Seasonal influenza is a preventable infectious disease with mostly respiratory symptoms. It is caused by influenza virus and is easily transmitted, predominantly via the droplet and contact routes and by indirect spread from respiratory secretions on hands, tissues, etc. Additionally, aerosol transmission plays a part in influenza virus transmission. (Killingley, 2013)

Seasonal influenza causes 4 -50 million symptomatic cases in EU/EEA each year, and 15 000 – 70 000 European citizens die every year of causes associated with influenza. Despite the often short duration of illness, the yearly economic and healthcare burden of influenza is substantial.

In the northern hemisphere, including Europe, seasonal influenza generally occurs in epidemics between November and April each year, and in the southern hemisphere between June and October. Influenza surveillance is carried out worldwide, including in the EU.

A number of other viruses and bacteria cause similar symptoms so that much of influenza-like illness (ILI) is not actually caused by influenza. At irregular intervals there are influenza pandemics.

The pathogen

Influenza viruses are RNA viruses from the family Orthomyxoviridae, and have a worldwide distribution.

Influenza viruses are usually classified into three types: A, B and C, according to differences in antigenic and biologic properties. There is also evidence of a fourth type: D (Ducatez, 2015).

Influenza A viruses are further divided into subtypes. The subtypes are determined by two glycoproteins on the virus surface, haemagglutinin (HA) (H1–H18) and neuraminidase (NA) (N1–N11). Antibodies against these glycoproteins are associated with immunity against influenza.

Type B viruses cause somewhat less severe disease and tend to cause fewer complications than some type A viruses. Type B does not have subtypes but two antigenically distinct lineages: Victoria and Yamagata.

Type C viruses cause some human disease but only comparatively few outbreaks.

Type A and B viruses are the predominant virus types causing disease in humans and are the focus of this factsheet.

At any one time there is a mix of influenza viruses circulating in the human population. Since the most recent influenza pandemic in 2009 seasonal influenza consists of variable mixes of influenza A(H3N2), A(H1N1)pdm09 - the latter caused the 2009 pandemic, and the two B virus lineages.

The genome of influenza viruses is subject to a significant spontaneous mutation rate, known as antigenic drift. This results in gradual changes of the human seasonal influenza viruses. In addition, the influenza A and B genome consists of eight separate RNA segments. Re-assortment of the genome segments results in considerable antigenic variability, particularly of the HA of the influenza A viruses.

Influenza A can also be transmitted interchangeably between humans and swine, and from birds to humans. In birds H1-H16 and N1-N9 have been detected. All these influenza A viruses that have been detected in mammals or poultry originated at some point from wild aquatic birds. H17-18 and N10-11 have been detected in bats. Read more about avian influenza and swine influenza.

Only type A viruses are able to cause pandemics as they have a reservoir in animals. Pandemics are the result of larger genetic changes called antigenic shift. A shift can occur e.g. through inclusion of HA and NA subtypes from avian or swine origin by re-assortment, i.e. the exchange of at least one RNA segment. Re-assortments are not that rare but only very occasionally lead to a viable influenza A virus, with ability to infect humans, cause disease in humans, cause sustained person-to-person transmission, and for which many or most humans have little or no immunity. That is then a pandemic strain (see Edwin D. Kilbourne, 2006; Influenza Pandemics of the 20th and 21st Century).

In many languages people may use the term ‘flu’ not exclusively for influenza virus but also for mild diseases caused by other infectious agents.

Clinical features and sequelae

Uncomplicated seasonal influenza disease

Uncomplicated seasonal influenza disease presents as rapid onset of the following combination of systemic and respiratory symptoms:

fever or feverishness;

headache;

muscle pain;

general feeling of ill-health;

runny nose;

sore throat;

non-productive cough.

Children may also present with gastrointestinal symptoms such as vomiting or diarrhea, apart from fever and respiratory symptoms.

Not all infected present all the symptoms. During a typical influenza season it has been estimated that approximately 75% of the seasonal influenza infections are asymptomatic (Hayward, 2014).

In uncomplicated adult cases systemic symptoms usually last a few days. Sore throat and runny nose may last longer. Cough, fatigue, and malaise may last some weeks.

