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Influenza: Epidemiology and pathogenesis

Influenza: Epidemiology and pathogenesis
Literature review current through: May 2024.
This topic last updated: Apr 25, 2024.

INTRODUCTION — Influenza is an acute viral respiratory disease that affects individuals of all ages worldwide.

The epidemiology of influenza, including morbidity and mortality, will be reviewed here. Other information related to influenza is discussed separately:

(See "Seasonal influenza in adults: Clinical manifestations and diagnosis".)

(See "Seasonal influenza in nonpregnant adults: Treatment".)

(See "Seasonal influenza in adults: Role of antiviral prophylaxis for prevention".)

(See "Seasonal influenza vaccination in adults".)

(See "Seasonal influenza and pregnancy".)

(See "Seasonal influenza in children: Clinical features and diagnosis".)

(See "Seasonal influenza in children: Management".)

(See "Seasonal influenza in children: Prevention with antiviral drugs".)

(See "Seasonal influenza in children: Prevention with vaccines".)

(See "Avian influenza: Epidemiology and transmission".)

(See "Avian influenza: Clinical manifestations and diagnosis".)

(See "Avian influenza: Treatment and prevention".)

EPIDEMIOLOGY

Transmission — Issues related to transmission and incubation period are discussed separately. (See "Infection control measures for prevention of seasonal influenza", section on 'Transmission'.)

Risk factors for complications — Groups at increased risk for influenza complications are summarized in the table (table 1).

In one regression analysis including more than 33,000 laboratory-confirmed influenza-associated hospitalizations, the adjusted odds ratio (aOR) for hospitalization among patients ≥65 years of age (relative to patients 5 to 17 years of age) was 9.2 (95% CI 8.7-9.7) [1]. African Americans had aOR of 1.67 (95% CI 1.60-1.73) compared with Whites, and Hispanics had aOR of 1.21 (95% CI 1.16-1.26) compared with non-Hispanics.

Seasonal influenza epidemics — An influenza epidemic occurs when influenza activity in a region is higher than the baseline level of influenza activity during months when influenza viruses are not widely circulating in humans [2]. A seasonal epidemic of influenza occurs nearly every year in the United States.

Factors influencing the severity of a given influenza season are often uncertain; factors include transmissibility of the virus and the susceptibility of the population.

Temperate versus tropical climates — Patterns of influenza activity differ by geographic region:

Temperate climates − In temperate climates, human influenza A and B viruses cause seasonal epidemics of disease, typically during the winter months (in the Northern hemisphere: October to March (figure 1); in the Southern hemisphere: April to September). Less commonly, individual influenza infections and outbreaks occur during warm weather months.

Influenza A epidemics typically begin abruptly, peak over a two- to three- week period, and last for two to three months. In most seasons, the earliest indication of influenza activity occurs among children. (See "Seasonal influenza in adults: Clinical manifestations and diagnosis".)

Between seasonal epidemics, how influenza virus persists remains poorly understood. Episodes of sporadic illness may be caused by influenza (but not diagnosed as such) or influenza may be imported from geographically distant sites.

Tropical climates − In tropical and subtropical climates, influenza activity may occur year-round, often peaking during cooler or rainy-season months [3,4].

Burden of illness

United States – In the United States between 2010 and 2020, an estimated 9 to 45 million illnesses, 4 to 21 million medical visits, 140,000 to 810,000 hospitalizations, and 12,000 to 61,000 deaths occurred during annual seasonal influenza epidemics [5]. On average, approximately 8 percent of the United States population develops symptomatic influenza illness each season (range 3 to 11 percent) [6].

In the United States during the 2023 to 2024 influenza season, there were [7]:

33 to 61 million illnesses

15 to 28 million medical visits

370,000 to 770,000 hospitalizations

24,000 to 67,000 deaths

Worldwide − In a global modeling study using death records and surveillance data to estimate mortality in 33 countries between 1999 and 2015, the estimated mean annual influenza-associated mortality rates were 0.1 to 6.4 per 100,000 individuals among those <65 years of age, 2.9 to 44.0 per 100,000 among 65 to 74 years, and 17.9 to 223.5 per 100,000 among those ≥75 years of age [8].

