Figure 1 Genesis of pandemic 2009 H1N1 viruses. The NA and M genes were derived from an Eurasian avian-like swine virus (yellow). The remaining six genes were derived from triple resssortant swine viruses that possessed genes originating from classical H1N1 swine (red), North American avian (blue) and human H3N2 (green) viruses.

Reproduced from Neumann et al. 2009, DOI: 10.1038/nature08157, with permission from Nature Publishing Group.

Russian influenza

The causative agent of the Russian influenza pandemic (1977) was essentially identical to viruses circulating in humans in the 1950s. Given the propensity of influenza viruses to evolve continually in animals, it is highly unlikely that the Russian virus was maintained in an animal host for over 20 years without change. Likely, the virus was maintained in a freezer until it was somehow introduced into the human population. The relatively low death rate in this pandemic can be attributed to the pre-existing immunity of persons over 20 years of age who had been infected with the virus when it circulated earlier in the century.

Outbreaks of avian H5N1 viruses

In May of 1997, an H5N1 influenza virus was isolated from a 3-year-old boy in Hong Kong, who died of extensive influenza pneumonia complicated by Reye syndrome. By the end of 1997, 18 Hong Kong residents had been infected with H5N1 influenza viruses, six of whom died (Claas et al., 1998a, b; Subbarao et al., 1998). The human H5N1 isolates were not reassortants like the 1957 and 1968 pandemic strains; rather, all of the viral genes originated from an avian virus. Epidemiological studies suggested direct transmission of the virus from birds to humans; evidence of human-to-human transmission was limited to a few cases.

Since their first appearance in Hong Kong, several waves of avian H5N1 virus outbreaks have occurred. These viruses have diverged into several HA clades/subclades, and their ‘internal genes’ have undergone frequent reassortment resulting in a number of different gene constellations. Avian H5N1 viruses are now endemic in poultry populations in regions of Asia and Europe and have spread across three continents. They infect humans and cause severe respiratory disease with a high mortality rate (approximately 60%); however, they do not spread efficiently among humans.

H7N7 virus outbreak in The Netherlands

In 2003, an outbreak of highly pathogenic avian influenza virus (H7N7 subtype) occurred in poultry farms in The Netherlands and spread to the surrounding countries. Poultry farm workers and their families reported conjunctivitis and the H7N7 virus was subsequently detected in numerous conjunctival samples. A veterinarian succumbed to infection with an H7N7 virus (Fouchier et al., 2004).

2009 H1N1 influenza virus pandemic

In April 2009, elevated numbers of pneumonia/influenza-like illness were reported in Mexico, and soon after, a swine-origin H1N1 virus was isolated from specimens from infected individuals. As stated earlier, this virus possesses the M and NA segments from an Eurasian avian-like swine virus and its remaining six segments from triple reassortant swine viruses (Garten et al., 2009; Dawood et al., 2009; Smith et al., 2009). Within a few weeks, this virus caused a pandemic. Most human cases are mild, although severe symptoms with fatal outcome are reported in some infected individuals. Severe disease may, at least in part, be explained by lower respiratory tract infections; in contrast, seasonal influenza viruses typically replicate in the upper respiratory tract. Similarly, the novel H1N1 virus is more pathogenic in animal models than contemporary human H1N1 influenza viruses (Itoh et al., 2009; Maines et al., 2009; Munster et al., 2009). However, the overall morbidity and mortality in humans is lower than originally expected, possibly because of low levels of cross-protective immunity to pandemic 2009 H1N1 influenza viruses in human populations.

Interpandemic epidemics

Antigenic drift in influenza viruses between pandemics causes periodic epidemics. There is no discernible pattern in the development and severity of these epidemics.

Transmission and seasonality of influenza in humans

The spread of influenza viruses is promoted in most cases by small-particle aerosols of virus-laden respiratory secretions, generated by coughing, sneezing or talking. Spread by direct contact also occurs. The incubation period for influenza ranges from 1 to 4 days.

