#94424: Influenza: A Comprehensive Review

Influenza belongs to the orthomyxovirus family and consists of a single-stranded, helically shaped ribonucleic acid (RNA) virus. There are three types of influenza viruses designated A, B, and C. The differentiation is made by the type of proteins within the nucleus, specifically antigenic properties in their internal nucleocapsid and matrix proteins. The individual types have different effects on the humans who become infected.

Influenza type A is the virus that causes moderate-to-severe illness in all age groups and is highly infectious, with an attack rate of 10% to 20%. It also causes influenza in pigs, birds, and other animals. There are several subtypes of influenza A.

Influenza type B generally causes milder disease. It primarily affects children but has also caused outbreaks in military camps and occasionally in long-term care facilities. It does not cause illness in animals and birds and, as a result, tends to be more stable with less antigenic change. Subtypes have not been defined for influenza B.

Influenza type C is rarely ever reported, probably because any disease it causes is usually subclinical or mild. It does not affect animals and birds.

Because type A influenza virus causes more severe illness and also occurs in animal and birds, this course will focus on influenza A.

Influenza A subtypes are defined by the occurrence of the glycoproteins hemagglutinin (H) and neuraminidase (N), which are surface antigens on the virus. The hemagglutinins H1, H2, and H3 are involved in attaching the virus to cells. The neuraminidases N1 and N2 facilitate virus penetration into cells. There are 15 different subtypes of hemagglutinins and 9 different subtypes of neuraminidases leading to several possible combinations, which are indicated in the name of the virus (e.g., H1N2, H2N3). Many combinations of the various hemagglutinin and neuraminidase antigen subtypes are possible. However, H1N1, H1N2, H2N2, and H3N2 have historically occurred in humans.

Pigs are susceptible to three of the same subtypes of influenza. Historically, they have not been infected by the H2N2 subtype. Wild waterfowl, in contrast, appear to acquire all influenza A subtypes. An additional difference is that the virus causes respiratory illness in humans, pigs, and other mammals but infects the gastrointestinal tract in wild birds without causing disease. However, the virus is shed in the bird droppings, leading to the contamination of water supplies, barnyards, farms, fields, and animal food supplies.

The genes of influenza viruses are carried on eight separate segments of RNA rather than on one long single molecule. This means that if two or more subtypes of influenza virus infect the same cell in a host, these viruses can exchange RNA segments during replication and create viruses with new gene combinations. This reassortment is termed "antigenic shift." It often occurs in pigs and is the source of influenza epidemics because the human population has little immunity to the new subtype that results.

In comparison, "antigenic drift" refers to changes in the surface glycoproteins. This does not result in a new subtype but does influence the choice of the particular influenza viral subtypes for the annual influenza vaccine. Depending on the degree of antigenic drift, immunity developed to one virus may be adequate to protect against the related virus. In other situations, the drift has resulted in enough change that there is little protection.

In the past, the influenza subtypes present in birds did not directly infect humans. A different host was usually required to complete the shift from an avian subtype to a subtype capable of infecting humans. This host has been the pig, which can be infected with avian, human, and swine influenza viruses. A possible scenario is that the food or water supply of the pig is contaminated by bird feces containing a subtype or subtypes of influenza A. The pig also acquires different influenza subtypes from other pigs and/or humans. Reassortment of the viral RNA occurs in the pig host, thus infecting other pigs. Farm workers catch the new subtype from the pigs and develop highly contagious influenza because they do not have immunity against this new subtype. Thus, a new influenza strain is launched [14]. It is possible that antigenic shift could occur in a person who acquires a strain from a bird and also has a human strain. Realignment of H and N in the person's cells would result in a new strain. This new strain could become a pandemic if there is very little or no immunity in the human population and there is efficient, effective transmission from person to person [3].

Major pandemics of 1889–1891, 1918–1920, 1957–1958, and 1968–1969 have resulted from antigenic shifts. Characteristics of a pandemic are high attack rates in all age groups and a high mortality rate. Historically, pandemics have moved along trade routes, with rapidity of spread matching available transportation methods [3]. Rapid movement of people around the world by aircraft and fewer border restrictions by partners such as the European Union allow new influenza subtypes to spread quickly. However, cooperation among the World Health Organization (WHO), the CDC in the United States, and the European Centre for Disease Prevention and Control, which was established in 2005, has contributed to slowing the spread of the virus. Also, minimizing the transmission of influenza virus from any of the hosts to any of the other hosts (e.g., birds, pigs, humans) will decrease the antigenic shift and lessen the development of new subtypes to which the population has not developed immunity [14].

Research has shown that work-related travel rates affect the spread of influenza more than geographical distance or air travel [15]. Based on 30 years of weekly data, influenza imported into a state with many inflows and outflows of workers, such as California, spreads much faster than if it enters a less-connected state, such as Wyoming. Epidemics also tend to start and spread from more populated states. This information is especially important in the event of the appearance of a new virus to which most of the population is susceptible. It usually takes five to seven weeks for annual influenza disease to spread across the continent. However, if a new strain originates in a highly connected state, it could spread to all states within two to four weeks. The study also revealed that adults, not children, are responsible for the transmission of influenza across regions because they travel farther and more frequently. One proposed intervention is to limit interregional travel to slow the spread [15].

The name of each influenza virus is developed following this formula [3]:

This was the principal virus isolated in the United States during most of the 1997–1998 influenza season.

Thus A/New Caledonia/20/99/(H1N1) would be read influenza A, which was first isolated in New Caledonia, strain number 20, isolated in 1999, with hemagglutinin subtype 1 antigen and neuraminidase subtype 1antigen.

As noted, before the emergence of COVID-19, it was relatively easy to diagnose influenza. This is no longer the case, as the viral infections cause similar symptoms [194]. Uncomplicated influenza (and COVID-19) is characterized by an abrupt onset of:

Initially, there are more constitutional than respiratory symptoms. If there are no complications, the chest is usually clear to auscultation.

Children may also experience any of the accompanying effects of fever, such as listlessness, irritability, anorexia, and convulsions. In addition, otitis media, nausea, vomiting, and diarrhea are frequently reported in children with influenza [8]. Pneumonia and encephalopathy are serious complications in children with influenza [17]. Elderly patients may exhibit confusion in addition to other symptoms.

The patient with influenza usually appears febrile and fatigued with hot, moist skin, a flushed face, and red watery eyes. More than half of patients infected with the influenza virus will have nasal discharge with obstruction and pharyngeal redness. Younger patients may have nontender cervical lymphadenopathy [18].

Influenza onset is so abrupt that many patients can pinpoint the hour in which they became ill. This is an important feature that helps distinguish influenza from other diseases with flu-like symptoms. The fever is generally 101 to 102 degrees F (38.3 to 39 degrees C). Children may run higher fevers. Patients may complain of body aches. Myalgia often localizes in the back muscles. These systemic symptoms usually last from two to three days and may persist as long as five days. Most systemic symptoms respond to antipyretics and analgesics. It is important to remember that any medications containing aspirin should never be used in children or teenagers because of the risk of Reye syndrome [3]. This will be discussed in more detail later in this course.

Uncomplicated influenza is generally a self-limiting illness. Fever, myalgia, and respiratory symptoms usually resolve in five to seven days, but most patients experience some degree of malaise and fatigue for a week or more after resolution of acute symptoms (Figure 1).

COURSE OF INFLUENZA IN ADULTS

Figure 1

Source: Author

Influenza is highly contagious, with an attack rate of 10% to 20% from the day before symptoms begin through approximately five days after onset in adults. It is spread from person to person through coughing and sneezing by the infected individual. Influenza is spread by the airborne route, which means that a person coughing in the room can transmit the virus to others in the room without close personal contact. This is in contrast to droplet transmission in which heavier particles (droplets) are transmitted to those with close contact (less than 3–6 feet, depending on the organism). Droplet transmission also probably occurs in influenza. Airborne transmission is especially significant in congregate situations like institutions, daycare facilities, airplanes, and cruise ships [19].

As noted, the influenza virus may be transmitted between humans and pigs. More than 25 examples of transmission from pigs to humans have been documented in the medical literature [14]. It is assumed that many more undocumented cases occur in individuals who work with swine. Usually, this swine-human connection is missed because the flu seasons in both pigs and people overlap. However, this connection should not be minimized. Its influence in antigenic drift or shift and the introduction of new subtypes is important to traditional transmission patterns.

Contaminated hands are a frequent source of transmission and infection. Contagious individuals cough or sneeze into their hands and deposit virus on whatever they touch. Or, they cough or sneeze the virus into the air, which settles on objects in the area. Others handle these objects and then touch their eyes, nose, or mouth and are infected. Following an incubation period of one to four days (average: two days), the individual develops symptoms. Another major factor in the spread of influenza is that it is transmitted to others before infected individuals even realize that they are sick [20].

Children are another source of infection, as they can be contagious for 10 or more days. In addition, young children can shed virus for up to six days before illness onset [16]. This is one reason to discourage the practice of kissing infants and children on the mouth.

Obviously, an accurate diagnosis of influenza on the basis of symptoms alone is difficult. The quickest way to decide if the patient has influenza, COVID-19, or some other disease, is to use rapid diagnostic tests for influenza and COVID-19. However, medical practitioners should be aware that false-negative and false-positive results do occur. All patients with flu-like symptoms should now be administered rapid diagnostic tests to identify influenza and/or COVID-19 infection(s) [194].

The Advisory Committee on Immunization Practices recommends clinicians should use rapid molecular assays (i.e., nucleic acid amplification tests) over rapid influenza diagnostic tests in outpatients to improve detection of influenza virus infection.

(https://academic.oup.com/cid/article/68/6/e1/5251935 Last Accessed: October 27, 2022)

Level of Evidence: A-II (Good evidence to support a recommendation based on one or more well-designed clinical trials, without randomization; from cohort or case-controlled analytic studies (preferably from more than one center); from multiple time-series; or from dramatic results from uncontrolled experiments)

Within three to four days after onset of influenza, the virus can be found from throat and/or nasopharyngeal swabs. Highest viral shedding occurs during the first four days of illness. Nasopharyngeal specimens generally are more accurate. There are several rapid diagnostic tests available, and these tests usually require only about 15 minutes of laboratory time [22,23]. The specimen to collect and the information provided by the results vary according to the test being used. These various rapid diagnostic tests for influenza A are 65% to 95% accurate [21]. The accuracy rate depends on the particular rapid diagnostic test used and collection of the specimen at the optimum time [22]. Other factors that may improve the accuracy of these tests include knowledge that influenza is circulating in the community and obtaining the specimen from a patient within the first four days of illness [23]. The package insert should always be consulted as to the percentage of inaccurate results for the specific test. The rapid diagnostic test, therefore, can leave the medical practitioner with the need to base decisions about diagnosis and treatment on his or her clinical judgment [22]. Recent immunization with intramuscular (IM) influenza vaccine will not affect a rapid diagnostic test. Intranasal vaccine will affect any serology test [24]. In an institutional setting, such as a nursing home, use of a rapid test combined with a viral culture will help provide more effective treatment and allow for rapid prevention and control measures [21].

