Influenza, colloquially known as “flu” is an infectious disease and public health issue. On a global level, the flu infects millions of people worldwide and circulates yearly. In the United States, “flu season” occurs predominantly in the winter, but can begin as early as October and extend through May. Many people confuse the flu with a common cold, and though both are caused by viruses, unlike a cold, the flu can kill! The 2017-2018 flu season has seen increased hospitalizations and deaths due to Influenza across the country. This year’s flu has been quite severe, particularly in children.

According to the CDC (Centers for Disease Control and Prevention), 22 pediatric deaths from Influenza have been reported nationally, since the start of 2018 (it is now mid-February), bringing the current total of Influenza associated deaths in children to 84 for the 2017-2018 flu season. That number is likely to increase before the end of it all.

Influenza affects everyone, but the elderly and children, primarily infants under 6 months of age, are most susceptible and at risk for suffering severe illness or death. Children are also primarily responsible for the spread of Influenza throughout a community, since they shed the virus for a longer time period after infection, than adults.

What Is the Flu?

Influenza is a highly contagious, acute respiratory infection, caused by single-stranded RNA viruses belonging to the virus family Orthomyxoviridae. The viruses from this family, responsible for illness in humans, are Influenza virus types A, B, and C.  There are differences between the types of Influenza that affect their infectivity and pathogenicity. Influenza A and B have 2 distinct glycoproteins that project from the surface of a lipid envelope, known as Hemagglutinin and Neuraminidase. Hemagglutinin allows the virus to attach to and enter the host cells membrane. Neuraminidase is responsible for viral penetration of the mucous layer protecting the epithelial cells of the respiratory tract. More importantly, neuraminidase cleaves sialic acid from the surface of infected host cells, allowing replicated virion inside the cell to escape and infect more cells. Influenza C does not have neuraminidase, but its major surface glycoprotein is analogous to hemagglutinin. Influenza A is most common and causes the most severe form of the disease in both children and adults. Influenza C infections are rare in comparison, and causes mild illness in children.

How Flu spreads

Influenza is a communicable disease, meaning it is spreads person-to-person by close contact with an infected person, usually via contact with aerosolized droplets from their cough or sneeze. It can also be picked up from hard surfaces and objects, where the virus can linger after droplets have settled.

There are high infection rates in young school aged children, owing to crowded classrooms, hand-to-mouth behavior in children, and the fact that young kids are immunologically naïve, not having previous or considerable experience with exposure to Influenza.

Signs, Symptoms, & Complications

Signs & Symptoms

Once infected, it takes on average, two days for symptoms to appear. There is a sudden onset of fever, chills, headache, muscle ache or soreness, weakness, and non-productive cough. These classic signs of the flu do not always present in young children, instead they may display high fevers, cough, sore throat, loss of appetite, and congestion. Preschool aged children may not have headaches or sore muscles, which is common in older children and adults. Children are also more likely than adults to have abdominal pain, vomiting and diarrhea in response to the flu, which makes them more susceptible to dehydration and electrolyte imbalance. Children are also more likely to experience febrile seizures. They may also develop tenderness in the legs as a result of myositis. Myositis is an inflammation of the muscles that causes tenderness or weakness in leg muscle, and may lead to rhabdomyolysis (muscle death). If Rhabdomyolysis occurs, proteins from deteriorating muscle fibers can enter the bloodstream and ultimately damage the kidneys.

Flu symptoms generally last 2 to 7 days, but cough and fatigue can persist after the infection has resolved. Influenza is communicable starting as early as 1 day before symptoms develop, up to 5 or 7 days after in adults. However, children can continue to shed the virus for up to  10 days after the onset of symptoms.

Complications

Influenza can worsen underlying health conditions, which can lead to complications that increase the risk of hospitalization and death. Pre-existing medical conditions in children that are exacerbated by influenza are: Diabetes Mellitus, HIV, Sickle-cell Anemia, seizure disorders, renal disease, cardiovascular disease, and pulmonary disease.

Influenza that results in death is often due to secondary bacterial infections. Sometimes bacterial co-infections with the flu can occur, other times the flu can induce susceptibility to bacterial infections that occur after the flu has cleared. Children are already more likely than adults to acquire respiratory infections because their lungs are still developing, have smaller airways, and children have higher ventilation rates. As a result, flu in children can more readily cause life-threatening bronchitis and pneumonia in otherwise healthy kids, and exacerbate asthma and other pre-existing respiratory tract conditions like cystic fibrosis or pulmonary dysplasia.

Though rare, Influenza can also cause complications in the CNS (central nervous system), like encephalomyelitis, encephalopathy, and seizures.

Influenza Induced Pneumonia

Influenza rarely kills by itself. Fatality is usually the result of a secondary bacterial infection resulting in pneumonia. Bacteria that normally inhabit the nasal and upper respiratory tract, known as, commensal flora, are ordinarily harmless. However, Influenza weakens the immune system, allowing bacteria to travel down the respiratory tract where they are harmful.

