Influenza

Influenza in short

• a viral respiratory disease
• symptoms include fever, headache and severe malaise
• most people recover within 1–2 weeks, complications may occur in high-risk groups
• an effective vaccine is available, vaccination needs to be repeated every year with the adequate vaccine for the currently circulating viral subtype
• experts estimate that influenza causes between 250,000 and 500,000 deaths each year

Influenza in detail

Pathogenic agent
There are three types of influenza viruses named A, B and C. Types A and B are responsible for annual epidemics in humans, with type A possessing the potential to cause worldwide "flu" outbreaks (an influenza pandemic). Type C induces only mild respiratory disease and does not cause epidemics.

Influenza viruses belong to the family of Orthomyxoviruses. These are single-stranded RNA viruses with a segmented genome. Influenza viruses possess eight genome segments that are associated with a nucleoprotein complex. Each segment codes for one or two viral protein(s). The envelope of influenza viruses is "spiked" with two antigens: haemagglutinin (HA) and neuraminidase (N). These proteins - 16 different HA and 9 different N - are used to characterize the viral subtype; influenza A subtypes H3N2 and H1N1, for example, are those currently associated with most deaths during epidemics. Subtypes A and B can be further broken down into strains. Another important envelope protein is called matrix protein (M2). It is targeted by the drug Amantadin, which is effective against subtype A infections.

Minor genetic changes, known as antigenic drift, typically affect the HA and N antigens on the viral surface. The changes happen continually over time and produce new viral strains that are not recognized by flu-specific immunity previously generated by the immune system. That is why flu vaccination is needed each year.

Antigenic shift - in contrast - describes a rapid and more drastic change of the virus that leads to a complete new haemagglutinin and/or new haemagglutinin/neuraminidase antigen. An antigenic shift results in a new influenza A subtype. It may occur when the eight genomic segments of one virus mix with the segments of another virus, which could result from infection of a single cell with two different viruses (for example in a pig that is susceptible to human and avian influenza viruses). Antigenic shift might also occur as a consequence of mutation. New viral subtypes resulting from antigenic shift have the potential to cause a pandemic because people have little or no protection against the new virus.

During the 20th century, three pandemics occurred: 1918/19 ("Spanish influenza", H1N1), 1957 ("Asian influenza", H2N2) and 1968 ("Hong Kong influenza", H3N2).

Transmission/ pathogenesis
Influenza is a contagious disease. The viruses are passed from one infected person to another through the air, mainly by droplets and small particles that are released when an infected individual coughs or sneezes. They enter the body through the upper respiratory tract, commonly through the nose or throat, and then spread to the lower respiratory tract. Outside the body, the virus can survive for several hours, especially when it is cold and dry. In cool water it can even persist for months.

Symptoms
After infection, it takes 1–3 days before symptoms develop; these include sudden, usually high fever, dry cough, muscle aches, headaches, tiredness and a sore throat. After a week, symptoms vanish. Patients can infect others starting ~24 hours before the first symptoms show and remain contagious for another 3 to 5 days.

Complications
Severe disease is often seen in the elderly, primarily in people with heart or pulmonary diseases or in those with other chronic conditions such as asthma or diabetes; these individuals often experience a worsening of their chronic condition and are prone to the development of pneumonia due to bacterial superinfection. According to the World Health Organization (WHO), most deaths currently associated with influenza occur in industrialized countries among the elderly over 65 years of age. Young children also have a higher risk of complications such as middle ear infections (otitis media).

Treatment
Antiviral treatment is normally not needed; otherwise healthy flu patients require symptomatic treatment only. For the treatment of high-risk individuals or the prevention of an influenza epidemic, four antiviral agents are available. When taken before infection occurs, they may prevent infection; when taken during early stages of infection, they reduce the severity of symptoms as well as their duration (by 1 to 2 days).

The drugs belong to two different groups:
Amantadin and rimantadine block the viral membrane protein M2 and thus prevent the virus from entering cells. They are only effective against type A influenza and may cause severe side effects such as delirium and seizure. Furthermore, viral resistance develops quickly under treatment.

Zanamivir and oseltamivir belong to the group of neuraminidase inhibitors. They block the viral neuraminidase and thus the release of new viruses out of the host cell. They are effective against influenza type A and B viruses, and side effects as well as resistance are less common. As they are quite expensive, they are not available in many countries.