Culture of the virus takes a minimum of 48 hours. Another one to two days are needed to identify the virus type. Viral culture can take as long as 10 days to complete. Obviously, these tests provide information as to the virus responsible for the illness but are not practical for individual case management. Knowing the virus or viruses responsible, however, allows more accurate planning for vaccine preparations. This information also helps evaluate the effectiveness of the formulation used in the current vaccine [3].

There are several ways that the influenza diagnosis can be confirmed [23,25]:

For more information on available tests, please refer to the CDC's website at https://www.cdc.gov/flu/professionals/diagnosis. Monitoring the status of influenza circulating in the community through the information provided by the CDC can also assist the practitioner in the diagnosis [23].

Because both influenza and the common cold are caused by viruses that affect the respiratory tract, distinguishing between them is important. Adults rarely develop fever with a cold (coryza) but usually have a fever of 101 to 102 degrees F (38.3 to 39 degrees C) with the flu. Headaches, muscle aches, and extreme exhaustion are mild or nonexistent with a cold but are usual and severe with the flu. The prodromal signs of sneezing, runny nose, and sore throat signal that a cold is developing and may be present for one or more days before onset. These symptoms may occur with influenza but usually occur concurrently with the sudden onset rather than signaling an approaching illness. The flu develops suddenly, without warning. Like influenza, a cold may have a dry (nonproductive) cough. Some use a simple rule to distinguish between a cold, in which symptoms are from the neck up, and influenza, which is systemic (Table 1).

There are many other illnesses that initially look like influenza. For discussion and consideration in making a diagnosis, these diseases are sometimes grouped into influenza-like illnesses (ILI). Adults will average one to three ILI a year. Children can average three to six ILI in a year. The common cold is one of these, and the differences between influenza and colds have been discussed above. Other bacteria that cause ILI are Chlamydia pneumoniae, Mycoplasma pneumoniae, Streptococcus pneumoniae, and Legionella pneumophila. In addition, respiratory syncytial virus (RSV) has similar symptoms. None of these ILIs are as significant as biologic agents that may be used by a terrorist, such as anthrax, ricin, plague, and smallpox, all of which may present with influenza-like symptoms. However, they are a significant source of disease and should be considered when deciding if a patient has influenza or something else. Because bacterial diseases are treatable with antibiotics, but influenza is not, an accurate diagnosis is important. Much of the overuse of antibiotics occurs when patients request them for any illness or when careful diagnosis is not made between viral and bacterial diseases.

It may be helpful to consider the time of year in which the diagnosis is being made. Generally, pneumococcal disease peaks in the winter, as does influenza and RSV. Mycoplasma and legionellosis are more common during the summer and fall. Rhinoviruses and parainfluenza virus peak during the fall and spring. Adenoviruses circulate throughout the year [21]. COVID-19 has had severe winter peaks but has been unpredictable thus far, with lesser peaks several times each year, corresponding with the emergence and spread of new variants [47]. Information on the presence of influenza and predominant strains in the community can usually be found from the surveillance system maintained by the local health department [16].

Other information to consider is that, in healthy individuals, influenza is a self-limiting disease that strikes suddenly with most of its fury, maintains that level of illness for three to five days, and then shows improvement, even though the aftereffects of weakness and tiredness may persist for a week or more. In most other ILI diseases the patient's condition continues to worsen.

These last two considerations are not meant to figure in the diagnosis but to guide thinking about the patient's illness. For instance, if a greater than usual number of cases of ILI are being seen and it is the wrong time of year for influenza, another disease or a terrorist attack should be considered.

The major complication of influenza is pneumonia, and three types have been well-described in association with influenza epidemics: primary influenza (viral) pneumonia, secondary bacterial pneumonia, and mixed influenza/bacterial pneumonia. The incidence and mortality are highest in the elderly and in persons with underlying chronic illness, especially those with heart, lung, and renal diseases. However, in pandemic periods, half the deaths from pneumonia are seen in persons younger than 65 years of age [18].

Primary influenza pneumonia is the least common but most devastating form. It arises when the virus directly invades lung parenchyma and tends to present early as a rapidly deteriorating illness with high fever, profound dyspnea, and progressive respiratory failure. Patients with conditions that cause elevated left atrial pressures, such as heart failure and third-trimester pregnancy, are particularly at risk. Chest radiographs show bilateral diffuse reticulonodular opacities and basal (lower lobe) consolidation. Mortality is high.

Secondary bacterial pneumonia is the most common type and constitutes the major cause of excess morbidity and mortality in the elderly. The typical clinical presentation is a patient who appears to be convalescing from influenza only to experience an exacerbation of symptoms with renewed fever, worsening cough, purulent sputum, pleuritic chest pain, and radiographic evidence of a localized pulmonary infiltrate. The pathogens most often responsible are Streptococcus pneumoniae (50%), Staphylococcus aureus (20%), and Haemophilus influenzae. A number of factors affecting lung defense mechanisms are at play in the pathogenesis of bacterial superinfection, including [18]:

As might be expected, mixed influenza/bacterial pneumonia is a third type encountered during influenza outbreaks. This type of patient is vulnerable to severe, direct infection of the lung and happens, at the same time, to be colonized by a virulent respiratory bacterial pathogen (e.g., pneumococcus or staphylococcus).

Signs that a patient has developed pneumonia are [18]:

An unfortunate complication of influenza in patients younger than 18 years of age is Reye syndrome. Much education for parents has focused on the danger of giving aspirin to anyone younger than 18 years of age with a fever. This education has led to a decrease in Reye syndrome. Unfortunately, acetylsalicylic acid or salicylic acid is a component in some over-the-counter preparations and may be unintentionally given to a child with a fever. Influenza virus, especially influenza A virus, and varicella (chicken pox) interact with acetylsalicylic acid to produce Reye syndrome. Symptoms are nausea and vomiting, decreased consciousness and/or convulsions caused by cerebral edema, hypoglycemia, and liver failure. Parents must be reminded to read the labels of all medications and that aspirin is listed as acetylsalicylic acid [18].

Myositis (inflammation of muscle tissue) and rhabdomyolysis (involving striated muscle tissue) can be complications of influenza. These complications occur most often in children and are manifested by extreme muscle tenderness, especially in the legs. Myoglobulinuria may lead to renal failure in these patients. Serum creatinine phosphokinase (CPK) is markedly increased [18].

Influenza can be complicated by Staphylococcus aureus, leading to pneumonia as discussed above. Superinfection with S. aureus, leading to bacteremia, endocarditis, or epidural abscess, can also occur following influenza. Influenza B and S. aureus have led to toxic shock.

Other less common complications from influenza are myocarditis (inflammation of the cardiac tissues), and pericarditis (inflammation of the pericardial lining). A study conducted in Australia from 2008 to 2010 showed that recent influenza vaccination was significantly protective against acute myocardial infarction [26].

Besides the more common complication of bacterial or viral pneumonia, influenza can lead to the worsening of chronic bronchitis and other chronic pulmonary diseases.

Encephalitis, postencephalitic Parkinson disease, transverse myelitis, Guillain-Barré syndrome (GBS), and possibly amyotrophic lateral sclerosis have followed cases of influenza. There has been research suggesting that cases of Parkinson disease resulted from the "Spanish flu" pandemic of 1918–1919 [55,56,57,58,59,60].

Any person with a serious medical condition can be placed in jeopardy by influenza, not only from the complications listed above, but also from exacerbation of the underlying condition [18].

A vaccine containing an increased amount of the hemagglutinin antigen of the influenza virus was licensed by the U.S. Food and Drug Administration (FDA) in 2009 [4]. In 2021, the trivalent version was replaced with a quadrivalent formulation [8]. It is a single-dose, inactivated, quadrivalent, injectable vaccine sold under the brand name Fluzone High-Dose, manufactured by Sanofi-Pasteur. This high-dose vaccine was developed for individuals 65 years of age and older who are at a greater risk of hospitalization and death from seasonal flu and are known to develop lower antibody titers to the influenza virus. The vaccine is available for the 2022–2023 flu season [8].

Prelicensure clinical trials showed no preference for the new vaccine over other inactivated trivalent influenza vaccines. All were equally safe and equally effective at producing immunity [4]. However, the high-dose formulation resulted in significantly higher hemagglutination inhibition titers against each strain than the standard formulation [8]. A 2014 trial showed that recipients had 25% greater protection against influenza illness. A comparison between the standard and high-dose flu vaccines showed that in each 0.5-mL dose the standard vaccine contained 45 mcg while the high-dose vaccine had 180 mcg [8].

As with the standard vaccine, the high-dose should not be given to anyone with a known severe reaction to egg proteins or other components of the vaccine. Vaccination with the high-dose formulation produced more frequent injection site reactions and systemic adverse events than the standard formulation, but typically they were mild and transient [4,8].

In the event of a vaccine shortage, the following high-risk groups should receive the vaccination first.

Persons 50 years of age and older have the highest fatality and hospitalization rate from influenza and its complications. Of the annual deaths from influenza, 90% occur in those 65 years of age and older. In addition, 58% of the hospitalizations are in this age bracket [2]. Those who are between 50 and 64 years of age are high risk because of the high prevalence of chronic diseases in this population. These patients often do not receive the vaccine because the publicity about the need to receive the vaccine has tended to focus on those 65 years of age and older. Only 48.1% of persons 50 to 64 years of age receive the vaccination; the vaccination rate among persons 65 years of age and older is 69.1% [183]. In addition, Medicare pays for the vaccine after the person reaches 65 years of age. Therefore, individuals who fall into the 50 to 64 age group may be disinclined to receive the vaccine.

