Influenza

Influenza, commonly known as the flu, is an infectious disease caused by influenza viruses. It can cause symptoms like fever, runny nose, sore throat, muscle pain, headache, coughing, and fatigue. These symptoms usually start one to four days after someone is exposed to the virus and can last for about two to eight days. In children, diarrhea and vomiting may also happen. Sometimes, the flu can lead to more serious problems like pneumonia, either from the virus itself or from a bacterial infection.

There are four types of influenza viruses: A, B, C, and D. Aquatic birds are the main source of influenza A virus, which can also infect many mammals, including humans and pigs. Influenza B virus and influenza C virus mainly affect humans, with influenza B causing seasonal outbreaks and influenza C leading to mild illness in children. Influenza D virus is found in cattle and pigs but does not usually make humans sick. The virus spreads mainly through respiratory droplets when an infected person coughs or sneezes, but it can also spread through aerosols and touching surfaces contaminated with the virus.

To help stop the spread of the flu, it’s important to practice frequent hand washing and to cover your mouth and nose when coughing or sneezing. Wearing a mask can also help. Getting an annual vaccination is one of the best ways to protect against the flu. Because flu viruses change often, especially influenza A virus, vaccines are updated each year to match the strains that are circulating. While most healthy people recover from the flu on their own, it can be serious for young children, older adults, and those with health problems. Every year, between five to 15 percent of people around the world get the flu, leading to millions of severe cases and many deaths.

Signs and symptoms

The signs and symptoms of the flu are like a cold, but usually worse and less likely to include a runny nose. Symptoms usually start one to four days after someone is exposed to the virus, most often within one to two days. Many people may not show any symptoms at all.

Symptoms often come on quickly and can include fever, chills, headaches, muscle pain, feeling tired, loss of appetite, and confusion. Respiratory symptoms such as a dry cough, sore or dry throat, hoarse voice, and a stuffy or runny nose are also common. Coughing is the most frequent symptom. In children, stomach-related symptoms like nausea, vomiting, diarrhea, and stomach pain can also happen. Flu symptoms usually last from two to eight days. Some people may feel unwell for longer, similar to how some feel after having COVID-19.

Virology

Types of virus

Influenza viruses are of four main types, each belonging to its own group. These four types make up four of the seven groups in the family Orthomyxoviridae. They are:

• Influenza A virus, group Alphainfluenzavirus
• Influenza B virus, group Betainfluenzavirus
• Influenza C virus, group Gammainfluenzavirus
• Influenza D virus, group Deltainfluenzavirus

Influenza A virus causes most serious cases of illness, as well as seasonal outbreaks and occasional worldwide epidemics. It affects people of all ages but is especially hard on older adults, young children, and those with long-term health problems. Birds, especially water birds like ducks and geese, are the main source of influenza A virus, though the virus can also spread among mammals such as pigs, horses, and sea animals.

Subtypes of Influenza A are defined by the combination of two viral proteins called haemagglutinin (H) and neuraminidase (N) on the viral envelope; for example, “H1N1” is an IAV subtype that has a type-1 hemagglutinin (H) protein and a type-1 neuraminidase (N) protein. Nearly all possible combinations of H (1 through 16) and N (1 through 11) have been found in wild birds. Influenza A virus subtypes that affect humans are H1N1 and H3N2.

Influenza B virus mainly infects humans but has also been found in seals, horses, dogs, and pigs. Influenza B virus does not have subtypes like influenza A virus but has two different groups, called the B/Victoria/2/1987-like and B/Yamagata/16/1988-like groups. Both groups circulate among humans, mostly affecting children. However, the B/Yamagata group may have disappeared in 2020/2021 because of COVID-19 pandemic measures. Influenza B viruses cause seasonal outbreaks together with influenza A viruses but have never been linked to a worldwide epidemic.

Influenza C virus, like influenza B virus, is found mostly in humans, though it has also been seen in pigs, wild dogs, dromedary camels, cattle, and dogs. Influenza C virus infection usually affects children and often causes mild, cold-like symptoms, though more serious symptoms such as stomach issues and lung infection can occur. Unlike influenza A and B viruses, influenza C virus has not been a major focus for developing medicines, vaccines, and other prevention methods. Influenza C virus is divided into six genetic groups.

