Influenza: The disease

Dr Terry Besselaar and Prof Barry Schoub

It's that time of year again - when the influenza virus stops young and old, big and small. What is the 'flu exactly? Who decided on the vaccine? What is the vaccine? Your questions answered by the "'flu police".

Influenza: The disease

Transmitting the virus - Photo Courtesy of Centers for Disease Control and PreventionInfluenza is a potentially serious viral respiratory disease associated with high morbidity and a significant death rate. The disease is seasonal with infection occurring predominantly in the winter. The reason for the seasonality of the disease is unknown, but it may be related to the closer proximity of people in colder weather, which may facilitate the transmission of infected respiratory droplets from an infected to a susceptible person.

Influenza differs from the common cold in a number of ways. The onset of influenza is usually very sudden and may include the following symptoms: High fever of 38.9 - 40.0°C, which lasts 3-4 days. Headaches, chills and a dry cough are common as well as general muscle aches and pains that can be severe. Nasal congestion and a sore throat can also be present. Extreme tiredness can last 1 -2 weeks. Some children may also feel nauseous, or have vomiting and diarrhoea. The majority of people who get influenza will recover in 1- 2 weeks, but some people will develop life-threatening complications such as pneumonia. Other complications include bronchitis, sinus and ear infections.

Influenza viruses

There are three types of influenza virus, A, B and C. Types A and B viruses cause epidemics of disease almost every winter, while type C viruses only cause a mild respiratory illness and are not considered clinically important. Influenza type A viruses are divided into subtypes based on two proteins on the surface of the virus, the haemagglutinin (HA) and neuraminidase (NA). The current subtypes of influenza A viruses that infect humans are A (H1N1) and A (H3N2). Influenza A viruses are found in many different animals, including birds, pigs, horses, whales and seals. Wild aquatic birds are the reservoir for all subtypes of influenza A viruses. There are fifteen different haemagglutinin and nine different neuraminidase types that occur in influenza A viruses in wild birds. Unlike influenza A viruses, influenza B viruses are not divided into subtypes and have only been isolated from humans and recently from seals.

Virus structure

The influenza virions. Picture © Copyright Linda M Stannard, 1995. The influenza viruses are RNA viruses belonging to the Orthomyxoviridae family. The core genome is comprised of multiple, segmented single strands of RNA contained within an outer lipoprotein envelope. Under the electron microscope the virus generally appears rounded, but may be long and filamentous. "Spikes" protruding from the envelope can be visualized. These protuberances represent the two surface proteins, the HA and NA proteins. The HA protein attaches the virus to the host cell receptor. Various studies have also shown that there are five antigenic sites on the HA protein and that this protein is important in inducing neutralizing antibodies in the infected host. The NA protein promotes the release of newly formed virus particles, which promotes the spread of the infection within the organism.

Antigenic changes

Influenza viruses can change in two different ways. The first way is referred to as "antigenic drift" and occurs by continuous mutations taking place during the replication cycle of the virus. These changes are unpredictable and if they occur within the five defined antigenic sites on the HA protein, can give rise to an antigenically novel virus. The new variant virus can escape the host's previously acquired immunity, and can then spread rapidly through a susceptible population.

The second type of change, "antigenic shift", occurs in influenza A viruses. Antigenic shift is an abrupt, major change due to gene reassortment and results in an influenza A virus with new haemagglutinin and/or neuraminidase proteins. When a new subtype of virus appears after antigenic shift that can cause both illness in humans and can also spread easily from person to person, an influenza pandemic (worldwide epidemic) can occur. During the last century three influenza pandemics occurred. In 1918 -1919, the "Spanish flu" caused approximately 40 million deaths worldwide. The virus that caused it , influenza A (H1N1), was unique because almost half of the people who died were young, healthy adults. The next pandemic, the "Asian flu" occurred during 1957- 1958 and was the result of an antigenic shift producing an H2N2 virus. In 1968, a new subtype (H3N2) emerged and was referred to as the "Hong Kong flu" since it was first detected in Hong Kong before it spread globally causing the third pandemic. 

Novel subtypes can also be introduced directly from animals or birds to humans - the 1918/19 pandemic was probably introduced directly from pigs to humans.

Who monitors the virus?

Due to the antigenic drift of the virus, monitoring the antigenicity of the viruses in circulation each year is necessary to identify any new variant strains so that influenza vaccines can be updated annually with closely matching strains. Influenza surveillance is carried out globally by a network of between 125 -140 laboratories under the auspices of the World Health Organisation (WHO). The influenza laboratories at the National Institute for Communicable Diseases (formally National Institute for Virology) in Johannesburg, South Africa serve as one of the National Influenza Centres of the WHO.

An active influenza surveillance programme was established in 1984 at the National Institute for Virology to obtain virus isolates and to monitor influenza epidemics. The viruses that are isolated from patients are characterised antigenically and the HA gene is partially sequenced to assess the extent of antigenic drift from the vaccine strains.  Influenza activity is monitored using proxy indices such as monitoring school absenteeism, utilization of pharmaceuticals related to respiratory infections and also mortality data. All the South African data is gathered together and presented at a meeting held annually to decide what virus strains should be included in the formulation for the Southern Hemisphere influenza vaccine.