Staphylococci, Pneumococci, and H. Influenzae are all bacteria that can invade the airways and lungs during or after infection with influenza viruses. On average Influenza induced pneumonia kills twenty thousand people a year. It is the main cause of influenza deaths, especially in the elderly. In children, secondary bacterial infections can manifest as ear infections.

Co-infections of bacteria and Influenza can make it difficult to treat either infection, as anti-inflammatory treatment to reduce flu symptoms may weaken the body’s ability to fight of bacterial infections.

Prevention & Treatment

The primary course of prevention of Influenza is vaccination. Though not 100 percent, the flu shot is effective in preventing influenza, hospitalization, and Influenza induce pneumonia. When diagnosed early, treatment with antivirals can decrease the duration of the illness, prevent hospitalization, secondary bacterial infection, and contagiousness.

Vaccination

The flu shot is safe and has been routinely recommended since 1963. Vaccination raises neutralizing antibodies that predominantly target the hematoglutinin (the H glycoprotein responsible for infectivity).  There are currently two types of routine Influenza vaccines; Inactivated Trivalent Influenza Viral vaccine and Live-attenuated Influenza vaccine.

The Inactivated Trivalent vaccine contains two viral strains of the predominant circulating Type A influenza and one Influenza Type B . The viruses are highly purified, and because they are inactivated, are noninfectious. Therefore, the vaccine CANNOT cause the flu. The vaccine is injected parenteraly and induces systemic immunity. When the viral strains chosen to comprise the vaccine match the circulating strains, efficacy of the vaccine is 70 to 90 percent.

Live attenuated virus vaccines, which were licensed and available in the United States since 2003, are given intranasally via inhalation, and confer local respiratory immunity. This vaccine was thought to induce an immune response more comparable to natural infection, and to be more protective in children than the inactivated vaccine. However, since the 2016-2017 flu season, the CDC has recommended against using it in children because no considerable difference in efficacy was found between the two vaccines (live attenuated vaccines are harder and more costly to produce).

Antivirals

Antivirals can reduce the severity and duration of Influenza when administered within 48 hours from the start of signs and symptoms. This is because antivirals inhibit viral replication, which occurs early on (24 to 72 hours after the symptoms show). Once the viral load is high, antivirals won’t reduce the infection beyond that of the immune response that has already been mounted by the body. Late administration of antivirals is only recommended in the most severe of infections; in cases where it is evident that the bodies own ability to quench the virus is impaired.

Antivirals can also be use prophylactically to prevent infection in those who are at high risk of infection or immunocompromised.

Adamantamines

Amantadine and Rimantadine are tricyclic amine antivirals that inhibits the replication of Influenza A viruses by interfering with viral uncoating inside the host cell. However effective, their use is limited as they are associated with several toxic side effects and with the rapid development of drug-resistant strains of Influenza. Currently they are recommended for prophylactic use.

Neuraminidase Inhibitors

Antivirals known as, Neuraminidase Inhibitors, inhibit both Influenza type A and B viruses. They prevent the release of the virus from the cell, which prevents cell-to-cell transmission. The three neuraminidase inhibitors currently in use in the United States are, Oseltamivir, Zanamivir, and Peramivir. The first two are prescribed for treatment and prevention, while the latter is administered intravenously as a single dose, and used only as a treatment in clinically-confirmed Influenza. Since it has low bioavailability, Zanamivir is inhaled, allowing it to act directly in the respiratory tract. Conversely, Oseltamivir is given orally; it is readily absorbed in the gastrointestinal tract and distributes throughout the entire body. The neuraminidase inhibitors significantly reduce mortality, complications, duration, and severity of disease.  Additionally, inhibition begins almost immediately; reducing the likelihood of drug-resistant strain formation, which is a problem associated with the Adamantamines. Also, by decreasing viral burden, antivirals prevent Influenza from weakening the immune system. Thereby, antiviral treatment can also protect against secondary bacteria infections, which also reduces the use of antibiotics, preventing the subsequent emergence of antibiotic-resistant bacteria.

Why the Flu Shot isn’t 100% preventative

Through worldwide surveillance and identification, the flu vaccine is designed to contain a mixture of the Influenza viruses that are expected to be in circulation for the up-coming season. As mentions before, there are 3 types of Influenza viruses: A, B, and C. The types of Influenza circulating each year are mainly Types A and B and are responsible for epidemic outbreaks. The strains circulating this 2017-2018 flu season are H1N1, H3N2, and Influenza B. Recommendations on which strains should be included, have to be made 6 to 8 months before the vaccine is produced. In this time, there is a potential for the expected dominant circulating Influenza strain to change. As a result, it is not guaranteed that the vaccine will prevent all cases of Influenza. Variations in subtypes of circulating Influenza strains compared to vaccine strains, cause people who have been vaccinated to still be able to get the flu. The circulating strains of Influenza may be different from previously predicted, due to constantly occurring or sporadic mutations of Influenza viruses.