Influenza D virus has been found in pigs and cattle, with cattle being the natural source. Infection has also been seen in humans, horses, dromedary camels, and small hoofed animals such as goats and sheep. Influenza D virus is distant from influenza C virus. While cattle workers have sometimes shown signs of past infection with influenza D virus, it is not known to cause illness in humans. Influenza C virus and influenza D virus change less over time than influenza A virus and influenza B virus. Because of this stability, relatively few new groups appear.

Influenza virus nomenclature

Every year, millions of influenza virus samples are studied to track changes in the virus’ characteristics and to help develop vaccines.

To clearly describe a specific sample of virus, scientists use an internationally agreed-upon naming system for influenza viruses. This system includes details such as the type of animal the virus was found in, the location, and the year of discovery. For example – "A/chicken/Nakorn-Patom/Thailand/CU-K2/04(H5N1)":

• "A" shows the type of influenza virus (A, B, C or D).
• "chicken" is the animal species where the sample was found (note: samples from humans do not include this and are identified as human samples by default)
• "Nakorn-Patom/Thailand" is where this specific virus was discovered
• "CU-K2" is the laboratory number that identifies it from other influenza viruses found in the same place and year
• "04" is the year of discovery 2004
• "H5" shows the fifth known type of the protein hemagglutinin.
• "N1" shows the first known type of the protein neuraminidase.

The naming system for influenza B, C, and D viruses, which change less, is simpler. Examples are B/Santiago/29615/2020 and C/Minnesota/10/2015.

Genome and structure

Influenza viruses have a single-stranded RNA genome that is divided into pieces. The genome’s negative sense means it can be used as a template to make messenger RNA (mRNA). Influenza A virus and influenza B virus have eight genome pieces that make 10 main proteins. Influenza C virus and influenza D virus have seven genome pieces that make nine main proteins.

Three pieces make three parts of an RNA-dependent RNA polymerase (RdRp) complex: PB1, a transcriptase, PB2, which recognizes 5' caps, and PA (P3 for influenza C virus and influenza D virus), an endonuclease. The M1 matrix protein and M2 proton channel share a piece, as do the non-structural protein (NS1) and the nuclear export protein (NEP). For influenza A virus and influenza B virus, hemagglutinin (HA) and neuraminidase (NA) are each made from one piece, while influenza C virus and influenza D virus make a hemagglutinin-esterase fusion (HEF) protein from one piece that combines the jobs of HA and NA. The last genome piece makes the viral nucleoprotein (NP). Influenza viruses also make extra proteins, such as PB1-F2 and PA-X, through different open reading frames and these help in avoiding the host’s defenses, causing illness, and making the virus harmful.

The virus particle, called a virion, can be different shapes. Clinical samples are usually mixed shapes, while lab-grown strains are often round. Thread-like virions are about 250 nanometers (nm) by 80 nm, rod-shaped ones 120–250 by 95 nm, and round ones 120 nm wide.

The center of the virion contains one copy of each genome piece linked to NP nucleoproteins in separate ribonucleoprotein (RNP) complexes for each piece. There is one copy of the RdRp, with all its parts, linked to each RNP. The genetic material is wrapped by a layer of M1 matrix protein which gives structure to the outer layer, the viral envelope. The envelope is a lipid bilayer membrane with HA and NA (or HEF) proteins sticking out. HA and HEF proteins have a distinct “head” and “stem” shape. M2 proteins form proton channels through the viral envelope that help the virus enter and leave cells. Influenza B viruses have a surface protein called NB in the envelope, but its job is unknown.

Life cycle

The virus’s life cycle starts by attaching to a target cell. This attachment is done by the virus’s HA proteins on the envelope’s surface, which stick to cells that have sialic acid receptors. For some N1 types with the “G147R” change and N2 types, the NA protein can also help the virus enter. Before attaching, NA proteins help by breaking down mucus, clearing the way to target cells. After attaching, the virus is taken inside the cell by an endosome. The endosome becomes acidic, which changes the HA protein shape, allowing the viral envelope to merge with the endosomal membrane. At the same time, hydrogen ions enter the virion through M2 channels, breaking apart internal protein links to release RNPs into the cell’s cytosol. The M1 protein shell around RNPs breaks down, fully releasing RNPs into the cytosol.

RNPs are then moved into the nucleus with help from viral signals. There, the virus’s RNA polymerase transcribes mRNA using the genome’s negative-sense strand as a guide. The polymerase takes 5’ caps from cell RNA to start mRNA making and the mRNA ends are polyadenylated. Once viral mRNA is made, it leaves the nucleus and is translated by cell ribosomes to make viral proteins. RdRp also makes matching positive-sense strands of the genome in a matching RNP complex, which are then used to make copies of the negative-sense genome. During these steps, RdRps from bird influenza viruses work best at higher temperatures than those from human influenza viruses.

