• fact that the infection and disease are often preventable;
• the high number of cases that take place each year;
• the substantial cumulative social and economic burdens (through loss of work), despite the fact that the illnesses are often short in duration;
• the burden on health services, often at times of the year when they are busy with many other infections and ill health (‘winter pressures’); and
• a smaller number of people who get severely ill and die prematurely.

It is a seasonal disease which in Europe generally occurs in epidemics between October and March every winter. In most recent years it has peaked early, usually around New Year.  

Influenza spreads predominantly via the droplet and contact routes when people cough and sneeze and by indirect spread from respiratory secretions on hands, tissues, etc. The incubation time for influenza ranges from one to five days, but the average is two days.

Influenza is only one of the many infections that contribute to colds and respiratory tract infections in the winter. There are many other important viruses that cause these, notably respiratory syncytial virus (RSV), which can mimic influenza and especially affects children.   

The pathogen

• Human influenza viruses are RNA viruses from the family Orthomyxoviridae, which have a worldwide distribution. They are usually classified into three broad types: A, B and C, according to differences in the antigenic properties of their external coat. Influenza A viruses, clinically the most important, are further divided into subtypes based on two proteins on the external coat , the hemagglutinin (HA) (H1–H16) and the neuraminidase proteins (NA) (N1–N9). Type B viruses are somewhat less severe, and Type C viruses do not cause significant human disease, so only type A and B viruses are of concern. Currently circulating A virus subtypes are A(H3N2) and A(H1N1), the type that caused the 2009 pandemic. Seasonal influenza consists at present of variable mixes of these two influenza A viruses plus B viruses.
• Like other RNA viruses, the genome of influenza viruses is subject to a significant spontaneous mutation rate. In addition, the genome consists of eight separate segments. Re-assortment of the genome segments result in considerable antigenic variability, particularly of the HA and NA of the influenza A viruses.
• Gradual changes in the level and type of human viruses in seasonal influenza is the result of what is known as antigenic drift, the continuous change of the viral HA and NA due to the high mutation rate of the genome and the fact that RNA viruses lack the proof-reading ability of DNA polymerases.
• This means also that influenza can quickly evolve to evade the human immune responses that follow natural infection or immunisation. 
•  Pandemics are the result of larger changes sometime called antigenic shift. These are large genetic changes, for example through inclusion in the virus of HA and NA subtypes from avian or swine origin by reassortment. These reassortments are not that rare but only very occasionally lead to a viable, transmissible influenza A virus for which many or most humans lack immune protection. That is then a pandemic strain (see Edwin D. Kilbourne, Influenza Pandemics of the 20th Century).

Mild disease: common clinical features and sequelae

Straightforward influenza disease usually presents as rapid onset of the following combination of systemic and respiratory (both upper and lower) symptoms:

• fever or feverishness;
• headache;
• muscle pain;
• runny nose;
• sore throat;
• non-productive cough; and a
• a general feeling of ill-health. 

Not every person who is infected gets all the symptoms and some experience hardly any or even no symptoms at all.

The fever and general malaise usually last for only a few days but cough, sore throat and runny nose may last longer. Mild and asymptomatic cases also occur, but with the more typical infections a person rarely properly recovers within a week. What is confusing is that many people use the term ‘flu’ or ‘grippe’ loosely and state they have ‘a touch of flu’ when their mild disease is caused by other infections. Also a number of other viruses and some bacteria can cause similar symptoms so that much influenza-like illness is just that, similar to influenza but not actually influenza. 

More severe disease and complications: groups at greater risk – the elderly and people with chronic ill health

In some cases the disease becomes more severe due to more extensive spread of the virus in the body (viraemia) or a second, usually bacterial, infection due to organisms like the Streptococcus pneumoniae, Staphylococcus aureus or Haemophilus influenzae. These most commonly result in severe lung infections (pneumonias) or even death. Quite often the initial cause of influenza is not recognised and the death is not classified as being due to influenza. These complications can occur in anyone, but are more common as people age and in people of any age with chronic medical conditions. Finally it seems that influenza precipitates severe disease and death due to circulatory or cerebro-vascular causes in some people with underlying pathology (Warren-Gash et al.).

The list of specific conditions which make people vulnerable to influenza is long. Rather than try to list all of them, ECDC considers the following broad groups (Nicoll et al., 2008):

• metabolic diseases (e.g. diabetes);
• chronic lung conditions (e.g. chronic bronchitis);
• cardiovascular disease (e.g. coronary artery disease);
• chronic kidney diseases (e.g. chronic renal failure);
• chronic neurological conditions and physical handicap (e.g. cerebral palsy); and
• conditions and treatments that suppress the immune function (e.g. people receiving chemotherapy).

