Influenza

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. Vaccination is the most effective preventive measure. In select patient populations, pre- or postexposure prophylaxis may help prevent or mitigate the severity 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.

• Pathogen: Influenza virus A and B (and rarely influenza C)
  • RNA viruses of the family orthomyxoviruses
  • Enveloped virus with a helical capsid
  • Single-stranded, negative-stranded, segmented (8 segments)
  • Replication in cell nucleus
• Person-to-person transmission: directly via respiratory droplets (sneezing or coughing) or indirectly through contact with contaminated surfaces

References:^[2]

• Influenza A (e.g., H1N1)
  • 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 → risk of epidemics is much lower

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 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 (N) cleaves the neuraminic acid → virions 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
  • Minor changes in antigenic structure (hemagglutinin and/or neuraminidase) via random point mutation
  • Does not alter the subtype (e.g., H5N1 or “avian flu”).
  • Causes epidemics (limited to a specific population or region)

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”.

• Incubation period: a few hours to several days
• Sudden onset of high fever, chills, headache, arthralgia, myalgia, 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:^[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]

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
  • Serologic testing and viral cultures: not recommended for diagnosis
  • Blood tests are not routinely indicated, but if performed, may show:
    • Normal or slightly elevated inflammatory markers
    • Relative lymphocytosis

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:
  • Blood tests: CBC, procalcitonin, CRP ^{[10][12][13][14]}
  • Bacterial cultures
  • Chest imaging
• See “Diagnosis of pneumonia” for further details.

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

• Common cold
• COVID-19
• Acute rhinosinusitis
• Acute tonsillopharyngitis
• Laryngitis
• Epiglottitis
• Croup
• Pertussis
• Allergic rhinitis
• Infectious mononucleosis
• See also “URTIs.”

The differential diagnoses listed here are not exhaustive.

Supportive treatment ^[10]

• Oral rehydration therapy
• Antipyretics and oral analgesics ^[11]
• Antitussives to relieve dry cough

Antiviral therapy for influenza

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][15]

The quality of some of the underlying evidence for the use of neuraminidase inhibitors is part of an ongoing and controversial debate. ^[16][17]

• All patients with suspected or documented influenza and ≥ 1 of the following:
  • Severe or progressive illness
  • Hospitalization required
  • High risk for complications of influenza
  • Age < 5 years ^[15]
• Consider treating patients with suspected or confirmed influenza and ≥ 1 of the following:
  • Onset ≤ 48 hours prior to presentation
  • Close contact with infants < 6 months of age or high-risk patients ^[15]

Do not delay the initiation of antiviral therapy while awaiting the results of testing. ^[15]

Treatment options ^[10][15]

The medications listed below are FDA-approved for use within 48 hours of symptom onset; however, they may be used off-label in patients with symptom onset > 48 hours before presentation.

• 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 ^[18]
  • Commonly used agents
    • Oral oseltamivir : preferred agent in case of hospitalization or severe influenza and in children with influenza A or B ^[15]
    • Inhaled zanamivir : acute, uncomplicated influenza ^[10][15]
    • Intravenous peramivir (off-label in children < 2 years) : acute, uncomplicated influenza ^[10][15]
• Cap-dependent endonuclease inhibitor
  • Oral baloxavir : acute, uncomplicated influenza ^[15][19]

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]

Individuals at high risk for complications of influenza ^[10][20][21]

• Adults ≥ 50 years of age, especially those ≥ 65 years of age ^[20]
• Children < 5 years of age, especially those < 2 years of age ^[15]
• Children aged 6 months–18 years on long-term salicylate therapy ^[20]
• Individuals who are or will be pregnant or ≤ 2 weeks postpartum during influenza season ^[20][22]
• Individuals with chronic medical conditions (e.g., asthma; , heart disease, CKD, diabetes mellitus, neurologic and neurodevelopmental disorders)
• Immunocompromised individuals
• Individuals with a BMI ≥ 40 kg/m² (adults) or BMI ≥ 95^thpercentile (children) ^[15]
• Residents of nursing homes or long-term care facilities
• American Indian, Alaska Native, Black, and Hispanic individuals ^[21][23]

Pneumonia ^[24][25][26]

Primary influenza pneumonia ^[27]

• Description
  • Caused by direct infection of the lung parenchyma by the influenza virus ^[27][28]
  • Hemorrhagic pneumonia; associated with a poor prognosis
• Epidemiology: less common than secondary bacterial bronchitis or pneumonia
• Clinical features
  • Acute clinical deterioration 2–5 days after the onset of flu-like symptoms ^[27]
  • Dyspnea, hypoxemia, cyanosis ^[25]
  • May progress to acute respiratory distress syndrome (ARDS) and multiorgan failure
• Diagnostics
  • Blood tests may show leukocytosis or leukopenia; ESR is usually normal.
  • Chest x-ray may show perihilar congestion and diffuse or multifocal infiltrates.
  • See “Diagnosis of pneumonia” for further details.
• Management
  • Antiviral therapy for influenza
  • Lung protective ventilation is often necessary. ^[27]
  • See “Management of ARDS” for further details.