Influenza viruses are isolated from humans worldwide during every month of the year; however, epidemics in Europe, North America and Asia tend to occur from December to March, although outbreaks during the summer months are not uncommon. The winter seasonality of influenza in temperate climates has been explained on the basis of prolonged survival of the virus in conditions of low relative humidity and low temperature.

Public Health Aspects of Influenza Virus Outbreaks and Pandemic Preparedness

Interpandemic periods

During interpandemic periods, the direct cost of influenza virus infections can reach $1 billion annually, whereas the indirect costs, including loss in productivity, can amount to $2–4 billion annually. Influenza viruses attack 10–20% of susceptible populations during epidemics, but the attack rate can be considerably higher, from 40% to 50%, in specific age groups such as schoolchildren. Elderly individuals with influenza are often admitted to hospital during the later stages of epidemics. Both influenza A and B viruses contribute to cases of respiratory illness in nursing homes and other long-term care facilities.

Many epidemics are also associated with excess mortality; in fact, an estimated 500000 deaths worldwide with up to 36000 deaths in the United States are attributed to influenza each year and more than 20000 excess deaths were attributed to influenza during each of the nine different epidemics that occurred between 1972 and 1991 in the United States. Although excess mortality occurs mainly in the elderly, it can affect all age groups, especially those at increased risk of complications of influenza. Increased mortality by influenza results not only from the pulmonary effects of the virus but also from cardiopulmonary and other chronic diseases that can be exacerbated by the virus.

Pandemics

Pandemic outbreaks typically attack 20–40% of the world population and cause significant excess mortality. The three pandemics in the past century resulted in 20–50 million excess deaths for the ‘Spanish influenza’ worldwide, and 70000 and 33800 excess deaths in the United States for the so-called Asian and Hong Kong pandemics in 1957 and 1968, respectively. On the basis of these numbers, future pandemics are estimated to cause illness in 30 million individuals in the United States alone, resulting in up to 9.9 million hospitalisations and up to 1.9 million excess deaths. As of February 13, 2010, the Centers for Disease Control (CDC) estimated 42–86 million cases of pandemic 2009 H1N1 virus infection in the United States with 8520–17620 deaths. Therefore, to this date, the newest pandemic has been less severe than originally feared.

Clinical Features

Influenza viruses produce a broad range of signs and symptoms – from asymptomatic infection to respiratory illness with systemic manifestation; complications that affect the lung, heart, brain, liver, kidneys and muscles and death due to primary viral or secondary bacterial pneumonia. The clinical outcome of infection is heterogeneous, depending on the age of the patient, preceding infection with an antigenically related strain, intrinsic properties of the virus and whether or not the individual has pre-existing chronic medical conditions such as heart or lung disease, renal failure or immunological disorders. Pregnancy, smoking and obesity can also adversely affect outcomes. Cough, malaise, chills, headache, fever (>37.8°C), anorexia, coryza, myalgia, sore throat, dizziness, hoarseness, chest pain, vomiting, diarrhoea and abdominal pain are manifestations of uncomplicated influenza infection. In most influenza-infected persons, the symptoms and signs last for 3–4 days, although cough, lassitude and malaise may persist for 1–2 weeks after the fever has resolved.

Influenza C virus antibodies are commonly detected in adults, but virus isolation from subjects with influenza signs and symptoms is rare. Generally, the severity of influenza B virus infection is greater than that produced by seasonal H1N1 influenza A viruses, but less than that associated with H3N2 viruses.

Immune Response

Influenza infection elicits both B- and T-cell immune responses. Neutralising antibody to HA is the principal immune mediator of protection against infection and clinical illness produced by the virus. This protection is augmented by mucosal and systemic elements of the immune responses.

Humoral immunity

Resistance to infection correlates with serum anti-HA antibody levels. Immunity to NA alone does not appear to confer protection, as the 1968 Hong Kong pandemic was caused by a virus that possessed the same NA as the immediate preceding strain. Despite evidence that CD8+ T cells play the chief role in clearing influenza virus from infected hosts, it is now clear that passively transferred antibodies can eliminate the virus in mice that lack B and T cells. Antibodies to type-specific NP and M1 proteins are also produced.

Cellular immunity

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