Severe influenza

In some cases the disease becomes more severe due to the influenza virus infection or a secondary, usually bacterial, infection e.g. by Streptococcus pneumoniae or Staphylococcus aureus. This most commonly manifests itself in pneumonia, and at times even death. Severe disease may also include myocarditis or encephalitis, which may be fatal. However, quite often the initial influenza infection is not recognised and the death is not classified as being due to influenza. Overall influenza-associated mortality has been estimated to 13.8 per 100,000 person-years (Thompson, 2003).

Furthermore, exacerbations of underlying disease, e.g. cardiovascular disease, may also occur.

The severity of seasonal influenza depends on the virus, host factors, and other factors, e.g. access to care. The complications can potentially occur in anyone, but hospitalisations are more common in older persons (≥65 years of age, 309/100,000 person-years) (Zhou, 2012) and in the youngest children (<1 year of age, 151/100,000 person-years) (Zhou, 2012).

The elderly on average have a greater risk of developing severe complications, such as pneumonia. They frequently have underlying diseases which reduce their resistance to infection, and their immune response may also be less effective. The young have an increased risk of being infected because they have not developed immunity to the virus. Apart from the age-related increased risk, the risk of complications is increased for people of any age with particular chronic medical conditions:

metabolic diseases (e.g. diabetes);

chronic lung conditions (e.g. chronic bronchitis);

cardiovascular disease (e.g. coronary artery disease);

hepatic disease;

haematologic conditions;

morbid obesity (body mass index >40);

genetic conditions;

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. chemotherapy).

Moreover, healthy pregnant women have been found to be at increased risk of becoming hospitalized due to respiratory illness during influenza seasons (Dodds, 2007).

Epidemiology

Influenza A and B

Type A viruses are responsible for the highest burden of disease during seasonal epidemics, although both influenza A and B types are able to cause epidemics, significant disease and deaths.

Type B infections are less common and usually milder than influenza A(H3N2).

Moreover, only influenza type A viruses are responsible for the occasional pandemics. The usual experience following a pandemic is that the pandemic strain dominates the annual epidemics for some years. In some cases the pandemic strain replaces one of the previously circulating strains. Seasonal epidemics during those years can be more severe than during the years before the pandemic. However this may not always occur. It may e.g. depend on the nature of the pandemic influenza virus, immunization coverage and pre-existing immunity in the population.

Annual epidemics

In Europe, and the rest of the northern hemisphere, seasonal influenza generally occurs in regular annual epidemics in winter, between November and April. These usually affect most of the countries for one to two months and last in Europe for about four months overall (Paget et al., 2007). Sporadic infections 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 between June to October.

European influenza seasons have been recorded for several years and are continuously under ECDC surveillance. During the influenza surveillance season ECDC and WHO Europe jointly publish weekly updates on influenza in Europe, based on information provided by experts, virologists and medical doctors throughout the wider European region.

A global overview is also available from WHO.

All age groups are affected, though the proportions of the groups vary from year to year according to the dominating viruses and the level of population immunity.

Burden of influenza

The burden from seasonal influenza has two aspects. 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 characteristics of the circulating virus strain and the immunity in the population, contributes to variations in disease burden from year to year, which makes it hard to estimate the annual number of deaths or economic impact. Based on published literature (Dawood, 2010; Hayward, 2014; Ortiz, 2014; Thompson 2003), mainly from the USA and extrapolated to an EU/EEA population of approximately 512 million, the burden of seasonal influenza has been estimated (Figure 1). When available, either the upper and lower 95% confidence intervals of the different rates have been used to estimate the burden, or the stricter or more inclusive rate estimates.

There are a number of other estimates of excess deaths from European countries (Gran et al., 2010; Nogueira et al., 2009; Zucs et al., 2005).

Overall, estimates of influenza morbidity and mortality should be interpreted with caution. Read more in Influenza-related deaths - available methods for estimating numbers and detecting patterns for seasonal and pandemic influenza in Europe (Nicoll et al., 2012).

Transmission

Influenza spreads predominantly via the droplet and contact routes when people cough and sneeze, and by indirect spread through respiratory secretions on hands, tissues, etc. If the infected person doesn’t cover his or her mouth and nose people within a range of two meters can be infected. There is also some evidence that infectious aerosols may play a role in influenza transmission.

