A primer for those who want to know more (long read, but GOOD info):
Epidemiology of influenza
Author: Raphael Dolin, MD
Last literature review version 17.1: January 2009
Influenza occurs in distinct outbreaks of varying extent nearly every year. This epidemiologic pattern reflects the changing nature of the antigenic properties of influenza viruses, and their subsequent spread depends upon the susceptibility of the population. Influenza A viruses, in particular, have a remarkable ability to undergo periodic changes in the antigenic characteristics of their envelope glycoproteins, the hemagglutinin and the neuraminidase.
Influenza hemagglutinin is a surface glycoprotein that binds to sialic acid residues on respiratory epithelial cell surface glycoproteins. This interaction is necessary for the initiation of infection. After viral replication, progeny virions are also bound to the host cell. Neuraminidase cleaves these links and liberates the new virions; it also counteracts hemagglutinin-mediated self-aggregation entrapment in respiratory secretions [1].
Major changes in these glycoproteins are referred to as antigenic shifts and minor changes are called antigenic drifts. Antigenic shifts are associated with epidemics and pandemics of influenza A, while antigenic drifts are associated with more localized outbreaks of varying extent.
Among influenza A viruses that infect humans, three major subtypes of hemagglutinins (H1, H2, and H3) and two subtypes of neuraminidases (N1 and N2) have been described. Influenza B viruses have a lesser propensity for antigenic changes, and only antigenic drifts in the hemagglutinin have been described.
The epidemiology of influenza, including morbidity and mortality, will be reviewed here. The clinical manifestations, complications, diagnosis, prevention, and treatment of this infection are discussed separately. (See “Clinical manifestations and diagnosis of influenza in adults” and see “Influenza vaccination in adults” and see “Antiviral drugs for the prevention of influenza in adults” and see “Antiviral drugs for the treatment of influenza in adults”).
ANTIGENIC SHIFTS — There is a strong association of antigenic shifts with the occurrence of pandemics (show table 1) [2].
Pandemic of 1918
The extremely severe and extensive pandemic of 1918 and 1919 (swine influenza or Spanish influenza) was associated with the emergence of antigenic shifts in both the hemagglutinin (H1) and the neuraminidase (N1) of influenza A [3]. The pathogenicity of this virus has been well-characterized. (See “Pathogenesis” below).
Other pandemics
In 1957, the shift to H2 and N2 in 1957 resulted in a severe pandemic. In 1968, an antigenic shift occurred that involved only the hemagglutinin (from H2N2 to H3N2); the resulting pandemic was less extensive than that seen in 1957 [4].
In 1977, an influenza A virus emerged that had shifted to H1N1. The resulting pandemic affected primarily young individuals who lacked preexisting immunity to H1N1, ie, those born after H1N1 viruses had last circulated in 1918 to 1957.
Since 1977, A/H1N1 and A/H3N2 subtypes along with influenza B viruses have frequently circulated at the same time [5].
ANTIGENIC DRIFTS — Between the years of antigenic shifts, antigenic drifts have occurred almost annually and have resulted in outbreaks of variable extent and severity. Outbreaks due to antigenic drifts are usually less extensive and severe than the epidemics or pandemics associated with antigenic shifts.
Antigenic drifts are believed to result from point mutations in the RNA gene segments that code for the hemagglutinin or the neuraminidase; they are thought to occur sequentially as the virus spreads through a susceptible population [6]. Changes in the hemagglutinin which result in antigenic shifts are of such great magnitude that they cannot be accounted for by point mutations; thus, the origin of pandemic strains is unknown.
Influenza viruses have a segmented genome that can result in high rates of reassortment among viruses coinfecting the same cell. A novel reassortment strain influenza A H1N2 viruses appeared in humans in the 2001 to 2002 season in North America, Europe, the Middle East, and Southeast Asia [7-9]. This new strain circulated along with H3N2 strains and did not cause extensive outbreaks. The vaccines containing A/New Caledonia/20/99(H1N1) and A/Moscow/10/99(H3N2) were expected to cover this H1N2 strain [9], and this virus was not widely reported during the 2002 to 2003 influenza season.
The major circulating influenza A strain in 2003 to 2004 in the United States represented a drift from the A/Panama/2007/99 (H2N3) included in the vaccine manufactured for the season. Among 461 virus isolates characterized, 21.6 percent were antigenically similar to A/Panama, while 78.4 percent were similar to a drift variant A/Fujian/411/2002 (H3N2) [10]. This variant was responsible for an early appearance of influenza during the season and 93 deaths among children from October 2003 to January 6, 2004 [11].
However, it was not possible in early January 2004 to predict the overall characteristics of this season's outbreak since overall activity in the United States decreased between December 21, 2003 and January 3, 2004. If disease activity continued to decrease without another peak later in the season, the outbreak due to this drift strain would appear notable mainly for its early onset.