Persons with chronic health problems who are 6 months of age or older are at high risk for complications from influenza or exacerbation of their condition. Such chronic conditions include:

Persons with compromised immune systems from any cause—human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS), autoimmune conditions, cancer, long-term steroid treatment, and medications—should receive the inactivated vaccine [8]. Because the vaccine is inactivated (killed), it can and should be given to immunosuppressed people. However, because of the depressed immune system of this group of people, the expected antibody response may not be obtained. HIV-infected patients with minimal AIDS-related symptoms and high CD4 T-lymphocyte cell counts have been shown to develop substantial antibody titers against influenza. For those with more advanced HIV disease and low CD4 T-cell counts, the vaccine might not induce protective antibody titers, and a second dose has not been shown to increase the titer. Some studies have shown that there is a temporary (two- to four-week) increase in replication of HIV after receiving the influenza vaccine [62]. However, other studies have not demonstrated this increase nor has progression of HIV disease been shown to occur following the administration of the influenza vaccine. Each immunocompromised individual should be evaluated before the vaccine is administered because an increase in plasma HIV levels and/or a decrease in CD4 count has been transient in most, but not all, cases of those receiving the influenza vaccine [62].

Persons with conditions or diseases that may compromise respiratory function or increase the risk of aspiration should also be vaccinated against influenza to prevent any possible complications or damage.

All healthcare providers should receive the influenza vaccine annually. Additionally, healthcare facilities are encouraged to make available the vaccine to their workers. In its 2012 recommendations, the ACIP encouraged healthcare facilities to obtain a signed declination form from healthcare workers who refuse influenza vaccination [63]. Those who refuse vaccination may be required to wear a mask during influenza season. This issue is not specifically discussed in the 2021–2022 recommendations [8].

Persons who reside in skilled nursing facilities (nursing homes) or other chronic care facilities are at high risk for influenza-related problems because of their weakened physical state and close living arrangements.

Persons 6 months to 18 years of age on long-term aspirin therapy should be immunized against influenza because of the interaction of the influenza virus and aspirin that can lead to Reye syndrome.

Women who are pregnant during influenza season have the same complication and hospitalization rate from influenza as persons with chronic diseases and, therefore, should receive the vaccine. This would include women who will deliver from the beginning of October through the end of May. Increased severity of influenza among pregnant women was reported during the pandemics of 1918–1919, 1957–1958, and 2009–2010 [8]. Severe infections among postpartum women also were observed in the 2009–2010 pandemic, and 56 deaths (36 during the third trimester) were reported among 280 pregnant women admitted to intensive care units. Although there are some recommendations that a woman should not receive the influenza vaccine before the 14th week of gestation, the ACIP and the American Congress of Obstetricians and Gynecologists (ACOG) recommend influenza vaccination for all women who are or will be pregnant during the influenza season, regardless of trimester [8,64]. There is a coincidental association of spontaneous abortion, which is common in the first trimester. Also, many practitioners avoid any exposure to vaccines during the first trimester. However, no adverse fetal effects have been associated with influenza immunization [8,65]. Infants born to women who contracted the 1918 flu during their second and third trimesters had higher rates of cardiovascular disease at 60 to 82 years of age [66]. For men this rate of increase was 23.1%; for women, it was 17%. In addition, individuals exposed prenatally were less successful economically and educationally. Studies of other influenza pandemics have shown schizophrenia risk is three times higher in those exposed to influenza in utero [66]. This information should help healthcare workers to recognize the importance of immunizing pregnant women.

All children 6 to 59 months of age, especially children 6 to 23 months of age, even without any chronic conditions, should receive the annual influenza immunization because they are at a substantially increased risk for influenza-related hospitalizations [8]. Many of the hospitalizations are due to dehydration that can occur rapidly in a child who has a fever and will not drink fluids. The hospitalization rate in this age group matches the hospitalization rate for other groups at high risk for complications and death from influenza. At this point, these higher hospitalization rates cannot be totally assigned to influenza because RSV circulates at the same time. Since 2003, the Vaccines for Children (VFC) program has covered the cost of the influenza vaccine for all eligible children 6 to 23 months of age and all eligible children 2 to 18 years of age who are household contacts of a child 0 to 23 months of age [16]. The ACIP, the American Academy of Pediatrics, the ACOG, and the American Academy of Family Physicians (AAFP) published the Recommended Immunization Schedule for Persons Age 0 Through 18 Years, which includes a recommended yearly influenza immunization for all children 6 months of age and older [8,67]. Data from two studies showed that a side benefit from the influenza vaccine has been a reduction in otitis media [8].

Other groups who should receive vaccine during a shortage include American Indians/Alaskan Natives; the morbidly obese (body mass index ≥40); household contacts/caregivers of children younger than 6 months of age for whom there is no vaccine; and persons with medial conditions that put them at higher risk for severe complications from influenza [8].

Before 2004, influenza-related deaths in children were not on the list of deaths that should be reported. When it became apparent that a significant number of children were dying, the CDC requested that all influenza-related deaths of children younger than 18 years of age be reported to the appropriate state health department. Any postmortem tissue specimens that were collected or autopsy reports that were completed were also asked to be sent to the CDC [25]. However, in the subsequent years there have been even more deaths of children. As noted, in the 2017–2018 flu season, there were 183 deaths among persons younger than 18 years of age [2]. During the 2009 H1N1 pandemic, 32% of hospitalizations and 10% of deaths (approximately 1,250 deaths) were children younger than 18 years of age [68].

Persons who provide essential services, such as law enforcement personnel and firefighters, should be immunized. This is especially important in a pandemic situation. Students living in dormitories should receive the vaccine in order to avoid disruption of their studies.

Travelers should be evaluated for influenza immunization when "travel shots" are being recommended. Influenza in temperate climates occurs in the winter months (October through March in the Northern hemisphere; April through September in the Southern hemisphere); it occurs year-round in tropical climates. People taking a cruise could be infected with influenza at any time of the year because many of the service crew members are from tropical areas and a cruise ship is a closed community, which helps to assist in the spread of the virus [65].

The need for healthcare workers to be immunized against influenza cannot be overemphasized. All healthcare workers should receive the influenza vaccine. Not only does it protect the patient, but it also protects the healthcare worker. Healthcare workers who have been immunized tend to remember to advise their patients to get the immunization. This can strengthen the advice by example and can also provide anecdotal reassurance about the pain or side effects experienced. Studies have shown that residents in long-term care facilities have fewer deaths from influenza when their caregivers have been immunized against influenza [16].

Persons with a severe allergic reaction to eggs should not be given most types of influenza vaccine [8]. A person with a severe hypersensitivity to eggs may develop an anaphylactic reaction (e.g., sudden sense of great uneasiness or anxiety, pounding headache, hypotension, urticaria, dyspnea). Most influenza vaccines are grown in eggs, and although they go through a purification process, a small amount of egg protein remains. This minute amount could trigger a reaction in those who are severely allergic to eggs. A dislike for eggs, mild gastrointestinal symptoms, or hives (alone, without other, more severe symptoms) following ingestion of eggs is not a contraindication for the inactivated influenza vaccine. Usually, asking a person receiving the influenza vaccine for the first time if they can eat soft-cooked eggs without a problem is a quick screening tool and an adequate precaution. In 2013, the FDA approved the first vaccine that is not grown in eggs, eliminating any risk for those with severe allergic reactions to eggs [185]. Persons who have experienced only hives after exposure to egg may receive any appropriate influenza vaccine. In the case of cell-culture and recombinant vaccines, previous history of severe allergic reaction (e.g., anaphylaxis) to any influenza vaccine is considered a precaution rather than a contraindication [8]. In these instances, administration of the cell-culture or recombinant vaccines should occur in a medical setting under the supervision. However, a severe or anaphylactic reaction to the cell-culture or recombinant vaccine is considered a contraindication to the use of that vaccine [8].

Persons with acute respiratory or other active infections or illnesses should be advised to wait until they have recovered to receive the vaccine [8].

Persons with a history of GBS are more prone to another episode of this syndrome [8]. Because GBS is such a rare condition, it is impossible to know if the influenza vaccine is involved in its occurrence. During the 1976 swine flu epidemic, there was an increase of GBS (1 additional case per 100,000 vaccinated) in those who had received the vaccine [8]. However, an increased incidence of GBS following administration of other influenza vaccine formulations since 1976 is extremely low (1 additional case per 1 million vaccinated). According to the package insert for Fluzone, for patients who have recovered from GBS, it is better to err on the side of caution and avoid giving them the influenza vaccine until more information is available [65]. The Epidemiology and Prevention of Vaccine-Preventable Diseases, known as the "Pink Book," states that persons who have developed GBS within six weeks of receiving the influenza vaccine would be wise to avoid a subsequent flu shot [3,8]. However, the recommendation of the ACIP is that recovered GBS persons with risk factors that increase their vulnerability to the complications of influenza should receive the vaccine because the risk of complications is greater than the risk of a recurrence of GBS [8].

Persons with an allergic reaction to dry natural latex rubber should be evaluated before being given the vaccine because the stopper in some of the vials contains dry natural latex rubber [8]. According to data provided to CDC, Fluvirin and Fluad (manufactured by Seqirus) are the only vials that are expected to possibly contain latex.

Note: Influenza immunization is NOT contraindicated in breastfeeding persons. In fact, it should be encouraged because the patient could transmit influenza to a vulnerable infant if she gets the disease [8]. The patient could also be liable to a decreased milk supply because of decreased fluid intake and fever and would have the added burden of infant care and breastfeeding while experiencing exhaustion and other flu symptoms.

Because of antigenic drift, each year the ACIP and the FDA must decide which influenza strains to include in the formulation of the season's vaccine. Because the formulation changes each year to provide protection against the expected circulating strains, an annual influenza immunization is needed. Obviously, the point is to include the strains that will be expected to spread globally. There are two type A strains included in the trivalent formulations, because type A influenza strains are usually those that lead to more complications, hospitalizations, and deaths. The third strain included is always a type B; the quadrivalent formulation includes a second type B strain. In the 2003–2004 influenza season, the expected dominant strain killed the embryonated egg where the virus was grown due to the virulence of the strain [17]. A virus that was close to the expected circulating strain was chosen instead. However, the match was not close enough to the circulating strain for the vaccine to be as effective as it usually is. To the credit of the ACIP, this was only the second mismatch in 15 years [74,75]. In some cases, antibodies produced against one strain can overcome another strain, but the strains must be closely related. Antibodies produced by the strains in the 2003–2004 formulation were not close enough to the dominant circulating strain to destroy it, so people who had received the vaccine still developed influenza. In fact, the choice of which strains to include is based on the current knowledge as to which will be the most virulent strains in circulation. Due to the fact that there are only three strains in the vaccine and there are multiple influenza strains, people who are vaccinated can still develop illness from a strain of influenza virus that was not included in the vaccine.

Another extremely significant factor in the choice of a strain is the ability to grow the strain so that the vaccine can be produced in millions of doses. When vaccine distribution is delayed, it is often due to the fact that one particular strain would not reproduce well or quickly enough. As noted, some strains kill the culture medium.