Among viruses that infect humans influenza is moderately infectious. On average an infectious person will infect less than two non-immune people. However, immunity to influenza viruses and vaccines wane over time and a large part of the population is susceptible each season.

The incubation time for seasonal influenza is on average two days, but ranges from one to four days.

In most cases, virus is found in specimens from nose and throat from one day before symptom onset to four to five days after onset. However, the level of virus shedding before symptoms start is lower than for a few days after. Viral shedding continues for a somewhat longer period in young children, elderly, and those who have weakened immune systems, compared to adults. Moreover, some people become infected, shed virus, yet are subclinical or asymptomatic cases - their role in transmission is not conclusively determined.

Overall, it is hard to control seasonal influenza. Some of the main underlying reasons for this are: imperfect vaccine effectiveness, influenza cases do not always seek healthcare, and delayed and rare use of antiviral treatment.

Diagnostics

Routine laboratory diagnostics for influenza are usually performed by detecting the virus antigen or genome in specimens from the respiratory tract. Sampling can e.g. consist of swabbing the nose and nasal cavity.

The tests performed in laboratories include RT-PCR, enzyme-linked immunoassay, immunofluorescence, and virus culture. Except for virus culture these results can be available within approximately 1-2 days, and can help adjust the treatment.

There are also rapid point of care tests (quick test) that require less time. However these tests generally have a low sensitivity but high specificity, and do not allow subtype determination.

It is important that specimens are collected as early as possible after symptom onset. However, when flu is widespread in the community, the diagnosis is often presumed without laboratory testing, by simply identifying patients with typical symptoms of influenza-like illness (ILI).

Serology usually plays no role in routine clinical diagnosis because subsequent blood samples are required to identify an increase in the serum level of influenza-specific antibodies.

Apart from assisting in diagnosing the patient, the collected influenza virus specimens also provide material for characterization of viruses and contribute to seasonal vaccine development. This virological surveillance in the EU is of the utmost importance and contributes to the WHO Global Influenza Surveillance and Response System (GISRS) that monitors the evolution of influenza viruses. These data contribute to the bi-annual WHO expert meetings where the recommendations of the influenza vaccine composition for the next season are formulated.

Case management and treatment

Symptomatic treatment

Most simple seasonal influenza cases are managed symptomatically and are advised bedrest at home to minimize the risk for infecting others in the community. Treatment focuses on reducing fever and relieving the symptoms. The diagnosis can be confirmed by taking specimens for laboratory analysis. It is considered important that patients monitor themselves to detect if their condition deteriorates and they require medical intervention.

Disease specific treatment and prophylaxis - antivirals

Although vaccination is the preferred option for preventing influenza, antivirals can be useful when the vaccine fails or is unavailable, for example, due to: antigenic mismatch with circulating virus, waning immunity in elderly, patient being immunocompromised, the vaccine not yet available, or during an outbreak of an emerging influenza strain or pandemic.

Neuraminidase inhibitors, oral oseltamivir and inhaled zanamivir, are useful for treatment and prophylactic use. Since 1999 inhaled zanamivir is authorised in all EU/EEA Member States except Cyprus, and since 2002 oral oseltamivir is authorised in all EU Member States.

The use of these drugs is very variable between European countries (Kramarz et al., 2009), as are the policies.

For the best clinical benefit, treatment with antivirals should be given early in the infection, within 48 hours, (the earlier the better). However, at least one observational study of A(H1N1)pdm09 found improved survival in the severely ill when antiviral treatment was provided within five days of symptom onset (Louie, 2012).

Resistance to antivirals

The early antivirals, adamantane compounds (amantadine and rimantadine), act as M2 inhibitors and are active against influenza A. But, since 2009 the majority of the circulating influenza A viruses are resistant to the adamantane compounds. Due to the high resistance (>99%) adamantanes are no longer recommended.

