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Myxovirus - Influenza (Orthomyxoviridae)

2nd Year MBBS Microbiology | Based on Sherris & Ryan's Medical Microbiology (8th Ed.) and Jawetz, Melnick & Adelberg's Medical Microbiology (28th Ed.)

Note: Apurba Sastri's textbook is not available in the digital library. The content below is drawn from equivalent standard microbiology references (Jawetz and Sherris & Ryan) which cover the same syllabus topics.

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1. DEFINITION

• Orthomyxoviridae - the influenza viruses (ortho = true/straight)
• Paramyxoviridae - parainfluenza, mumps, measles, RSV

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2. ORTHOMYXOVIRIDAE - FAMILY CHARACTERISTICS

Classification and Structure

• Family: Orthomyxoviridae
• Types: Influenza A, B, and C (classified by antigenic differences in their ribonucleoprotein [NP] and matrix [M] protein antigens)
• Shape: Enveloped, pleomorphic (spherical to filamentous), helical nucleocapsid
• Genome: Single-stranded, negative-sense, segmented RNA
  • Influenza A and B: 8 segments
  • Influenza C: 7 segments
• Size: 80-120 nm
• Replication: Occurs in the nucleus (unlike paramyxoviruses, which replicate in the cytoplasm)

Key Structural Proteins

Differences Among Influenza Viruses (Table)

• Sherris & Ryan's Medical Microbiology, 8th Ed., p. 314

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3. INFLUENZA INFECTION - EPIDEMIOLOGY

• Transmission: Direct droplet spread (most common), contaminated hands/surfaces
• Incubation period: 1-4 days (average 2 days)
• Infectivity period: Begins about 1 day before symptoms, lasts 5-7 days
• Seasonal pattern: Winter epidemics in temperate climates
• Epidemic waves: Influenza A every 2-3 years; Influenza B every 3-6 years
• Pandemic: Every 10-40 years when a new influenza A subtype appears
• Known pandemics: 1918 H1N1 (Spanish flu), 1957 H2N2 (Asian flu), 1968 H3N2 (Hong Kong flu), 2009 H1N1 (Swine flu)

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4. ANTIGENIC VARIATION

A. Antigenic Drift (Minor change)

• Definition: Gradual, progressive change in H or N antigens due to accumulation of point mutations in viral RNA
• Mechanism: RNA polymerase lacks proofreading ability, so errors accumulate. Mutant strains that escape the host's immune response are selected by immunological pressure
• Frequency: Occurs every year to every few years; can occur multiple times in a single epidemic
• Affects: All three influenza types (A, B, and C), but most prominently A
• Result: Previously immune individuals can be reinfected by the new variant
• Implication: Annual reformulation of influenza vaccines is required

B. Antigenic Shift (Major change)

• Definition: Abrupt, drastic change in H or N antigen due to genetic reassortment (exchange of whole RNA segments) between two different influenza A strains co-infecting the same cell (usually an intermediate host like a pig)
• Mechanism: When a human influenza A virus and an animal influenza A virus co-infect the same cell (often a pig), the 8 genome segments can mix, producing a novel reassortant virus with entirely new H or N antigens
• Frequency: Unpredictable; occurs every 10-40 years
• Affects: Only Influenza A (because types B and C are restricted to humans; animal reservoirs of A allow reassortment)
• Result: A new subtype against which the population has no pre-existing immunity -> pandemic

• Jawetz Medical Microbiology, 28th Ed., p. 595

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5. VIRULENCE FACTORS

1. Hemagglutinin (HA):
   • Mediates attachment to sialic acid receptors on respiratory epithelial cells (SA α2,6 receptors in upper respiratory tract for human strains)
   • HA must be cleaved into HA1 + HA2 by host cell proteases to be infectious
   • More virulent strains use ubiquitous enzymes (e.g., plasmin) enabling systemic spread
   • HA2 amino-terminal provides fusion activity at low pH for viral entry
2. Neuraminidase (NA):
   • Lowers viscosity of mucus, exposing cell surface receptors
   • Promotes spread of virus to lower respiratory tract
   • Facilitates release of newly formed virions from infected cells
3. RNA Polymerase (lack of proofreading):
   • Drives antigenic drift, enabling immune escape
4. Segmented genome:
   • Enables antigenic shift/genetic reassortment, generating pandemic strains
5. NS1 protein (Non-structural):
   • Interferon antagonist - blocks host innate immune response
6. PB1-F2 protein:
   • Induces apoptosis in immune cells (macrophages, monocytes)

• Jawetz Medical Microbiology, 28th Ed., p. 589

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6. PATHOGENESIS

1. Entry: Virus enters via inhalation of infectious droplets. Deposited in respiratory mucosa
2. First-line defense: May be cleared by cough reflex, neutralized by secretory IgA, or inactivated by mucus inhibitors
3. Attachment: HA binds to sialic acid receptors on ciliated respiratory epithelial cells
4. Entry: Virus is endocytosed; low pH in endosome triggers HA2 conformational change -> membrane fusion -> genome released into cytoplasm
5. Replication: Genome transported to nucleus; viral RNA polymerase transcribes mRNAs; replicated in nucleus (unique among RNA viruses)
6. Spread: NA cleaves sialic acid from cell surfaces, reducing mucus viscosity and allowing spread to lower respiratory tract. Newly formed virions bud from infected cells
7. Cell damage: Virus kills infected respiratory epithelial cells -> desquamation of mucosa, ciliary dysfunction -> loss of the mucociliary escalator (mechanical clearance mechanism)
8. Systemic effects: Cytokine storm (IL-1, TNF, IL-6, interferons) causes fever, myalgia, headache
9. Secondary bacterial invasion: Loss of ciliary clearance and disrupted mucosal barrier -> bacterial superinfection (most common cause of death in seasonal influenza)
10. Viremia: Uncommon in usual influenza; virus generally stays confined to respiratory tract

