Factsheet about seasonal influenza

Seasonal influenza is a preventable infectious disease, mainly involving respiratory symptoms. Caused by the influenza virus which is moderately infectious, influenza is predominantly spread via droplets and contacts, or indirectly via respiratory secretions on hands, tissues, etc. Aerosol transmission can also play a part in spread of the virus (Killingley, 2013).

Each year, seasonal influenza is responsible for up to 50 million symptomatic cases in the European Union/European Economic Area (EU/EEA), and 15 000–70 000 European citizens die of causes associated with influenza. Despite the usually short duration of illness, the annual economic and healthcare burden of influenza is substantial.

In the northern hemisphere, 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.

Since a number of other viruses and bacteria cause similar symptoms, a considerable amount of influenza-like illness (ILI) is not actually caused by influenza. Influenza pandemics can also occur at irregular intervals.

The pathogen

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

Influenza viruses are usually classified as three types: A, B or C, according to differences in antigenic and biological properties. There is also evidence of a fourth type D, but it does not seem to affect humans (Ducatez, 2015).

• Influenza A viruses are 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 sub-types 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, the predominant virus types causing disease in humans, are the focus of this factsheet.

At any given time there may be a mix of influenza viruses circulating in the human population. Since the most recent influenza pandemic in 2009, seasonal influenza has consisted of variable mixes of influenza A(H3N2), A(H1N1)pdm09, which 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 genomes consist 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 pigs, and from birds to humans. In birds H1−H16 and N1−N9 have been detected. All the influenza A viruses that have been detected in mammals or poultry originated from wild aquatic birds. In addition, H17−18 and N10−11 have been detected in bats.

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

In many languages people use the term ‘flu’ for mild respiratory diseases caused by other infectious agents, rather than exclusively for influenza virus.

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.

In addition to fever and respiratory symptoms, children may also present with gastrointestinal symptoms such as vomiting or diarrhoea.

Not all of those infected present all 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 while sore throat and runny nose may last longer. Coughing, fatigue, and malaise may continue for some weeks.

Severe influenza

In some cases the disease becomes more severe, either directly due to the influenza virus infection or as a result of a secondary, usually bacterial, infection (e.g. Streptococcus pneumoniae or Staphylococcus aureus). This commonly causes pneumonia, but may occasionally even result in death. Severe disease may also include myocarditis or encephalitis, which may be fatal. However, the initial influenza infection is often not recognised and the death 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, underlying diseases (e.g. cardiovascular disease) may also be exacerbated.

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

On average, the elderly are at 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. Children are at 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 certain 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 or physical handicap (e.g. cerebral palsy);
• conditions and treatments that suppress the immune function (e.g. chemotherapy).

Moreover, healthy pregnant women have been found to be at increased risk of hospitalisation 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 a few years. In some cases the pandemic strain replaces one of the previously circulating strains. During these years, seasonal epidemics can be more severe than during the years before the pandemic. However, this may not always be the case as it is dependent on the nature of the pandemic influenza virus, immunisation coverage and pre-existing immunity in the population.

Annual epidemics

In Europe, and the rest of the northern hemisphere, seasonal influenza generally occurs as regular annual epidemics during the winter, between November and April. These epidemics usually affect most countries for one or two months, lasting for about four months overall in Europe (Paget et al. 2007). Sporadic infections occur outside of the influenza season, though the incidence is very low during the European summer and infections are often the result of imported cases from equatorial areas (where transmission is more year-round) and the southern hemisphere where most infection occurs between June and October.

European influenza seasons have been recorded for several years and are continuously under ECDC surveillance. During the influenza surveillance season ECDC and the World Health Organization’s Regional Office for Europe (WHO Europe) publish weekly joint 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, depending on the dominating viruses and the level of population immunity.

Burden of influenza

The burden from seasonal influenza is two-fold. Firstly, there is the direct health impact caused by severe disease and deaths due to influenza. Secondly, there is the economic impact of the large number of mild-to-moderate cases resulting in time off work, losses to production and pressure and costs on health and social care services.

