Jessica C. Njoku and Elizabeth D. Hermsen
KEY CONCEPTS
Influenza is a viral illness associated with high mortality and high hospitalization rates among persons older than age 65 years. The aging of the population is contributing to an increased disease burden in the United States.
Seasonal influenza epidemics are the result of viral antigenic drift, which is why the influenza vaccine is changed on a yearly basis. Antigenic drift forms the foundation of the recommendation for annual influenza vaccination.
The acquisition of a new hemagglutinin and/or neuraminidase by the influenza virus is called antigenic shift, which results in a novel influenza virus that has the potential to cause a pandemic.
The primary route of influenza transmission is person-to-person via inhalation of respiratory droplets, and transmission can occur for as long as the infected person is shedding virus from the respiratory tract.
Clinical diagnosis of influenza is difficult. Classic signs and symptoms include abrupt onset of fever, muscle pain, headache, malaise, nonproductive cough, sore throat, and rhinitis. These signs and symptoms usually resolve within 1 week of presentation.
In the United States, the primary mechanism of influenza prevention is annual vaccination. Vaccination not only prevents influenza illness and influenza-related hospitalizations and deaths but also may decrease healthcare resource use and the overall cost to society.
The trivalent influenza vaccine (TIV) and the live-attenuated influenza vaccine (LAIV) are the two commercially available vaccines for prevention of seasonal influenza. Both vaccines contain influenza A subtypes H3N2 and H1N1 and influenza B virus, which are initially grown in hens’ eggs.
Antiviral drugs for prophylaxis of influenza should be considered adjuncts to vaccine and are not replacements for annual vaccination.
The sooner the antiviral drugs are started after the onset of illness, the more effective they are.
Oseltamivir and zanamivir are neuraminidase inhibitors that have activity against both influenza A and influenza B viruses, while the adamantanes have activity against only some influenza A H1N1 viruses. Antiinfluenza agents are most effective if started within 48 hours of the onset of illness.
Influenza causes significant morbidity and mortality, particularly among young children and the elderly. Seasonal influenza epidemics result in 25 to 50 million influenza cases, approximately 200,000 hospitalizations, and more than 30,000 deaths each year in the United States. Globally, influenza causes nearly 500,000 deaths each year. More people die of influenza than of any other vaccine-preventable illness. Significant societal consequences associated with influenza include visits to physicians’ offices and emergency departments and days lost from school and/or work. The societal costs associated with influenza are more than $40 billion in the United States alone.1
Vaccination is the primary mechanism of influenza prevention in the United States. The antiviral armamentarium for treatment and prophylaxis of influenza is limited, which further emphasizes the importance of prevention with vaccination and appropriate use of infection control measures during outbreaks. Research toward the development of novel antivirals and vaccines is needed for effective control of seasonal epidemics and for pandemic preparedness.
ETIOLOGY AND EPIDEMIOLOGY
Influenza infection can occur at any time during the year with the highest rates of influenza-associated illness during the winter months. The highest rate of infection occurs in children, but the highest rates of severe illness, hospitalization, and death occur among those older than age 65 years, young children (<2 years old), and those who have underlying medical conditions, including pregnancy and cardiopulmonary disorders, that increase their risk of complications from influenza. 
The seasonal influenza epidemics from 1993 to 2008 resulted in an average annual influenza-associated hospitalization rate of 63.5 (95% CI, 37.5 to 236.6) per 100,000 person-years. Influenza-associated hospitalization rates were four times higher among infants aged <1 year compared with among those aged 1 to 4 years.2Similarly, influenza-associated hospitalization rates were 18 times higher, and 5 times higher, among persons aged ≥65 years compared with among those aged 5 to 49 years, and 50 to 64 years, respectively.2In 2006 alone, an estimated 37,000 hospital discharges were attributed to influenza.1,2 Approximately 90% of seasonal influenza-related deaths occur in those older than age 65 years.3 Thus, the aging of the population is contributing to an increased disease burden. Deaths associated with influenza often result from secondary bacterial pneumonia, primary viral pneumonia, and/or exacerbation of underlying comorbidities.
Influenza Viruses A, B, and C
Influenza virus types A, B, and C are members of the Orthomyxoviridae family and affect many species, including humans, pigs, horses, and birds. Influenza A and B viruses are the two types that cause disease in humans. Influenza A viruses are responsible for the regular, seasonal epidemics of the flu, whereas influenza B viruses are typically associated with sporadic outbreaks, particularly among residents of long-term care facilities. Influenza A viruses are further categorized into different subtypes based on changes in two surface antigens—hemagglutinin and neuraminidase (NA). Influenza B viruses are not categorized into subtypes.
Hemagglutinin allows the influenza virus to enter host cells by attaching to sialic acid receptors and is the major antigen to which antibodies are directed on exposure.4 NA allows the release of new viral particles from host cells by catalyzing the cleavage of linkages to sialic acid.4
Sixteen hemagglutinin subtypes (H1 to H16) and nine NA subtypes (N1 to N9) of influenza A have been isolated from birds. However, the only influenza A subtypes that have circulated among humans since the 1918 pandemic (see Antigenic Drift and Antigenic Shift below) are H1 to H3 and N1 and N2.4 The primary subtypes of influenza A that have been circulating among humans for the past 3 decades are H3N2 and H1N1.
Antigenic Drift and Antigenic Shift
Immunity to influenza virus occurs as a result of the development of antibody directed at the surface antigens, particularly hemagglutinin. However, immunity to one influenza subtype does not offer protection against other subtypes or types of influenza. Moreover, immunity to one antigenic variant of a subtype of influenza may not confer protection against other antigenic variants. Antigenic variants are created by point mutations in the surface antigens of a particular subtype, resulting in small changes in the hemagglutinin and/or NA molecules, which is called antigenic drift. Antigenic drift is the basis for seasonal epidemics of influenza, the reason for changes in the annual influenza vaccine, and the rationale behind the recommendation for annual vaccination.