The highest estimated mortality rates were in sub-Saharan Africa (2.8 to 16.5 per 100,000), Southeast Asia (3.5 to 9.2 per 100,000), and among individuals ≥75 years of age (51.3 to 99.4 per 100,000). In addition, it was estimated that 291,000 to 645,000 seasonal influenza-associated deaths occur annually worldwide (4.0 to 8.8 per 100,000). These estimates are higher than previous estimates, likely due to the inclusion of resource-limited countries in the analysis.

Effect of COVID-19 pandemic — During the coronavirus disease 2019 (COVID-19) pandemic between October 2020 and May 2021, influenza activity was lower than during any previous influenza season in the United States since 1977 (the first season for which data are available). Among more than 1 million specimens tested during this period, 0.05 percent were positive for influenza, of which 60 percent were positive for influenza A and 40 percent were positive for influenza B [9]. Activities of several other common viral respiratory pathogens also decreased during this time.

The reasons for the reduced activity of influenza and other common respiratory viruses are uncertain; a number of alterations in human behavior (reduced travel, mask use, and physical distancing) may have played a part [9].

VIROLOGY — Human influenza A and B viruses cause seasonal epidemics of disease nearly every winter in temperate climates [10]. Both influenza A and B viruses can cause illnesses ranging from mild to severe. Influenza C virus is a relatively uncommon cause of respiratory illness [11].

Influenza A

Surface proteins — Influenza viruses bind to receptors on the surface of respiratory epithelial cells through the hemagglutinin glycoprotein for initiation of infection.

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

In humans, three major subtypes of hemagglutinins (H1, H2, and H3) and two subtypes of neuraminidases (N1 and N2) have been described. Influenza A virus subtypes that routinely circulate in humans include A(H1N1) and A(H3N2).

More than 130 influenza A subtype combinations have been identified in nature, primarily from wild birds. There are many more potential combinations given the propensity for virus reassortment, a process by which influenza viruses swap gene segments. Reassortment can occur when two influenza viruses infect a single cell in a host at the same time and swap genetic information.

Influenza A viruses are the only influenza viruses known to cause global influenza pandemics. A pandemic can occur when a new influenza A virus emerges that has the ability to spread efficiently among humans.

Influenza A viruses are found in many different animals, including birds, pigs, and other animals. (See 'Role of animals' below.)

Antigenic drift and shift — Antigenic “drift” refers to minor HA or NA gene mutations causing changes in the viral protein antigenicity. Antibodies (produced in response to prior infection or vaccination) do not bind well to antigenically drifted virus strains. Therefore, antigenic drift drives seasonal epidemics, necessitating year-round and worldwide influenza surveillance and annual updating of vaccine antigens.

Antigenic “shift” refers to major HA or NA gene mutations, leading to emergence of a novel influenza A virus that is antigenically and genetically distinct from viruses previously circulating in humans. Novel influenza A viruses can cause sporadic human infections from exposure to infected animals (usually birds or pigs); in addition, these viruses are capable of causing pandemics if most of the population lacks immunity to the novel virus. (See 'Global pandemics' below.)

Influenza B — Influenza B viruses are classified into two lineages: B/Yamagata and B/Victoria. In general, the genetic and antigenic properties of influenza B viruses change more slowly than influenza A viruses.

Influenza B viruses circulate widely only in humans.

PANDEMIC AND EMERGING VIRUSES

Global pandemics — An influenza pandemic is a global outbreak of an influenza A virus that is very different from recent circulating seasonal influenza A viruses [12]. Pandemics occur when viruses emerge which have not previously infected large segments of the population and are able to spread from person to person in an efficient and sustained fashion. Because such viruses may be relatively new to large segments of the population, very few individuals may have immunity, and an effective vaccine may not be widely available.

A brief timeline of influenza pandemics is summarized below (table 2) [13]:

1918-1919 pandemic (H1N1) – The 1918-1919 influenza pandemic was caused by an H1N1 virus with genes of avian origin [14]; there is no consensus regarding where it originated [15]. It is estimated that about 500 million people (one-third of the world’s population) became infected with this virus [16].

The number of deaths was estimated to be at least 50 million worldwide, with about 675,000 deaths in the United States. Mortality was high in people <5 years, 20 to 40 years, and ≥65 years of age (figure 2) [17,18]. The high mortality among healthy younger adults was a unique feature of this pandemic. The properties that made it so devastating are not well understood.

