
Classification of influenza viruses

Influenza is caused by any of several closely related viruses in the family Orthomyxoviridae (a group of RNA viruses). Influenza viruses are categorized as types A, B, and C. The three major types generally produce similar symptoms but are completely unrelated antigenically, so that infection with one type confers no immunity against the others. The A viruses cause the great influenza epidemics, and the B viruses cause smaller localized outbreaks; the C viruses are not important causes of disease in humans. Influenza A viruses are classified into subtypes, and both influenza B and subtypes of influenza A are further divided into strains. Subtypes of influenza A are differentiated mainly on the basis of two surface antigens (foreign proteins)—hemagglutinin (H) and neuraminidase (N). Examples of influenza A subtypes include H1N1, H5N1, and H3N2. Strains of influenza B and strains of influenza A subtypes are further distinguished by variations in genetic sequence.

Evolution and virulence of influenza viruses

Between worldwide outbreaks, known as pandemics, influenza viruses undergo constant, rapid evolution (a process called antigenic drift), which is driven by mutations in the genes encoding antigen proteins. Periodically, the viruses undergo major evolutionary change by acquiring a new genome segment from another influenza virus (antigenic shift), effectively becoming a new subtype. Viral evolution is facilitated by animals such as pigs and birds, which serve as reservoirs of influenza viruses. When a pig is simultaneously infected with different influenza A viruses, such as human, swine, and avian strains, genetic reassortment can occur. This process gives rise to new strains of influenza A.

Newly emerged influenza viruses tend to be initially highly infectious and virulent in humans because they possess novel antigens to which the human body has no prepared immune defense (i.e., existing antibodies). Once a significant proportion of a population develops immunity through the production of antibodies capable of neutralizing the new virus, the infectiousness and virulence of the virus decreases. Although outbreaks of influenza viruses are generally most fatal to young children and the elderly, the fatality rate in people between ages 20 and 40 is sometimes unexpectedly high, even though the patients receive treatment. This phenomenon is believed to be due to hyper-reaction of the immune system to new strains of influenza virus. Such reaction results from the overproduction of inflammatory substances called cytokines. The release of excessive amounts of these molecules causes severe inflammation, particularly in the epithelial cells of the lungs. Individuals whose immune systems are not fully developed (such as infants) or are weakened (such as the elderly) cannot generate such a lethal immune response.

Pandemics and epidemics

Influenza pandemics are estimated to occur on average once every 50 years. Epidemics happen much more frequently, and seasonal influenza appears annually in most parts of the world, sometimes in epidemic proportions. Influenza type A virus is the most frequent cause of seasonal influenza. When an influenza A virus undergoes an antigenic shift, a pandemic affecting most of the world can occur within a matter of months. The influenza pandemic of 1918–19, the most destructive influenza outbreak in history and one of the most severe disease pandemics ever encountered, was caused by a subtype of influenza A known as H1N1. During this pandemic an estimated 25 million persons throughout the world died of the so-called Spanish flu, which was first widely reported in Spain but originated in the U.S. state of Kansas.

Subsequent outbreaks of influenza have been much less severe. For example, influenza A subtype H2N2, or Asian flu, apparently began in East Asia early in 1957, and by midyear it had circled the globe. After 10 years of evolution that produced annual epidemics, the Asian flu disappeared in 1968, only to be replaced by a new influenza A subtype, H3N2. This virus, also known as Hong Kong flu, is still in circulation. The Hong Kong flu outbreak in 1968 produced the first influenza pandemic since that of 1918–19. However, unlike the earlier pandemic, the Hong Kong flu resulted in less than one million deaths. In 1997 a type of avian influenza, or bird flu, virus broke out among domesticated poultry in Hong Kong and then infected a small number of people, killing some of them. This same virus, H5N1, reappeared among chicken flocks in Southeast Asia during the winter of 2003–04, again infecting some people fatally. Today several other subtypes of bird flu viruses are known, including H7N2, H7N3, and H9N2. Though these subtypes rarely cause infection in humans, they are recognized as having epidemic and pandemic potential.