Immunity to one subtype of influenza does not confer protection against other subtypes or types. 
Antigenic shift occurs when the influenza virus acquires a new hemagglutinin and/or NA via genetic reassortment rather than point mutations.4 Most likely, the genetic reassortment occurs when an animal that supports the growth of multiple subtypes of influenza, such as a pig, is concurrently infected with two subtypes of the influenza virus. Conversely, antigenic shift may occur directly from avian strains that have gained competency in the human host. Antigenic shift results in the emergence of a novel influenza virus and carries the potential of causing a pandemic. However, novelty alone is insufficient to cause an influenza pandemic; the virus must be able to replicate in humans, spread person-to-person, and affect a susceptible population.4
Spanish Influenza of 1918
The influenza pandemic of 1918 was the most significant infectious disease outbreak known to humans, causing approximately 40 to 50 million deaths in a year, with more than 500,000 deaths occurring in the United States.4–6Although the reports of the first illnesses associated with this pandemic occurred in Spain, there is no evidence that the virus associated with this pandemic actually originated there, indicating a misnomer. The pandemic occurred almost concurrently in Europe, Asia, and North America.5
The 1918 pandemic was caused by a particularly virulent influenza A H1N1 virus, which was entirely of avian origin.7 In contrast to the other pandemics of the 20th century, the 1918 pandemic resulted in an unusual mortality pattern. The mortality peaked for those younger than age 4 years, those between the ages of 25 and 35 years, and those older than 65 years of age, which resulted in a W-shaped mortality curve, as opposed to the U- or J-shaped curve typically associated with influenza.6 Over half of the deaths occurred in persons aged 20 to 40 years. The death toll associated with this pandemic culminated in an almost 10-year drop in the life expectancy of the population at the time.6
Asian Influenza of 1957
The Asian flu pandemic began when a new H2 subtype of influenza A surfaced in Hunan province in China in 1957.6 The virus appears to have formed from coinfection with an avian H2N2 virus and a human H1N1 virus in a common host, possibly a pig or a human.8 The H2N2 virus quickly spread to Japan, South America, the United States, New Zealand, and Europe, resulting in approximately 4 million deaths worldwide, with 70,000 deaths occurring in the United States.5,6 Unlike the Spanish flu of 1918, the mortality curve for the Asian flu pandemic was U- or J-shaped, with infants and elderly being most affected.5
Hong Kong Influenza of 1968
The H2N2 virus of the Asian flu circulated in the human population until 1968, when a new H3 subtype emerged in China and Hong Kong5 following genetic reassortment with the H2N2 virus.5,6 The H3N2 virus quickly spread to the United States and later to Europe. This pandemic caused more than 30,000 deaths in the United States and approximately 2 million deaths worldwide.5,6 The lower morbidity and mortality associated with the Hong Kong flu may be explained by previous exposure of the population to the N2 subtype. Similar to the Asian flu of 1957, the mortality curve for the Hong Kong flu pandemic was U- or J-shaped, primarily affecting infants and elderly.5
Avian Influenza
Influenza viruses are in circulation in southern China during all months of the year.4 Given this fact and the close proximity of dense populations of people, pigs, and wild and domestic birds, this area proves ideal for the development of new influenza viruses via genetic reassortment (antigenic shift), as demonstrated by the pandemics of 1957 and 1968 and, most recently, the emergence of what is known as avian influenza.4
The first report of human infection with the avian H5N1 virus occurred in 1997 in Hong Kong in a 3-year-old who had a direct link with chickens and later died.9 This was followed by 18 confirmed cases and 6 deaths.10 The virus reemerged in 2003 as an antigenically and genetically different virus that has spread widely through wild and domestic bird populations in Asia, Africa, and Europe as well as infecting humans in 15 countries: Azerbaijan, Bangladesh, Cambodia, China, Djibouti, Egypt, Indonesia, Iraq, Lao People’s Democratic Republic, Myanmar, Nigeria, Pakistan, Thailand, Turkey, and Vietnam.5,11 As of August 10, 2012, a total of 608 cases and 359 deaths caused by H5N1 infection have been reported.11 The current overall case fatality is 60%.
The spread of avian influenza viruses from person to person has been reported very rarely, and has been limited, inefficient, and unsustained.12,13 The precise mode of transmission is unknown, but most cases have occurred as a result of close and prolonged person-to-person contact. Cases of transmission via aerosolization have not been reported.14 Clinical presentation includes high fever and influenza-like illness, and watery diarrhea without blood may occur up to 1 week prior to respiratory symptoms.16 Almost all patients have clinically apparent pneumonia. Progression to death, most commonly as a consequence of respiratory failure, occurs a mean of 9 to 10 days after the onset of illness.14 The NA inhibitors, oseltamivir and zanamivir, have activity against the H5N1 virus, although higher doses may be needed. Oseltamivir resistance has been detected in several patients infected with the H5N1 virus who were treated with oseltamivir.14 Amantadine and rimantadine are ineffective against H5N1. An inactivated monovalent influenza virus vaccine against H5N1 is available for vaccination of persons 18 to 64 years of age at increased risk of exposure to the H5N1 influenza virus. Two 1-mL doses given intramuscularly 28 days apart (range, 21 to 35 days) are recommended. The vaccine is supplied in a 5-mL multidose vial, with ~50 mcg thimerosal per dose added as a preservative.15 At the present time, the vaccine is being stockpiled for use if H5N1 begins transmitting easily from person to person. Individuals at high risk, for example, those who work with poultry and H5N1 poultry outbreak responders, are encouraged to receive annual seasonal influenza vaccine to minimize the risk of coinfection with human and avian influenza A viruses.
