Influenza Virus and Its Impact

Burden of Influenza Virus

• Influenza virus causes acute febrile illness with variable degrees of systemic symptoms, ranging from mild fatigue to respiratory failure and death.
• The World Health Organization (WHO) estimates that 3-5 million cases of severe illness and about 250,000 to 500,000 deaths occur annually.

Pandemics

• The 1918 Spanish Flu (H1N1) caused 20-40 million deaths.
• The 1957 Asian Flu (H2N2) caused 1-4 million deaths.
• The 1968 Hong Kong Flu (H3N2) caused 1-4 million deaths.
• The 1977 H1N1 pandemic occurred.
• The 2009 H1N1 pandemic (Swine Flu) caused thousands of deaths and was a hybrid of swine, avian, and human strains (Influenza A (H1N1)).

Influenza Virus Structure

• Influenza viruses are RNA-enveloped viruses.
• They have RNA-dependent RNA polymerase, which is important for infectivity and has transcription errors (~1:10kb of the genome).
• The RNA is single-stranded, negative sense, and approximately 8 segments (types A and B) or 7 segments (type C).

Haemagglutinin (H or HA)

• Haemagglutinin is a glycoprotein that allows the virus to adhere to endothelial cells in the respiratory tract by binding to sialic acid-containing receptors.
• It is the main determinant of immunity and stimulates the production of neutralizing antibodies.
• Haemagglutinin agglutinates certain species' erythrocytes.

Neuraminidase (N or NA)

• Neuraminidase is an enzyme that allows the release of newly formed viruses within the host.
• It is a determinant of disease severity.
• There are 9 serotypes of Neuraminidase (not in type C).

Antigenicity

• Influenza viruses have two types of antigens: group-specific antigens and type-specific antigens.
• Group-specific antigens are determined by Ribonucleoproteins and distinguish types A, B, and C.
• Type-specific antigens are HA and NA, and are used for serotyping.

Antigenic Changes

• Antigenic shift occurs in type A and leads to pandemics.
• Antigenic shift involves the reassortment/swapping of genetic RNA, leading to a major change and the appearance of new HA and NA.
• Antigenic drift occurs in all types and leads to outbreaks/epidemics.
• Antigenic drift involves the accumulation of mutations in HA and NA, making the immune response no longer fully protective.

Physical and Biological Characteristics

• Influenza viruses can survive in cold sea water for several weeks.
• They can stay in dust for more than 2 weeks/1 week on the human body.
• They are inactivated by heat, ether, phenol, ethanol, formaldehyde, soaps, and many others.
• Type A has many hosts, type B infects humans only, and type C infects humans and pigs.

Lifecycle

• The lifecycle of influenza viruses involves:
  • HA attachment to cell receptors (sialic acid receptors)
  • Penetration of the cell into endosomes
  • Acidic changes (M2 protein) leading to virus uncoating
  • Transcription of genomic RNA into mRNA
  • Translation of mRNA into viral proteins
  • Progeny synthesis in the nucleus
  • Assembly in the cytoplasm
  • Release by budding (facilitated by NA)

Pathogenesis

• Influenza virus pathogenesis is multifactorial, involving host factors, viral factors, and environmental factors.
• The mechanism involves:
  • Structural and functional damage of respiratory cells
  • Desquamation and affectation of respiratory clearance mechanism
  • Stimulation of inflammatory response
  • Direct tissue toxicity
  • Increased susceptibility to bacterial infections (superinfection)

Host Response and Recovery

• The initial control involves:
  • Interferon production
  • Rapid generation of natural killer cells
  • Class I major histocompatibility complex (MHC)–restricted cytotoxic T cells
• The host response then involves:
  • Appearance of local and humoral antibody (inhibits spread)
  • Evolving cellular immunity
• Finally, tissue damage is repaired (2-10 weeks).

Clinical Features

• Mode of transmission: Respiratory droplets/airborne (more in winter, crowded areas)
• Incubation period: 1-4 days (symptoms may last 3-7 days on average)
• Main symptoms (mainly type A):
  • Sudden onset: fever, chills, headache, myalgia, cough, anorexia, rhinitis, and ocular symptoms
  • Note: type B is somewhat milder; type C is usually afebrile
• Severity is more in:
  • Extreme ages and immunocompromised
  • Chronic lung and heart diseases
• Pulmonary complications:
  • Croup (young children)
  • Primary influenza virus pneumonia
  • Secondary bacterial infection (Streptococcus pneumoniae, Staphylococcus aureus, Hemophilus influenzae)
• Non-pulmonary complications:
  • Cardiac: myositis (rare, more in children, more with type B)
  • Liver and CNS: Rey's syndrome (encephalopathy + liver degeneration, precipitated by aspirin)
  • Peripheral nervous system: Guillian-Barré syndrome/Ascending paralysis (autoimmune disease)

Diagnosis

• Diagnosis involves culturing the virus from nasopharyngeal samples (takes 7 days) or serology to detect at least a 4-fold increase in antibody titer (needs 2 serum samples during the acute illness and 10-14 days later).