Influenza Overview and Historical Perspectives

INFLUENZA

Introduction to Influenza

  • Influenza is of great interest to the general public for several reasons:

    • It is a common disease that individuals are likely to encounter at least once during their lifetime.

    • Notably absent in summer, it primarily occurs in winter months.

    • It has a short incubation period (a few days), enabling swift community outbreaks.

    • Often leads to unexpected time off from work or school.

Nature of Influenza Virus

  • Influenza is caused by a virus known as Orthomyxovirus.

Orthomyxovirus Characteristics:

  • The name derives from Greek, where "ortho" means correct or normal and "myxa" refers to mucus.

    • Virion Structure:

    • Quasi-spherical or filamentous in shape.

    • Contains a compact helical nucleocapsid.

    • Envelope derived from the plasma membrane.

    • Diameter: 80 - 120 nm.

    • Genome:

    • Linear single-stranded RNA.

    • Composed of 8 different segments, with each segment encoding one protein.

Distinctive Features of Orthomyxovirus:

  • The RNA genome is segmented, allowing for genetic reassortment between different strains.

    • This reassortment leads to the development of new viral strains responsible for pandemics, primarily due to changes in surface antigens.

Types of Influenza Viruses

  • Influenza Type A Viruses:

    • Infect various hosts: humans, swine, avian species, equine, and marine mammals.

    • Associated with significant pandemics, causing substantial morbidity and mortality.

  • Influenza Type B Viruses:

    • Exclusively infect humans and are not associated with pandemics.

    • Generally cause milder disease.

  • Influenza Type C Viruses:

    • Infect humans and swine but are also not associated with pandemics.

    • Typically cause mild disease.

Influenza A Viruses Dynamics

  • Major Surface Antigens:

    • Hemagglutinin (HA):

    • Serves as the key attachment site to the host cell and initiates infection.

    • 18 antigenically distinct HA types identified (H1 through H18), with H1, H2, and H3 being relevant for humans.

    • Neuraminidase (NA):

    • Functions as an enzyme that cleaves sialic acid from glycoproteins, facilitating viral replication and maturation.

    • 11 antigenically distinct NA types identified (N1 through N11), with N1 and N2 specific to human influenza A viruses.

Antigenic Variation in Influenza A Viruses:

  • A distinguishing characteristic of influenza A viruses is their high frequency of antigenic changes, leading to significant epidemiological impact.

    • Antigenic Variation: Involves both HA and NA and can be classified into:

    • Antigenic Drift:

      • Minor changes in the virus's antigens, occurring approximately every year.

      • Associated with mutations in HA, leading to seasonal epidemics (average of every 2.4 years).

    • Antigenic Shift:

      • Major changes producing newly identified strains (subtypes) to which the population lacks herd immunity.

      • This variation can trigger pandemics, which often occur unpredictably every 10 to 12 years.

Genetic Structure Contribution to Antigenic Shift:

  • The influenza A genome comprises 8 distinct segments of single-stranded RNA.

    • Each RNA segment is responsible for critical components of the viral structure (e.g., segment 4 encodes for HA, and segment 6 for NA).

    • Co-infection of a cell by two unrelated viruses can lead to genetic reassortment, producing new viruses, particularly when cross-species infection occurs.

Transmission of Influenza

  • The virus spreads via respiratory droplets, making human infectious doses as low as 1 - 5 viral particles.

  • R0 Value: Ranges from 0.9 to 2.1, indicating the virus's transmissibility.

  • Remains infectious for over 24 hours after aerosolization in low humidity conditions, and can last for 1-2 days on hard surfaces.

  • Fomites (contaminated surfaces) may play a role in transmission.

Pathogenesis of Influenza

  • The initial site of infection is the respiratory tract mucosa.

  • Incubation period: Usually between 1 to 4 days (average of 2 days).

  • Virus shedding starts about a day prior to the onset of symptoms, which present abruptly with significant systemic illness alongside respiratory symptoms.

  • Virus shedding can last generally for 3 to 7 days, with viral loads of 10^5 to 10^7 infectious particles/mL in nasal washings.

  • Symptoms: Usually, fever and systemic symptoms decrease after about 7 days, while recovery may be prolonged due to lingering cough and malaise lasting 2 to 4 weeks.