The potential for H5N1 to cause a pandemic is of concern as it could spread more quickly than pandemics of the past because of the mobility of people in today’s world. International travel has increased 73% since 1990, with 763 million people crossing international borders in 2004.16 A severe pandemic, like that of 1918, could cause more than 9 million hospitalizations and more than 1.9 million deaths, whereas a moderate pandemic, like those of 1957 and 1968, could result in more than 800,000 hospitalizations and more than 200,000 deaths in the United States alone.5
Swine Influenza of 2009
An outbreak of a novel influenza A H1N1 (formerly swine origin influenza virus [SOIV]) was initially detected in Mexico in March 2009 and subsequently in the United States in April 2009 in California and Texas.17–19 The virus then spread throughout North America, Europe, Asia, and subsequently worldwide, prompting the World Health Organization (WHO) on June 11, 2009 to declare phase 6, indicating widespread human infection, for the influenza pandemic.18 Since 1998, triple reassortant swine influenza A (H1) viruses, containing genes from swine, avian, and human lineages, have circulated among swine in the United States.19 However, the novel influenza A H1N1 virus is unique in that although much of the genome is similar to the triple reassortant swine viruses previously seen in the United States, the genes encoding for NA and matrix (M) proteins are most similar to those circulating in the Eurasian swine population. This particular genetic combination has not been seen before.19 The virus has since become the predominant influenza A H1N1 in circulation, effectively replacing traditional seasonal influenza A (H1N1).
Several characteristics of the novel influenza A H1N1 outbreak differ from those of a typical seasonal influenza outbreak. Symptomatology associated with the novel influenza include fever (94%), cough (92%), sore throat (66%), diarrhea (25%), and vomiting (25%).19,20 An estimated 43 to 89 million cases of 2009 H1N1 occurred between April 2009 and April 2010 with a median 274,000 hospitalizations. Globally, 18,500 laboratory-confirmed H1N1-related deaths were reported; however, this may represent an underestimation of true disease burden.20,21 The majority of the cases occurred in otherwise healthy children and young adults <65 years of age including pregnant women, with the highest incidence reported among those aged 18 to 64 years.20 Contrary to seasonal influenza where about 60% of hospitalizations and 90% of deaths occur in people ≥65 years, approximately 90% and 87% of 2009 H1N1-related hospitalizations and deaths, respectively, occurred in people <65 years. However, like seasonal influenza, people with underlying health conditions had greater risk of hospitalizations and death. Among those who were deceased due to novel H1N1 infection, the median age was ~40 years and 59% of deaths (respiratory and cardiovascular) occurred in Southeast Asia and Africa.20,21
Variant Influenza A (H3N2), 2012
In August 2011, the U.S. Centers for Disease Control and Prevention (CDC) reported the first case of an influenza infection due to influenza A H3N2 variant virus (H3N2v).22 Since then, 319 cases (12 from 2011, and 307 from 2012) were reported from 12 states in the United States resulting in 13 hospitalizations and 0 deaths.23 As at the time of this publication, no human infection with H3N2v had been documented outside of the United States. The H3N2v is considered a variant virus because it is different from influenza A viruses circulating among humans. Infections due to variant influenza viruses, for example, A(H1N1)v, A(H3N2)v, and A(H1N2)v of swine origin, have been documented in the past.22 The H3N2v virus contains genes from avian, swine, and human viruses and the M gene from the 2009 H1N1 pandemic virus (A[H1N1]pdm09).24 The virus was originally detected in pigs in 2010 but human infection was first documented in July 2011. The virus appears to spread more readily from pigs to people than other variant viruses, but has limited person-to-person transmission. The main risk factor for infection with the virus based on evaluation of available cases is exposure to pigs, mostly in fair settings.22 Since the virus is related to human flu viruses from the 1990s, most adults have some immunity against it.25 Hence, most cases to date have occurred in children, who have little immunity against this virus.
The symptoms and severity of H3N2v have mostly been mild and similar to those of seasonal influenza (fever, cough, sore throat, body aches, etc.), but like seasonal influenza, serious illness with H3N2v infection is possible.22Vaccination remains key to preventing H3N2v infection. Additionally, the CDC has encouraged people at high risk of influenza complications to stay away from swine barns at the fair.26People who are at high risk of serious complications from influenza, including H3N2v virus infection, are: children <5 years old, people ≥65 years old, pregnant women, and people with certain chronic medical conditions (asthma, diabetes, heart disease, immunocompromised, and neurologic or neurodevelopmental conditions). The treatment of H3N2v virus infection is similar to that of seasonal influenza. NA inhibitors are the mainstay of treatment. The adamantanes should not be used due to high resistance.26
PATHOGENESIS
The route of influenza transmission is person-to-person via inhalation of respiratory droplets, which can occur when an infected person coughs or sneezes.26 Transmission may also occur if a person touches an object contaminated with respiratory secretions and then touches his or her mucus membranes. The incubation period for influenza ranges between 1 and 7 days, with an average incubation of 2 days.26 Transmission can occur for as long as the infected person is shedding virus from the respiratory tract. Adults are considered infectious within 1 day before until 7 days after onset of illness. Children, especially younger children, might potentially be infectious for longer periods (>10 days).22,27 Viral shedding can persist for weeks to months in severely immunocompromised people.
The pathogenesis of influenza in humans is not well understood. The severity of the infection is determined by the balance between viral replication and the host immune response.4 Severe illness is likely a result of both a lack of ability of host defense mechanisms to inhibit viral replication and an overproduction of cytokines leading to tissue damage in the host.28
CLINICAL PRESENTATION Diagnosis of Influenza
General
• The clinical diagnosis of influenza can be difficult because the presentation is similar to a number of other respiratory illnesses. The sensitivity of clinical diagnosis ranges from 38% for children to 77% for adults and largely depends on the relative prevalence of influenza and other respiratory viruses circulating in a community.29
• The clinical course and outcome are affected by age, immunocompetence, viral characteristics, smoking, comorbidities, pregnancy, and the degree of preexisting immunity.