Vaccination
Safe and effective influenza vaccines have been used for more than 60 years. The WHO recommends the vaccination for the elderly and any individual considered at high risk due to underlying health conditions. Because of constant genetic changes in influenza viruses, vaccination has to be repeated each year with the updated or reformulated vaccine. In healthy people, vaccination offers protection of about 90%. The protection rate in the elderly is lower, but vaccination in this group significantly reduces the risks of complications, hospitalization and death.

Incidence and mortality
According to WHO data, 5–15% of the population is affected during annual influenza epidemics. Worldwide, approximately 3 to 5 million cases of severe illness occur, leading to between 250,000 and 500,000 deaths each year. Deaths mainly occur in high-risk groups.

H5N1- Avian influenza („bird flu“)
Influenza A viruses are found not only in humans, they also infect many other animals including chicken, ducks, pigs, horses and whales. Wild birds seem to be the main reservoir for the viruses; they usually do not get sick from infection or develop only mild disease, but they spread the virus to other animals that can get severely ill and die.

During an outbreak of avian influenza among poultry, the virus may be transmitted from birds to humans. Since 1997 several cases that resulted from close contact between humans and infected birds or excretions from birds have been reported. An aggressive avian influenza variant, the subtype H5N1, is currently in circulation among birds. It is highly contagious and can be deadly to birds. Humans are usually not infected, but some severe cases resulting in death have occurred. Human-to-human transmission has only very rarely been reported.

Nevertheless, experts are concerned that H5N1 might change genetically to better infect humans and spread easily between them; this could cause an influenza pandemic. Therefore, outbreaks of avian influenza and human infections with H5N1 are closely monitored. In the years 2003 to 2008, 393 confirmed human cases of H5N1 "avian" influenza, including 248 deaths, were reported to the WHO. For more information see: www.who.int/csr/disease/avian_influenza/en/index.html

Novel H1N1 (previously called "swine influenza")
Swine influenza ("swine flu") is a respiratory disease of pigs caused by influenza A viruses, classically of the subtype H1N1. Other important subtypes in pigs are H1N2, H3N2 and H3N1. Humans do not normally get infected with swine influenza; rare cases are reported in people who have close contact with pigs. In the beginning of 2009, however, an A/H1N1 virus capable of person-to-person transmission was detected in humans. It was originally named "swine flu", but research has revealed that it is quite different from the virus commonly circulating in pigs. The newly detected virus contains genes from flu viruses found in pigs, birds and humans and is now referred to as "novel H1N1 flu".

Novel H1N1 is probably transmitted between humans the same way seasonal flu is, mainly through coughing and sneezing of infected people. It is also possible to become infected by touching a virus-contaminated surface (e.g. doorknob) and then touching the mouth or the nose. Symptoms are also similar to those of seasonal flu, including fever, dry cough, muscle aches, headaches, tiredness, and a sore throat. Furthermore, diarrhoea and vomiting have been reported. Effective treatment of infection is possible with neuraminidase inhibitors (oseltamivir, zanamivir); Adamantanes such as amantadin and rimantadine are apparently not effective because the new H1N1 virus is resistant to them.

As the population has no immunity to novel H1N1, the virus has the potential to spread worldwide and cause an influenza pandemic. Therefore, on April 29 the WHO raised the influenza pandemic alert from phase 4 to phase 5. Nevertheless, WHO experts believe that, "the world is better prepared for an influenza pandemic than at any time in history". Experts worldwide have been monitoring H5N1 infections (bird flu) for years and have thereby gathered much experience. In preparation for a long-anticipated influenza pandemic, countries around the globe have established pandemic preparedness plans that can now be activated. Furthermore, large stocks of antiviral drugs have been produced and are therefore quickly available.

To date (May 2009), novel A/H1N1is causing relatively mild infections. However, it is possible that the virus will change its behaviour over time and becomes more aggressive. It is not known whether a certain group of people (e.g. children younger than five or the elderly) are at greater risk of novel H1N1 flu-related complications.

More information:
- WHO: www.who.int/csr/disease/influenza/en/
- WHO on avian influenza: www.who.int/csr/disease/avian_influenza/en/index.html
- The Centers for Disease Control and Prevention (CDC): www.cdc.gov/flu/

Literature:
- WHO: www.who.int/csr/disease/influenza/en/
- WHO on avian influenza:
- www.who.int/csr/disease/avian_influenza/en/index.html
- The Centers for Disease Control and Prevention: www.cdc.gov/flu/
- Robert Koch Institut: www.rki.de/cln_100/nn_196658/DE/Content/InfAZ/I/Influenza/IPV/IPV__Node.html