Production of influenza vaccine involves the following steps [65]:

Thimerosal is a preservative used in multi-dose vials to inhibit bacterial growth that might occur because of multiple introductions of needles to withdraw individual doses. It is a compound containing 49.6% mercury. Because of the allegation that thimerosal is connected to conditions such as autism and the fact that there have been warnings to avoid fish that has a high mercury content, thimerosal has been removed from most childhood vaccines. Vaccines without thimerosal are packaged in single-dose vials. However, thimerosal is still used in multi-dose vials (5-mL dose vials) [8]. There are 25 mcg of mercury in each 0.5-mL dose of multi-dose vaccine. One should note that there have been no studies proving any link between mercury poisoning and autism. Thimerosal is made from ethyl mercury, which is different from methyl mercury, the compound named in the government warning about consumption of or exposure to mercury [74]. More influenza vaccine without thimerosal has been made each year and should be used for those who have a severe allergic reaction to thimerosal. At least 93% of the 175 million doses of vaccine available for the 2022–2023 flu season will be thimerosal-free or thimerosal-reduced [76].

These production methods have been used for decades and do not apply some of the modern technology available in the production of vaccines against other organisms, such as hepatitis A or hepatitis B. As noted, most influenza vaccine is incubated in fertilized chicken eggs. It takes one egg to produce one dose. More than 80 million doses are made for annual distribution in the United States alone. The number of chickens and eggs needed for this production is almost beyond comprehension. Also sobering is the thought of what would happen if one or more of the major flocks used for producing the eggs for the vaccine became infected with an avian influenza, which would require destruction of the flock(s).

Another issue involved is the amount of time required to produce the annual influenza vaccine—about six to eight months. Any new strain of influenza could circulate around the world much faster than the vaccine could be produced, resulting in a pandemic. Experimentation is being conducted on faster ways to produce the vaccine. Some companies are experimenting with caterpillar cells to incubate the virus. Experiments have indicated that the vaccine can be produced more quickly and that it would be available to protect people against emerging strains. Phase I trials indicated that the vaccine incubated in caterpillar cells is safe. In a clinical trial of 400 elderly people, the vaccine stimulated the production of nearly twice the number of antibodies as the vaccine produced using eggs. In addition, there were no adverse effects. Phase II trials in 400 elderly participants showed that 97% of them developed antibodies if the highest dose of the vaccine was used [77,78].

Another approach being explored in influenza vaccine production is to genetically engineer cells to replicate continuously. Such a process would lead to faster production and a more consistent vaccine [79]. One example of this is the Flublok vaccine, which uses protein-producing machines to make hundreds of copies of hemagglutinin, the small piece of the influenza virus needed for immunity [80]. Flublok is available for the 2021–2022 influenza season.

Other experimentation is being done using DNA-based approaches to develop a broadly protective vaccine that utilizes influenza virus proteins from multiple strains. Several companies are working to develop new ways to grow the antigens that cause the immune system to fight infection [79,81].

Using the reverse genetics method, in which genomes of the influenza viruses are manipulated in order to transfer genes between viral strains, seed viruses for vaccine manufacture can be rapidly generated. In addition, highly pathogenic influenza viruses can be altered so that they are safer for vaccine manufacturers to handle [81].

Another method of vaccine development, cell culture, has been well tolerated and has successfully led to antibody development in trials. Some research has shown that vaccines developed based on cell culture have been efficacious against all strains of influenza A, including H5N1 [81]. Using cell-based vaccines creates a more consistent manufacturing process and could reduce production time to 9 to 12 weeks. Although there are some side effects from cell-based vaccines, including headaches and injection site reactions, they appear to have a similar tolerability profile to egg-based vaccines [27].

In another area, one small study has been conducted that indicates that mild exercise before having a flu shot may make the vaccine more effective. Lifting weights before a flu shot increased antibody response in women but reduced the response in men. However, the cell-mediated response in men was increased by weight lifting. The researchers suggest that exercise increases the number of immune cells in muscle tissues, which in turn increases activity in the lymph nodes and creates a more efficient immune response [29,30].

The following information pertains to the egg-based vaccine in use. As is the case for all vaccines, the package insert should be consulted for proper handling and storage in order to preserve its effectiveness. Influenza vaccine should be stored at a temperature of 36 to 46 degrees F (2 to 8 degrees C) [8]. It should be transported in insulated containers with cold packs; however, it should not be directly in contact with the cold packs nor should it be placed anywhere in a refrigerator where it can be frozen. Freezing destroys the effectiveness of influenza vaccine. The vaccine can tolerate being out of the refrigerator while an influenza clinic is being prepared or conducted. However, only enough vaccine for the first half hour should be taken from the refrigerator at a time. When immunizing individual patients in an office setting, the vaccine vial should be returned to the refrigerator as soon as the dose has been withdrawn.

It is important that the temperature of the vaccine storage refrigerator be checked and recorded each morning before starting to dispense immunizations and each evening before leaving for the day. Older refrigerators can develop cold spots where items can freeze, or they may not maintain a constant temperature. All inactivated vaccines, like influenza vaccine, are destroyed by freezing. Large bottles of water should be kept in the refrigerator at all times to help maintain an even temperature and to preserve cold longer in case of a power outage. Some live vaccines, such as chickenpox and oral polio (no longer used in the United States), must be kept frozen. Vaccine should never be stored on the shelves in the door as the temperature there is erratic.

Each year the CDC and the ACIP provide updated recommendations for the prevention and control of seasonal influenza [8]. A variety of vaccines are available for the 2022–2023 flu season. These include standard-dose inactivated vaccines, high-dose inactivated vaccines, and recombinant and live attenuated vaccine, all of which are quadrivalent formulations. U.S.-licensed influenza vaccines for the 2022–2023 season contain hemagglutinin derived from an influenza A/Victoria/2570/2019 (H1N1)pdm09-like virus (for egg-based vaccines) or an influenza A/Wisconsin/588/2019 (H1N1)pdm09-like virus (for cell culture-based and recombinant vaccines); an influenza A/Darwin/9/2021 (H3N2)-like virus (for egg-based vaccines) or an influenza A/Darwin/6/2021 (H3N2)-like virus (for cell culture-based or recombinant vaccines); an influenza B/Austria/1359417/2021 (Victoria lineage)-like virus; and an influenza B/Phuket/3073/2013 (Yamagata lineage)-like virus [8].

In addition, the age indication for Flucelvax Quadrivalent has been expanded from 2 years of age or older to 6 months of age or older [8]. The approved dose volume is 0.5 mL per dose for all patients.

Various influenza vaccines have been licensed and approved for the 2022–2023 season. More than one type or brand might be appropriate within approved indications and ACIP recommendations. Current prescribing information should be consulted for authoritative, up-to-date information. Children younger than 18 years of age should not receive Flublok (IM) or Afluria administered with a jet injector [8]. The following inactivated or recombinant influenza vaccines (all quadrivalent) are expected to be available for the 2022–2023 influenza season: Fluad, Fluarix, Flublok, Fluzone High-Dose, Fluzone, Flucelvax, and Afluria; the live, attenuated vaccine FluMist will be available (Table 2).

Monitoring the 2010 influenza season in Australia produced data indicating that Afluria (marketed as Fluvax in the Southern Hemisphere) was associated with increased frequency of fever and febrile seizures in children 6 months through 4 years of age when compared to previous years [33]. Generally, the fever occurs 4 to 24 hours after the vaccine is given [33]. It would be prudent to instruct the parents or caregivers of these children to monitor the child's temperature and give nonaspirin fever-reducing medication as needed. In some public health immunization clinics, parents are instructed to give a dose of a fever-reducing medication to the child as soon as they get home, as a preventive measure. In a 2009 clinical trial in the United States, increased fever was noted among recipients of Afluria 6 months through 8 years of age. For the 2010–2011 influenza season, the U.S. Department of Health and Human Services Vaccine Adverse Event Reporting System (VAERS) and Vaccine Safety Datalink reviewed adverse event reports carefully for febrile seizures in children younger than 9 years of age [33].

The influenza vaccine discussed in this section is for IM use only; the intranasal and intradermal preparations are discussed later in the course. The IM vaccine is for all people 6 months of age or older. In order to assure that the vaccine is given IM, it is necessary to use needles of the proper length. Vaccine that is administered subcutaneously because of improper technique or a needle that is too short is ineffective.

The recommended site for adults and for children 3 years of age and older is the deltoid muscle [8]. A 1-inch needle will reach the deltoid in most children and adults. Some patients with large arms will need a 1.5-inch needle. One should be careful to make sure that the patient's sleeve can go high enough so that the needle can be inserted in the middle of the arm, about 1.5 inches below the top of the shoulder. Usually the firmness of the deltoid can be felt in that area. In patients who are very thin, it is wise to squeeze the deltoid between the thumb and finger to avoid hitting the bone. Administration of the vaccine distal in the deltoid is more painful. The posterior portion of the arm should not be used.

In children younger than 3 years of age, the deltoid is usually not big enough to receive the vaccine. The vastus lateralis muscle should be used [8]. This is the muscle on the outer aspect of the child's thigh and can usually be palpated. At times, when the infant kicks, the outline of the muscle can be seen. Two key elements to administering an injection to a child are to have the child properly and quickly restrained. An assistant, either the parent or a helper, should position the child so that the leg or arm where the injection will be given will not move. The upper body, the leg not being used for the shot, and the foot of the leg being used should be held tightly by the parent. Young children 3 years of age and older should sit sideways on the parent's lap so that the child's legs can be clamped between the parent's knees. The arm that will not be used for the injection should go around the parent's waist and be clamped under the parent's arm. The hand of the arm being used for the injection should be held by the parent. The person giving the vaccination should have all injections prepared so that they can be administered quickly. It is also good to distract the older child by having them blow, count, or see how loudly they can say "ouch."

Children should receive split-virus vaccine. This is not an issue in the United States as all vaccines are split-virus. Because some influenza vaccine comes in multidose vials, a small amount of thimerosal is in the vaccine [8]. For parents who are unwilling to accept the studies showing no connection between thimerosal and autism or other negative health effects, several thimerosal-free preparations are available [8,65].

FluMist, Fluarix, Flulaval (single-dose), Fluzone (single-dose), and Flublok do not contain thimerosal. There are additional vaccines in use with reduced or no thimerosal. Information on the amount of thimerosal present in each vaccine dose is available on the CDC website [8].