• Complications of influenza may include exacerbation of underlying comorbidities, primary viral pneumonia, secondary bacterial pneumonia or other respiratory illnesses (e.g., sinusitis, bronchitis, otitis), encephalopathy, transverse myelitis, myositis, myocarditis, pericarditis, and Reye’s syndrome.
Signs and Symptoms
• Classic signs and symptoms of influenza include rapid onset of fever, myalgia, headache, malaise, nonproductive cough, sore throat, and rhinitis.
• Nausea, vomiting, and otitis media are also commonly reported in children.30
• Signs and symptoms typically resolve in approximately 3 to 7 days, although cough and malaise may persist for more than 2 weeks.
• Primary viral pneumonia, occurring predominantly in pregnant women and in those with underlying cardiovascular disease, usually begins with fever and dry cough, which changes to a productive cough of bloody sputum. This rapidly progresses to dyspnea, hypoxemia, and cyanosis with radiologic evidence of bilateral interstitial infiltrates.31
• Secondary bacterial pneumonia is usually seen in individuals with underlying pulmonary disorders and presents during the early stages of defervescence from the influenza infection. These patients usually present with fever, productive cough, and radiologic evidence of consolidation.31
Laboratory Tests
• Complete blood count and chemistry panels should be obtained to assess the overall status of the patient.
• The gold standard for diagnosis of influenza is viral culture, which can provide information on the specific strain and subtype. Viral culture has a high sensitivity but can take as long as a week to develop, limiting the clinical relevance of the results.
• Tests such as the rapid antigen and point-of-care (POC) tests, direct fluorescence antibody (DFA) test, and the reverse-transcription polymerase chain reaction (RT-PCR) assay may be used for rapid detection of virus.
Other Diagnostic Tests
• Cultures of potential sites of infection should be obtained if coinfection, superinfection, or secondary infection is suspected.
• Chest radiograph should be obtained if pneumonia is suspected.
Rapid Tests
• Rapid tests have allowed for prompt diagnosis and initiation of antiviral therapy and decreased inappropriate use of antibiotics. Rapid antigen or POC tests use enzyme immunoassay (EIA) technology to provide results within 1 hour of specimen collection. Appropriate specimens for collection, in decreasing order of sensitivity, are nasopharyngeal aspirates, nasopharyngeal swabs/washes, and oropharyngeal swabs.29 POC tests allow for differentiation of influenza viruses A and B, with sensitivity and specificity ranging from 57% to 90% and 65% to 99%, respectively.29 In general, use of POC tests is contraindicated in those who have had symptoms for longer than 3 days, and results may be confounded following recent immunization with live-attenuated influenza vaccine (LAIV).29
• DFA testing requires more technical expertise and infrastructure than POC tests. The advantages of DFA are increased sensitivity over POC tests and simultaneous detection of other respiratory viruses, such as respiratory syncytial virus and adenovirus.30 DFA provides results between 1 and 4 hours after specimen collection and may serve as a confirmatory assay for a POC test.
• RT-PCR assay is a nucleic acid amplification test and is the most sensitive, specific, and versatile diagnostic test for influenza.29 RT-PCR is replacing viral isolation as the reference standard and can determine the type, subtype, and strain of influenza. Results are provided within 4 to 6 hours of specimen collection.
PREVENTION
The best means to decrease the morbidity and mortality associated with influenza is to prevent infection through vaccination.26,27 Appropriate infection control measures, such as hand hygiene, basic respiratory etiquette (e.g., cover your cough, throw tissues away), and contact avoidance, are also important in preventing the spread of influenza. Additionally, chemoprophylaxis is useful in certain situations.
Vaccination
The primary means of influenza prevention employed in the United States is annual vaccination. Vaccination can help prevent hospitalization and death among those at high risk, decrease influenza-like illness, decrease visits to physicians’ offices and emergency rooms, decrease otitis media in children, and prevent school and/or work absenteeism. Annual vaccination is now recommended for all persons aged 6 months or older and caregivers (e.g., parents, teachers, babysitters, nannies) of children <6 months of age. Vaccination is also recommended for those who live with and/or care for people who are at high risk, including household contacts and healthcare workers.
The ideal time for all influenza vaccination is during October or November to allow for the development and maintenance of immunity during the peak of the influenza season.26,27 Table 87–1 lists the vaccination coverage rates and goals for various patient populations.
