Influenza, also called the “flu”, is a viral disease that affects humans and many animals. It most commonly causes a fever and respiratory problems. There are three groups of influenza viruses, called type A, B, or C. Influenza type A is the primary group affecting both humans and animals. Influenza A viruses also have many different subtypes. Most only infect a single species (e.g., birds or pigs), while other subtypes can affect more than one species (e.g., birds, pigs and humans). Influenza A viruses can undergo rapid genetic changes (antigenic shift) which then allow them to infect new species of animals.

FLU Symptoms

Flu is different from a cold, as it usually comes on suddenly. The most common symptoms include: high fever, runny nose, sore throat, muscle pains, headache, coughing, sneezing, and feeling tired. These symptoms typically begin two days after exposure to the virus and most last less than a week. The cough, however, may last for more than two weeks.  In children, there may be diarrhea and vomiting, but these are not common in adults. Diarrhea and vomiting occur more commonly in gastroenteritis, which is an unrelated disease and sometimes inaccurately referred to as "stomach flu" or the "24-hour flu".

Flu and the common cold are both respiratory illnesses but they are caused by different viruses. Because these two types of illnesses have similar symptoms, it can be difficult to tell the difference between them based on symptoms alone. In general, flu is worse than the common cold, and symptoms are more intense. Colds are usually milder than flu. People with colds are more likely to have a runny or stuffy nose. Colds generally do not result in serious health problems, such as pneumonia, bacterial infections, or hospitalizations. Flu can have very serious associated complications. Because colds and flu share many symptoms, it can be difficult (or even impossible) to tell the difference between them based on symptoms alone. Special tests that usually must be done within the first few days of illness can tell if a person has the flu. 

Spread

The flu viruses spread mainly by tiny droplets made when people with flu cough, sneeze or talk. These droplets can land in the mouths or noses of people who are nearby. Less often, a person might get flu by touching a surface or object that has flu virus on it and then touching their own mouth, nose or possibly their eyes.

Types 

There are four types of influenza viruses: A, B, C and D. Human influenza A and B viruses cause seasonal epidemics of disease almost every winter. The emergence of a new and very different influenza A virus to infect people can cause an influenza pandemic. Influenza type C infections generally cause a mild respiratory illness and are not thought to cause epidemics. Influenza D viruses primarily affect cattle and are not known to infect or cause illness in people.

Influenza A viruses are divided into subtypes based on two proteins on the surface of the virus: the hemagglutinin (H) and the neuraminidase (N). There are 18 different hemagglutinin subtypes and 11 different neuraminidase subtypes. (H1 through H18 and N1 through N11 respectively.)

Influenza A viruses can be further broken down into different strains. Current subtypes of influenza A viruses found in people are influenza A (H1N1) and influenza A (H3N2) viruses. In  2009, a new influenza A (H1N1) virus  emerged to cause illness in people. This virus was very different  from the human influenza A (H1N1) viruses circulating at that time. The new virus caused the first influenza pandemic in more than 40 years. That virus (often called “2009 H1N1”) has now replaced the H1N1 virus that was previously circulating in humans.

Influenza B viruses are not divided into subtypes, but can be further broken down into lineages and strains. Currently circulating influenza B viruses belong to one of two lineages: B/Yamagata and B/Victoria.

Classification of influenza virus

-  The antigenic type (e.g., A, B, C)

-  The host of origin (e.g., swine, equine, chicken, etc. For human-origin viruses, no host of origin designation is given.)

-  Geographical origin (e.g., Denver, Taiwan, etc.)

-  Strain number (e.g., 15, 7, etc.)

-  Year of isolation (e.g., 57, 2009, etc.)

 For influenza A viruses, the hemagglutinin and neuraminidase antigen description in parentheses (e.g., (H1N1), (H5N1) For example:

-  A/duck/Alberta/35/76 (H1N1) for a virus from duck origin

-  A/Perth/16/2009 (H3N2) for a virus from human origin

The influenza virus may result in seasonal influenza, pandemic influenza, and zoonotic or variant influenza.