Children younger than 9 years of age receiving influenza vaccine for the first time should receive two doses, one month apart. The dose for a child is age-related [35]. Children from 6 to 35 months of age should be given 0.25 mL administered IM with a 1-inch needle in the outer aspect of the thigh. If it is the first time the child has received a flu shot, a second 0.25 mL dose IM should be given one month later [35]. In subsequent years, the child will receive only one influenza vaccine each year. Children 3 years of age and older should be given 0.5 mL IM using a 1-inch needle in the deltoid. Children who are 3 to 8 years of age receiving influenza vaccine for the first time will need a second vaccine in one month. These second doses in those not previously immunized against influenza are given to maximize a satisfactory antibody response to all antigens in the vaccine. Preferably, the series should be started as soon as possible after the vaccine becomes available [8,36,74]. Late-season immunization is acceptable and should be encouraged for those who have not received the vaccine [63].

As an inactivated vaccine, influenza can be administered with other vaccines if required. Separate needles and separate sites should always be used. In fact, for patients 65 years of age or older who have never received the immunization against pneumococcal disease, that vaccine should be given at the same visit. This is also an excellent time to check on the status of the patient's tetanus immunization. Tetanus vaccine should be given every 10 years, a fact that is often forgotten in adults, especially older individuals.

All patients or their parent/guardian must receive the Vaccine Information Statement (VIS) appropriate to the vaccine being administered. The patient signs that he or she has read the VIS. The record the patient signs must contain the date that the VIS was provided to the patient. Many people think that they are signing permission for the vaccine to be given. Actually, they are signing that they have read the VIS [37].

Children younger than 18 years of age should not be given any vaccines without a parent/guardian present. Grandparents who are not legal guardians frequently bring children to immunization clinics. A written permission from the child's parent/guardian should be presented to the staff before the vaccine is administered.

During the 2022–2023 influenza season, it is expected that SARS-CoV-2 will continue to circulate in the United States, and COVID-19 vaccinations are expected to continue. Current guidance for the use of COVID-19 vaccines indicates that these vaccines can be coadministered with other vaccines, including influenza vaccines [8]. Influenza vaccination during the COVID-19 pandemic is particularly important, as preventing influenza will avoid burdening and already stressed healthcare system. There is also evidence that respiratory virus activity has increased in 2022, leading some to predict a worse-than-usual influenza season [189]. If influenza and COVID-19 vaccines are administered at the same visit, they should be given at different sites (separated by at least 1 inch [190]. If used, high-dose or adjuvant influenza vaccines should be administered on a separate limb from the COVID-19 vaccine, if possible. There is no requirements regarding which vaccine is administered first.

There is little experience to guide recommendations for providing influenza vaccines to persons with COVID-19. In general, those who are in quarantine or isolation should not be brought to a vaccination setting if doing so could expose others to COVID-19. For those who have moderate or severe COVID-19, vaccination should generally be deferred until they have recovered [8]. For persons who have mild or asymptomatic COVID-19, further deferral might be considered to avoid confusing COVID-19 illness symptoms with postvaccination reactions.

The most common side effect following influenza immunization is a local reaction—soreness, redness, or induration at the injection site—that occurs in 15% to 20% of the recipients. Generally, these effects last only one or two days. Some people (<1%) experience fever, chills, malaise, and myalgias, usually within 6 to 12 hours. This effect occurs most often in those receiving the vaccine for the first time. As with the local reaction, these systemic reactions last only one to two days. In a comparative study with a placebo, the systemic reactions occurred as often with the placebo as with the influenza injection. Neurologic reactions to influenza do occur, but they are rare [8].

A certain percentage of people will be incubating an influenza virus when they receive the influenza injection. When they have symptoms of influenza within a few days of vaccination, they are certain it is the result of the flu shot. Healthcare workers should try to reassure their patients that the vaccine cannot be responsible because the virus in it is split and dead.

Immediate severe allergic reactions can occur after administration of influenza vaccine. These reactions are probably due to hypersensitivity to a component of the vaccine, usually a severe egg allergy. As noted, this concern may be eliminated with new technologies that have become available. The CDC recommends that all patients receiving the influenza vaccine, especially for the first time, should be carefully screened for severe egg allergy. However, the American Academy of Allergy, Asthma, and Immunology and the American College of Allergy, Asthma, and Immunology updated their practice parameter in 2017 and now assent that any appropriate, licensed influenza vaccine may be safely used for persons with egg allergy of any severity, eliminating the need for careful prescreening [186]. If a person has a severe allergic reaction to thimerosal, a thimerosal-free vaccine should be used. For those allergic to eggs but who have factors that increase their risk of complications from influenza infection, protocols to vaccinate them are available. Flublok or Flucelvax may be used in these patients as they are egg-free [8]. A sheet with the symptoms of anaphylaxis and the dosage of therapeutic epinephrine should be posted near the preloaded epinephrine syringe and should be readily available and known to all staff. In addition, crushable packets of ammonia should be available in any area in which immunizations will be administered. It should be noted that anaphylactic reactions are extremely rare. Patients, especially teenagers, may faint and the crushed ammonia passed quickly under the nose is enough to revive them. Never ignore a patient who verbalizes fear of shots or mentions that they have fainted in the past. Make sure such a patient is seated or lying down if in an exam room. Reassure the patient and administer the vaccine as quickly as possible. Position your body in such a way as to be able to support the patient if he or she begins to faint.

Adverse events are any unusual conditions, such as fever, dizziness, behavior change, or serious allergic reactions (e.g., difficulty breathing, hoarseness or wheezing, hives, paleness, weakness, tachycardia), following influenza vaccine. The National Childhood Vaccine Injury Act of 1986 mandates that healthcare providers report adverse events following vaccination to VAERS. Providers are additionally encouraged to report any clinically significant adverse event following vaccination to VAERS [8]. Any person can report an adverse event following the administration of any vaccine by calling VAERS or by obtaining a form online. Adverse events usually occur within 48 hours of vaccine administration. However, GBS may occur as long as six weeks after administration. The VAERS form will ask for detailed information on the vaccine, such as lot number, administration site, administrator, and date. Patients to whom influenza vaccine is administered should be instructed to call a physician if there is an adverse event. Careful investigation follows the receipt of a VAERS report. The provider is notified of the results of the investigation usually several months after the report was made. Therefore, it is important to keep a copy of the report in the patient's file and a copy in a special file for VAERS reports. As the report is investigated, the provider may be contacted for clarification or additional information.

The effectiveness of any vaccine depends upon the age and immunocompetence of the person receiving the vaccine. Most children and young adults receiving the vaccine have a good antibody response to the strains included in the vaccine and develop titers sufficient to protect them against those strains. For healthy adults younger than 65 years of age, if the vaccine strains match the circulating strains, illness will be prevented in 70% to 90% of those adults. In children, various studies have shown that children as young as 6 months of age develop antibodies. Children at high risk to develop complications with influenza may have a lower antibody response than healthy children. Also, children receiving the vaccine in the second year exhibit lower attack rates. Otitis media rates are lowered in some studies but not in others. Overall, because the vaccine is beneficial to children in preventing disease and lowering hospitalization rates, the ACIP recommends a yearly influenza immunization for all children 6 months of age and older [4,8].

In adults 60 years of age and older who are not institutionalized, a randomized trial showed that the vaccine was 58% effective against influenza respiratory illness. Efficacy might be lower in those older than 70 years of age. However, the vaccine appears to be effective in preventing secondary complications, hospitalization, and death among older adults, both those who are healthy and those with chronic medical conditions. Among noninstitutionalized older adults, the vaccine prevented hospitalization for pneumonia and influenza 30% to 70% of the time. Among institutionalized older adults, the vaccine can be 50% to 60% effective in preventing hospitalization or pneumonia and 80% effective in preventing death even though it is only 20% to 40% effective in preventing respiratory illness among this population [8]. Overall, in those 65 years of age and older, influenza immunizations have reduced hospitalization by 70% and death by 85% [36].

In preventing illness among younger workers, the vaccine may help reduce economic losses caused by absenteeism. Decreasing hospitalization rates of healthy infants and toddlers, of older noninstitutionalized and institutionalized adults, and of persons with chronic conditions is cost-effective. Studies have demonstrated that flu-related hospitalizations are decreased 40% to 42% overall with vaccination, that there is a 25% decrease in antibiotic usage for secondary illness associated with influenza, and that there is possibly a decrease in lost workdays. A 2014 study found that a vaccinated child's risk of being hospitalized due to influenza was reduced 74%; for individuals 50 years of age or older, flu-related hospitalization risk was reduced 57% [84]. These statistics indicate a significant annual savings of healthcare dollars for each person who received influenza vaccine. In an era of escalating healthcare costs and increasing antibiotic resistance, these are important figures [8].

Live attenuated influenza vaccines (LAIVs) have been in development in the United States since the 1960s [43,44]. FluMist (a LAIV trivalent formulation), manufactured by MedImmune, LLC, was originally approved in June 2003. FluMist quadrivalent LAIV contains two subtype A strains and two subtype B strains. It was approved by the FDA in February 2012 and was first available for the 2013–2014 flu season [45,46]. FluMist, which is delivered intranasally, is licensed only for healthy, nonpregnant persons 2 to 49 years of age. Live vaccines are unsuitable for healthcare workers who care for immunocompromised patients [8].

For two flu seasons, FluMist was not recommended based on data indicating inefficacy of the formulation. However, FluMist was reintroduced in the 2018–2019 season [8,187]. People with chronic health conditions should not be given the intranasal vaccine. The ACIP does not recommend the use of LAIV in immunosuppressed patients, and family members of close contacts of severely immunocompromised individuals are advised to avoid contact with them for at least seven days following vaccination [45]. LAIV can be administered at the same time with other vaccines, live and inactivated, but if not given at the same time, should be given four weeks after any other vaccine. Family members or close contacts of severely immunocompromised patients should not be given LAIV [45,61].

LAIV appears to induce both mucosal and serum antibodies. It is easier to administer than an IM injection, and it is preferred in some cases. In addition, no serious illnesses have been reported among unvaccinated contacts who were infected by those who had received the live vaccine [8].

One of the major factors influencing people with conditions that put them at high-risk for complications, hospitalization, and death from influenza is the misconception that the flu shot will give them the flu. This misconception is fueled by the fact that, in such a large cohort receiving the influenza immunization, a certain percentage will already be incubating the virus. When the symptoms of influenza appear one day or so after getting the shot, the natural assumption is that the illness came from the shot. Some take the opposite view that the flu shot will protect them against colds, so they are disappointed the "the flu shot didn't work" when they get a cold [84]. The same would be true about a bacterial infection or another ILI, such as RSV.