Complications and Mortality

  • Complications can include:

    • Secondary bacterial pneumonia.

    • Acute central nervous system manifestations.

  • Deaths usually result from:

    • Pulmonary complications due to secondary infections.

    • Excessive cytokine response (cytokine storm).

    • Severe hemorrhage.

CDC Reporting on Seasonal Influenza Deaths

  • The exact number of annual deaths from seasonal influenza is uncertain, as states are not required to report deaths of adults over 18 from influenza.

  • Seasonal influenza fatalities are often attributed to exacerbation of preexisting health conditions (e.g., congestive heart failure).

  • It's common for fatalities to occur without confirmatory testing for virus infection.

Estimations of Influenza Deaths

  • CDC utilizes mathematical modeling to estimate annual deaths, reporting fluctuation between:

    • A low of 12,000 deaths (2011 - 2012) and a high of 56,000 deaths (2012 - 2013).

Epidemiological Trends

  • Influenza typically follows a U-shaped epidemic curve.

  • Mortality rates are notably high among young individuals and older adults.

Morbidity and Mortality Impacts

  • Higher excess morbidity and mortality rates are seen in:

    • Individuals with cardiovascular diseases.

    • Patients with pulmonary conditions (e.g., asthma).

    • Those with chronic metabolic diseases (e.g., renal dysfunction).

    • Immunocompromised individuals (e.g., HIV/AIDS).

  • Nursing home residents may experience death rates as high as 2.8% per year due to influenza.

Antiviral Drugs for Influenza

  • Four FDA-recommended antiviral drugs for influenza prevention and treatment include:

    • Rapivab (peramivir)

    • Relenza (zanamivir)

    • Tamiflu (oseltamivir)

    • Xofluza (baloxavir marboxil)

  • Timing of Treatment:

    • Antiviral therapy is most effective when started within the first 24 hours after the onset of symptoms; efficacy diminishes after 48 hours.

Inhibitors of Virus Maturation

  • Influenza viruses exhibit a unique behavior during the release from host cells.

  • Hemagglutinin (HA) binds to sialic acid receptors to allow viral entry.

  • During virus replication, HA's action at the culmination inhibits the release of newly formed viruses from the host cell.

  • Neuraminidase (NA) cleaves the sialic acid from glycoproteins, facilitating the release of progeny viruses.

    • Without functional NA, viruses remain attached to the host cell and cannot spread.

  • Antivirals like Rapivab, Relenza, and Tamiflu are designed to competitively inhibit NA to block sialic acid cleavage, thus preventing viral release.

Xofluza (Baloxavir marboxil)

  • FDA-approved in 2018 for treating acute uncomplicated influenza A and B in individuals aged 12 years and older, symptomatic for no more than 48 hours.

  • Administered as a single dose, it may reduce symptom duration by approximately one day.

  • Works by inhibiting the "cap snatching" process during mRNA transcription essential for synthesizing influenza virus RNAs.

Vaccines for Influenza

  • Egg-based Vaccines:

    • Grown in embryonated chicken eggs, purified, and formalin-inactivated.

    • Typically contains two influenza A subtypes and one B subtype (Trivalent) or an additional B subtype (Quadrivalent).

    • Administered via injection (flu shot). Immune protection typically develops in about 2 weeks, lasting several months to a year.

    • Healthy adults show ~90% seroconversion, with 70% - 90% protection when there is a good match between the vaccine and circulating strains.

    • The vaccine cannot cause influenza since it is killed and contains no live virus.

2024 – 2025 Vaccine Formulations

  • Trivalent Vaccine formulations:

    • A/Victoria (H1N1)-like virus.

    • A/Thailand (H3N2)-like virus.

    • B/Austria-like virus.

  • Quadrivalent Vaccine: Similar to Trivalent, with the addition of B/Phuket-like virus.

  • Additional Trivalent Vaccine formulations:

    • A/Wisconsin (H1N1)-like virus.

    • A/District of Columbia (H3N2)-like virus.

    • B/Austria-like virus.

  • Quadrivalent Vaccine: Same as Trivalent with the addition of B/Victoria-like virus.

