Influenza

Last updated: May 18, 2022

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Influenza is a highly contagious viral infection that typically occurs during the winter months. It is caused by influenza A, B, and C viruses. There are various subtypes of influenza A viruses, which are classified based on their hemagglutinin (H) and neuraminidase (N) surface antigens. Influenza viruses frequently mutate, resulting in the emergence of new subtypes and strains. Symptomatic patients may present with sudden onset of high fever, headache, myalgias, arthralgias, nonproductive cough, and malaise. Inflammatory markers are usually normal or slightly elevated. The diagnosis can often be established based on clinical presentation, but PCR testing may be used to confirm the diagnosis. Usually, symptoms are self-limited and supportive treatment is sufficient. However, antiviral therapy may be considered for patients with early or severe disease, especially in those at high risk for complications. Antiviral therapy may reduce the severity and shorten the duration of symptoms, and reduce the risk of developing complications. Rarely, patients may develop secondary bacterial pneumonia, most commonly caused by Staphylococcus aureus or Streptococcus pneumoniae. Hand hygiene, respiratory hygiene, and vaccination can help prevent the spread of influenza.

  • Distribution: worldwide
  • Seasonal pattern: Most infections occur during the fall and winter (influenza season).

References:[1]

Epidemiological data refers to the US, unless otherwise specified.

References:[2]

References:[3]

Replication cycle [4][5][6][7]

  1. Influenza viruses bind to the respiratory tract epithelium.
  2. Viral hemagglutinin (H) binds sialic acid residues (neuraminic acid derivatives) on the host cell membranevirus 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 (N) cleaves the neuraminic acidvirions exit the cell
  6. Host cell dies → cellular breakdown triggers a strong immune response

Genetic mutations [8]

  • Antigenic shift
    • Two subtypes of viruses (e.g., human and swine influenza) 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
    • Causes pandemics (limited to a specific time period)
  • Antigenic drift

Small shifts in a panda's habitat can cause epic dread: Shifts can cause pandemics and drifts cause epidemics.

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

References:[9]

General principles [10][11]

  • During periods of high influenza activity, a clinical diagnosis can often be made based on the presence of typical flu-like symptoms.
  • In general, testing should only be carried out in outpatients if the results will influence management.
  • Testing should not delay treatment.

Influenza can present in atypical ways and can also trigger exacerbations in patients with chronic cardiopulmonary diseases. [10]

Indications for testing [10]

Indications for influenza testing [10]
High influenza activity Low influenza activity
Outpatients
  • Patients at high risk for complications of influenza with any respiratory symptoms
  • Acute onset of respiratory symptoms and one of the following:
    • Worsening of chronic cardiopulmonary disease
    • Potential complications of influenza
  • Consider for patients with any respiratory symptoms who are likely to be discharged home.
Inpatients
  • Hospitalization for acute respiratory illness or worsening of chronic cardiopulmonary disease
  • Patients at high risk for complications of influenza with any respiratory symptoms
  • Onset of acute respiratory symptoms during hospital stay

Laboratory studies [10]

  • Confirmatory studies
    • Molecular assays are the preferred method for detecting influenza virus infection. ; [10]
      • RT-PCR: preferred test for inpatients
      • Rapid molecular assay: preferred test for outpatients
    • Rapid antigen test: can detect various influenza A/B antigens, usually via nasal or pharyngeal swabs
      • High specificity but limited sensitivity
      • Only indicated if more sensitive tests are unavailable
  • Additional studies

Consider bacterial coinfection in patients with elevated inflammatory markers (e.g., CRP). [12]

Further evaluation [10]

  • Evaluate for coinfection (e.g., bacterial superinfection, and/or complications) if any of the following are present:
    • Presentation with severe illness
    • Clinical deterioration after initial improvement
    • Consider evaluation if there is no improvement within 3–5 days of symptom onset.
  • Evaluation should be guided by symptoms and may include:
  • See “Diagnosis of pneumonia” for further details.

Consider simultaneous initiation of empiric antibiotic treatment in patients undergoing evaluation for bacterial coinfection.

Overview of acute upper respiratory tract infections

Condition

Most common pathogens Distinct clinical features Distinct physical examination findings Treatment
Common cold [15]
  • No prominent localizing features
  • None
  • Symptomatic
Influenza [9]
COVID-19 [16]
  • None
Sinusitis [17]
Tonsillitis [18]
Laryngitis [19]
  • Hoarseness
  • Barking cough
Epiglottitis [20]
  • Drooling and dysphagia
  • Respiratory distress
  • Muffled voice
  • Unwell appearance
Croup [21]
  • Barking cough (worse at night)

The differential diagnoses listed here are not exhaustive.

Supportive treatment [10]

Antiviral therapy

Most cases of influenza are self-limited and do not require specific treatment. If antiviral treatment is indicated, treatment should be initiated as soon as possible.

Indications [10]

The following recommendations are in line with the 2018 update of the IDSA guidelines on seasonal influenza. The quality of some of the underlying evidence for the use of neuraminidase inhibitors is part of an ongoing and controversial debate. [10][22][23]

  • All patients with suspected or documented influenza and ≥ 1 of the following:
  • Consider treating patients with suspected or confirmed influenza and ≥ 1 of the following:
    • Onset ≤ 48 hours prior to presentation
    • Close contact with high-risk patients

Do not delay the initiation of antiviral therapy while awaiting the results of testing.

Treatment options

  • Neuraminidase inhibitors
    • Mechanism of action: inhibits the release of viruses from the host cell
    • Greatest benefit if started within the first 48 hours of symptom onset [24]
    • Commonly used agents
      • Oral oseltamivir (preferred agent in case of hospitalization or severe influenza) [10]
      • Inhaled zanamivir (acute, uncomplicated influenza) [10]
      • Intravenous peramivir (acute, uncomplicated influenza) [10]
  • Cap-dependent endonuclease inhibitor

Consider a longer duration of antiviral treatment in patients with immunosuppression and those who require hospitalization.

Do not use amantadine to treat influenza because of the risk of antimicrobial resistance. [10]

Patients at high risk for complications of influenza [10][26]

  • Adults ≥ 65 years of age
  • Children < 5 years of age, especially those < 2 years of age
  • Patients who are pregnant and in the first 2 weeks postpartum
  • Patients with chronic medical conditions (e.g., asthma; , heart disease, CKD, diabetes mellitus; , immunosuppression)
  • Those with a BMI ≥ 40 kg/m2
  • Nursing home residents
  • American Indian, Alaska Native, Black, and Hispanic individuals [26][27]

Pneumonia [28][29][30][31]

Primary influenza pneumonia

Secondary bacterial bronchitis and pneumonia

Other complications [28]

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

  • Mortality [37][38]
    • 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

Influenza vaccine [39]

Infection prevention and control

Chemoprophylaxis [10]

Postexposure prophylaxis may be offered in conjunction with influenza vaccination in unvaccinated individuals at very high risk for complications of influenza and unvaccinated close contacts of these individuals.

  • Definition: a type of influenza that originates from animal strains
Most common types of zoonotic influenza
Avian flu [42] Swine flu [43]
Etiology
  • Direct or indirect contact with infected birds or their saliva/feces
  • Direct or indirect contact with infected pigs or their saliva/feces
Clinical features
  • See “Clinical features” above.
Diagnostics
Treatment
Prevention
  • Avoid touching animals directly.
  • Always wash hands after being near animals.
  • Stay away from animals that show symptoms of a cold or flu.

Influenza during pregnancy

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