Newly made viral polymerase parts and NP proteins are moved to the nucleus to speed up viral copying and make RNPs. HA, NA, and M2 proteins move with M1 and NEP proteins to the cell membrane through the Golgi apparatus and are placed into the cell’s membrane. Viral non-structural proteins such as NS1, PB1-F2, and PA-X control cell processes to stop anti-virus responses. PB1-F2 also works with PB1 to keep polymerases in the nucleus longer. M1 and NEP proteins gather in the nucleus later in infection, link to viral RNPs and help them leave the nucleus to the cell’s interior where they move to the cell membrane with help from reused endosomes and are grouped into genome pieces.

New viruses leave the cell by budding from the cell membrane, starting with M1 proteins building up on the cell side of the membrane. The viral genome is wrapped in a viral envelope made from parts of the cell membrane that have HA, NA, and M2 proteins. At the end of budding, HA proteins stick to cell surface sialic acid until they are cut off by the sialidase action of NA proteins. The virion is then freed from the cell. The sialidase action of NA also cuts sialic acid off the virus’s surface, helping new viruses not to clump together near the cell and improving infection ability. Like other parts of influenza copying, NA work is best at certain temperatures and pH levels. In the end, large amounts of viral RNA in the cell cause apoptosis (programmed cell death), started by cell factors to limit virus copying.

Antigenic drift and shift

Two main ways influenza viruses change are antigenic drift and antigenic shift. Antigenic drift is when the virus’s antigens change because of slow changes over time in the antigen’s (HA or NA) gene. This can happen because of evolutionary pressure from the host’s immune system. Antigenic drift is common in the HA protein, where just a few amino acid changes in the head part can count as antigenic drift. This leads to new strains that can avoid existing antibody protection. Antigenic drift happens in all influenza types but is slower in B than in A and slowest in C and D. Antigenic drift is a main reason for seasonal influenza, and it means flu vaccines need to be updated every year. HA is the main part of inactivated vaccines, so monitoring looks at antigenic drift of this antigen in spreading strains. Antigenic change in human influenza viruses seems faster than in pig and horse viruses. In wild birds, within-type antigenic variation seems limited but has been seen in poultry.

Antigenic shift is a sudden, big change in the virus’s antigen, usually HA. During antigenic shift, differently antigened strains that infect the same cell can mix genome pieces with each other, making hybrid offspring. Since all influenza viruses have pieces of genome, they can all mix. Antigenic shift mostly happens among influenza A viruses. Mixing is very common in bird influenza viruses, creating many types in birds, but is rare in human, horse, and dog types. Pigs, bats, and quails have receptors for both human and bird influenza A viruses, so they can be “mixing bowls” for reassortment. If an animal strain mixes with a human strain, a new strain can appear that can spread human-to-human. This has caused pandemics, but only a few, so it is hard to guess when the next will happen. The Global Influenza Surveillance and Response System of the World Health Organization (GISRS) tests millions of samples every year to watch for the spread and change of influenza viruses.

Mechanism

Influenza, or the flu, spreads when infected people breathe, talk, cough, or sneeze. These actions release tiny drops and particles into the air that contain the virus. Healthy people can catch the flu by touching these drops or particles, especially if they then touch their face.

The flu usually spreads from one day before symptoms start until about a week after. Children are especially good at spreading the virus. Factors like cold weather, dry air, and crowded spaces can make the flu spread more easily.

Prevention

Further information: Prevention of influenza

Vaccination

Getting a flu shot every year is the best way to stay safe from the flu and its problems, especially for those who are more at risk. Flu vaccines work against certain types of the virus, and there are two main kinds: one with dead viruses and another with weakened viruses that are sprayed up the nose. Most flu shots are given with a needle, while the nasal spray is for older children and adults.

Vaccines for the flu change depending on where you live. Some places suggest everyone over a certain age get vaccinated, while others focus on those more likely to have serious problems from the flu. Very young babies can't get the vaccine, but if their mothers get the shot while pregnant, it helps protect the baby. Flu vaccines help stop the virus from changing too much.

