses. Complete global spread is likely to occur in 6 months or less, due to increased travel and urbanisation. It is likely that the usual inter-pandemic pattern of age-specific mortality will deviate temporarily towards higher mortality in younger adults. The extent to which this will happen is unclear, as the shift was extreme in 1918–1919 but less so in subsequent pandemics. Nevertheless, this may have important implications for the protection of essential workers such as health care, emergency service and military personnel. The extent to which elderly persons will be affected will depend upon previous exposure to similar influenza viruses. It is impossible to predict the likely increase in excess mortality that will occur when a new pandemic virus emerges. However, whilst mortality on the scale experienced in 1918–1919 is probably unlikely, there was a high level of mortality among those infected with the A/H5N1 virus in 1997, so it cannot be assumed that a future pandemic will be as mild as those in 1957–1958 or 1968–1969. There is likely to be more than one wave of infection and health services in most countries will be hard pressed to provide vaccines or to manage populations with clinical attack rates of ≈25–30% and concomitant increases in demand for both primary and secondary health care services.

Introduction

The occurrence of influenza in human populations has been documented in considerable detail for at least the past 3 centuries, but actual accounts of influenza in humans probably date back further than this, to the 12th century [1]. Possible pandemics are documented as far back as 1510, but the first one to be clearly recognised was in 1580 [2], [3]. Even so, reliable epidemiological data are sparse until the pandemic of 1889–1892. Most lessons about the epidemiology of pandemic influenza have, therefore, been learned from the three well-documented pandemics of the 20th century, which occurred in 1918–1919, 1957–1958 and 1968–1969.

It should be noted that the influenza virus was first isolated in 1933 [4]. However, through retrospective analysis of sera collected from individuals born as early as 1857, there is evidence that influenza A/H2N2 virus circulated from ≈1889 until 1901 and may have been responsible for the 1889–1892 pandemic. Influenza A/H3N8 virus circulated from ≈1900 to 1918 and may have caused a mild pandemic in 1900; influenza A/H1N1 virus circulated from ≈1908 onwards [5], [6], [7], [8], [9], [10]. The pandemics of the 20th century are now known to have been due to an A/H1N1 virus related to swine influenza in 1918–1919 [11], [12], an A/H2N2 virus in 1957–1958 [13] and an A/H3N2 virus in 1968–1969 [14]. Thus, there is evidence that at least two of the pandemics of the 20th century were associated with the re-emergence of viruses similar to those which circulated in previous eras, a process referred to as antigenic recycling.

Section snippets

Virological mechanisms for pandemic influenza

Influenza pandemics occur when a novel influenza virus emerges against which the vast majority of the world’s population has no immunity. This has been observed only with influenza A viruses, which exist in nature as a number of antigenically distinct subtypes, and is due to the emergence of a novel haemagglutinin on the surface of the virus, with or without a concomitant change in neuraminidase, the other major surface antigen. This process is referred to as antigenic shift. Fifteen

Pandemic threats and alerts

In addition to the antigenic shifts known to have been responsible for the three pandemics of the 20th century, a true antigenic shift also occurred in 1977 when influenza A/H1N1 virus was re-introduced into circulation after an absence of 20 years [19]. However, infections occurred mainly in younger persons and were not sufficiently widespread to produce a pandemic [20]. Furthermore, this re-emergent virus began to co-circulate alongside influenza A/H3N2 virus without displacing it or

The epidemiology of pandemic influenza

The epidemiological impact of pandemic influenza is best appreciated when compared with the more familiar patterns associated with inter-pandemic disease. In inter-pandemic periods, in northern and southern temperate regions, the epidemiology of influenza is characterised by extremely low-level transmission of influenza viruses in the summer months [38], [39], [40], [41], [42], [43], [44], followed by an annual upsurge in winter seasonal activity [45], [46], [47], [48], [49], [50]. The upsurge

Phasing and the geographical spread of pandemics

The phasing and geographical spread of influenza pandemics both have important implications for future planning; Potter has reviewed these features in detail [58]. Pandemic influenza is less constrained by season and in each of the three pandemics of the 20th century there were multiple waves of infection following the emergence of the virus. The evidence for this phenomenon is most clear in relation to the 1918–1919 pandemic. The first wave occurred in spring 1918 in the USA and among elements

Excess mortality in pandemics

A large number of studies have established that, during inter-pandemic periods, influenza-related complications and deaths are more likely to occur in persons suffering with underlying chronic illnesses who are principally but not exclusively elderly [67]. Childhood morbidity and mortality related to influenza are concentrated in those <3 years of age [68], [69], [70], [71], [72], [73], and infants <1 year appear to be hospitalised at rates similar to those of high-risk adults [74]. The

Age-specific mortality of pandemics

In inter-pandemic years, the vast majority of influenza-related deaths occur in the elderly, although deaths are also reported in infants and young children [67], [75]. A similar pattern of age-specific mortality occurred in the first quarter of 1918 in England and Wales (Fig. 1) [78]. During this period, the death rate in children aged 0–4 years was about 80 per 1000, falling to <40 per 1000 in older age groups before rising sharply after the age of 50 years to peak at >130 per 1000 in those

The morbidity impact of pandemics

In the late 19th and early part of the 20th centuries, access to healthcare was limited for the majority of persons and most countries had poorly developed healthcare systems; thus, morbidity data from this period are limited. Nevertheless, the estimated clinical attack rates in all four pandemics since 1889–1892 were remarkably similar. The clinical attack rate during the 1889–1892 pandemic was estimated to be 25–50% [91]. In the 1918–1919 pandemic, it is estimated that 50% of the world’s

The clinical features of infection in pandemics

Data also exist on the clinical features of pandemic influenza. In 1918–1919, patients presented with the sudden onset of severe but typical influenza symptoms: high fever, headache, myalgia/arthralgia, anorexia, nausea, vomiting and cough lasting 2–4 days. Epistaxis was also a frequent but unusual feature [96]. Although most patients recovered, some died very quickly, being rapidly overwhelmed by a tracheobronchitis associated with dyspnoea and the appearance of mahogany spots around the

Conclusions

The three influenza pandemics of the 20th century indicate what can be expected when the first pandemic of the 21st century makes its appearance. The pandemic virus may emerge in China or a nearby country and could include surface antigens or virulence factors derived from animal influenza viruses, much like the avian A/H5N1 virus that emerged in Hong Kong in 1997. Once the new virus acquires the ability to be transmitted efficiently from person to person, it will spread rapidly throughout the

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