Another factor is that patients rely on their physician's advice. Unfortunately, physicians may not specifically recommend that their patients get the influenza vaccine. This leads the patient to think that it is not important or it would have been mentioned. Physicians can assess whether needle fears or phobias are preventing vaccination and could suggest or offer the LAIV4 vaccine. The CDC estimates that 2 in 3 children and 1 in 4 adults have a strong fear of needles [195]. It can be helpful to understand needle-fear triggers and have a variety of strategies to help patients manage the fear and pain.

Cost may be a prohibitive factor for those too young for Medicare, which covers influenza and pneumococcal immunizations. Some people may assume that the influenza immunization is effective for several years. Others feel that a healthy person should not take anything, like a flu shot, that might make them sick or may have side effects [84]. Some patients do not realize how effective the influenza vaccine is in preventing complications, hospitalizations, deaths, and actual influenza disease when the vaccine antigens correspond to the circulating antigens.

Probably one of the biggest factors affecting influenza immunization rates is the fact that influenza is so common—a true illustration of "familiarity breeds contempt." Few are aware of the number of hospitalizations and deaths and the economic burden associated with influenza. Additionally, vaccine hesitancy for a number of reasons, including distrust of medicine and science, compounded by misinformation found in certain media and now proliferated online, has had a negative influence on vaccine uptake.

Good handwashing is difficult to practice, is rarely known or taught, and is one of the single most effective ways to prevent transmission of many diseases, including influenza. Everyone knows to wash their hands before eating and after using the restroom. However, few do little more than remove obvious dirt. Good handwashing involves removing the skin oils where organisms can remain even when the hands look clean. A quick pass under the water faucet and fast dry with a towel removes visible dirt, but the oils and organisms remain.

To effectively remove the oils and organisms, the process should take at least 20 seconds (e.g., the amount of time that it takes to sing "Twinkle, Twinkle Little Star"). The hands should be soaped and rubbed vigorously for 15 seconds to create a good lather and to assure that all parts of each hand are soaped and rubbed well. Then the hands should be rinsed thoroughly and dried, preferably with a paper towel. The towel should be used to turn off the water and then properly thrown away. Such handwashing removes the oils that harbor the organisms, but 20 second s can seem like a long time in the busy life of a healthcare provider. If there is no visible dirt or contamination, a waterless hand sanitizer with at least 60% alcohol can be used between patients. However, nothing is as good as washing well with soap and water. Some mistakenly think that hot water must be used to kill the organisms. Water hot enough to kill organisms would be too hot to touch. Warm water mainly adds to comfort and hopefully encourages better washing technique. Careful attention to handwashing and cleansing may result in chapped skin, so medical professionals should find the proper lotions to care for their hands [90,91].

The eyes, nose, and mouth are entryways for bacteria and viruses. Everyone tends to unconsciously touch their eyes, nose, and mouth when going about their activities. Because organisms are not visible and handwashing is often less than adequate, infection occurs. Though difficult, persons trying to prevent illness should make a conscious effort to avoid touching their face [92].

Covering a cough or sneeze is of primary importance however it is done [93]. Ideally, disposable paper tissues will be readily available during cold and flu season and used to cover the nose and mouth when coughing or sneezing. Patients and children should be instructed that, when this is not possible, they should cough or sneeze into their upper sleeve or elbow instead of into their hands. This will avoid contaminating the hands with an offending virus or bacteria [93]. In those instances when coughs and sneezes are covered with only the bare hands, the hands should be cleaned with soap and water or with an alcohol-based hand sanitizer as soon as possible to prevent transfer of the organisms to another person. Coughing, sneezing, or blowing nasal secretions into a cloth handkerchief is not recommended as this results in creating a moist, viable culture that is then carried in the pocket or purse, potentially resulting in prolonged episodes of re-infection or transfer from cross-contamination.

During cold and flu season, trips to the store, school, church, and workplace bring contact with those who are coughing and sneezing. If at all possible, avoid close contact. This is an excellent time to consciously work on keeping your hands away from your face. Good handwashing should be done as soon as possible after contact with high-touch surfaces or someone exhibiting symptoms of respiratory illness. Help the immune system to overcome the organisms by getting enough rest, drinking six to eight glasses of water per day, and eating fresh fruits and vegetables [94]. Healthcare providers can lessen the spread of influenza by utilizing proper cough etiquette, providing tissues and safe disposal, using rapid diagnostic tests and antiviral chemoprophylaxis for suspected flu in healthcare workers, and recommending that influenza sufferers stay home [95].

Antiviral medications can also be used to prevent influenza. Three of the four antiviral drugs used to treat illness due to influenza can also be used to prevent it, although this is complicated by growing resistance to available agents. Amantadine (Symmetrel) and rimantadine (Flumadine) have been approved for treatment and prevention, but both of these agents have also been associated with decreasing effectiveness due to viral resistance and are no longer recommended for these uses [45,96,97]. Oseltamivir (Tamiflu) is an effective treatment of uncomplicated acute illness due to influenza A and B viruses in adults and children older than 2 weeks of age, and it is approved as a preventive treatment in persons 1 year of age and older. In 2007, the Japanese Ministry of Health, Labor, and Welfare issued a warning that oseltamivir may cause psychiatric problems and suicide in patients 10 to 19 years of age [98]. This warning has been the subject of much controversy, and no such warning has been issued in the United States. Zanamivir (Relenza) is approved for prophylaxis in persons 5 years of age and older; ACIP recommends that prophylaxis with zanamivir be considered for individuals at high risk of influenza complications, for unvaccinated healthcare workers exposed to influenza, and for eligible residents of institutions that house high-risk patients when outbreak control is needed [45].

A physician's order is required to obtain antivirals. In the past, amantadine and rimantadine prevented influenza A illness 70% to 90% of the time [16]. However, the increasing incidence of amantadine- and rimantadine-resistant strains of influenza in the United States has made these medications less effective [96]. Therefore, they are no longer recommended for treatment or prophylaxis of circulating influenza A strains [45,97].

Antiviral medications can make a person less contagious to others, so they are prescribed for contacts of people who are at high risk for complications from the flu. A subclinical infection may develop in a patient taking an antiviral. This allows the body to make antibodies against the virus. If any antiviral medication is to be totally effective, it must be taken as long as influenza is active in the community. Some studies indicate that taking an antiviral during peak influenza activity in a community is also effective. Of course, the less expensive single application vaccine is the best choice in preventing influenza in contacts of high-risk persons. However, in situations in which the individual has a hypersensitivity to one of components of the vaccine, or the needed two weeks to develop immunity are not available before contact, an antiviral medication can be used. Another reason to use an antiviral prophylaxis would be if the available vaccine does not match the circulating virus.

Antivirals are also used in closed environments, such as institutions or cruise ships, to control flu outbreaks. In such cases, it is best to combine the vaccine with an antiviral to provide protection for those exposed but who have not developed illness until the vaccine can stimulate the immune system to make protective antibodies. This also avoids the protracted use of the antiviral medication. The antiviral will not interfere with the antibody response elicited by the vaccine [3,16,99].

Zanamivir belongs to the antiviral group of neuraminidase inhibitors. It is effective against both influenza A and B and was approved in 1999 to treat uncomplicated illness due to influenza virus in adults and children 7 years of age and older. The dosage is 10 mg twice daily by inhalation for five days. Doses should be 12 hours apart. It may also be used to prevent influenza virus in adults and children 5 years of age and older. The dosage is two 10-mg inhalations once daily for seven days after last known exposure [45,101]. Zanamivir can lead to a decrease in respiratory function and bronchospasm. It is not recommended for patients with asthma, obstructive pulmonary disease, or other chronic lung diseases. More common (>10%) side effects include headache, throat/tonsil discomfort or pain, nasal signs and symptoms, and cough. Other effects that occur in less than 10% of patients include diarrhea, nausea, headache, dizziness, nasal infections, sinusitis, and bronchitis [45]. Some allergic responses of oropharyngeal or facial edema have also occurred [16,22,100,102].

Oseltamivir also is a neuraminidase inhibitor and effective against both influenza A and B viruses. It is marketed as Tamiflu, which should not be confused with Theraflu. Like zanamivir, it was approved in 1999. It can be used as treatment in adults and children who have been symptomatic for no more than two days. The treatment dosing for adults and children 13 years of age and older is 75 mg twice daily. The treatment dosing for children younger than 13 year of age is weight dependent [101]:

Oseltamivir can also be used as a preventive in anyone 1 year of age or older, but such usage should be rare [97]. The dose is 75 mg twice daily by mouth for adults and once daily for children and adolescents who weigh more than 40 kg (88 lbs.) [45]. Studies have shown that oseltamivir reduces the incidence of complications that may require antibiotics. Although the neuraminidase inhibitors promote a drug-resistant mutant of the virus, less resistance appears to occur with oseltamivir than with zanamivir. The reported side effects with oseltamivir are nausea and vomiting, which are lessened if the medication is taken with food [8,16,22,100,102].

Since 2005, some resistance to all of the antivirals has been documented. However, the 2009 H1N1 outbreak remained sensitive to oseltamivir except in a few cases [8]. Serious reactions to the four antiviral medications should be reported to the FDA MedWatch program.

Peramivir is a neuraminidase inhibitor for use in patients 6 months of age or older with acute uncomplicated influenza who have shown symptoms for no longer that two days [45,97]. Peramivir injection preparation is a 200 mg/20 mL single-use vial, stored at 59 to 86 degrees F (15 to 30 degrees C). After being diluted, it should either be administered immediately or refrigerated and administered within 24 hours [159]. Peramivir is typically given in a single 600-mg dose; the dose should be adjusted based on renal function. The most common side effect is diarrhea (8%) [45]. An efficacy study showed that overall symptoms were relieved 21 hours sooner in participants given peramivir compared to those given placebo [32]. Efficacy studies have primarily been conducted in patients with A type influenza viruses, and it is effective for 2009 H1N1 [45,159].

In 2018, the FDA approved the first antiviral influenza treatment with a novel mechanism of action in nearly 20 years—baloxavir. Baloxavir is a selective inhibitor of influenza cap-dependent endonuclease. It is approved for use in persons 5 years of age and older if administered within 48 hours of onset of symptoms [121]. It is also approved for avian influenza strains and strains with proven resistance to oseltamivir. In 2022, approval of baloxavir was extended to include post-exposure prevention in persons 5 years of age or older who have been exposed to influenza [45]. Studies indicate that baloxavir, which has the advantage of once-a-day dosage, is as effective as oseltamivir in alleviating symptoms and shortening the duration of illness [10]. Baloxavir is administered as a single oral dose of 40 mg for persons 40 to <80 kg or 80 mg for persons ≥80 kg. The most common side effects are diarrhea and nasopharyngitis [121].