Resistance to neuraminidase inhibitors was rare in seasonal influenza until the emergence of resistant seasonal A(H1N1) viruses in 2007-2008 (Moscona, 2005; Meijer, 2009). By the end of 2008-2009 a majority of seasonal influenza A(H1N1) exhibited oseltamivir resistance. However, in 2009-2010, when the most recent influenza pandemic took place,, A(H1N1)pdm09 replaced A(H1N1). For A(H1N1)pdm09 oseltamivir resistance has so far only been detected at very low levels in Europe.

The level of antiviral resistance is closely followed by public health authorities. Summary information on antiviral resistance from influenza viruses in Europe is published in the weekly influenza update Flu News Europe.

Public health control measures

Personal protective measures

Apart from vaccination and antiviral treatment the public health management includes personal protective measures:

Regular hand washing with proper drying of the hands. Hands should be washed thoroughly with soap and water, and dried. For at least 40-60 seconds each time, especially after coughing or sneezing. Alcohol-based hand sanitisers reduce the amount of influenza virus on contaminated hands. When hand-washing is not possible, alcohol-based hand sanitisers are an option.

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, feverish and having other symptoms of influenza.

It is thought that all of these measures may reduce the risk of transmission of influenza though in fact the evidence base is weak. Expert opinion is supportive (Jefferson, 2008) but there have been few randomised trials with laboratory-confirmed influenza as end points (Cowling et al., 2009; MacIntyre et al., 2009).

Other measures include:

Avoiding close contact with sick people, e.g. by maintaining a distance of at least one meter from someone with symptoms of influenza, and avoiding crowded situations. When distance cannot be maintained, reducing the time of close contact with people who might be ill may be an option.

Avoiding touching one’s eyes, nose or mouth. Viruses may be spread when a person touches something that is contaminated with the virus and then touches his or her eyes, nose, or mouth.

There is some evidence supporting that surgical masks worn by ill people may reduce infections among close contacts when influenza is circulating.

Seasonal influenza vaccination

Vaccination is the most effective form of influenza prevention.

Antibodies to one type or subtype of influenza do not necessarily protect against other influenza virus types or subtypes (so called cross protection). Equally, cross-immunity following infection or vaccination against an influenza strain does not protect completely against subsequent variants of the same type or subtype. Moreover, immunity from vaccination wanes over time so annual vaccination is necessary for the vaccine to protect against influenza.

Injected inactivated influenza vaccines are most commonly used throughout the world. In 2011, a live attenuated influenza vaccine was also approved in the EU for children and adolescents.

The European seasonal influenza vaccination approach is generally to reduce the risk of people at greater risk of complications when infected.

In 2003 The World Health Assembly, which includes all EU/EEA countries, lent its support to targets for vaccination uptake in the elderly of 50% by 2006 and 75% by 2010. Moreover, an EU target was set by the Health Council of all Health Ministers of 75% vaccination coverage by 2014/15 in the older age groups, and if possible extended to people with chronic conditions.

Influenza risk groups are people who are more likely than others develop complications should they be infected. WHO recommends seasonal influenza vaccination for the following risk groups: pregnant women, children aged 6-59 months, the elderly, and individuals with chronic medical conditions. WHO also recommends vaccination of healthcare workers. Influenza vaccine is not licensed for children less than 6 months old.

Antivirals

Pre-exposure prophylaxis with influenza antivirals can be prescribed for longer or shorter time periods when an exposure is expected, for example in healthcare settings.

Post-exposure prophylaxis with influenza antivirals, for example for an at-risk unvaccinated person, is dependent on timely prescription given that the incubation period is 1-4 days. It is usually not prescribed for more than 10 days.

Prescription of prophylaxis depends on several factors e.g. individual factors, type of exposure, and risk associated with the exposure.

References

Cowling B, Chan K-H, Fang VJ, Cheun CYK, Fung ROP, Wai W. et al. Facemasks and hand hygiene to prevent influenza transmission in households: a cluster randomized trial Annals of Internal medicine 2009; 151: 437-446.

Cowling BJ, Fung ROP, Cheng CKY, Fang VJ, Chan KH, et al. (2008) Preliminary Findings of a Randomized Trial of Non-Pharmaceutical Interventions to Prevent Influenza Transmission in Households. PLoS ONE 3(5): e2101.

