Influenza

Jessica C. Njoku and Elizabeth D. Hermsen

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.² Similarly, 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.² In 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.^4–6 Although 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.²² Vaccination 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.²⁶ People 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