Amantadine was approved in 1966 as a treatment for uncomplicated respiratory tract illness caused by influenza. It belongs to a group of chemically related drugs called adamantanes (tricyclic amines) and is effective only against influenza A viruses. Rimantadine, approved in 1993, is also in the adamantanes group. Therefore, it is also only effective against influenza A. However, circulating influenza A (H3N2) and 2009 H1N1 viruses are resistant to adamantanes. As a result, these medications are no longer recommended for the treatment or prophylaxis of influenza A [45,103].

All antiviral treatment for influenza should begin within 48 hours of symptom onset to be effective [45,97]. In most individuals without underlying medical conditions, influenza is a self-limiting disease. Recovery usually occurs after one week, although fatigue and malaise may persist two or more weeks. The decision to use an antiviral is influenced by the type of work the patient does. In an epidemic or pandemic, persons providing critical services should be treated because shortening their absence by one or two days is important. For other personnel, the decision should be based on the comparison between the wages that would be lost and the cost of the medication [100]. If an outbreak of influenza occurs in an institution, antiviral medications should be used for both treatment and prophylaxis [104].

Some people may desire treatment because of upcoming plans or because they do not like to be sick. These individuals should be encouraged to obtain the annual influenza vaccine in the future, as disease that develops in spite of the vaccine is usually milder unless the vaccine strains do not match the circulating strains.

Antiviral treatment with oral or enterically administered oseltamivir is recommended as soon as possible for patients with confirmed or suspected influenza who have severe, complicated, or progressive illness or who require hospitalization [97]. Oral oseltamivir is also recommended for outpatients with confirmed or suspected influenza who are at higher risk for influenza complications on the basis of their age or underlying medical conditions [96,97]. Antiviral treatment also may be considered on the basis of clinical judgment for any outpatient with confirmed or suspected influenza who does not have known risk factors for severe illness if treatment can be initiated within 48 hours of illness onset.

Pregnancy should not be considered a contraindication to the use of oseltamivir or zanamivir; however, peramivir and baloxavir are not recommended for these patients. Pregnant women are known to be at higher risk for complications from infection with seasonal influenza viruses, and if influenza is confirmed or suspected in these patients, it should be treated with oseltamivir or zanamivir; fever should be treated with acetaminophen. [101]. Because antivirals have a potential but unknown risk during pregnancy, it is important to continue to vaccinate pregnant women. The seasonal flu shot has been given to pregnant women for many years without any harm to the women or their fetuses. Vaccines that contain thimerosal result in exposure to only trace amounts of mercury and are not associated with toxicity; however, most (93%) of available vaccines are thimerosal-free or thimerosal-reduced formulation. All single-use vaccines are thimerosal-free, and the LAIV4 nasal vaccine is also thimerosal-free [45,76].

Family members or friends should be located to care for the high-risk patient who lives alone. With enough community support (e.g., home health, neighbors, "Meals on Wheels"), a patient might be able to remain alone, but it would require careful planning and coordination among all involved. During an epidemic or a pandemic, it may be necessary to set up temporary facilities, such as a shelter for medically fragile patients, to provide care. A normally healthy adult living alone may only need help in the form of shopping.

Points in the care of the patient include: careful observation, providing symptomatic relief, help with activities of daily living, helping the patient remain hydrated, and emotional support (Appendix 1).

Attention should also be given to the person(s) caring for the patient with influenza in the home to protect him/her from the disease. This would include influenza immunization, with or without an antiviral medication for two weeks, instruction on effective handwashing, wearing a mask when providing care or when the patient is coughing, getting adequate rest, consuming five to nine or more fruits, fruit juices, and vegetables each day, and drinking eight glasses of water every day (Appendix 2).

Of course, the most important aspect of self-care is obtaining the immunization. However, should one develop influenza and not be at high risk for complications, there are a few general steps to speed recovery and protect others [105]:

By keeping a written record of observations, a patient's subtle changes become more apparent, and the information will also help a physician. As discussed, there are many diseases that initially present like influenza or conditions that can be complicated by influenza; therefore, each person with influenza should be watched. The patient with influenza usually starts to improve after a few days. Patients and/or caregivers should be given a list of symptoms that indicate when a physician should be notified (Appendix 3). Any difficulty in breathing, a fever that is not responding to antipyretics, change in mental state, inability to maintain hydration, or worsening of symptoms should be reported to a physician, or the patient should be taken to the emergency room if a physician is unavailable.

The healthcare professional should review the following items with patients with influenza or their family member(s), so a physician can be notified appropriately and promptly [105]:

Infection control procedures should be followed carefully as soon as any contact with a patient with influenza or an ILI occurs so that transmission can be prevented. In order to protect staff, posters prominently displayed or warning signs at the sign-in desk should request that the staff be informed if the patient has any respiratory symptoms.

Patient education posters about flu, the vaccine, and cough etiquette should be displayed in emergency rooms, waiting rooms, exam rooms, elevators, and other appropriate traffic areas used by patients and visitors. Messages should be brief but clear. Pictures could also be included for children who cannot read or for non-English speakers. All education materials should be provided in the major languages of the community.

As a result of the evolving racial and immigration demographics in the United States, interaction with patients for whom English is not a native language is inevitable. Because patient education is such a vital aspect of the prevention and treatment of influenza, it is each practitioner's responsibility to ensure that information and instructions are explained in such a way that allows for patient understanding. When there is an obvious disconnect in the communication process between the practitioner and patient due to the patient's lack of proficiency in the English language, an interpreter is required.

In this multicultural landscape, interpreters are a valuable resource to help bridge the communication and cultural gap between clients/patients and practitioners. Interpreters are more than passive agents who translate and transmit information back and forth from party to party. When they are enlisted and treated as part of the interdisciplinary clinical team, they serve as cultural brokers, who ultimately enhance the clinical encounter.

Educational materials might include:

The hemagglutinin antigens that historically have caused human influenza are H1, H2, and H3. Although all known hemagglutinin subtypes occur in birds, H5, H7, H9, and H10 have been implicated more in recent outbreaks. Various combinations with the neuraminidase antigens occur. All of these AI viruses are type A, as B and C do not infect birds. Some of the cases focused on in the past decades have included the following [111,119,120,125]:

Fortunately, although in some of these outbreaks bird-to-human transmission did occur, human-to-human transmission has been extremely rare. Limited transmission possibly did occur between humans in the Netherlands, but no sustainable transmission occurred, so an epidemic or pandemic did not follow. There were 14 cases and 12 deaths (11 children) from H5N1 virus in Vietnam. The viruses isolated from those who expired in Vietnam were mostly resistant to amantadine and rimantadine. Studies are continuing as to the effectiveness of oseltamivir and zanamivir against H5N1 viruses. There is some evidence that the 2004 H5N1 virus in Asia is sensitive to oseltamivir [113,114,116]. However, some evidence of resistance to oseltamivir has been reported in highly pathogenic avian influenza H5N1 viruses isolated from human cases [122]. Most of the 2004 H5N1 outbreaks were controlled by veterinarian officials or spontaneously died out. However, H5N1 continues to fulminate in poultry in Egypt [123].

Most cases of AI in humans have resulted from contact with infected poultry or contaminated surfaces. It is also possible for the virus to become aerosolized and then land on exposed surfaces of the mouth, nose, or eyes. Aerosolized virus could also be inhaled directly into the lungs. Eating poultry products has not been associated with the development of AI. Influenza viruses are destroyed by adequate heat. Because of the pathogens found in poultry, all patients should be reminded to cook all poultry, including eggs, thoroughly. Chicken should be cooked until the internal temperature reaches 180 degrees F. All utensils and surfaces that have come in contact with raw poultry should be washed well with soap and water immediately following use. A separate cutting board should be used to cut raw poultry. In order to retard bacterial or viral replication, all poultry products should be defrosted in the refrigerator, not at room temperature.

Some patients might become concerned about contaminated poultry products from other countries entering our food supply. Some countries will not permit poultry to be imported from countries in which there were detections of AI, such as China's ban of U.S. chicken in 2015. However, the risk of AI spreading through the global chicken industry is low because most chickens on the international market are killed and frozen or chilled. All documented transmission to date has been from live birds [124,125].

Humans have no immunity to AI viruses, so illness tends to be severe and the fatality rate high. Prevention is difficult because the viruses tend to be highly contagious. Because of the mobile nature of people and efficient, rapid transport, any virus can spread quickly around the world. The current manufacturing process of influenza vaccine requires several months. The elements are all in place for a pandemic.

In 2007, a team of scientists at the National Institute of Allergy and Infectious Diseases reported that it had developed a way to generate vaccines and therapeutic antibodies that could target constantly mutating influenza viruses, such as H5N1. The team focused on mutations that enable H5N1 hemagglutinin protein to better recognize and enter human cells and those mutations that will elicit antibodies. This information will enable researchers to consider how to design potential vaccines that will protect people from future emerging AI virus mutants, possibly helping to contain a pandemic in its early stages [126].

In order to understand how influenza viruses mutate, researchers have been working to synthesize the hemagglutinin responsible for the 1918 influenza ("Spanish flu") pandemic. The success of this endeavor was reported in 2004, and scientists have since discovered how subtle alterations enabled the virus to move from birds to people [127].

The H5N2 avian influenza virus continues to be monitored around the world by scientists. It is highly virulent but has not been transmitted person to person yet [4,112]. In 2015, H5N2 avian influenza virus (along with H5N8 and H5N1) were found in more than 200 bird samples, indicating the likelihood that 40 million farm and backyard birds had been infected in 20 states [48]. In 2022, the largest H5N1 avian influenza outbreak in the United States in seven years occurred, affecting at least 48 million poultry birds and was detected in 3,000 wild birds (as of October 2022) [34]. One human case was reported in April 2022. Large outbreaks of H5N1 avian influenza were also reported in Europe in 2021–2022, with nearly 48 million poultry birds culled (as of September 2022) [39]. Canada also experienced a H5N1 large avian influenza outbreak in 2022, with at least 3 million birds affected (as of October 2022) [40].

Like all flu viruses, 2009 H1N1 is mainly spread among people by coughing, sneezing, talking, and occasionally via fomites. It is not spread by food or by eating pork or pork products. There have been no cases acquired from influenza-contaminated drinking water. Chlorine treatment of drinking water has been shown to inactivate the highly pathogenic H5N1 virus, and H1N1 would be similarly affected. A documented case of influenza from any water exposure (drinking or recreational) has not occurred.