TABLE 87-1 Influenza Vaccination Rates and Goals by Patient Population26
The two vaccines currently available for prevention of seasonal influenza are the trivalent influenza vaccine (TIV) and the LAIV. Both vaccines contain two influenza A subtypes (H3N2 and H1N1) and influenza B virus; the specific strains included in the vaccine each year change based on antigenic drift. The viruses used for both vaccines are initially grown in embryonated hens’ eggs, which explain the precautionary measures for vaccination of persons with a severe allergic reaction to eggs.26 The Advisory Committee on Immunization Practices (ACIP) has made the following recommendations regarding the vaccinations of persons with reports of egg allergy: (a) vaccination with TIV rather than with LAIV for persons with a history of egg allergy that involves only hives. Vaccination should be done by a healthcare provider who is familiar with possible manifestations of egg allergy and the recipient should be observed for at least 30 minutes after dose. (b) Persons with severe allergic reactions such as angioedema, respiratory distress, light-headedness, or recurrent emesis or required epinephrine after an egg exposure should be referred to a physician with expertise in the management of allergic reactions for the receipt of an influenza vaccination. (c) Severe allergic reaction to influenza vaccine is a contraindication to receiving future vaccinations.26 The CDC encourages individuals to use the Vaccine Adverse Event Reporting System to aide in collecting and analyzing adverse events following influenza vaccinations.26
Trivalent Influenza Vaccine
Intramuscular TIV is FDA approved for use in people older than 6 months of age, regardless of their immune status. Of note, several commercial products are available and are approved for different age groups (Table 87–2). The intradermal vaccine, Fluzone Intradermal®, is approved by FDA for use in adults 18 to 64 years of age and is another vaccination option for people in this age group. TIV is made with killed viruses, meaning it cannot cause signs and symptoms of influenza-like illness (Table 87–3). Age and immune status can affect the efficacy of TIV as can the similarity of the vaccine to the viruses in circulation. Afluria® brand of TIV vaccine is contraindicated in patients with hypersensitivity to neomycin or polymyxin. Afluria® is also not recommended first line in children 6 months to 8 years, due to reports of high febrile episodes following administration.26,32
TABLE 87-2 Approved Influenza Vaccines for Different Age Groups—United States, 2012–2013 Season26
TABLE 87-3 Comparison of Trivalent (TIV) and Live-Attenuated Influenza Vaccine (LAIV)
In children between 6 and 24 months of age, a 2-year randomized study of intramuscular TIV exhibited 89% seroconversion and efficacy of 66% in year 1 and 7% in year 2 versus culture-confirmed influenza.33 In children between 1 and 15 years of age, the efficacy of TIV was 91.4% and 77.3% against culture-confirmed influenza A H1N1 and H3N2, respectively. Two doses of TIV are important for children under the age of 9 years, supporting the rationale for the recommendation of a booster dose of TIV at least 1 month after the initial dose in children between 6 months and less than 9 years of age (see Table 87–2).26
TIV is also effective in adult populations under and older than the age of 65 years. A double-blind, randomized controlled trial evaluating intramuscular TIV in healthy adults younger than the age of 65 years demonstrated an efficacy of 50% against serologically confirmed influenza during a season in which the vaccine and the circulating viruses were not well matched and an efficacy of 86% during a season in which the vaccine and the circulating viruses were well matched.34 These findings were corroborated by a large Cochrane Database System review, which found that TIV had an efficacy of 70% in healthy adults younger than 65 years of age, regardless of virus and vaccine concordance.35 Vaccination of those younger than 65 years old during seasons when the virus and vaccine are well matched results in decreased work absenteeism and healthcare resource use.34,35
Intradermal TIV in adults 18 to 64 years of age provides immune response similar to the intramuscular injection.36 Both vaccines were similar in their safety profile. In clinical trials Fluzone® intradermal was noninferior to Fluzone® intramuscular in eliciting immune response as measured by hemagglutination inhibition antibody geometric mean titers (GMTs).36 The rate of seroconversion was similar between the two vaccines against influenza strains A (H1N1 and H3N2), but not for strain B. The most common adverse reactions were injection site related, which were transient (resolving in 3 to 7 days), and include erythema (>75%), swelling (>50%), induration (>50%), pain (>50%), and pruritus (>40%). Compared with the intramuscular vaccine, Fluzone® intradermal contains 40% less antigen (Table 87–2).
Adults older than the age of 65 years benefit from influenza vaccination, including prevention of complications and decreased risk of influenza-related hospitalization and death. However, people in this population may not generate a strong antibody response to the vaccine and may remain susceptible to infection. In patients older than the age of 60 years who do not reside in a long-term care facility, TIV efficacy was 58% against influenza illness.26Although the efficacy against influenza illness for those living in long-term care facilities is between 30% and 40%, the vaccine is 50% to 60% effective in preventing influenza-related hospitalization or pneumonia and 80% effective in preventing influenza-related death.26
The most frequent adverse effect associated with TIV is soreness at the injection site that lasts for less than 48 hours. TIV may cause fever and malaise in those who have not previously been exposed to the viral antigens in the vaccine.26 Allergic-type reactions (hives, systemic anaphylaxis) rarely occur after influenza vaccination and are likely a result of a reaction to residual egg protein in the vaccine.
The 1976 swine influenza vaccine was linked to a rise in the incidence of Guillain-Barré syndrome (GBS), and this has propagated the belief that TIV may cause GBS.26 However, there is insufficient evidence to establish causality. Although several studies have failed to establish a relationship between influenza vaccination and increased frequency of GBS, two studies have demonstrated a small but significant increase in GBS following influenza vaccination.37,38 Therefore, vaccination should be avoided in persons who are not at high risk for influenza complications and who have experienced GBS within 6 weeks of receiving a previous influenza vaccine.26 The potential benefits of influenza vaccination in terms of prevention of severe illness, hospitalization, and mortality significantly outweigh the risks of GBS, and vaccination is recommended for all groups previously discussed.
The multidose vials and a few of the single-dose preparations of intramuscular TIV contain trace to small amounts of a preservative, thimerosal, which is a mercury-containing compound (see Table 87–2). Some individuals are concerned about thimerosal exposure, particularly among children, because of the unfounded belief that thimerosal exposure is linked to the development of autism. No scientifically persuasive evidence exists to suggest harm from thimerosal exposure from a vaccine. Conversely, accumulating evidence reports the lack of harm from such exposure.39–41 Thus, similar to GBS, the potential benefits of influenza vaccination in terms of prevention of severe illness, hospitalization, and mortality significantly outweigh the theoretical risk associated with thimerosal exposure, and vaccination is recommended for all groups previously discussed. However, to maximize the public health benefit and placate concerned individuals, thimerosal-free vaccine is available (see Table 87–2).
Live-Attenuated Influenza Vaccine
LAIV is made with live, attenuated viruses and is approved for intranasal administration in healthy people between 2 and 49 years of age (see Table 87–3). Advantages of LAIV include its ease of administration, intranasal rather than intramuscular administration, and the potential induction of broad mucosal and systemic immune response.26 The mucosal response occurs at the site of viral entry and may prevent infection before viral replication occurs. LAIV is more expensive than TIV and is approved for use in a more limited population.