Vaccination

Influenza is largely a vaccine-preventable disease, but the benefits of vaccination are generally underestimated. The vaccine is relatively inexpensive and is very safe. The effectiveness of the vaccine depends on how well the vaccine strains match the strains of influenza that actually circulate that year.

The vaccine contains representative strains for each of the two subtypes of influenza A virus (H1N1 and H3N2) as well as influenza B. One or more of the three strains may be changed every year in order to keep up with the constantly evolving virus. The strains that were recommended for incorporation into the 2002 influenza vaccine are the following: A/Moscow/10/99-like strain Influenza A (H3N2) A/New Caledonia/20/99 -like strain Influenza A (H1N1) B/Sichuan/379/99-like Influenza B.

The names of the strains denote the place where the virus originated or was first isolated. The name is followed by a laboratory number and then the year of isolation. These labels, however, are not indicative of any biological, epidemiological or clinical property of the virus.

Who should be vaccinated?

Individuals who are at high-risk of developing complications of influenza, particularly pneumonia, should be vaccinated. This includes elderly persons (over the age of 65 years), and people of any age with chronic underlying medical conditions. Individuals who are HIV positive and who have mild to moderate immunosuppression should be vaccinated because of the increased danger of complications associated with secondary infection. In severely immunosuppressed individuals i.e. those with CD4 counts less than 200/ml, the vaccine however has poor efficiency. Pregnant women who would be in their second or third trimester during the influenza season should also be vaccinated because of the greater risk of pneumonia due to poor ventilation as a result of increased abdominal mass.

Contacts of high-risk individuals i.e. healthcare personnel as well as persons, including children, living under the same roof as a high-risk person, should be vaccinated. Studies on annual influenza vaccination in the workplace have also shown this to be very cost-effective as a result of the reduction in absenteeism as well as the savings in medical costs due to influenza.  An increasing number of healthy individuals are also choosing to be vaccinated annually to avoid a potentially debilitating illness. Influenza vaccination should ideally be administered from mid-March onwards as it takes 10 -14 days before protective antibodies develop.

Antiviral agents

A recently licensed antiviral drug, Zanamivir, is available in South Africa. The drug is specifically active against the neuraminidase enzyme of influenza A and B and causes a reduction in the duration of influenza symptoms.

2002 influenza season

Despite the extensive monitoring of influenza globally, there are no scientific tools available to reliably predict the severity of a forthcoming epidemic due to the unpredictability of the virus. In 1998, South Africa experienced a major epidemic caused by the introduction of A/Sydney/5/99-like H3N2 influenza strains into the country. Since then, the influenza seasons have been fairly mild.

The influenza strains that circulated in the Northern Hemisphere 2001/02 season were both influenza A (H3N2) viruses as well as influenza B strains. A small number of influenza A (H1N1) viruses were also isolated. While the influenza A viruses were still similar to the vaccine strains, a number of the B viruses were antigenically very different to the B/Sichuan/379/99-like vaccine strain. These strains were referred to as B/Hong Kong/330/01-like viruses. The B/Sichuan/379/99-like vaccine strain offers reduced protection against the B/Hong Kong-like viruses.

Several B/Hong Kong/330/01-like viruses have recently been isolated at the NICD and it is anticipated that they will spread throughout the country. A few influenza A (H3N2) viruses have also been isolated and these have been shown to be closely related to the H3N2 vaccine strain.

Good News: Not too late to be vaccinated

Much of the illness and death due to influenza can be prevented by annual vaccination. Despite the fact that the influenza season has started in South Africa, it is not too late to be vaccinated. For further information on influenza, visit the www.flu.co.za web site.

References

Besselaar TG, Schoub BD, McAnerney J, Blackburn NK. (1999) Impact of the introduction of A/Sydney/5/97 H3N2 influenza virus into South Africa. J Med Virol; 59, 561-568

Bridges CB, Thompson WW, Meltzer MI et al. (2000) Effectiveness and cost-benefit of influenza vaccination of healthy working adults: A randomised controlled trial. JAMA, Oct 4, 284 (13), 1655-1663

Gubareva LV, Kaiser L, Hayden FG. (2000) Influenza virus neuraminidase inhibitors. Lancet; 355, 827-835

Hayden FG, Osterhaus AD, Treannor JJ, et al. (1997) Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenza virus infections. N Engl J Med; 337, 874-880

Martin DJ, Schoub BD (1997) Benefit: Cost evaluation of influenza vaccination in South Africa. Occupational Health SA, 3 (1), 23-28

Osterhaus AD, Rimmelzwaan GF, Martina BE, Bestebroer TM, Fouchier RA. (2000) Influenza B virus in seals. Science; May 12, 288 (5468), 1051-1053

Rota PA, Hemphill ML, Whistler T, Regnery HL, Kendal AP. (1992) Antigenic and genetic characterization of the haemagglutinins of recent cocirculating strains of influenza B virus. J Gen Virol; 73, 2737-2742

 

June 2002