Flu vaccines work best when they match the virus types that are going around. Making these vaccines takes time, usually six to eight months, because they are grown in special chicken eggs. Different places may choose which virus types to include based on what they see is spreading. There are also other ways to make vaccines, such as using special cells or a method that uses viruses to help make the vaccine.

Antiviral chemoprophylaxis

The flu can sometimes be stopped or made less severe by using special medicines after someone has been exposed to the virus. Two of these medicines, oseltamivir and zanamivir, can help people who are at higher risk or can't get the vaccine. These medicines need to be taken very soon after exposure to work best.

Infection control

The flu spreads mainly in a few ways: when someone with the flu sneezes or coughs into another person's eyes, nose, or mouth; when tiny drops in the air are breathed in; or by touching contaminated surfaces and then touching the face. Good health habits are very important to stop the spread of the flu. These include washing hands often, covering coughs and sneezes, staying away from sick people, and staying home when sick. While face masks can help when caring for someone with the flu, their use for everyone is not clearly proven to work.

Since the flu can spread through the air and by touching surfaces, cleaning those surfaces can help. Using alcohol or special cleaning products can kill the flu virus. In hospitals, stronger cleaners are used, but at home, simple cleaning with bleach can work.

Because flu viruses can also live in animals like birds and pigs, keeping these animals healthy and separate from people is important. This includes cleaning farms, keeping animals away from water and other animals, and sometimes vaccinating them. Closing markets where live birds are sold has helped stop the spread of some dangerous flu types in the past. If a new flu virus appears, quick action like cleaning, separating sick animals, and sometimes vaccinating them can help stop it from spreading further.

Diagnosis

When someone has the flu, doctors can figure out if it’s really the flu by looking at their symptoms and doing tests. If a person has severe symptoms like pneumonia or is very sick, doctors will want to test to confirm it’s the flu.

There are different ways to test for the flu. One way is to take a sample from the nose or throat. These samples can show if the flu virus is present. Some tests give results very quickly, while others take a few hours. The quickest tests are easy to use and cheap, but they might not tell the exact type of flu virus. More detailed tests can tell the exact type of flu and are used when it’s needed.

Management

Main article: Treatment of influenza

When someone has a mild or moderate case of the flu, doctors suggest using medicines like acetaminophen and ibuprofen to help with fever, drinking plenty of fluids to stay hydrated, and getting plenty of rest. Cough drops and throat sprays can help with a sore throat. It's important not to drink alcohol or smoke while sick. Aspirin should not be given to children because it can cause a serious health problem called Reye syndrome. Corticosteroids are not usually recommended unless treating a serious condition like septic shock or a health problem such as chronic obstructive pulmonary disease or asthma that is getting worse, because they can sometimes make things worse.

If a bacterial infection happens after the flu, antibiotics might be needed.

Antivirals

Special medicines called antivirals are used to help people who are very sick with the flu, especially those whose bodies don’t fight infections well. These medicines work best when given within the first two days of feeling sick. They can still help later for people with weaker immune systems, more severe symptoms, or a higher chance of getting worse from the flu. Antivirals are also recommended for people in the hospital with suspected flu before test results come back and if symptoms are getting worse.

Most flu antivirals fall into two groups: neuraminidase (NA) inhibitors and M2 inhibitors. Baloxavir marboxil is another option that works against both flu A and flu B viruses.

NA inhibitors stop the flu virus from spreading. They include oseltamivir, which is taken as a pill and changed into its working form in the liver, and zanamivir, which is a powder breathed in through the nose. These medicines can help prevent complications, hospital stays, and serious outcomes, and they shorten the time people feel sick. Other NA inhibitors are laninamivir and peramivir, which can be used if someone can’t take oseltamivir.

The drugs amantadine and rimantadine used to block a part of the flu virus, but they don’t work well anymore because the virus has changed. Oseltamivir resistance is mostly seen in people taking the medicine, especially those with weaker immune systems and young children. Oseltamivir is usually the first choice for most people, but different medicines might be needed for those with weaker immune systems or certain types of flu. Resistance to zanamivir is rare, and resistance to peramivir and baloxavir marboxil is possible.

Prognosis

For most healthy people, the flu usually gets better on its own and is not dangerous. Symptoms often last from 2 to 8 days. The flu can make people miss work or school and may make older adults feel less able to do everyday tasks. Even after feeling better, some people might feel tired for several weeks.