Controlled studies support the use of LAIV in healthy people between the ages of 2 and 49 years. Although LAIV was previously FDA approved for children who were at least 5 years old, three pivotal trials led the FDA to approve LAIV for children who were at least 2 years old.42 LAIV recipients aged 2 to 5 years had 52.5% and 54.4% fewer cases of influenza illness against matched and mismatched strains, respectively, as compared with TIV recipients.
Although LAIV is FDA approved for adults younger than the age of 49 years, LAIV is effective in healthy adults between 18 and 64 years old.43 Vaccination reduced the number of severe febrile illnesses by 18.8% and febrile upper respiratory tract illnesses by 23.6%.43 Additionally, vaccination led to fewer days of illness, fewer days lost from work, fewer visits to healthcare providers, and decreased use of prescription antibiotics and nonprescription medications.43
The adverse effects typically associated with LAIV administration include runny nose, congestion, sore throat, and headache. Because LAIV contains live, attenuated viruses, viral shedding may occur for several days following vaccination with LAIV, although this should not be equated with person-to-person transmission.26 Additionally, because LAIV contains live-attenuated viruses, which carry a theoretical infection risk, LAIV should not be given to immunosuppressed patients or given by healthcare workers who are severely immunocompromised. Moreover, for the reasons discussed in Trivalent Influenza Vaccine above, LAIV should not be administered to persons with a history of GBS or hypersensitivity to eggs.
In February 2012, the FDA approved FluMist® Quadrivalent vaccine for influenza prevention in people aged 2 to 49 years.44 FluMist® Quadrivalent vaccine contains four strains of the influenza viruses, two influenza A strains and two influenza B strains. This is the first influenza vaccine of this modality. The inclusion of a second B strain in the vaccine is thought to increase the likelihood of adequate protection against circulating influenza B strains. Like the already approved FluMist® trivalent, the quadrivalent vaccine is made of attenuated viruses and is administered as a spray into the nose. Studies of FluMist®trivalent, in addition to three new clinical trials with the quadrivalent vaccine in 4,000 children (2 to 17 years) and adults (18 to 49 years) in the United States, provide supporting evidence on the efficacy and safety of FluMist® Quadrivalent.44 The studies showed that immune responses were similar between FluMist® Quadrivalent and FluMist® trivalent. Also, adverse reactions reported were similar among those receiving FluMist® Quadrivalent and FluMist® trivalent. The most commonly reported adverse reactions were runny or stuffy nose in both children and adults, and headache and sore throat in adults. The quadrivalent vaccine will replace the trivalent LAIV formulation for the 2013 to 2014 influenza season (Table 87–2).
Clinical Controversy…
LAIV is not recommended in several populations, including people older than 50 years and pregnant women, largely because the vaccine has not been studied extensively in these populations. However, many clinicians believe the use of LAIV in these populations is acceptable.
Postexposure Prophylaxis
Antiviral drugs available for prophylaxis of influenza should be considered adjuncts but are not replacements for annual vaccination. Historically, the adamantanes and NA inhibitors are two classes of antiviral drugs available for influenza prophylaxis and treatment. However, the adamantanes are no longer recommended for prophylaxis or treatment in the United States (because of widespread resistance among influenza viruses) until susceptibility is reestablished among influenza A virus.45–47 Both of the NA inhibitors, oseltamivir and zanamivir, are effective prophylactic agents against influenza in terms of preventing laboratory-confirmed influenza when used for seasonal prophylaxis (67% and 85% effective for zanamivir and oseltamivir, respectively) and preventing influenza illness among persons exposed to a household contact who was diagnosed with influenza (79% to 81% and 68% to 89% effective for zanamivir and oseltamivir, respectively).38,48,49 Additionally, oseltamivir was 92% effective against influenza and also reduced associated complications when used as seasonal prophylaxis among immunized, institutionalized, elderly patients.50 Both of these agents remain active against all influenza viruses, including influenza A H3N2v (Tables 87–4 and 87-5). During the time of pandemic H1N1 influenza in 2009, the FDA expanded the use of oseltamivir to children 3 months or older under its emergency use authorization (EUA) guidance. However, the EUA has since expired in June 2010 and oseltamivir is limited to its approved indications in individuals aged 1 year or above. In practice, clinicians continue to apply the expanded dosage recommendations for children 3 to 11 months of age, which are endorsed by the American Academy of Pediatrics and Pediatric Infectious Diseases Society (PIDS).27,47 Table 87–6gives dosing recommendations.
TABLE 87-4 Antiviral Susceptibilities of Circulating Viruses
TABLE 87-5 Interim Recommendations for the Selection of Antiviral Treatment Based on Confirmed Influenza Subtypes45,47
TABLE 87-6 Recommended Daily Dosage of Influenza Antiviral Medications for Treatment and Prophylaxis—United States27,45,47
In those patients who did not receive the influenza vaccination and are receiving an antiviral drug for prevention of disease during the influenza season, the medication should optimally be taken for the entire duration of influenza activity in the community. The use of prophylaxis requires clinical judgment and depends on a variety of factors, but prophylaxis for seasonal influenza should be considered during influenza season for the following groups of patients:
1. Persons at high risk of serious illness and/or complications who cannot be vaccinated
2. Persons at high risk of serious illness and/or complications who are vaccinated after influenza activity has begun in their community since the development of sufficient antibody titers after vaccination takes approximately 2 weeks
3. Unvaccinated persons who have frequent contact with those at high risk
4. Persons who may have an inadequate response to vaccination (e.g., advanced human immunodeficiency virus [HIV] disease)
5. Long-term care facility residents, regardless of vaccination status, when an outbreak has occurred in the institution
6. Unvaccinated household contacts of someone who was diagnosed with influenza
Prophylaxis for novel H1N1 influenza should be considered in the following groups:
1. Persons at high risk of serious illness and/or complications who have had close contact with persons with laboratory-confirmed or clinically confirmed novel H1N1 infection during those persons’ infectious period
2. Healthcare/public health personnel who have had recognized, unprotected close contact with persons with laboratory-confirmed or clinically confirmed novel H1N1 infection during those persons’ infectious period
LAIV should not be administered until 48 hours after influenza antiviral therapy has stopped, and influenza antiviral drugs should not be administered for 2 weeks after the administration of LAIV because the antiviral drugs inhibit influenza virus replication.38 No contraindication exists for concomitant use of TIV and influenza antiviral drugs.