With no protective vaccine and no antibiotics for treatment of secondary bacterial infections, control efforts were limited to interventions such as isolation, personal hygiene, use of masks and disinfectants, and limitations of public gatherings. Human influenza virus was first isolated and identified in 1933.

1957-1958 pandemic (H2N2) − In 1957, a new influenza A (H2N2) virus emerged in East Asia [19]. This virus was comprised of three different genes from an H2N2 virus that originated from an avian influenza A virus, including the H2 hemagglutinin and the N2 neuraminidase genes. It was first reported in Singapore in February 1957, Hong Kong in April 1957, and in coastal cities in the United States in summer 1957. The estimated number of deaths was 1.1 million worldwide, with 116,000 deaths in the United States.

1968-1969 pandemic (H3N2) − The 1968 pandemic was caused by an influenza A (H3N2) virus comprised of two genes from an avian influenza A virus, including a new H3 hemagglutinin, but also contained the N2 neuraminidase from the 1957 H2N2 virus. It was first noted in the United States in September 1968. The estimated number of deaths was 1 million worldwide and about 100,000 in the United States. Most excess deaths were in people 65 years and older. The H3N2 virus continues to circulate worldwide as a seasonal influenza A virus [20].

1977-1978 pandemic (H1N1) − In 1977, a new influenza A virus emerged that had shifted to H1N1. It was first reported in China, followed by Siberia and the Soviet Union. The resulting epidemic affected primarily young individuals born since 1957. Influenza A H1N1 strains circulating between 1918 and 1957 were replaced in 1957 first by H2N2, then H3N2 strains, leaving, in 1977, those under 20 to 25 years of age susceptible to H1N1. The 1977-78 H1N1 pandemic, which occurred primarily in young adults, resulted in approximately 700,000 deaths. Since 1977, H1N1 and H3N2 subtypes have cocirculated as seasonal influenza [21].

2009-2010 pandemic (H1N1) – In the spring of 2009, a novel influenza A virus was first detected in the United States and spread quickly across the world [22]. This new virus, designated (H1N1)pdm09 virus, contained a unique combination of influenza genes not previously identified in animals or humans. This virus had two genes from influenza viruses that normally circulate in pigs in Europe and Asia, three genes that normally circulate in North American pigs, as well as genes from influenza viruses from birds and humans [23].

Few young people had any existing immunity (as detected by antibody response) to the (H1N1)pdm09 virus, but nearly one-third of people >60 years old had antibodies against this virus, likely from prior exposure to an H1N1 virus earlier in their lives.

Vaccination with seasonal influenza vaccines offered little cross-protection against infection with this virus, even though they contained H1N1 strains. A monovalent vaccine was produced but was not available in large quantities until after the peak of illness had come and gone in the United States.

Between April 2009 and April 2010, the United States Centers for Disease Control and Prevention (CDC) estimated there were more than 60 million cases, 274,000 hospitalizations, and 12,000 deaths in the United States [24]. Worldwide, an estimated 284,400 (range 151,700 to 575,400) people died from infection during the first year it circulated [25].

Globally, 80 percent of deaths related to (H1N1)pdm09 virus were estimated to have occurred in people <65 years of age. This differs from typical seasonal influenza epidemics, during which about 70 percent to 90 percent of deaths are estimated to occur in people ≥65 years of age.

In August 2010, the World Health Organization (WHO) declared an end to the 2009 (H1N1)pdm09 virus pandemic. However, this virus continues to circulate worldwide as a seasonal influenza virus.

Role of animals — Influenza A viruses are found in many different animals, including pigs, birds, and other animals. A number of pandemics have been attributed to influenza virus strains with genes originating from animals. (See 'Global pandemics' above.)

Pigs – Pigs can be infected with influenza A viruses (known as swine influenza A viruses) [26]. These viruses are different from influenza A viruses that spread among humans. Rarely, influenza viruses can spread between pigs and humans. Since 2005, more than 500 infections with swine influenza viruses have been identified in the United States.

H3N2 variant influenza – H3N2v is a nonhuman influenza virus that normally circulates in pigs but has also infected humans. Infection with H3N2v has been associated with prolonged exposure to pigs at agricultural fairs. The severity of human illness associated with H3N2v resembles that of seasonal flu.

In 2011, an H3N2 virus was detected in the United States with genes from avian, swine, and human viruses, including the 2009 H1N1 pandemic virus M gene [27]. The acquisition of the 2009 M gene may allow this virus to infect humans more easily than other swine influenza viruses.