In some countries it is considered that well children and pregnant women are also in risk groups. While that was certainly the case in some countries in the 2009 pandemic it is not clear if is the case in European Countries for seasonal influenza (ECDC 2007b). 

The burden of disease from seasonal influenza

The burden from influenza is two-fold. Firstly there is the severe disease and deaths. Secondly, but of greater economic impact, are the large numbers of mild to moderate cases which result in time off work, losses to production and pressure and costs on the health and social care services. The burden varies from year to year, which makes it hard to estimate the annual number of deaths or economic impact. One estimate looking at excess deaths due to influenza found that in milder influenza seasons there were around eight deaths per 100,000 population, while in more severe but non-pandemic years the figure would be 44 per 100,000 (Tillett 1980). Another independent estimate found something similar with an average estimated number of excess deaths of 25 per 100,000 on average between 1989 and 1998 (Fleming 2000). There are a number of other estimates from European countries based on excess of deaths seen during winter epidemics (Gran et al.; Nogueira et al. 2009; Zucs et al. 2005). A more recent analysis from the United States has given estimates of excess deaths for that country (CDC 2010a). Applying these figures to the EU population as a whole (around 500 million in 2010) would result in around 38,500 premature deaths but with considerable season-to-season variation (ECDC 2010). These are imprecise figures but it is possible to generalise that in the seasons before the 2009 pandemic, when A(H3N2) viruses dominated, mortality was higher than in other years, especially in older people, while influenza B was mildest and the then influenza A(H1N1) in between the two (Simonsen et al. 1997).

Though much attention is paid to the impact of pandemics, many more people die in the intervening years because of the seasonal influenza epidemics than during the pandemics themselves. Applying a conservative estimate of 25 per 100,000 population would mean that, over a theoretical hundred years, there would be 12.5 million excess deaths from seasonal influenza. This compares to the estimated 1.1 million that would die from a re-run of the 1918 (the worst recorded) pandemic in the EU (Murray 2006). Certainly in the 20th century, the combined mortality from influenza in seasonal or inter-pandemic influenza considerably exceeded that seen in the pandemic years.

Transmission

Influenza spreads predominantly via the droplet and contact routes when people cough and sneeze and by indirect spread from respiratory secretions on hands, tissues, etc. The incubation time for influenza ranges from one to five days, but the average is two days. In most cases, virus is found in specimens from nose and throat from one day before symptoms to four to five days after onset of disease. However, the level of virus shedding before symptoms start is low and highest in the few days after symptoms start, when the patient is feeling worst. Viral shedding continues for somewhat longer in young children than in adults. Cases of influenza where people cannot recall any contact with ill people suggest there are a few cases where the person catches infection and passes it on without any symptoms at all, or only very mild symptoms.

Diagnosis

The most common method for diagnosing the flu is an antigen detection test, which is done by swabbing the nose and throat, then sending a sample to the laboratory for testing. The results of these tests can be available rapidly, and can help decide if specific treatment is appropriate. However, when flu is widespread in the community, the diagnosis is often presumed by simply identifying patients with typical symptoms without laboratory testing. Serology plays no role in diagnosis.

Case management for public health purposes (1)

Most simple seasonal influenza cases are just managed symptomatically, that is patients are sent home to bed and isolated so that they cannot infect other persons. They are given medicines that will reduce their temperatures and relieve the general feeling of illness and sore muscles. Doctors may or may not attempt to confirm the diagnosis by taking specimens for laboratory analysis. It is considered important that patients monitor themselves to detect if they are deteriorating and perhaps develop a secondary infection for which intensive medical interventions are needed. Since the 1990s, antiviral drugs have been demonstrated to be effective for treatment and especially for prophylaxis (Moscona 2005a). However, many consider they have to be used early in the infection (best within 24 hours after the symptoms start and within 48 hours). The early antivirals amantadine, rimantadine were made ineffective by antiviral resistance but the neuraminidase inhibitors oral oseltamivir and inhaled zanamivir are useful for treatment and prophylactic use. The use of these drugs is very variable between European countries (Kramarz et al. 2009). Vaccination is the preferred option for preventing influenza, but antivirals can be particularly useful when the vaccine fails (due to antigenic mismatch with circulating virus, waning immunity in elderly, patients being immunocompromised, etc.), when vaccine is not (yet) available, as well as during an outbreak of ‘avian’ influenza or an emerging pandemic. At least one EU country (the UK) makes specific recommendations on when to use antivirals according to the levels of circulating influenza viruses as determined by surveillance.