Pregnant Women and Immunocompromised Hosts
Pregnant women and immunocompromised hosts are special populations at increased risk of influenza complications and are also populations in whom careful consideration must be given in regard to prevention strategies.
Pregnant women, regardless of trimester, should receive annual influenza vaccination with TIV but not with LAIV.26 No studies have demonstrated an increased incidence of adverse effects in mothers or their infants related or potentially related to TIV, but no such data exist for LAIV.51 TIV is also safe for breast-feeding mothers. No data exist for LAIV and breast-feeding, but caution is warranted because of the potential for viral shedding.26
Immunocompromised hosts should receive annual influenza vaccination with TIV but not with LAIV. TIV was 100% effective against laboratory-confirmed influenza in HIV-positive patients with no significant effect on viral load or CD4 cell count.52 However, antibody titers may not be as high as in immunocompetent individuals and are not improved with a second dose of vaccine.53 Similarly, antibody titers may not be as high in solid-organ transplant patients as in immunocompetent persons, but, conversely, antibody titers were increased significantly after a second dose of TIV in adult liver transplant patients.54 Although this suggests a potential benefit from a two-dose regimen, such a regimen is not currently recommended for solid-organ transplant recipients. Data are currently limited in this arena for the intradermal TIV. In a study of intradermal TIV involving immunocompromised patients compared with healthy controls, humoral responses (GMTs and protection rates [PRs]) were significantly better among healthy controls than those among immunocompromised patients.55 This is not surprising given an already attenuated immune system. But it was also noted that compared with the standard intramuscular TIV, GMTs and PRs were similar within all tested groups. Immune response to vaccine may be less than desired in immunocompromised patients.26
Large clinical trials evaluating the use of influenza antivirals for prophylaxis are lacking in immunocompromised hosts. Viral shedding occurs for prolonged periods in this population and may promote the development of antiviral resistance, which has already been documented with oseltamivir in HIV-positive patients.56,57
TREATMENT
When prevention efforts fail or are not used, clinicians must turn to the agents available for treatment of influenza. Currently, the antiviral treatment options are limited, particularly in the face of resistance to the adamantanes and oseltamivir.
Goals of Therapy
The four primary goals of therapy of influenza are to control symptoms, prevent complications, decrease work and/or school absenteeism, and prevent the spread of infection.
General Approach to Treatment
In the era of pandemic preparedness and increasing resistance, early and definitive diagnosis of influenza is crucial. 
The currently available antiviral drugs are most effective if started within 48 hours of the onset of illness. Moreover, the sooner the antiviral drugs are started after the onset of illness, the more effective they are. Antiviral drugs shorten the duration of illness and provide symptom control. Adjunct agents, such as acetaminophen for fever or an antihistamine for rhinitis, may be used concomitantly with the antiviral drugs.
Nonpharmacologic Therapy
Patients suffering from influenza should get adequate sleep and maintain a low level of activity. They should stay home from work and/or school in order to rest and prevent the spread of infection. Appropriate fluid intake should be maintained. Cough/throat lozenges, warm tea, or soup may help with symptom control (cough, sore throat).
Pharmacologic Therapy
The NA inhibitors are the only antiviral drugs available for treatment and prophylaxis of influenza and are oseltamivir and zanamivir. IV peramivir is another NA inhibitor under investigation for treatment of influenza. The adamantanes (amantadine and rimantadine) are no longer recommended due to high resistance among influenza viruses. A limited discussion of adamantanes and peramivir can be found below, but the focus will be on oseltamivir and zanamivir.
Adamantanes
The adamantanes (amantadine and rimantadine) block the M2 ion channel, which is specific to influenza A viruses, and inhibit viral uncoating. Historically, the adamantanes were used for the treatment of seasonal influenza A H1N1, as they do not have activity against influenza A H3N2 or influenza B viruses. The novel influenza A H1N1 that emerged during the 2009 to 2010 influenza season, which has now replaced seasonal influenza A H1N1 as the predominant seasonal virus, was found to be discriminatorily resistant to the adamantanes. Data from the 2009 to 2010 influenza season showed that 81.8% of influenza A (H3N2) and 99.6% of influenza A (2009 H1N1) strains were resistant to adamantanes.58 As a result, the CDC only recommends the use of NA inhibitors for the treatment and prophylaxis of influenza A, until susceptibility of adamantanes is reestablished among influenza A viruses. Resistance to adamantanes is often conferred by a single point mutation, and this is problematic because it results in cross-resistance to the entire class.45,46
Neuraminidase Inhibitors
Oseltamivir and zanamivir are NA inhibitors that have activity against both influenza A and influenza B viruses.45,46 Without NA, release of the virus from infected cells is impaired, and, thus, viral replication is decreased. When administered within 48 hours of the onset of illness, oseltamivir and zanamivir may reduce the duration of illness by approximately 1 day versus placebo.45 In a pivotal trial, oseltamivir reduced the time to return to normal health in adults by 1.9 days and the time to return to normal activity by 2.8 days.59 These reductions have a significant effect on not only the quality of life for the patient but also the societal costs associated with influenza. Of note, the benefits of treatment are highly dependent on the timing of the initiation of treatment, with the ideal initiation period being within 12 hours of illness onset.60
Oseltamivir treatment in adults and adolescents with documented influenza illness resulted in a 26.7% reduction in overall antibiotic use, a 55% reduction in lower respiratory tract complications (bronchitis, pneumonia), and a 59% reduction in hospitalizations.61 Zanamivir treatment in adults and adolescents with influenza-like illness resulted in a 28% reduction in antibiotic use and a 40% reduction in lower respiratory tract complications.62 The data in these studies largely come from healthy individuals rather than those at highest risk for complications associated with influenza. The impact of appropriate treatment in high-risk populations may be even greater than that which has been documented to date.