The characteristics of the circulating virus strain and immunity in the population contribute to variations in disease burden from year to year, which makes it hard to estimate the annual number of deaths or economic impact. Even though reliable global disease burden data have historically been absent, the Global Burden of Disease Study has estimated that 54.5 million lower respiratory tract infections (LRTIs) attributable to influenza occurred in 2017. A total of 8.2 million of these infections were severe and resulted in 145 000 (95% uncertainty interval: 99 000–200 000) deaths (GBD Influenza Collaborators, 2019). Using a less conservative method based on respiratory death, a global annual burden of ~ 290 000–650 000 influenza-associated respiratory deaths (4.0–8.8 per 100 000 individuals) has been calculated for the influenza seasons between 1999 and 2015 (Iuliano et al. 2018).

There are a number of other estimates of excess deaths from European countries (Gran et al. 201; Nogueira et al. 2009; Zucs et al. 2005). However, 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 is predominantly spread via droplets and contact when people cough or sneeze, and indirectly via respiratory secretions on hands, tissues, etc. If the infected person does not cover their mouth and nose when coughing or sneezing, those within a range of one metre may be infected. There is also some evidence that infectious aerosols may play a role in influenza transmission.

The influenza virus is moderately infectious and, 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.

On average, the incubation period for seasonal influenza is two days, but ranges from one to four days.

In most cases, the virus is found in specimens taken from the nose and throat between one day before symptom onset and five-to-seven days after onset. The level of virus shedding before symptoms start is lower than after symptom onset. Viral shedding continues for a somewhat longer period in young children, the elderly, and those who have weakened immune systems, compared to healthy adults. However, the role in transmission of those who become infected and shed the virus, but are sub-clinical or asymptomatic has not yet been determined conclusively.

Overall, it is hard to control seasonal influenza. Some of the main underlying reasons for this are imperfect vaccine effectiveness; individuals with influenza not always seeking healthcare and delayed/rare use of antiviral treatments.

Diagnostics

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

The tests performed in laboratories include RT-PCR, enzyme-linked immunoassay, immunofluorescence, and virus culture. With the exception of virus culture, the results can be available within approximately 1−2 days and can help adjust the treatment. There are also rapid point-of-care tests (rapid tests) that require less time for the results to be processed.

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.

During the recent COVID19 pandemic the possibility of testing for flu as well as for other respiratory illnesses, including COVID-19, at the same time was not excluded. Since some of the symptoms of flu and COVID-19 are similar, it is hard to tell the difference between them based on symptoms alone. Diagnostic testing can help determine whether a patient is sick with flu, COVID-19, or another respiratory infection. Therefore, there is a diagnostic multiplex RT-PCR test that can detect seasonal flu type A and B viruses as well as SARS-CoV-2, the virus that causes COVID-19.

In addition to assisting with diagnosis, the influenza virus specimens collected can also provide material for characterisation 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. The data contribute to the bi-annual WHO expert meetings where the recommendations for the next season’s influenza vaccine composition are formulated.

Case management and treatment

Symptomatic treatment

Most simple seasonal influenza cases are managed symptomatically and are advised to stay at home and rest to minimise the risk of 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 whether 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. This could be due to antigenic mismatch with circulating virus, waning immunity in the elderly, a patient being immunocompromised, the vaccine not yet being available, or during an outbreak of an emerging influenza strain or pandemic.