Resistance to antivirals

Resistant mutants to the M2 inhibitors have been detected in a number of countries for many years so that these are not recommended. There had been few instances of resistance to the neuraminidase inhibitors in seasonal influenza until the emergence of resistant seasonal A(H1N1) viruses that were capable of transmitting on (Moscona 2005b; Meijer 2009). Antiviral resistance in Europe is monitored by the VIRGIL project in collaboration with the European Influenza Surveillance Network Scheme (EISN) and by a number of individual national influenza centres (Meijer 2006).

Epidemiology

Although both influenza A and B types are able to cause epidemics, significant disease, and deaths, type B infections are usually milder and therefore more often detected in the context of localised outbreaks. In contrast, type A viruses, which cause more severe symptoms, are those responsible for the highest burden of disease during seasonal epidemics. Only A viruses are responsible for the occasional worldwide pandemics. In Europe, influenza occurs in regular annual epidemics in the winter. These usually affect most of the countries for one to two months and last in Europe for about four months (Paget et al. 2007). Sporadic infections also occur outside of the influenza season, though the incidence is very low in the European summer when infections may be the result of imported cases from equatorial areas (where transmission is more year round) and the southern hemisphere where most infection takes place in the European summer. A global overview is always available from WHO Global Influenza Surveillance Network  summaries. All age groups are affected, though the proportions of the exact groups vary from year to year and according to the dominant viruses and the level of population immunity. Some years it’s mostly children, other years it’s other age groups.

The usual experience after a pandemic is that the new pandemic strain comes to dominate the annual epidemics for some years which are then more vigorous and severe than in the years before the pandemic. However this may not necessarily occur after the 2009 A(H1N1) pandemic in Europe because of the more benign nature of the new influenza A(H1N1). Also there has been large scale immunisation in some countries against the virus and many older people are immune. This has been discussed in the ECDC Forward Look Risk Assessment.

Public health management and personal protection and prevention

The public health management includes the strong promotion and adoption of the ECDC-recommended personal protective measures: 

• Regular hand washing with proper drying of the hands.
• Good respiratory hygiene – covering mouth and nose when coughing or sneezing, using tissues and disposing of them correctly.
• Early self-isolation of those feeling unwell and feverish and having other symptoms of influenza, which is considered to reduce the risk of people acquiring or transmitting infections.

It is thought that all of these reduce the risk of transmission of influenza though in fact the evidence base is weak. Expert opinion is supportive (Jefferson 2009) but there have been hardly any randomised trials with laboratory-confirmed influenza as end points (Cowling et al. 2010; Macintyre et al. 2009).

Seasonal influenza vaccination: human immunity to influenza

Vaccination is the most effective form of prevention. Human influenza viruses are well adapted to their hosts. That is they infect humans easily and transmit readily from one human to another, usually without killing their hosts. Immunity comes either from experiencing infection or from vaccination. Cross-immunity following infection by one strain or vaccination with a specific type or subtype often does not protect completely against subsequent variants of the same type or subtype. The extent to which influenza A(H3N2), A(H1N1), and B viruses circulate may vary by season. In addition, as the antigenic properties of these viruses might change due to continuous evolution of these viruses under immune pressure (antigenic drift), the virus strains of A(H3N2), A(H1N1) and B included in the vaccine have to be reviewed by the WHO annually and possibly changed. Also new vaccines may have to be made when variants of the virus emerge through antigenic shift (Gerdil 2003).

Most of the acquired protection against influenza comes from antibodies in the blood. Some additional protection comes from cell-based immunity and IgA antibodies produced on mucous membranes, like those of the respiratory tract. After the first (primary) infection, or vaccination, virus-neutralising antibodies to the haemagglutinin and neuraminidase appear in the blood in about one to two weeks and rise to a peak in about four weeks. Antibodies inhibit haemagglutination, agglutination of red blood cells due to multiple red blood cells bound by one virus, and so this is referred as haemagglutination inhibition (HAI). HAI correlates fairly well with virus neutralisation (Ada 1986). Hence often the levels of these specific antibodies are used as a proxy for the presumed level of protection, with higher titres of more than 1:40 or 1:80 (in the older person) taken to indicate immunity.  