Alternative Vaccination Methods

  • Cell or Recombinant-based Vaccines:

    • Produced in mammalian cell culture, purified, and formalin-inactivated.

    • Formulations similar to egg-based vaccines but may offer different efficacy rates.

    • Generally have 90% seroconversion rates, similar to egg-based vaccines, with the inability to cause influenza infections.

  • HA Subunit Influenza Vaccine (Flublok):

    • Quadrivalent vaccine using CDC-identified strains.

    • Produced utilizing a novel platform expressing HA cDNA in insect cells causing simpler glycosylation, enhancing antigenic site accessibility.

    • Induces higher levels of broadly cross-reactive HA regions compared to egg-derived vaccines, potentially more protective against drift variants.

    • Approved for ages > 9 years.

  • Live Attenuated Intranasal Vaccine (FluMist):

    • Consists of attenuated quadrivalent viruses replicating at cooler temperatures found in the nasal passage.

    • Induces an IgA mucosal immune response mimicking natural infection responses, more acceptable to patients aged 2 - 49.

    • Mucosal immunity is achieved in 85% of young children, with lower rates in adults; efficacy around 85%.

Historical Perspective of Influenza

Early Epidemics

  • Respiratory disease epidemics have been recorded every 1 - 3 years for over 500 years.

    • The first European record was in 1510, with approximately 299 epidemics and three pandemics reported from 1510 to 1800.

    • During the Middle Ages/Renaissance, various diseases were prevalent; influenza, with its relatively low mortality (~1%) was perceived as a minor inconvenience.

Changing Perceptions

  • The perception of influenza evolved through history, initially regarded somewhat flippantly:

    • 16th Century: Noted as "the new acquaintance" or "the gentle correction."

    • 17th Century: Referred to as "the new delight" or "la grippe."

    • 18th Century: Named "the influence."

Epidemic of 1782

  • Italians attributed the widespread effects to astrological conditions, leading to the name "influenza," derived from "the influence."

The 1918-1919 Influenza Pandemic

  • A significant shift in society's perception occurred after the devastating pandemic from 1918 to 1919, leading to the recognition of the virus's potential lethality.

    • This pandemic claimed the lives of approximately 20 to 100 million individuals within one year, marking a fatality rate between 4% to 20% across the globe.

    • Symptoms were observed in nearly 500 million people, approximately one-third of the world’s population at the time.

    • Infamously known as the Spanish Flu due to the first press coverage of the epidemic from Spain, it unfolded in three waves:

    • First Wave (January 1918): Similar to prior pandemics, predominantly affecting the young and elderly.

    • Second Wave (August 1918): Characterized by a highly virulent strain; high mortality among younger adults (20 - 40 years).

    • Third Wave (December 1918): Less virulent than the second wave but continued to have substantial impacts. The pandemic concluded in March 1919, with extensive aftereffects such as encephalitis lethargica observed in the following decade.

Factors in Pandemic Emergence

  • An array of factors contributed to the 1918 pandemic's emergence including:

    • Overcrowding.

    • Interactions between various domesticated and wild animal species (e.g., pigs, ducks, chickens).

    • Environmental pollutants and gases likely contributing to viral mutation.

Analysis of 1918 Pandemic Virus

  • Using RT-PCR assay techniques, researchers have recovered virus RNA from preserved lung tissue samples tied to the 1918 pandemic, revealing sequences associated with swine influenza.

Subsequent Influenza Events

  • 1976 Swine Influenza Scare:

    • Isolation of a new swine influenza virus prompted the National Immunization Program, with rapid vaccine development resulting in vaccination of approximately 45 million people.

    • However, incidences of Guillain-Barré syndrome were reported as a rare autoimmune reaction among vaccinated individuals, with notable mortality statistics in affected groups, yet the virus failed to spread widely among the populace.

  • 2009 Swine Influenza Pandemic:

    • A notable outbreak of H1N1 linked to swine influenza genetics occurred in the summer, impacting mainly those aged 20 to 40 years but with significantly lower mortality than the 1918 pandemic.

    • Despite its peak in October and November 2009, the cases later declined, revealing resistance to antiviral treatments such as Tamiflu.