An outbreak of a previously unknown strain of H1N1 occurred in 2009. Originally called swine flu because the virus was suspected to have been transmitted to humans from pigs, the illness first broke out in Mexico and then spread to the United States. The H1N1 virus that caused the outbreak was discovered to possess genetic material from human, avian, and two different swine influenza viruses. The 2009 H1N1 outbreak was not nearly as deadly as the Spanish flu. However, the virus was highly contagious and spread rapidly from Mexico and the United States to a number of other countries, including Spain, New Zealand, Canada, the United Kingdom, and Israel. The pandemic potential of the new H1N1 virus was made clear to the international community by the World Health Organization (WHO), which declared a level 5 pandemic alert on April 29, 2009. This prompted the rapid implementation of mitigation procedures, including the distribution of drugs to treatment facilities, in countries worldwide. Despite these measures, the virus continued to spread globally. On June 11, 2009, following an increase in cases in Chile, Australia, and the United Kingdom, WHO raised the swine flu alert level from 5 to 6, meaning that the outbreak was officially declared a pandemic. It was the first influenza pandemic of the 21st century.

Influenza pandemic preparedness

Because influenza epidemics and pandemics can devastate large regions of the world very quickly, WHO constantly monitors influenza disease activity on a global scale. This monitoring is useful for gathering information that can be used to prepare vaccines and that can be disseminated to health centres in countries where seasonal influenza outbreaks are likely to occur. Monitoring by WHO also plays an important role in preventing and preparing for potential epidemics and pandemics.

In the event that a potentially pandemic influenza virus emerges, WHO adheres to its influenza pandemic preparedness plan. This plan consists of six phases of pandemic alert. Phases 1–3, which are the early stages in pandemic preparedness, are designed to prevent or contain small outbreaks. In these early phases, isolated incidences of animal-to-human transmission of an influenza virus are observed and provide warning that a virus has pandemic potential. Later, small outbreaks of disease may occur, generally resulting from multiple cases of animal-to-human transmission. Phase 3 signals to affected countries that the implementation of efforts to control the outbreak is needed to prevent a pandemic. Phases 4 and 5 are characterized by increasing urgency in mitigating the outbreak. Confirmed human-to-human viral transmission, with sustained disease in human communities which subsequently spread so that disease transmission between humans occurred in two countries, indicates that a pandemic is imminent. Phase 6, the highest level of pandemic alert, is characterized by widespread disease and sustained transmission of the virus between humans. Influenza pandemics sometimes occur in waves. Thus, a post-pandemic phase, when disease activity decreases, may be followed by another period of high prevalence of disease. As a result, influenza pandemics may last for a period of months (see pandemic).

Transmission and symptoms

The flu may affect individuals of all ages, though the highest incidence of the disease is among children and young adults. Influenza is generally more frequent during the colder months of the year. Infection is transmitted from person to person through the respiratory tract, by such means as inhalation of infected droplets resulting from coughing and sneezing. As the virus particles gain entrance to the body, they selectively attack and destroy the ciliated epithelial cells that line the upper respiratory tract, bronchial tubes, and trachea. The incubation period of the disease is one to two days, after which the onset of symptoms is abrupt, with sudden and distinct chills, fatigue, and muscle aches. The temperature rises rapidly to 38–40 °C (101–104 °F). A diffuse headache and severe muscular aches throughout the body are experienced, often accompanied by irritation or a sense of rawness in the throat. In three to four days the temperature begins to fall, and the person begins to recover. Symptoms associated with respiratory tract infection, such as coughing and nasal discharge, become more prominent and may be accompanied by lingering feelings of weakness. Death may occur, usually among older people already weakened by other debilitating disorders, and is caused in most of those cases by complications such as pneumonia or bronchitis.

Treatment and prevention

The antiviral drugs amantadine and rimantadine have beneficial effects on cases of influenza involving the type A virus. However, viral resistance to these agents has been observed, thereby reducing their effectiveness. A newer category of drugs, the neuraminidase inhibitors, which includes oseltamivir (Tamiflu) and zanamivir (Relenza), was introduced in the late 1990s; these drugs inhibit both the influenza A and B viruses. Other than this, the standard treatment remains bed rest, ingestion of fluids, and the use of analgesics to control fever. It is recommended that children and teenagers with the flu not be given aspirin, as treatment of viral infections with aspirin is associated with Reye syndrome, a very serious illness.

Individual protection against the flu may be bolstered by injection of a vaccine containing two or more circulating influenza viruses. These viruses are produced in chick embryos and rendered noninfective; standard commercial preparations ordinarily include the type B influenza virus and several of the A subtypes. Protection from one vaccination seldom lasts more than a year, and yearly vaccination may be recommended, particularly for those individuals who are unusually susceptible to influenza or whose weak condition could lead to serious complications in case of infection. However, routine immunization in healthy people is also recommended. In order to prevent human-infecting bird flu viruses from mutating into more dangerous subtypes, public health authorities try to limit the viral “reservoir” where antigenic shift may take place by ordering the destruction of infected poultry flocks.