There are four antiviral drugs approved by the European Medicines Agency (EMA) available in the EU Member States to treat influenza: oseltamivir, zanamivir, peramivir and baloxavir. For the best clinical benefit, treatment with antivirals should be given early in the infection, within 48 hours, (the earlier the better), to reduce the fever and flu-like symptoms. Antivirals may also reduce the risk of complications such as ear infections in children, respiratory complications requiring antibiotics, and hospitalisation in adults. 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. However, since 2009 the majority of the circulating influenza A viruses have been 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 occurred, A(H1N1)pdm09 replaced A(H1N1). For A(H1N1)pdm09 oseltamivir resistance has so far only been detected at very low levels in Europe. A particular genetic change known as the ‘H275Y’ mutation in the neuraminidase protein is the mutation that is known to confer oseltamivir resistance in A(H1N1) pdm09 influenza viruses. Influenza viruses that have H275Y mutation show highly reduced inhibition when using oseltamivir in laboratory assays (Wang et al. 2010). The H275Y mutation also reduces the effectiveness of peramivir to treat infections caused by influenza viruses carrying this mutation.

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, public health management includes personal protective measures such as those set out below.

• Regular hand washing and proper drying of the hands. Hands should be washed thoroughly with soap and water for at least 40−60 seconds and dried, 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 and cough etiquette – covering the mouth and nose when coughing or sneezing, using tissues and disposing of them correctly, followed by proper hand hygiene after contact with respiratory secretions. Cough etiquette includes turning the head and covering the mouth when coughing and coughing/sneezing into a sleeve or elbow, rather than a hand.
• Those who feel unwell, feverish or have other symptoms of influenza should self-isolate as soon as possible. Persons with influenza-like symptoms should remain at home at least 24 hours after their fever has gone and their cough is beginning to clear up in order to avoid exposing other members of the public.

Other measures include:

• Avoiding close contact with sick people (e.g. by maintaining a distance of at least one metre 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.

The recommendations for mask wearing have changed substantially during the COVID-19 pandemic, as this has been one of the most important measures for containing and reducing ongoing community transmission. A great deal of evidence has emerged since the beginning of the pandemic regarding the effectiveness of masks in reducing the spread of SARS-CoV-2. Since influenza follows the same transmission route as SARS-CoV-2, ECDC recommends wearing a mask in confined public spaces, such as shops, supermarkets, transportation hubs and when using public transport. Wearing a face mask should be considered in crowded outdoor settings where physical distancing is not possible. Moreover, face masks should be considered during the period when influenza and SARS-CoV-2 are co-circulating, especially for vulnerable categories, such as the elderly or those with underlying medical conditions.

A face mask should be used correctly to achieve the desired effect. Incorrect usage may increase instead of decrease the spread of respiratory infections. If face masks are worn and disposed of properly, they will help prevent exposure and reduce the risk of infection, however they should be used along with other preventive measures, such as avoiding close contact and maintaining good hand hygiene.

Seasonal influenza vaccination

Vaccination is the most effective form of influenza prevention. For many years, flu vaccines were designed to protect against three different flu viruses: an influenza A(H1N1) virus, an influenza A(H3N2) virus and one influenza B virus, even though there are two different lineages of B viruses that circulate during most seasons. A B virus from the second lineage was added later to give broader protection against circulating flu viruses.

Antibodies to one type or sub-type of influenza do not necessarily protect against other influenza virus types or subtypes (so called cross-protection). Similarly, 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 the most common type of vaccine throughout the world. In 2011, a live attenuated influenza vaccine was also approved in the EU for children and adolescents.

The main objective of seasonal influenza vaccination is to reduce the risk for those who would be liable to complications if they were to become infected. 

In 2003, the World Health Assembly, which includes all EU/EEA countries, recommended targeting 50% of the elderly for vaccination uptake by 2006 and 75% by 2010. Moreover, an EU target was set by the Council of all EU ministers of health of achieving 75% vaccination coverage by 2014−15 in the older age groups, and if possible extending this to people with chronic conditions.

Influenza risk groups are those who would be more likely to develop complications should they become 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 licenced for children aged under six months.

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 (e.g. for an at-risk unvaccinated person) is dependent on timely prescription, given that the incubation period is 1−4 days. Antivirals are usually not prescribed for more than 10 days.

Prescription of prophylaxis depends on several factors, such as the type of patient, type of exposure, and risk associated with the exposure.

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