Influenza viruses are classified based on their protein composition. They are divided into types A, B, and C, with type A having numerous subtypes (NIAID 2011; Hayden 2011). Among the 3 types of influenza, type A viruses are the most dangerous to humans and are associated with the most severe disease (NIAID 2011). Influenza type C is less problematic because most people acquire antibodies to influenza C early in life (Gouarin 2008).
In nature, the flu virus continuously mutates (NIAID 2011). Every year or so, these mutations can create completely new viruses that are often not harmful (Hayden 2011). However, sometimes mutations can alter viral structure in such a way that the virus can suddenly jump the barrier between species and infect humans. In fact, it is the precise assortment of surface proteins that will dictate the severity of each influenza strain (NIAID 2011). This can occasionally result in the formation of a novel flu virus that is better able to evade the host’s immune system, becoming more dangerous to humans (NIAID 2011). These mutations can also allow influenza to evolve resistance to conventional antiviral drugs (Afilalo 2012).
Transmission of the influenza virus
The flu virus is mostly spread by tiny droplets (ie, aerosols) that are expelled when a person sneezes, coughs, or even speaks. These droplets contain virus-laden respiratory secretions and can transmit influenza if they land in the mouths or noses of bystanders. Also, an individual might become infected by touching their mouth, eyes, and/or nose after previously touching a surface where the virus has landed (CDC 2011a).
Once the virus has found its way to the host respiratory tract, it will attempt to invade the epithelium (ie, cells that line the tissue surface) (Afilalo 2012). Within 4 to 6 hours of invading a cell, the influenza virus will begin to replicate and the host cell will begin to release large numbers of replicated virus progeny in a process known as “virus shedding”. These released viruses are then free to invade any nearby susceptible cells, thus starting a new replication cycle in each newly infected cell. The time from initial infection to symptomatic illness (ie, incubation period) ranges from 1–4 days, with an average of 2 days (Hayden 2011). The contagious period generally begins 24 hours prior to symptom onset and can continue for up to a week after becoming sick. Young children and those with a weakened immune system may be contagious for longer periods (CDC 2012b).
Influenza among populations (epidemics and pandemics)
When disease outbreaks are confined to one geographical area, they are referred to as epidemics (Hayden 2011). An epidemic is upgraded to a pandemic once it has spread to a large number of people in other countries or continents through person-to-person contact (Hayden 2011; NIH 2012b; NIAID 2011). Out of the 3 influenza pandemics that occurred during the 20th century, the most deadly was the Spanish flu (influenza type A/H1N1) of 1918-1919, which caused approximately 50 million deaths worldwide (Gasparini 2012; Bavagnoli 2009; Taubenberger 2011). In 1997, the novel avian influenza virus (H5N1) first began infecting humans in China and has since been sporadically transmitting from birds to humans across a wide geographical area including Asia, Europe, and Africa (Gasparini 2012). The H5N1 is currently considered to be the most deadly influenza virus that has crossed the species barrier (Michaelis 2009).
The first pandemic of the 21st century was attributed to the swine-origin influenza A (H1N1) virus, which was originally identified in April 2009 in Mexico (Combes 2011; van Ierssel 2012). The H1N1 epidemic spread quickly and was confirmed worldwide in just a few weeks, forcing the World Health Organization to officially declare it a pandemic on June 11, 2009 (Combes 2011). Although most cases of H1N1 resulted in a self-limited respiratory illness, this infection also caused severe progressive pneumonia and death, even among young healthy individuals (Combes 2011; Bai 2011; van Ierssel 2012). Moreover, most of the deaths that resulted from H1N1 occurred among individuals younger than 65 years old (Hayden 2011). As of August 2010, the World Health Organization reported that H1N1 had crossed into at least 214 countries and was responsible for approximately 18 500 deaths worldwide (WHO 2010). Research suggests the true mortality rate may be 15-times higher than originally reported (Dawood 2012).
Seasonal influenza is also a major public health threat in the United States, as it is associated with significant suffering and death each year (Seidman 2012). The seasonal flu is a term used to describe the annual outbreaks of influenza that largely occur in late fall and winter in temperate climate regions (NIAID 2011; Atmar 2010).
Annual flu outbreaks are known for having a significant impact on not only the infected individual, but also society as a whole (Pedersen 2009). For example, between 5 and 20% of the United States population is infected by the seasonal flu each year (NIAID 2011). Globally, seasonal influenza epidemics account for 3–5 million severe cases of illness (Yoo 2011) and up to 1 million deaths each year (Music 2012). In the United States, seasonal influenza is associated with more than 200 000 hospitalizations and thousands of deaths each year (Lynch 2007; CDC 2011c; NFID 2012); thus, it represents a significant economic burden with up to about 5 billion dollars annually in medical costs (Lambe 2012; Mao 2012; Afilalo 2012).
Although a majority of the suffering and death attributable to seasonal influenza is due to infections among the elderly (Afilalo 2012), seasonal influenza has been known to cause clinical illness and hospitalization in all age groups (Banzhoff 2012). Outbreaks of seasonal influenza generally begin abruptly, with a surge in clinical cases of pediatric fever and respiratory illnesses, which is followed by a similar surge in symptoms among adults. These seasonal outbreaks usually last for about 3 months, and spread within a community during a 2–3 week peak period (Afilalo 2012).
Among otherwise healthy adults, seasonal influenza is typically associated with about 6–8 days of clinical symptoms such as sudden fever, general fatigue, headache, or muscle aches (Shobugawa 2012; Pedersen 2009; CDC 2012b). Additional common symptoms can include dry/unproductive cough, sore throat, and a runny/stuffy nose (CDC 2012b; Hayden 2011). The seasonal flu can also cause more serious complications, such as secondary bacterial pneumonia, ear infections, sinus infections, dehydration, and worsening of chronic medical conditions including asthma, diabetes, and congestive heart failure (CDC 2012b). Among those in the workforce, seasonal influenza infection is associated with an average of 4–5 days of sick leave each year (Pederson 2009). In fact, taking sick leave for influenza is recommended in order to decrease the risk of transmission (Pedersen 2009).
The Role of Cytokines
Cytokines are a multifunctional group of signaling proteins that regulate immune and inﬂammatory responses and are released by cells in response to infection. With most infections, the release of cytokines is controlled in order to maintain a balance between killing the virus and minimizing damage to healthy cells (Tisoncik 2012; Danese 2007). However, when certain severe types of influenza A virus (such as H5N1) invade endothelial cells and begin to proliferate, the cells will occasionally flare out of control and mount an excessive host immune response (Schmolke 2009). Also called a “cytokine storm,” this clinical phenomenon involves the massive overproduction of inflammatory cytokines, such as tumor necrosis factor (TNF), interferons (IFN), colony-stimulating factors (CSFs), and interleukins (ILs) (Tisoncik 2012; Walsh 2011a; Phung 2011; Teijaro 2011).