Oseltamivir is approved for treatment in those older than the age of 1 year, while zanamivir is approved for treatment in those older than the age of 7 years. During the H1N1 pandemic in 2009, the FDA issued an EUA for oseltamivir that expanded its use in children younger than 1 year of age. The EUA has since expired on June 23, 201063; however, the dosages in children 3 to 11 months are still used in clinical practice.27 The recommended doses vary by agent and age (see Table 87–6), and the recommended duration of treatment for both oseltamivir and zanamivir is 5 days.
During 2009 H1N1 influenza pandemic, FDA allowed the use of investigational peramivir for the treatment of hospitalized adult and pediatric patients under its EUA.64 However, like oseltamivir, this EUA has expired63 and individuals in need of peramivir therapy will have to be enrolled in an ongoing study. Preliminary data suggest that peramivir is as effective as oseltamivir, without severe adverse events. Based on an observational study, the 14-day, 28-day, and 56-day survival rates of 31 patients with severe 2009 H1N1 infection treated with peramivir were 77%, 67%, and 59%, respectively.65 The most common adverse event reported was rash.66
Neuropsychiatric complications consisting of delirium, seizures, hallucinations, and self-injury in pediatric patients (mostly from Japan) have been reported following treatment with oseltamivir.67–69 Since influenza itself can be associated with neuropsychiatric manifestations, a causal relationship between oseltamivir and neuropsychiatric effects has not been delineated.66,67 However, the label for oseltamivir has been updated to include neuropsychiatric events as a precaution,67 and their occurrence with use of oseltamivir should not be ignored.
Influenza resistance to the NA inhibitors has been documented but cross-resistance between the NA inhibitors has not been reported.45 Antiviral resistance remains relatively low. During the 2011 to 2012 influenza season, 98.6% of the tested 2009 H1N1 viruses were susceptible to oseltamivir, and 100% of the 2009 H1N1 viruses tested were susceptible to zanamivir; 100% of influenza A (H3N2) tested were susceptible to both oseltamivir and zanamivir; and 100% of influenza B viruses tested were susceptible to both oseltamivir and zanamivir.70 Antiviral susceptibility testing of circulating viruses confirmed that seasonal influenza A H3N2 and variant influenza H3N2 maintain susceptibility to oseltamivir and zanamivir.23,24 The burden of surveillance rests on clinicians to identify local patterns of influenza circulation to guide antiviral therapy.
Clinical Controversy…
Some clinicians debate the cost–benefit of the use of diagnostic tests for influenza as well as treatment of influenza in otherwise healthy individuals who are likely to experience resolution without treatment. This controversy is compounded by the fact that the diagnostic tests and the benefits associated with treatment of influenza are highest early in the disease process and many patients present after this time period.
Special Populations
Inadequate data exist regarding the use of antiinfluenza medications in special populations, such as immunocompromised hosts. Furthermore, limited data exist regarding use of influenza antivirals during pregnancy. The adamantanes are embryotoxic and teratogenic in rats, and limited case reports of adverse fetal outcomes following amantadine use in humans have been published. Oseltamivir and zanamivir have been used but lack solid safety clinical data in pregnant women. Pregnancy should not be considered a contraindication to oseltamivir or zanamivir use. Oseltamivir is preferred for treatment of pregnant women because of its systemic activity; however, the drug of choice for chemoprophylaxis is not yet defined. Zanamivir may be preferred because of its limited systemic absorption, but respiratory complications need to be considered, especially in women with underlying respiratory diseases. Both the adamantanes and the NA inhibitors are excreted in breast milk and should be avoided by mothers who are breast-feeding their infants. More studies are needed in these populations who are at high risk for serious disease and complications from influenza.
Clinical Controversy…
Some debate exists regarding the benefit of antiviral administration >48 hours after onset. While clinicians agree that the most benefit is achieved the earlier the medications are started, some data suggest benefit even beyond 48 hours after onset, albeit more limited.
PANDEMIC PREPAREDNESS
This chapter is not meant to provide an exhaustive review of the biology of influenza or pandemic preparedness. This topic is rapidly changing and interested readers are referred to the following websites: www.flu.gov, www.who.int/influenza/human_animal_interface/en/, and www.cdc.gov/h1n1flu.
A vital component of pandemic preparedness is forethought—plans must be established for how to effectively triage large numbers of ill patients, prioritize and/or ration vaccine and antivirals, and communicate with the public through mass media during a period of severe labor shortage (a result of stress and illness among healthcare workers) and supply shortfall (a result of societal and economic disruption).
EVALUATION OF THERAPEUTIC OUTCOMES
Patients should be monitored daily for resolution of signs and symptoms associated with influenza, such as fever, myalgia, headache, malaise, nonproductive cough, sore throat, and rhinitis. These signs and symptoms will typically resolve within approximately 1 week. If the patient continues to exhibit signs and symptoms of illness beyond 10 days or a worsening of symptoms after 7 days, a physician visit is warranted as this may be an indication of a secondary bacterial infection. Ideally, antiviral therapy should not be started until influenza is confirmed via the laboratory. However, therapy should be initiated within 48 hours of illness onset, emphasizing the need for rapid diagnosis. Repeat diagnostic tests to demonstrate clearance of the virus are not necessary.
ABBREVIATIONS
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