Influenza A strains receive their names based on their antigenicity or presentation of  antigens on the surface of the virion, known as, Hemagglutinin (H) and Neuraminidase (N). Changes can occur in the H and N antigens of influenza viruses through Antigenic Drifts and Antigenic Shifts. The changes can allow the virus to evade recognition or antibody neutralization by the immune system of  previously infected or vaccinated persons.

Antigenic Drifts are frequently occurring point mutations in Influenza viruses that result in the development of new subtypes or variants of an existing strain. This form of mutation can occur in all types of Influenza, since it occurs in both hemaglutinin and neuraminidase.  Antigenic Shifts, however, lead to the formation of entirely new strains of Influenza and only occur in Influenza Type A. Because the Influenza genome is segmented, when two different strains of Influenza A viruses replicate within a host cell, reassortment of segments can occur. This Antigenic Shift gives rise to new combinations of H and N antigens, and thus new strains of Influenza. Since there is no previous exposure to the new strain, there is no immunity within the population. As a result Influenza Type A can cause pandemic outbreaks.

 

• H1N1 has been the predominant circulating virus since 2009
• Three pandemics have been caused by H1N1, H2N2, H3N2 in the past 100 years
• Influenza A has many subtypes, but Influenza B only has 2 lineages; Victoria or Yamagata
• Influenza C does not undergo Antigenic Shift or Antigenic Drift

 

Influenza A is maintained in animal reservoirs; mainly aquatic birds, but also bats. Strains of Avian Influenza A can recombine with human strains, if they cause infection in the same host, at the same time.  In birds, Influenza A replicates in the intestinal tract, and spreads through oral-fecal contact via contaminated water. Chickens, turkeys, and other domesticated birds can be sickened by Avian flu, and close contact between birds and other farm animals or people can allow for the transmission across species. In mammals Influenza A replicates in the respiratory tract and  causes disease in such animals as, pigs, horses, ferrets, and seals.  

Though Influenza B can undergo antigenic drifts, there is only one subtype of Influenza B, but with two lineages; Victoria and Yamagata. This may be owing to the fact that there is no zoonotic reservoir for Influenza B; it can only infect humans. Current, seasonal Trivalent flu vaccines only contain one Influenza B at a time. New Quadravalent vaccines that contain both lineages have been developed to give greater vaccine efficacy through broad-spectrum protection against Influenza B.

Other Factors affecting Vaccine Efficacy

Additionally, vaccine efficacy is affected by varying immune responses to the Influenza vaccine amongst individuals. Factors such as, age, pre-existing conditions or underlying disease, and immunosuppression can affect antibody titers (the amount of antibodies in the blood). To improve the humoral and cell-mediated immune response, adjuvants  have been added to some vaccine preparations. Adjuvants are substances that improve the performance of vaccines, allowing for better immune response, and decreased dose requirements. In the past mixtures of water and mineral oil or emulsifiers with or without mycobacterium have been used as adjuvants. However emulsifiers without mycobacterium caused nodules in humans, and its use was discontinued. Alum is approved as an adjuvant for use in humans, but it is not very effective. New adjuvants made out of squaline, with or without vitamin E are being designed and may prove to be efficacious. Also, high dose vaccines may be useful in elderly people, who tend to mount a weaker immune response to the conventional flu shot.

Summary

Although the flu vaccine does not guarantee complete protection because of  constantly occurring variations in types and strains of Influenza viruses, it is the best defense. Antibodies present in the immune system from previous infections or vaccination, though not precisely matching currently circulating Influenza, can still offer some protection. Children, particularly infants and young children, who have not had the flu do not have immunity to Influenza, unless they are vaccinated, and are thus at the greatest risk of complications and death. In addition to being more likely than adults to contract Influenza, the physiological makeup of children’s respiratory system, make them susceptible to infection and complications. Making matters worse, a flu diagnosis in children is often missed because young children do not necessarily present with the classical signs and symptoms of the flu. Illness brought on by Influenza in children can be mistaken for other respiratory infections that are common in pediatric populations, and rapid influenza detection tests are not sensitive, and therefore false negative diagnosis is common. As such, prescription of antivirals coupled with antibiotics is common treatment in children.  Protection conferred by the inactivated influenza vaccine lasts for less than a year, so it is recommended that children under the age of 9, who have never had the flu, be given 2 doses of the vaccine (1 month apart). Children with conditions that may be complicated by Influenza, should also receive prophylactic antivirals in combination with vaccination. Vaccination is required annually, prior to each new flu season in order to prevent or lessen severity of the flu. If illness does occur, treatment for Influenza-like symptoms should be sought early, as antivirals are most effective with early diagnosis.