Sporadic infections with H3N2v have continued to be detected since. In the fall of 2021, a university outbreak included 745 cases [28]. In August 2022, five cases were reported [29].

Individuals born after 2001 have little to no immunity against H3N2v influenza. Individuals born before 2001 seem to have more immunity, perhaps because they might have been previously exposed to similar viruses in their lifetimes. Development of a vaccine against H3N2v is underway.

Other viruses associated with pigs – In August 2023, two human infections with influenza viruses from pigs were reported [30]. One case was a presumptive influenza A(H3)v virus infection; the other was a confirmed influenza A(H1N2)v virus infection [31]

Birds - Issues related to avian influenza are discussed further separately. (See "Avian influenza: Epidemiology and transmission".)

Tracking tools — The CDC, in collaboration with the WHO and its reporting network, tracks influenza virus isolates throughout the world. Surveillance information, which is updated weekly during influenza season, is available via the CDC through its website. In addition, FluNet, a database for global influenza virus surveillance, is available via the WHO website.

PATHOGENESIS — The pathogenesis of disease caused by influenza virus is not completely understood, particularly in molecular terms. Initial viral infection occurs in the upper respiratory columnar epithelium and then spreads distally in airways. Cell damage and death occurs through inhibition of host cell protein synthesis and induction of apoptotic changes in various cell types. Influenza infection may also result in secondary bacterial pneumonia, most commonly with Streptococcus pneumoniae or Staphylococcus aureus [32].

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (See "Patient education: Flu (The Basics)".)

Beyond the Basics topic (see "Patient education: Influenza symptoms and treatment (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Seasonal influenza epidemics

Definition − An influenza epidemic occurs when regional influenza activity is higher than the baseline level of influenza activity during months when influenza viruses are not widely circulating in humans. A seasonal influenza epidemic occurs in the United States nearly every year. (See 'Seasonal influenza epidemics' above.)

Temperate versus tropical climates (see 'Temperate versus tropical climates' above)–

-In temperate climates, human influenza A and B viruses cause seasonal epidemics of disease, typically during the winter months (in the Northern hemisphere: October to March (figure 1); in the Southern hemisphere: April to September).

-In tropical and subtropical climates, influenza activity may occur year-round, often peaking during cooler or rainy-season months

Burden of illness

United States - On average, approximately 8 percent of the United States population develops symptomatic influenza illness each season. (See 'Burden of illness' above.)

In the United States during the 2022 to 2023 influenza season, there were:

-26 to 50 million illnesses

-12 to 24 million medical visits

-290,000 to 670,000 hospitalizations

-17,000 to 98,000 deaths

Worldwide - Globally, estimated mean annual influenza-associated mortality rates between 1999 and 2015 varied by age:

-<65 years: 0.1 to 6.4 per 100,000 individuals

-65 to <75 years: 2.9 to 44.0 per 100,000 individuals

-≥75 years: 17.9 to 223.5 per 100,000 individuals

Risk factors for complications − Risk factors for complications are summarized in the table (table 1). (See 'Risk factors for complications' above.)

Influenza A

Surface proteins − Influenza A viruses are divided into subtypes based on two proteins on the surface of the virus: hemagglutinin (HA or H) and neuraminidase (NA or N). In humans, three major subtypes of hemagglutinins (H1, H2, and H3) and two subtypes of neuraminidases (N1 and N2) have been described. (See 'Surface proteins' above.)

Antigenic shift and drift (see 'Antigenic drift and shift' above)

-Antigenic "drift" refers to minor HA or NA gene mutations causing changes in the viral protein antigenicity. Antibodies (produced in response to prior infection or vaccination) do not bind well to antigenically drifted virus strains.

-Antigenic "shift" refers to major HA or NA gene mutations, leading to emergence of a novel influenza A virus that is antigenically and genetically distinct from viruses previously circulating in humans.

-Novel influenza A viruses can cause sporadic human infections from exposure to infected animals (usually birds or pigs); in addition, these viruses are capable of causing pandemics if most of the population lacks immunity to the novel virus

Influenza B − Influenza B viruses are classified into two lineages: B/Yamagata and B/Victoria; the genetic and antigenic properties of influenza B viruses change more slowly than influenza A viruses. Influenza B viruses circulate widely only in humans. (See 'Influenza B' above.)

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