After a second or further infection, or repeat vaccination, the antibodies appear and rise more quickly. The antibodies usually persist for months or years, although in people with weaker immune systems like the elderly and those with chronic illness they decline more quickly and vaccination is less effective (Simonsen 2007). Another problem with influenza vaccination is that antibodies to one type or subtype of influenza do not necessarily give protection to other influenza virus types or subtypes (so called cross protection). Equally they do not give full protection against subsequent drift variants of the same type or subtype. That is why seasonal influenza vaccines contain a mix of influenza virus types and subtypes and the composition has to be reviewed each year by the WHO (Gerdil 2003).

Virological surveillance

The contribution of virological surveillance in the EU cannot be overemphasised. For selection of vaccine candidate viruses matching the virus strain expected to circulate in the coming season and for keeping a close watch on the evolution of influenza viruses there is a Global Influenza Surveillance Network, managed by WHO and comprised of national influenza centres, including those that are supported by ECDC’s Community Network of Reference Laboratories for Human Influenza in Europe. These continuously report and share influenza viruses with a series of four highly specialist WHO Collaborating Centres. In Europe, a WHO Collaborating Centre is located in the UK (Mill Hill), where there is also the National Institute of Biological Standards and Controls (NIBSC) which further refines and prepares suitable viruses for passing on to industrial vaccine producers (ECDC 2007). Based on data arising from this surveillance each year, WHO convenes specialist meetings at which it agrees on recommendations on the composition of the influenza vaccine for the next season. Separate meetings and recommendations are made for the northern hemisphere (which includes Europe) and the southern hemisphere. Current influenza vaccines (2007) are recommended to contain antigens protecting against two influenza A subtypes, H3N2 and H1N1, and one of the two lineages of type B virus.

The influenza vaccines

Currently there are three types of vaccines used in Europe, all of them inactivated, some formulations are also adjuvanted:

• split virus vaccines consisting of virus particles disrupted by detergent treatment;
• subunit vaccines consisting essentially of haemagglutinin and neuraminidase from which other virus components have been removed; and
• whole virus vaccines consisting of inactivated viruses.

Live attenuated influenza vaccine given by nasal sprays are available in North America, though they have been mostly been developed for use in children for whom vaccination is not generally recommended in Europe (Fukuda 2006).

Vaccine strategies: people to whom influenza vaccine is recommended

The European approach with influenza is generally to reduce the risk of people at greater risk of complications from becoming infected. Hence, the approach is one of protecting the most vulnerable or selective vaccination.

Risk groups

VENICE surveys of the EU/EEA countries sponsored by ECDC found that all reporting countries were recommending annual vaccination to the two largest groups which are highlighted by the European Union Health Council (Council of the EU 2009) and WHO (WHO 2002):

1. Older people above a nationally defined age (usually 65 years and older).

2. All people over six months of age with chronic medical conditions: notably chronic heart or lung diseases, metabolic or renal disease, or immunodeficiencies.

Many countries emphasise the importance of annual vaccination of people in residential care for the elderly and disabled and there is excellent evidence that supports immunising those that care for them (Hayward et al. 2006). Few EU countries recommend vaccination of children or offering vaccines to pregnant women (Merecekiene et al. 2008). This is different from policy in the United States (CDC 2010). An expert panel convened by ECDC considered there was as yet insufficient evidence on the burden of infection in children to take any view for or against vaccination (ECDC Scientific Panel report 2007). During the pandemic, more countries decided to offer immunisation to pregnant women as recommended by WHO, though the evidence for this in European data is not clear.

Target groups: healthcare staff

In addition to the risk groups there are also other groups for who immunisation is often recommended – these are referred to as target groups. The most important of these are healthcare staff who are expected to prevent their infecting their patients with influenza-by-influenza vaccination as well as the other non-pharmaceutical measures. The vaccination will also protect the staff but its prime purpose is to prevent iatrogenic spread. Hence all countries in Europe recommend that all healthcare staff should be immunised against influenza. This is especially important for patients at higher risk of infection and disease and where immunisation is less likely to be effective. There is strong evidence that this protection works (Hayward 2005).