Influenza viruses have a segmented genome, which can result in high rates of reassortment among viruses that coinfect the same cell. It has been suggested that pandemic strains may arise by reassortment of genes between human and animal influenza viruses that simultaneously infect a human host [12]. There was concern that such a reassortment might have occurred when influenza A/H5N1 infections were detected in humans in Hong Kong in March 1997 at the time of an extensive outbreak of avian influenza A/H5N1 in poultry. However, no reassortment has been found. (See “Epidemiology, transmission, and pathogenesis of avian influenza”).
PATHOGENESIS — The extremely severe and extensive pandemic of 1918 and 1919 resulted in approximately 20 to 50 million deaths worldwide and was exceptional in the high death rates that were seen among healthy adults aged 15 to 34 years [13,14]. A similarly high death rate has not occurred in this age group in either prior or subsequent influenza A pandemics or epidemics.
The pathogenicity of the hemagglutinin of the 1918 pandemic virus was directly demonstrated in a mouse model using genetic recombination techniques [15,16]. Researchers constructed influenza viruses using hemagglutinin alone or hemagglutinin with neuraminidase from the pandemic strain. Both recombinant viruses led to widespread infection of the lungs, suggesting that hemagglutinin conferred enhanced pathogenicity in mice. Furthermore, these recombinant viruses could induce high levels of chemokines and cytokines, resulting in inflammatory cell infiltration and severe hemorrhage that were characteristic of the illness seen during the pandemic.
Scientists used reverse genetics to create an influenza virus with all eight gene segments of the 1918 pandemic strain in order to study its virulence in animal models [17]. After infection, the 1918 strain produced 39,000 times more virus particles in the lungs of mice compared to more contemporary H1N1 influenza strains. Furthermore, the ability of an influenza virus to replicate in the absence of protease is thought to be a critical determinant of pathogenicity in animal models; the 1918 strain was able to replicate equally well in the absence or presence of trypsin in vitro.
Scientists have fully sequenced the entire genome of the 1918 strain, which has given insight into the origins of the virus [18]. In the pandemics of 1957 and 1968, two to three gene segments from avian strains combined with the circulating human strain to form a reassortant virus. In contrast, sequence and phylogenetic analyses of the 1918 virus genome suggest that it was derived wholly from an ancestor that originally infected birds and adapted to humans. Some amino acid changes identified in the 1918 strain are also seen in H5N1 and H7N7 avian viruses that have caused human fatalities. (See “Epidemiology, transmission, and pathogenesis of avian influenza”).
CHARACTERISTICS OF INFLUENZA OUTBREAKS — Influenza outbreaks have a seasonal distribution and characteristic time course. Factors influencing the extent and severity of an outbreak are less clear.
Seasonality — Outbreaks of influenza occur almost exclusively during the winter months in the northern and southern hemispheres (which occur at different times of the year). It is highly unusual to detect influenza A viruses at other times, although individual infections and even outbreaks have been reported during the warm weather months.
Travelers to tropical regions should be reminded that influenza occurs throughout the year in the tropics. In addition, summertime outbreaks of influenza have occurred on cruise ships in the northern and southern hemispheres. Repeat vaccination is not necessary in those who received routine vaccination at the appropriate time in the previous fall or winter. Volume of airline travel has also been linked to transnational spread of influenza infection [19]. (See “Immunizations for travel”, section on Influenza).
How influenza A virus persists between outbreaks remains poorly understood. It is possible that sporadic cases of viral infection at other times are caused by influenza but not diagnosed as such or that virus is imported from geographically distant sites, in which outbreaks are occurring, by the travel of infected individuals.
Time course of an outbreak — Influenza A outbreaks typically begin abruptly, peak over a two to three week period, and last for two to three months [20]. In most outbreaks, the earliest indication of influenza activity is an increase in febrile respiratory illnesses in children, followed by increases in influenza-like illnesses in adults. Increases in absenteeism from work and school are usually later manifestations of outbreaks. (See “Clinical manifestations and diagnosis of influenza in adults”).
Most outbreaks have attack rates of 10 to 20 percent in the general population, but rates can exceed 50 percent in pandemics [21]. Extraordinarily high attack rates have been reported in institutionalized and semiclosed populations.
Factors determining the severity of an outbreak — The factors that determine the extent and severity of outbreaks are not fully understood. The susceptibility of the population, as determined by the prevalence of antibodies to circulating virus, clearly plays a major role. Some outbreaks cease when a large pool of susceptible individuals is no longer present in the population. However, some outbreaks appear to end when a large pool of susceptible individuals still exists. It has been suggested that influenza viruses may differ in “intrinsic virulence” such as their efficiency of transmission or their ability to cause symptomatic infection.