Dawood FS1, Fiore A, Kamimoto L, et al. Burden of seasonal influenza hospitalization in children, United States, 2003 to 2008. J Pediatr. 2010;157(5):808-14.

Dodds L, McNeil SA, Fell DB, et al. Impact of influenza exposure on rates of hospital admissions and physician visits because of respiratory illness among pregnant women. CMAJ. 2007;176(4):463-8.

Ducatez MF, Pelletier C, Meyer G. Influenza D virus in cattle, France, 2011-2014. Emerg Infect Dis. 2015;21(2):368-71.

Gran JM, Iversen B, Hungnes O, et al. Estimating influenza-related excess mortality and reproduction numbers for seasonal influenza in Norway, 1975–2004; Epidemiol Infect. 2010; 138(11):1559-68.

Hayward AC, Fragaszy EB, Bermingham A, et al. Comparative community burden and severity of seasonal and pandemic influenza: results of the Flu Watch cohort study. Lancet Respir Med. 2014;2(6):445-54.

Jefferson T, et al. Physical interventions to interrupt or reduce the spread of respiratory viruses: systematic review. BMJ 2008;336:77-80.

Kilbourne E. Influenza pandemics of the 20th century. Emerg Infect Dis; 2006.

Killingley B, Nguyen-Van-Tam J. Routes of influenza transmission. Influenza Other Respir Viruses. 2013;7 Suppl 2:42-51.

Kramarz P (2009), Monnet D, Nicoll A, Yilmaz C, Ciancio B. Use of oseltamivir in 12 European countries between 2002 and 2007 – lack of association with the appearance of oseltamivir-resistant influenza A(H1N1) viruses. Euro Surveill. 2009 Feb 5;14(5). pii: 19112.

Louie JK, Yang S, Acosta M, et al. Treatment with neuraminidase inhibitors for critically ill patients with influenza A (H1N1)pdm09. Clin Infect Dis. 2012;55(9):1198-204.

MacIntyre CR, Epid MA, Cauchemez S, Dwyer DE, Seale H, Cheung P, et al. Face mask use and control of respiratory virus transmission in households. Emerg Infect Dis. 2009. Available from http://www.cdc.gov/EID/content/15/2/233.htm

Meijer A, Lackenby A, Hungnes O, Lina B, van der Werf S, Schweiger B, et al. Oseltamivir-resistant influenza A (H1N1) virus, Europe, 2007–08 season. Emerg Infect Dis. 2009 April.

Moscona A (2005) Oseltamivir resistance – disabling our influenza defences. NEJM 2005; 353:2633-2636.

Nicoll A, Ciancio BC, Lopez Chavarrias V, Mølbak K, Pebody R, Pedzinski B, et al. Influenza-related deaths – available methods for estimating numbers and detecting patterns for seasonal and pandemic influenza in Europe. Euro Surveill. 2012; 17(18):pii: 20162.

Nogueira PJ, Nunes B, Machado A, Rodrigues E, Gomez V, Sousa L, et al. Early estimates of the excess mortality associated with the 2008-9 influenza season in Portugal. Euro Surveill. 2009 May 7;14(18).

Ortiz JR, Neuzil KM, Shay DK, et al. The burden of influenza-associated critical illness hospitalizations. Crit Care Med. 2014;42(11):2325-32.

Paget WJ, Marquet R, Meijer A, van der Velden J. Influenza activity in Europe during eight seasons (1999-2007): an evaluation of the indicators used to measure activity and an assessment of the timing, length and spread across Europe. BMC Infectious Diseases. 2007;7(1):141.

Thompson WW, Shay DK, Weintraub E, et al. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA. 2003;289(2):179-86.Webster RG, Monto AS, Braciale TJ, Lamb RA (editors). Textbook of Influenza. 2nd ed. Chichester: John Wiley & Sons Ltd; 2013.

Zhou H, Thompson WW, Viboud CG, et al. Hospitalizations associated with influenza and respiratory syncytial virus in the United States, 1993-2008. Clin Infect Dis. 2012;54(10):1427-36.

Zucs P, Buchholz U, Haas W, Uphoff H. Influenza-associated excess mortality in Germany, 1985-2001. Emerg Themes Epidemiol. 2005 Jun 21;2:6.