Vaccine efficacy and effectiveness

Estimates of vaccine efficacy and effectiveness – or the extent to which vaccines protect in optimal circumstances (efficacy) and in practice (effectiveness) – vary according to the match between vaccine and the circulating viral strain and by age group and clinical category. Generally, the vaccines work less well in the elderly and those with chronic ill-health. In trials, inactivated influenza vaccines have consistently been shown to prevent laboratory-confirmed illness in between 70% and 90% of healthy adults. The results are somewhat less in field effectiveness studies (Turner 2003; Treanor J et al. 1999; Nichol 2007; Skronowski 2007; Wilde 1999; CDC 2010a). The reduction in hospitalisations and deaths is less dramatic but still significant (Mangtani 2004). Trial data cannot help here as hospitalisations, pneumonia and deaths are too uncommon to be revealed by trial data which also usually exclude those most at risk. Instead, observational data have to be used. These data are more subject to bias (Simonsen 2007). However, modern epidemiological studies can compensate for these biases and when this is done, positive effects are consistently observed, although there are minority opinions that disagree (Jefferson 2005, 2006).

Contraindications to vaccination

On empirical grounds, as most viruses used for influenza vaccines are grown in eggs, egg-based vaccines should not be used for individuals with a definite history of serious allergic reactions to egg products.

Giving vaccines

Most inactivated influenza vaccines are injected into the muscle in the outer upper arm. A single injection annually is sufficient except for previously unvaccinated preschool children with medical conditions for whom WHO recommends two doses at least one month apart.

Reactions to vaccines

The three groups of inactivated influenza vaccine show minor differences in the mild reactions that sometimes follow vaccination. In trials, when whole virus vaccines are used, between one in five and one in six of those vaccinated experience local reactions in the arm, lasting for one or two days. Short-term reactions such as mild fever, malaise and muscle pains are reported in a much smaller proportion in the first few hours following vaccination. In contrast, trials of the split and subunit vaccines show even fewer reduced systemic reactions. There have been no strong temporal associations of the current vaccines with more severe reactions. Anaphylaxis is very rare but does occur as with all vaccines. More severe adverse events have been reported but they are extremely rare. One that has been reported historically with a particular vaccine in the 1970s is Guillain-Barré syndrome. With the modern influenza vaccines the seeming causative risk is either found to be very rare (0.8 per million doses) or there is no link found at all and more association is found with influenza infection than vaccination (Centers for Disease Prevention and Control 2010b; Stowe et al. 2009).

Vaccination coverage targets

The World Health Assembly, which includes all EU/EEA countries, supported a proposal in 2003 that there should be targets for uptake in the elderly of 50% by 2005 and 75% by 2010. Now there is a EU target set by the Health Council of all Health Ministers of 75% for the two large risk groups by 2014/15 (EU 2009). 

Prevention advice to travellers

As already mentioned, influenza spreads from person to person through coughing or sneezing, or by direct or indirect contact with respiratory secretions from infectious persons. Therefore, the risk of transmission of influenza can be significantly reduced by some simple methods.

Before travelling: If you have any underlying chronic disease, contact your doctor. Get familiar with simple methods how to protect yourself (see below).

During travelling: Simple methods to protect yourself are:

• Avoid close contact with sick people: signs of influenza may be one or more of the following symptoms: fever, cough, sore throat, runny nose, body aches, headache, chills and fatigue. Some people have reported diarrhoea and vomiting associated with infection by the new influenza virus.
   
• Wash or clean your hands frequently: washing or disinfecting your hands thoroughly will help protect you from viruses. Wash your hands thoroughly with soap and water, especially after you cough or sneeze. And do not just rinse them quickly; you should wash your hands for at least 20 seconds each time. Alcohol-based hand cleaners also effectively reduce the amount of influenza virus on contaminated hands and are easy to use. Liquids or gels are more effective than alcohol-soaked tissues.
• Avoid touching your eyes, nose or mouth: viruses are often spread when a person touches something that has been contaminated and subsequently touches their eyes, nose or mouth.
• If you are ill and suspect influenza, you should stay at home or in your hotel room unless you need to seek medical attention. Children with fever or influenza-like symptoms should seek prompt medical attention.
• The use of prophylaxis with neuraminidase inhibitors (e.g. Tamiflu, Relenza) is a decision to be taken by a physician, based on the individual risk assessment.

After travelling: In case you develop fever (38 ºC or more) and influenza-like symptoms within seven days of your return from travel, you should rapidly seek medical attention by telephone, informing the persons you consult about your recent travel, in accordance to your national health authorities’ recommendations.

The information contained in this fact sheet is intended for the purpose of general information and should not be used as a substitute for the individual expertise and judgement of healthcare professionals when it comes to patient care.

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1) These fact sheets do not contain specific details of individual patient treatment as that is beyond the remit of ECDC.