The flu can sometimes lead to other health problems, especially in people who are more at risk, like older adults, very young children, pregnant women, or those with health conditions such as heart or lung problems. These problems can include infections in the sinuses, lungs, or ears, and in rare cases, serious conditions affecting the heart or muscles. People with weakened immune systems or certain health issues are more likely to have complications from the flu.

Epidemiology

Further information: Flu season and Flu pandemics

The flu, caused by influenza viruses, often appears in certain times of the year and can spread around the world. Most flu cases happen during flu seasons, mainly caused by two types of viruses: influenza A and influenza B. Children often get the flu more easily, but severe cases usually affect older people, very young children, and those with weaker immune systems. Every year, about 5–15% of people worldwide get the flu, leading to millions of serious illnesses and hundreds of thousands of deaths from breathing problems.

During flu seasons, around 80% of healthy adults with a fever and cough have the flu. About 30–40% of people hospitalized with the flu develop lung infections, and the flu is a leading cause of serious breathing problems in both adults and children. In children, the flu is one of the main reasons for severe breathing issues, along with another virus called respiratory syncytial virus. The flu can also cause ear infections in about 3–5% of children each year.

In places with cold winters, flu cases change from season to season. Factors like less sunlight, dry air, cold temperatures, and small changes in the virus help the flu spread more in winter. In the northern hemisphere, flu season is usually from October to May, especially between December and April. In the southern hemisphere, it’s from May to October, especially June to September. In warmer areas, flu can happen anytime during the year. Flu viruses often start spreading from places like Asia and then move around the world.

Two main flu viruses, influenza A and B, spread in similar patterns. Another type, influenza C, mostly affects children under two and most adults have already been exposed to it by adulthood. Outbreaks of new flu viruses can happen and spread quickly if people haven’t been exposed to them before, leading to pandemics that can cause many deaths. These pandemics are caused by big changes in animal flu viruses and usually start in one place before spreading worldwide. After a pandemic, the new virus often becomes a regular part of seasonal flu.

History

The first known outbreak of influenza might have happened around 6000 BC in China. Descriptions of similar illnesses appear in old Greek writings from the 5th century BC. Over the centuries, many big outbreaks happened in Europe and later spread to other parts of the world. One major outbreak began in 1510 in East Asia and moved to Africa and Europe.

As time went on, scientists learned more about influenza. In 1918, a very serious flu outbreak happened during World War I, called the Spanish flu. It affected many people worldwide. Later, scientists discovered the viruses that cause flu and developed vaccines to help prevent it.

Research continued, and in the 1940s, the first flu vaccine was made in the United States. Since then, new kinds of flu have appeared, and scientists keep working to understand and stop them. Big outbreaks still happen, like the 2009 swine flu that started in Mexico.

Etymology

The word influenza comes from an Italian word meaning 'influence'. People long ago thought the disease might be caused by stars or cold weather. Over time, the word came to mean a widespread sickness, and today we often just call it the "flu".

In animals

Birds

Birds, especially water birds like ducks and geese, are the main source of influenza A viruses. These viruses can cause serious illness in chickens and other birds. There are two types of bird flu: one that makes chickens very sick and might kill them, and another that causes only mild symptoms. Scientists classify these viruses by how they affect chickens and by looking at their structure.

When birds get very sick from the flu, they might show signs like being very tired, not eating, laying fewer eggs, or having swollen heads. Some birds can carry the virus without showing any signs at all and can spread it to other birds over long distances. This happened in 2005 when a strain called H5N1 spread from China to many countries through migratory birds.

Pigs

Influenza in pigs is similar to the flu in humans and happens all over the world. Pigs might not always show symptoms, but when they do, they can include fever, coughing, and trouble breathing. Pigs can spread the virus to each other and to humans, and sometimes human flu viruses can infect pigs too. This mixing can create new flu viruses, like the one that caused the 2009 flu pandemic.

Other animals

Flu viruses have been found in many animals besides birds and pigs, including horses, dogs, cats, and even some sea animals. Most of these viruses originally came from birds. In horses, the flu usually causes breathing problems. In dogs, a type of flu from horses can sometimes cause illness. Scientists are studying these viruses to understand how they spread and affect different animals.

Some flu viruses have also been found in cattle and seals, often after they eat infected birds. These viruses can change over time to infect mammals better. There are also other types of flu viruses, like influenza B, C, and D, which can infect pigs, dogs, and cattle, sometimes causing breathing problems. Researchers are working on vaccines to protect animals from these diseases.