Seasonal influenza

Seasonal influenza viruses circulate and cause disease in humans every year. In temperate climates, disease tends to occur seasonally in the winter months, spreading from person-to-person through sneezing, coughing, or touching contaminated surfaces. Seasonal influenza viruses can cause mild to severe illness and even death, particularly in some high-risk individuals. Persons at increased risk for severe disease include pregnant women, the very young and very old, immune-compromised people, and people with chronic underlying medical conditions. Seasonal influenza viruses evolve continuously, which means that people can get infected multiple times throughout their lives. Therefore the components of seasonal influenza vaccines are reviewed frequently (currently biannually) and updated periodically to ensure continued effectiveness of the vaccines.There are three large groupings or types of seasonal influenza viruses, labeled A, B, and C. Type A influenza viruses are further divided into subtypes according to the specific variety and combinations of two proteins that occur on the surface of the virus, the hemagglutinin or “H” protein and the neuraminidase or “N” protein. Type C influenza causes milder infections and is    associated with sporadic cases and minor localized outbreaks. As influenza C poses much less of a disease burden than influenza A and B, only the latter two are included in seasonal influenza vaccines.

Pandemic influenza

A pandemic occurs when an influenza virus which was not previously circulating among humans and to which most people don't have immunity emerges and transmits among humans. These viruses may emerge, circulate and cause large outbreaks outside of the normal influenza season. As the majority of the population has no immunity to these viruses, the proportion of persons in a population getting infected may be quite large. Some pandemics may result in large numbers of severe infections while others will result in large numbers of milder infections, but the reasons behind these differences are not completely understood. The most notorious pandemic for which data are available was the “Spanish Flu” in 1918-1919 which caused an estimated 20-40 million or more deaths worldwide. Subsequent pandemics in 1957 and 1968 resulted in many fewer deaths in spite of large portions of the world’s population being susceptible to infection. In 2009, a strain of influenza A(H1N1) virus which had not ever been seen before, emerged, spread across the world and caused the 2009 H1N1 pandemic. This pandemic A(H1N1)2009 virus has been widely circulating across the globe since 2009, and is now established in human populations as a seasonal influenza virus, as described above. Currently there is no longer a pandemic virus circulating in the world. 

Zoonotic or variant influenza

 Humans can also be infected with influenza viruses that are routinely circulating in animals, such as avian influenza virus subtypes A(H5N1) and A(H9N2) and swine influenza virus subtypes A(H1N1) and (H3N2). Other species including horses and dogs also have their own varieties of influenza viruses. Even though these viruses may be named as the same subtype as viruses found in humans, all of these animal viruses are distinct from human influenza viruses and  do not easily transmit between humans. Some may occasionally infect humans, however, and may cause disease ranging from mild conjunctivitis to severe pneumonia and even death. Usually these human infections of zoonotic influenza are acquired through direct contact with infected animals or contaminated environments, and do not spread very far among humans. If such a virus acquired the capacity to spread easily among people either through adaptation or acquisition of certain genes from human viruses, it could start an epidemic or a pandemic.Over the past decades, there have been multiple instances of sporadic transmission of influenza  viruses between animals and humans. When viruses of subtype A(H3N2) circulating in swine, began to infect people in the USA in 2011, they were labeled “variant” (with a “v” placed after the name of the virus)  in order to distinguish them from human viruses of the same subtype2. Other animal viruses, e.g. avian influenza A(H5N1), A(H7N7), A(H7N9), and A(H9N2), infecting people are simply called “avian influenza3” or “zoonotic influenza” viruses. When animal influenza viruses infect their natural animal host, they are named for that host, as in avian influenza viruses, swine influenza viruses, equine influenza viruses, etc. As such, the term “swine flu” refers to swine influenza viruses infecting swine, and is never used when such viruses infect people

Mechanism of infection

The mechanisms by which influenza infection causes symptoms in humans have been studied intensively. One of the mechanisms is believed to be the inhibition of adrenocorticotropic hormone (ACTH) resulting in lowered cortisol levels. Knowing which genes are carried by a particular strain can help predict how well it will infect humans and how severe this infection will be.