Secondary bacterial bronchitis and pneumonia (postinfluenza pneumonia)

• Etiology: Common causative pathogens include S. pneumoniae, S. aureus (including MRSA), S. pyogenes, and H. influenzae. ^[29]
• Clinical features
  • Development of a purulent, productive cough; ∼ 4–14 days after an initial period of improvement ^[24]
  • Recurrent fever
  • Symptoms similar to community-acquired pneumonia
  • Postinfluenza S. aureus pneumonia can manifest with: ^[30]
    • Hyperacute onset of symptoms
    • Hypoxemia and cyanosis
    • Hemoptysis
    • Hypotension
• Diagnostics
  • Laboratory studies may show leukocytosis with left shift or leukopenia; ESR is typically elevated.
  • In pneumonia caused by S. aureus, a chest x-ray may show cavitations and pneumatoceles.
  • See “Diagnosis of pneumonia” for further details.
• Treatment ^[29]
  • Empiric antibiotic therapy for community-acquired pneumonia
  • Should include coverage for MRSA

Other complications ^[24]

• Upper respiratory tract infections
  • Acute otitis media
  • Sinusitis
  • Croup (especially in children) ^[31]
  • Parotitis ^[32]
• Exacerbation of chronic diseases: e.g., COPD, asthma, underlying ischemic heart disease, congestive heart failure
• Acute kidney injury
• Rare complications: include cardiac (e.g., pericarditis, myocarditis), musculoskeletal (e.g., myositis, rhabdomyolysis), and neurological complications (e.g., encephalopathy, encephalomyelitis, transverse myelitis, aseptic meningitis, Guillain-Barré syndrome)

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

Vaccination ^[20][33]

Influenza vaccine

• There are three types of influenza vaccines currently available.
• The 2024-2025 influenza vaccines are trivalent, containing influenza hemagglutinin proteins, which are surface glycoproteins, for two flu A strains, and one flu B strain. ^[15][20]
• To account for antigenic drift, vaccines are modified prior to each influenza season to include expected circulating strains.

The attenuated virus is temperature-sensitive and can replicate in the nose but not in the lung. ^[36]

Indications

• All individuals ≥ 6 months of age: annually, ideally prior to each flu season ^[33]
• Especially in the following groups: ; ^[20][37]
  • Individuals at or in close contact with those at high risk for complications of influenza
  • Close contacts or caregivers of infants < 6 months of age
  • Health care professionals
• Individuals traveling to areas with influenza activity ^[38]

In adults ≥ 65 years, high-dose inactivated influenza vaccine, recombinant influenza vaccine, or adjuvanted inactivated influenza vaccine are preferred over standard dose or unadjuvanted vaccines. ^[20]

Contraindications and precautions ^[20]

According to the Advisory Committee on Immunization Practices (ACIP), egg allergy of any severity is not a contraindication for influenza vaccines. ^[20]

Individuals (including health care personnel) who receive the live attenuated influenza vaccine should avoid contact with severely immunosuppressed individuals for 7 days after vaccination. ^[41]

Immunization schedule

• See “ACIP immunization schedule” for details.

Infection prevention and control

• Standard precautions
  • Educate patients on the importance of hand hygiene and respiratory hygiene.
  • Advise outpatients to stay at home until they have been afebrile for at least 24 hours.
  • Use personal protective equipment (including masks).
  • Clean surfaces with alcohol-based or aldehyde-based disinfectants.
• Isolation precautions
  • Isolate or cohort patients.
  • See “Droplet precautions” for further details.

Chemoprophylaxis

Preexposure prophylaxis ^[10]

• Not routinely recommended
• Indications: Consider if vaccination is not possible in the following situations.
  • Individuals at very high risk for complications of influenza
  • People who are in close contact with unvaccinated, very high-risk individuals
• Agents: Administer either oseltamivir or zanamivir for the entire influenza season. ^[10]

Postexposure prophylaxis ^[10][15]

• Not routinely recommended
• Indications: Consider in the following situations for individuals ≥ 3 months if antiviral agents can be initiated within 48 hours of exposure. ^[10][15]
  • Individuals at high risk for complications of influenza in whom vaccination is contraindicated, unavailable, or likely to be ineffective ^[10][15]
  • Unvaccinated close contacts of:
    • Individuals at high risk for complications of influenza
    • Unvaccinated children < 24 months of age ^[15]
• Agents ^[10][15][43]
  • Oseltamivir (off-label in children < 1 year and not recommended in children aged < 3 months) ^[10][15]
  • Zanamivir ^[10][15]
  • Baloxavir ^[15]

Peramivir is not approved for use in the prevention of influenza. ^[15]

Influenza during pregnancy

• Maternal effects
  • Associated with higher rates of hospitalization and admission to intensive care unit, more severe clinical course, and higher mortality ^[44][45]
  • Increased risk of preterm delivery and spontaneous abortion ^[46][47]
• Fetal effects: associated with an increased risk of birth defects (e.g., congenital heart defects, cleft lip, neural tube defects), fetal death, lower mean birth weight, and small size for gestational age ^[48]

Zoonotic influenza

• Zoonotic influenza is most commonly caused by certain influenza A viruses; these viruses usually circulate in animals and occasionally infect humans.
• Novel influenza A viruses are antigenically and genetically new viruses that primarily originate in birds or pigs; rarely, they can infect humans with the potential to cause a pandemic. ^[49][50]

Novel influenza A virus infection is a nationally notifiable disease in the US. Notify the state or local health department if a case is suspected. ^[51]

• Mortality ^[53][54]
  • Increased in individuals 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