What is the pathophysiology of influenza A?

Pathophysiology of Influenza A

Influenza A is characterized by its unique viral structure and replication cycle, causing respiratory infection through antigenic drift and shift mechanisms that allow it to evade host immunity and cause seasonal epidemics and occasional pandemics.

Viral Biology and Structure

• Influenza A is one of two types of influenza viruses (along with influenza B) that cause epidemic human disease 1
• The virus is categorized into subtypes based on two surface antigens: hemagglutinin (H) and neuraminidase (N), which are critical for viral attachment and release 1
• Since 1977, influenza A (H1N1) and A (H3N2) have been the predominant subtypes in global circulation, with A (H1N2) variants emerging after genetic reassortment between human A (H3N2) and A (H1N1) viruses 1

Antigenic Variation Mechanisms

• Influenza A undergoes frequent antigenic changes through two primary mechanisms:
  • Antigenic drift: Point mutations during viral replication create new variants, forming the basis for seasonal epidemics 1
  • Antigenic shift: Major changes in surface antigens through genetic reassortment between different influenza strains, potentially leading to pandemic strains 1
• Influenza A viruses undergo antigenic drift more rapidly than influenza B viruses 1
• These antigenic changes explain why antibodies against one variant provide limited or no protection against new variants of the same type or subtype 1

Transmission and Infection Process

• The virus spreads primarily through respiratory droplets from coughing and sneezing of infected persons 1
• The incubation period ranges from 1-4 days, with an average of 2 days 1, 2
• Infectivity begins the day before symptom onset and continues for approximately 5-6 days in adults, while children can be infectious for up to 10 days 2
• Severely immunocompromised individuals may shed virus for weeks or months 2

Cellular Pathophysiology

• Upon inhalation, the virus attaches to epithelial cells in the respiratory tract via the hemagglutinin protein binding to sialic acid receptors 3
• After entry, the virus hijacks the host cell machinery to replicate its RNA genome and produce viral proteins 3
• Neuraminidase enzymes cleave sialic acid residues, allowing newly formed virions to be released and spread to other cells 3

Immune Response and Inflammation

• Influenza infection triggers both innate and adaptive immune responses 4, 5
• The initial innate response includes production of interferons and activation of natural killer cells 3
• In severe cases, excessive inflammatory response leads to hypercytokinemia or "cytokine storm" characterized by overproduction of proinflammatory cytokines and chemokines 5, 6
• Key cytokines involved in pathogenesis include IL-6 and chemokines CCL-2/MCP-1, CCL-4/MIP-1β, CXCL-8/IL-8, CXCL-9/MIG, and CXCL-10/IP-10 5
• This inflammatory response is a "double-edged sword" - necessary for controlling infection but potentially causing lung damage and disease progression 4

Clinical Manifestations and Pathology

• Uncomplicated influenza presents with abrupt onset of fever, myalgia, headache, malaise, nonproductive cough, sore throat, and rhinitis 1
• The virus primarily infects the epithelial cells of the respiratory tract, causing cell death and inflammation 3
• In severe cases, the infection can progress to viral pneumonia, which may be complicated by secondary bacterial infections 1, 7
• Influenza can exacerbate underlying medical conditions (e.g., pulmonary or cardiac disease) 1
• The infection has also been associated with extrapulmonary complications including encephalopathy, transverse myelitis, Reye syndrome, myositis, myocarditis, and pericarditis 1

Disease Progression and Complications

• Most cases resolve within 3-7 days, though cough and malaise may persist for more than 2 weeks 2
• Severe disease can progress to acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) 3
• The risk for complications, hospitalizations, and death is higher among:
  • Persons aged >65 years
  • Very young children (especially those aged 0-1 years)
  • Individuals with underlying health conditions 1
• The pathogenesis of severe disease is attributed to both direct viral damage and the dysregulated host immune response 4, 6

Viral Clearance and Recovery

• Viral shedding decreases rapidly by 3-5 days after illness onset in most adults 2
• Most adults complete viral shedding by 5-7 days after illness onset 2
• Recovery depends on effective viral clearance by the immune system and repair of damaged respiratory epithelium 4