For instance, part of the process that allows influenza viruses to invade cells is the cleavage of the viral hemagglutinin protein by any one of several human proteases. In mild and avirulent viruses, the structure of the hemagglutinin means that it can only be cleaved by proteases found in the throat and lungs, so these viruses cannot infect other tissues. However, in highly virulent strains, such as H5N1, the hemagglutinin can be cleaved by a wide variety of proteases, allowing the virus to spread throughout the body.

The viral hemagglutinin protein is responsible for determining both which species a strain can infect and where in the human respiratory tract a strain of influenza will bind. Strains that are easily transmitted between people have hemagglutinin proteins that bind to receptors in the upper part of the respiratory tract, such as in the nose, throat and mouth. In contrast, the highly lethal H5N1 strain binds to receptors that are mostly found deep in the lungs. This difference in the site of infection may be part of the reason why the H5N1 strain causes severe viral pneumonia in the lungs, but is not easily transmitted by people coughing and sneezing. Common symptoms of the flu such as fever, headaches, and fatigue are the result of the huge amounts of proinflammatory cytokines and chemokines (such as interferon or tumor necrosis factor) produced from influenza-infected cells. In contrast to the rhinovirus that causes the common cold, influenza does cause tissue damage, so symptoms are not entirely due to the inflammatory response. This massive immune response might produce a life-threatening cytokine storm. This effect has been proposed to be the cause of the unusual lethality of both the H5N1 avian influenza, and the 1918 pandemic strain. However, another possibility is that these large amounts of cytokines are just a result of the massive levels of viral replication produced by these strains, and the immune response does not itself contribute to the disease. Influenza appear to trigger programmed cell death (apoptosis).

 Risk factors for complication

-    Asthma

-    Neurologic and neurodevelopment conditions

-    Blood disorders (such as sickle cell disease)

-    Chronic lung disease (such as chronic obstructive pulmonary disease [COPD] and cystic fibrosis)

-    Endocrine disorders (such as diabetes mellitus)

-    Heart disease (such as congenital heart disease, congestive heart failure and coronary artery disease)

-    Kidney disorders

-    Liver disorders

-    Metabolic disorders (such as inherited metabolic disorders and mitochondrial disorders)

-    People who are obese with a body mass index [BMI] of 40 or higher

-    People younger than 19 years of age on long-term aspirin- or salicylate-containing medications.

-    People with a weakened immune system due to disease (such as people with HIV or AIDS, or some cancers such as leukemia) or medications (such as those receiving chemotherapy or radiation treatment for cancer, or persons with chronic conditions requiring chronic corticosteroids or other drugs that suppress the immune system)

Other people at high risk from the flu:

-    Adults 65 years and older

-    Children younger than 2 years old

-    Pregnant women and women up to 2 weeks after the end of pregnancy

-    American Indians and Alaska Natives

-    People who live in nursing homes and other long-term care facilities

-     Although all children younger than 5 years old are considered at high risk for serious flu complications, the highest risk is for those younger than 2 years old, with the highest hospitalization and death rates among infants younger than 6 months old.

 Vaccination

The influenza vaccine is recommended by the World Health Organization for Prevention for high-risk groups, such as children, the elderly, health care workers, and people who have chronic illnesses such as asthma, diabetes, heart disease, or are immuno-compromised among others. In healthy adults it is modestly effective in decreasing the amount of influenza-like symptoms in a population.

Due to the high mutation rate of the virus, a particular influenza vaccine usually confers protection for no more than a few years. Every year, the World Health Organization predicts which strains of the virus are most likely to be circulating in the next year, allowing pharmaceutical companies to develop vaccines that will provide the best immunity against these strains. The vaccine is reformulated each season for a few specific flu strains but does not include all the strains active in the world during that season. It takes about six months for the manufacturers to formulate and produce the millions of doses required to deal with the seasonal epidemics; occasionally, a new or overlooked strain becomes prominent during that time. It is also possible to get infected just before vaccination and get sick with the strain that the vaccine is supposed to prevent, as the vaccine takes about two weeks to become effective.

