• Clinical science

Influenza (Flu)

Abstract

Influenza is a highly contagious disease that typically occurs during the winter months. It is caused by the influenza viruses A, B, and C. There are various subtypes of the type A viruses, which are classified based on their surface antigens H (hemaglutinin) and N (neuraminidase). Since the viruses constantly undergo genetic changes, new subtypes and strains develop fairly often. Most infected individuals do not show symptoms. However, if they are symptomatic, they typically present with sudden onset of high fever, headache, muscle/joint aches, nonproductive cough, and severe malaise. Inflammatory markers are usually normal or slightly elevated. Diagnosis can be established with the help of rapid antigen testing if acute infection is suspected (e.g., for hospitalized patients or nursing home residents). In some cases, bacterial superinfection (most commonly with Staphylococcus aureus and Streptococcus pneumoniae) may develop, which is associated with productive cough and high levels of inflammatory markers. Usually, supportive treatment (i.e., rehydration and antipyretics) is sufficient. However, antiviral therapy may be considered for patients with early or severe disease, especially those at high risk for complications. The most commonly used agents are the neuraminidase inhibitors oseltamivir and zanamivir. If therapy is initiated within 48 hours after the onset of symptoms, a decrease in symptoms, a shortened duration of disease, and a reduction of complications may be achieved. Hygiene precautions and vaccination (recommended for all persons aged 6 months and older) help prevent the spread of influenza viruses.

Epidemiology

  • Distribution: Influenza viruses have a worldwide distribution.
  • Seasonal pattern: Most infections occur during the fall and winter.

References:[1]

Epidemiological data refers to the US, unless otherwise specified.

Etiology

  • Virus: Influenza virus A and B (and rarely influenza C)
  • Person-to-person transmission: directly via respiratory droplets (sneezing or coughing) or indirectly through contact with contaminated surfaces

References:[2][3]

Classification

  • Influenza A: The term “influenza” typically refers to influenza A infections. Viruses are classified into various subtypes based on glycoproteins of the viral envelope.
    • Hemagglutinin (H): H1, H2, H3, and H5 most relevant
    • Neuraminidase (N): N1, N2, and N7 most relevant
  • Influenza B/C (less common): significantly milder course
    • No evidence of genetic shift in influenza B, Seals are the only known non-human host → risk of epidemics is much lower

References:[4]

Pathophysiology

Replication cycle

  1. Influenza viruses bind to the respiratory tract epithelium.
  2. Viral hemagglutinin binds sialic acid residues (neuraminic acid derivatives) on the host cell membrane → virus fusion with the membrane → entry into the cell
  3. The virus replicates in the nucleus of the cell.
  4. The new virus particles travel to the cell membrane → formation of a membrane bud around the virus particles (budding)
  5. Viral neuraminidase cleaves the neuraminic acidvirus exits the cell
  6. Host cell dies → cellular breakdown triggers a strong immune response

Genetic mutations

  • Antigenic shift
    • Causes pandemics
    • Two subtypes of viruses infect the same cell and exchange genetic segments (reassortment) to create new subtypes (e.g., H3N1 → H2N1).
    • Occurs in particular when human pathogenic and animal pathogenic influenza viruses exchange genetic information
  • Antigenic drift
    • Causes epidemics
    • Minor changes in antigenic structure; (hemagglutinin and/or neuraminidase) via random point mutation
    • Does not alter the subtype (e.g., H5N1 or “avian flu”).

The flu SPRED through! (Shift → new Subtypes): Pandemics + Reassortment; Epidemic: Drift)References:[5][6][7][8][9]

Clinical features

The clinical presentation of influenza infection is asymptomatic or mild in 75% of cases. Influenza presents with very characteristic features, hence the term “flulike symptoms.”

  • Incubation period: a few hours to several days
  • Sudden onset of high fever, chills, headache, muscle/joint aches, fatigue, and malaise
  • Patients often develop acute bronchitis with a cough that is usually dry but may produce small amounts of clear or blood-tinged sputum.
  • Hypotension and bradycardia are common (especially among women and older patients)

References:[10]

Diagnostics

  • Blood tests
  • Rapid antigen test
    • Used for early diagnosis
    • Detection of various influenza A/B antigens via nasal or pharyngeal swabs
    • High specificity, limited sensitivity
  • Serological testing (e.g., via complement fixation)
    • Used to diagnose an infection after it has resolved (not relevant in acute illness)
    • Infection is likely if serum antibody titers increase 4-fold within 1–2 weeks after acute illness

Bacterial superinfection in influenza may lead to a strong elevation in inflammation markers!

References:[11][12]

Treatment

Supportive therapy

Antiviral therapy

  • Indications
    • Patients with severe disease or patients at risk of developing complications (see “Complications” below)
    • Sometimes considered if there is a high suspicion of early disease (e.g., prodromal symptoms and recent exposure)
  • Should be initiated as soon as possible (within the first 48 hours)
  • Neuraminidase inhibitors: inhibit the release of viruses from the host cell.

Amantadine is no longer recommended for treating influenza! (It used to be an option for treating influenza A. But during the 2008/2009 flu season, the CDC found that 100% of seasonal H3N2 and 2009 pandemic viruses were resistant to amantadine.)

References:[13][14][15]

Complications

High-risk groups for complications

  • Elderly individuals ≥ 65 years of age
  • Children < 5 years of age, especially < 2 years of age
  • Pregnant women (and women up to two weeks after giving birth)
  • Individuals with chronic medical conditions; (e.g., asthma; , heart disease, diabetes mellitus; , immunocompromise)
  • Nursing home residents
  • Native American

Other complications

References:[16][17][18][19][20]

We list the most important complications. The selection is not exhaustive.

Prognosis

  • Mortality
    • Increased in patients at high risk for influenza-related complications (see “Complications” above)
    • Average number of annual influenza-related deaths in the US: 23,000 to 48,000

References:[21][22]

Prevention

Influenza vaccine

  • Recommendation
    • Annual flu shot for all persons aged 6 months and older, if possible by October (right after the vaccine becomes available)
      • Particularly important in health care professionals and individuals with an increased risk of influenza-related complications (see “Complications” above)
    • Egg allergy is no longer considered a contraindication
  • Vaccines
    • Live attenuated or inactivated vaccine (see contraindications for the live attenuated vaccine)
    • Trivalent or quadrivalent
      • The trivalent vaccine protects against two influenza A viruses (currently a H1N1 and a H3H2 subtype) and one influenza B virus.
      • In addition to these types, the quadrivalent vaccine protects against a second influenza B virus.

Hygiene

  • Hand hygiene
    • Wash hands with soap and water before and after each patient contact
    • Alternatively, use an alcohol-based hand rub
  • Avoid contact with infected individuals and stay home when sick
  • Adhere to standard precautions
    • Surface cleaning with alcohol- or aldehyde-based agents
    • Face mask
    • Gloves and gown for contact with potentially infectious material

Chemoprophylaxis

  • Antiviral medications may be considered in patients with exposure to an infected person under certain circumstances (e.g., high risk of complications, contraindications for the vaccine, and influenza outbreaks in nursing homes).
  • For recommended agents, see “Therapy” above.

References:[23][24][25]