Outbreaks caused by influenza B viruses are generally less extensive and are associated with less severe disease than those caused by influenza A viruses, although differentiating between influenza A and B infections in individual cases is not possible on clinical grounds alone [22,23]. Outbreaks of influenza B have been reported most frequently in schools and military camps and occasionally involve chronic care facilities and nursing homes. One outbreak was reported aboard a cruise ship sailing in the Baltics during June 23 through July 5, 2000; 45 crew members and 25 passengers with an influenza-like illness were identified and two crew members had influenza B confirmed by viral isolation [24]. Crew members with respiratory symptoms were isolated which was felt to lessen the scope of the outbreak.
ANTIBODY RESPONSE TO THE 1918 PANDEMIC STRAIN — In a study of 32 individuals born in or before 1915, all had neutralizing antibody responses to the H1N1 influenza strain that caused the 1918 pandemic, even nine decades after its occurrence [25]. Seven of eight individuals tested had circulating B cells that secreted antibodies that bound hemagglutinin (HA) from the 1918 pandemic influenza strain. Monoclonal antibodies that were generated from the B cells of three separate donors had potent neutralizing activity against the 1918 strain and bound to its HA protein with high affinity. They also cross-reacted with the genetically similar HA of a 1930 swine H1N1 influenza strain, but did not cross-react with HAs of more contemporary human influenza viruses.
INFLUENZA ACTIVITY — The United States Centers for Disease Control and Prevention (CDC), in collaboration with the World Health Organization and its reporting network, tracks influenza virus isolates throughout the world. This information, which is updated weekly during influenza season, is available via the CDC through its website (www.cdc.gov/flu/weekly).
Surveillance of internet searches for influenza-like illness may be able to provide information about influenza trends earlier than the CDC’s reporting network [26,27]. Further validation of these tracking systems is necessary.
MORBIDITY AND MORTALITY IN ADULTS — Using weekly national vital statistics from 1972 through 1992, influenza epidemics accounted for 426,000 deaths in the United States [28]. Because of the high attack rates, the morbidity caused by influenza in the general population is substantial. Increased rates of morbidity and mortality are associated with age, underlying comorbidities, and vaccination status [29].
Mortality associated with influenza disproportionately affects elderly persons [30,31]. In a study of the National Hospital Discharge Survey database, hospitalization rates for pneumonia increased by 20 percent from 1988-1990 to 2000-2002 for patients aged 65 to 85 years [31]. In addition, the risk of death during a hospitalization was 50 percent higher if the diagnosis was pneumonia compared with ten other common reasons for admission in the elderly population. The risk of pneumonia in this age group is increased in patients with comorbid conditions, such as chronic cardiac and pulmonary diseases or diabetes [30,31].
Excess hospitalizations for patients with chronic diseases who acquire influenza infection range from approximately 20 to more than 1000 per 100,000 individuals, with the highest rates occurring in those less than five and more than 64 years of age. Similar findings were noted in a retrospective cohort study of women under the age of 65 with and without chronic medical conditions [32]. Rates of hospitalization for acute cardiopulmonary events and mortality were higher during the influenza season and the presence of other comorbidities increased the risk of hospitalization and death.
Influenza vaccination was associated with a decrease in hospitalizations for cardiac disease and cerebrovascular disease among a large cohort of patients 65 years and older from three managed care groups compared to members who were not vaccinated [33]. The mortality rate from all causes was also significantly lower among the vaccinated group.
Factors that contribute to more severe influenza infections in elderly patients include decreased lung compliance, decreased respiratory muscle strength, declining cellular immunity, and decreased B cell responses to new antigens [29].
Mortality during pandemic influenza — Although death rates from influenza are usually disproportionately higher in elderly persons, a shift in the age distribution for mortality is seen during pandemics. When mortality was analyzed in relation to pandemics in the United States, approximately 50 percent of deaths occurred in individuals less than 65 years of age; the rate of excess deaths in this age group consistently fell 7- to 28-fold over the subsequent decade after the pandemic [34].
During a pandemic, excess mortality related to influenza may be higher in the first or second season depending on geographic location [35]. In a study using national vital statistics by age in six countries, geographical and temporal pandemic patterns in mortality were compared with the genetic drift of the A/H3N2 influenza viruses by analyzing hemagglutinin and neuraminidase sequences from GenBank. In North America, the majority of influenza-related deaths in 1968/1969 and 1969/1970 occurred during the first pandemic season; in contrast mortality was delayed until the second pandemic season in Europe and Asia. This phenomenon may be due to higher preexisting neuraminidase immunity (from the A/H2N2 era) in Europe and Asia than in North America, combined with a subsequent drift in the neuraminidase antigen during 1969/1970.
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