Pets, such as dogs, cats, and ferrets, can be infected with H1N1 from close contact with a sick human. All available information indicates that H1N1-infected dogs, cats, and ferrets do not transmit the illness to humans. So far, there is no H1N1 vaccine for animals. Most recover with supportive care [11].

When a swine influenza virus does become a source of widespread human illness, the transmission patterns change. Instead of being mainly limited to swine contact, the virus will spread by human-to-human contact. According to the CDC, available data indicate that the 2009 H1N1 virus is transmitted in ways similar to other influenza viruses, primarily via large-particle respiratory droplet transmission [92]. Because humans have little to no immunity to influenza viruses of swine origin, transmission may be common.

H1N1 survives on surfaces, including kitchen counters, door knobs, desk tops, and other fomites, for two to eight hours. Individuals can pick up the virus when they touch contaminated objects and unconsciously then touch their eyes, mouth, or nose. Thus it is vital for people to learn to keep their hands away from their mouths, eyes, and nose and to frequently wash their hands well with soap and water or use an alcohol-based hand sanitizer. An alcohol-based product, bleach solution, or hot, soapy water can be used to clean surfaces [148]. One positive result of the H1N1 pandemic, as indicated in a study conducted in Hong Kong, was that people were washing their hands more frequently and wearing face masks when having ILI or in public areas [149].

A major transmission concern with 2009 H1N1 was regarding newborns whose mothers had the virus. The CDC and State Health Departments strongly recommended vaccination for this population because of demonstrated risks to both infants and pregnant women. However, many disregarded the recommendation. It was then decided that infant and mother should be separated until the mother had been on antivirals for at least 48 hours, was afebrile for 24 hours without antipyretics, and could control her cough and respiratory secretions. Before visiting the infant, the mother was instructed to clean her hands well with soap and water or an alcohol-based hand sanitizer, wear a face mask, and observe respiratory/cough etiquette. If her gown had been contaminated with byproducts of coughing or sneezing, she was instructed to change to a fresh gown. Following these guidelines, the mother was then allowed to hold, feed, and care for the infant [8].

Like seasonal influenza, vaccination is the most important preventive measure. Other common sense preventive steps (e.g., appropriate cough cover, correct disposal of used tissues, adequate rest, good fluid intake, staying home when ill) should also be practiced.

Similar to seasonal flu, H1N1 symptoms include chills, fever, myalgia, fatigue, headache, cough, sore throat, and rhinitis. But unlike seasonal flu, there may be vomiting and diarrhea in some people. Others may have respiratory symptoms without fever [11,152].

Unless it becomes a pandemic, swine influenza infection in humans generally goes undistinguished from typical human influenza as a result of the overlapping flu seasons and the relatively mild clinical presentation. The disease is diagnosed by analysis of a sputum sample collected in the first four to five days of illness, when an individual is most likely to be shedding the virus [153]. In June 2010, the FDA authorized the CDC Influenza 2009 A (H1N1)pdm Real-Time RT-PCR panel (IVD) to detect human infections with 2009 H1N1. This test replaced the previous real-time RT-PCR diagnostic test authorized by the FDA in April 2009, just as the WHO declared that a pandemic was imminent [144,154]. There are now several RT-PCT and other molecular assays available to differentiate 2009 H1N1 [155].

In the case of the 2009 H1N1 virus, the CDC recommended that clinicians not routinely test for the virus when it was known to occur in the community, but that testing be prioritized in people who were hospitalized with suspected flu and in people for whom a diagnosis of flu would help their physician make decisions about their care [155]. As the 2009–2010 H1N1 epidemic progressed, it became apparent that those younger than 65 years of age were at greatest risk (Table 4) [8].

While most swine influenza cases were sufficiently mild to resolve spontaneously, antiviral medications were used if treatment was indicated. The specifically recommended agents were determined based on clinical and epidemiologic assessment of the virus. For example, in the case of the 2009 H1N1 outbreak in North America, the virus's susceptibility profile indicated that the preferred antivirals would be oseltamivir or zanamivir [97,156].

During the 2009–2010 H1N1 pandemic, the CDC recommended antiviral treatment for all persons with suspected or confirmed influenza requiring hospitalization [145]. In addition, early empiric treatment with oseltamivir or zanamivir was considered for persons with suspected or confirmed influenza who were at higher risk for complications, including [145]:

The recommended treatment for adult and adolescent patients is either 75 mg oseltamivir twice per day or 10 mg (two 5-mg inhalations) of zanamivir twice daily [45,145]. Children 7 years of age and older may be treated with the adult dose of zanamivir. However, calculating oseltamivir doses for children is more complicated and has been the source of medical errors [157]. It is important to note that while healthcare providers in the United States generally write prescriptions for liquid medications in milliliters, oseltamivir is dosed in milligrams [157]. For infants 2 weeks of age or older, the oseltamivir dosage is 3 mg/kg twice daily [45]. For children between 1 and 12 years of age, dosage is based on weight [45,145]:

Treatment should continue for five days [45]. Pregnancy is not considered a contraindication to the use of oseltamivir or zanamivir.

As of 2015, 2009 H1N1 was susceptible to both oseltamivir and zanamivir, with a few exceptions [96,103]. Those resistant to oseltamivir have been sensitive to zanamivir. Sporadic oseltamivir-resistant 2009 H1N1 virus infections have been identified, but the public health impact has been limited [103]. As of 2015, no evidence existed of ongoing transmission of oseltamivir-resistant 2009 H1N1 virus strains worldwide [103]. A study published in 2022 found that from 2017 to 2019 there were very few oseltamivir-resistant H1N1 viruses circulating in Brazil [188]. Australian research during their 2020–2021 flu season found 2 out of 1,538 samples that were resistant to oseltamivir [138].

A study at Utah State University examined the use of oseltamivir combined with T-705 (favipiravir), an antiviral in late-stage development by Toyama Chemical of Japan, on mice [158,160]. This combination was effective against H1N1, H3N2, and H5N1 influenzas. The study indicated that two antivirals may be a better strategy for treatment of humans with influenza. Favipiravir is a viral RNA polymerase inhibitor with a novel mechanism of action, inhibiting viral gene replication within infected cells to prevent their propagation [160].

The threat of an influenza pandemic has been overshadowed by the onset of the COVID-19 pandemic and resulting years of surveillance and response. However, some experts predict that an influenza pandemic has the potential to be even more deadly than the COVID-19 pandemic [41]. The risk of an influenza pandemic remains, and lessons should be learned from the challenges and failures of the COVID-19 response.

Should methods for containment of a new avian or swine influenza virus fail, a worldwide pandemic could follow. Because the population has no immunity to the new strain, as was the case with COVID-19, billions of people could be infected and several million could die. The 1918 pandemic afflicted 20% to 40% of the world's population and caused 50 million deaths, at least 675,000 of which were in the United States [161]. As a comparison, "seasonal" flu generally affects less than 20% of the population [162]. The WHO estimates that there could be 233 million outpatient visits, 5.2 million hospitalizations, and 7.4 million deaths globally within a very short period of time were an influenza pandemic to occur [163]. Waves of the outbreak could occur in any given community for approximately six to eight weeks, then reoccur months later, affecting the global population for at least one to two years [161]. The resulting strain on resources (possibly exceeding that of the COVID-19 pandemic) would be far more severe than a terrorist attack that is localized to one or a few areas and lasting from a few minutes to hours. However, planning for a bioterror attack and an influenza pandemic have many similarities, and each can enhance the other [164].

Medical practitioners, emergency departments, and clinics, especially walk-in facilities, will be the first contacts in a pandemic. Having a high index of suspicion and using rapid testing is vital to help slow the spread of the disease. Checking the CDC weekly influenza reports will help to clarify suspicions, but obviously, COVID-19 complicates diagnosis [166].

The WHO has defined phases for a pandemic that reflect a global risk assessment of each influenza virus with pandemic potential [168]:

The CDC has developed guidelines for public response in a pandemic situation. These stress that people should stay away from crowds, avoid close contact with anyone at work or school, stay home if they or anyone in the household is sick, wash hands frequently, practice covering all coughs and sneezes, and dispose of tissues safely. Industrial masks/N95 respirators should be worn by caregivers. N95 masks must fit closely (no air leaks) to be effective. Proper disposal of a mask is imperative, as it has the potential to become a source of infection rather than protection [106,169].

In planning for the inevitable pandemic, five areas should be covered. These include: surveillance and laboratory issues, communication, community services, medical care, and vaccines and drugs. In 2006, the California Department of Health Services developed the Pandemic Influenza Preparedness and Response Plan[170]. The plan was then revised in 2007. The 2007 plan includes sections on pandemic influenza surveillance and epidemiology, laboratory testing capacity, healthcare planning, infection control in the healthcare setting, case management, vaccine programs, antiviral drug programs, community disease control and prevention, and risk communication. These sections cover the responsibilities of the medical community (health practitioners, hospitals, and clinics) and public health departments and include prevention and mitigation plans [170].

For medical care providers, an influenza epidemic presents many challenges. These would be compounded by the increased number of cases in a pandemic. A group in Los Angeles studied the impact on emergency departments and outpatient facilities during seven influenza epidemics. Some of the lessons learned in order to better cope with an increased number of patients were that [147]:

During the SARS outbreak, nurses at Stanford University Medical Center set up receiving areas to prescreen hundreds of patients before they entered the emergency department. Those with ILI were diverted to negative pressure rooms for further testing. Screening questions were used to triage the patients [147]. Table 5 provides a list of questions that could be asked of patients to elicit extra information that may assist in a more rapid diagnosis. These questions should be asked in the receiving area of the hospital, clinic, or office in order to minimize the introduction of highly contagious organisms.

This receiving area would also be a place where educational materials could be provided for the "worried well." In an office situation, it might be possible to set up a small table outside the office door to screen patients and distribute masks and educational materials. Some public health department plans include supplying public health staff to emergency rooms to help answer questions and educate the worried well, allowing the hospital staff to assist in the care of those critically ill.

Although the COVID-19 pandemic is ongoing and the learning process is ongoing, the Lancet COVID-19 Commission highlighted several areas of failure that must be improved in order to prevent the magnitude of death witnessed globally, but particularly in the United States, in the event of another pandemic [42]:

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Usually the person with the flu gets very sick suddenly, stays very sick for a few days, and then starts to feel better. The flu can cause other problems. Below is a list of symptoms and signs that indicate that a person needs help from a physician.

As you take care of the person, write down the date and time when you take the temperature or notice a new sign or symptom. If you are having trouble getting the patient to drink fluids, write down the time the person had a drink and how much they drank. The following signs should be reported to a physician immediately.