Vaccines can cause the immune system to react as if the body were actually being infected, and general infection symptoms (many cold and flu symptoms are just general infection symptoms) can appear, though these symptoms are usually not as severe or long-lasting as influenza. The most dangerous adverse effect is a severe allergic reaction to either the virus material itself or residues from the hen eggs used to grow the influenza; however, these reactions are extremely rare.

For healthy adults, a 2018 Cochrane review showed that vaccines reduced the incidence of lab-confirmed influenza from 2.3% to 0.9%, which constitutes a reduction of risk of approximately 60%. However, for influenza-like illness which is defined as the same symptoms of cough, fever, headache, runny nose, and bodily aches and pains, vaccine reduced the risk from 21.5% to 18.1%. This constitutes a much more modest reduction of risk of approximately 16%. The difference is most probably explained by the fact that over 200 viruses cause the same or similar symptoms as the flu virus.

Diagnosis

Laboratory tests are required to diagnose human infection with zoonotic influenza. WHO, through its Global Influenza Surveillance and Response System (GISRS), periodically updates technical guidance protocols for the detection of zoonotic influenza in humans using molecular e.g. RT-PCR and others methods.

Rapid influenza diagnostic tests (RIDTs) have lower sensitivity compared to PCR and their reliability depends largely on the conditions under which they are used. Commercially available RDTs in general cannot provide subtype information. RIDTs are sometimes used in clinical settings, but their use in detection of zoonotic viruses is limited.

Treatment

Evidence suggests that some antiviral drugs, notably neuraminidase inhibitor (oseltamivir, zanamivir), can reduce the duration of viral replication and improve prospects of survival, however ongoing clinical studies are needed. Emergence of oseltamivir resistance has been reported.

In suspected and confirmed cases, neuraminidase inhibitors should be prescribed as soon as possible (ideally, within 48 hours following symptom onset) to maximize therapeutic benefits. However, given the significant mortality currently associated with A(H5) and A(H7N9) subtype virus infections and evidence of prolonged viral replication in these diseases, administration of the drug should also be considered in patients presenting later in the course of illness.

Treatment is recommended for a minimum of 5 days, but can be extended until there is satisfactory clinical improvement.

Corticosteroids should not be used routinely, unless indicated for other reasons (eg: asthma and other specific conditions); as it has been associated with prolonged viral clearance, immunosuppression leading to bacterial or fungal superinfection.    Most recent A(H5) and A(H7N9) viruses are resistant to adamantane antiviral drugs (e.g. amantadine and rimantadine) and are therefore not recommended for monotherapy.     Presence of co-infection with bacterial pathogens can be encountered in critically ill patients.

Prevention

Apart from antiviral treatment, the public health management includes personal protective measures like:

-    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, feverish and having other symptoms of influenza

-    Avoiding close contact with sick people

-    Avoiding touching one’s eyes, nose or mouth

Health care workers preforming aerosol generating procedures should use airborne precautions. Standard contact and droplet precautions and appropriate personal protective equipment (PPE) should be made available and used during epidemics.

Travelers to countries and people living in countries with known outbreaks of avian influenza should, if possible, avoid poultry farms, contact with animals in live poultry markets, entering areas where poultry may be slaughtered, and contact with any surfaces that appear to be contaminated with faeces from poultry or other animals. Good food safety and food hygiene practices e.g. hands washing with soap and water should be followed. Travelers returning from affected regions should report to local health services if respiratory symptoms suspecting zoonotic influenza virus infection. Pre-exposure or post-exposure prophylaxis with antivirals is possible but depends on several factors e.g. individual factors, type of exposure, and risk associated with the exposure.