• Jawetz Medical Microbiology, 28th Ed., p. 592

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7. CLINICAL MANIFESTATIONS

Typical (Uncomplicated) Influenza

• Incubation: 1-4 days (average 2 days)
• Onset: Abrupt, over a few hours
• Symptoms:
  • High fever (38-40°C)
  • Severe myalgia (muscle aches) - often the most distressing symptom
  • Headache
  • Chills (occasionally shaking rigors)
  • Within 6-12 hours: dry, nonproductive cough, pharyngitis, rhinitis
  • Respiratory distress in severe cases
• Duration: Acute phase 3-5 days
• Recovery: Feeling significantly better by 1 week, but fatigue, weakness, and cough persist for 2-6 weeks

Severe/Complicated Influenza

• Progressive involvement of tracheobronchial tree and lungs
• Primary viral pneumonia: Direct viral invasion of lung parenchyma
• CNS dysfunction
• Myositis (especially in children)
• Myocarditis
• Sherris & Ryan's Medical Microbiology, 8th Ed., p. 332

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8. SUPPURATIVE (PURULENT) COMPLICATIONS

1. Bacterial pneumonia - most common serious complication
   • Causative organisms (in order of frequency):
     • Streptococcus pneumoniae (most common)
     • Haemophilus influenzae
     • Staphylococcus aureus (most virulent; particularly associated with post-influenza necrotizing pneumonia)
   • Pattern: Patient initially improves, then suddenly deteriorates with worsening fever, purulent sputum, lobar/bronchopneumonia on X-ray
   • Can occur at any time during acute or convalescent phase
2. Sinusitis (bacterial)
3. Otitis media - particularly in children
4. Bacteremia - secondary bacteremia from lung with seeding of distant sites

• Sherris & Ryan's Medical Microbiology, 8th Ed., p. 333

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9. NON-SUPPURATIVE (NON-PURULENT) COMPLICATIONS

1. Reye Syndrome
   • Occurs especially in infants and children, 2-12 days after infection
   • Characterized by:
     • Severe fatty infiltration of the liver (hepatic dysfunction)
     • Cerebral edema (encephalopathy)
   • Risk dramatically increased by aspirin (salicylate) use during viral illness
   • Also associated with varicella and other systemic viral illnesses
   • Aspirin is CONTRAINDICATED in children with influenza
2. Primary Viral Pneumonia
   • Direct viral pneumonia without bacterial superinfection
   • More common with H5N1 and pandemic strains (e.g., 2009 H1N1)
   • Mechanism: cytokine storm, alveolar flooding, Na+ channel blockage
   • High mortality, particularly in young healthy adults
3. Encephalitis / CNS complications
   • Encephalopathy, febrile seizures in children
   • Rare but recognized
4. Myocarditis
   • Direct viral involvement of myocardium
5. Myositis / Rhabdomyolysis
   • Muscle inflammation, elevated CK
   • Myoglobinuria and renal failure in severe cases
6. Post-influenza asthenia
   • Prolonged fatigue and weakness for weeks after acute illness
7. Decompensation of underlying disease
   • Elderly and those with chronic cardiac or pulmonary disease are at high risk of decompensation from any respiratory infection

• Sherris & Ryan's Medical Microbiology, 8th Ed., p. 333-334

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10. LABORATORY DIAGNOSIS

Specimen Collection

• Nasopharyngeal swabs (highest yield), nasal swabs, or throat swabs
• Collected during the acute phase (first 48-72 hours of illness)
• Bronchoalveolar lavage in severe cases

Diagnostic Methods (in order of clinical use)

• Virus grows in the amniotic cavity of chick embryos (egg inoculation), forming hemagglutinins
• MDCK cell lines are the standard for viral culture
• Cytopathic effect (CPE) in cell culture is confirmed by hemadsorption
• RT-PCR is now the most commonly used diagnostic test
• Sherris & Ryan's Medical Microbiology, 8th Ed., p. 334; Jawetz Medical Microbiology, 28th Ed., p. 593

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11. TREATMENT

General/Supportive

• Bed rest, hydration, antipyretics (paracetamol/acetaminophen)
• Aspirin is CONTRAINDICATED in children (risk of Reye syndrome)

Antiviral Drugs

• Most effective when started within 48 hours of symptom onset
• Mechanism: Inhibit neuraminidase -> prevent release of new virions from infected cells -> reduce spread
• Resistance to NAIs is less common than M2 inhibitors

• Mechanism: Block M2 ion channel -> prevent uncoating
• No longer recommended due to widespread resistance (>99% of circulating H3N2 strains are resistant)
• Inactive against Influenza B (no M2 protein in influenza B)

Indications for Antiviral Treatment

• High-risk groups: elderly (>65 years), immunocompromised, chronic cardiac/pulmonary/renal disease, pregnant women, children <2 years
• Hospitalized patients
• Within 48 hours of onset for outpatients

Prophylaxis

• Annual influenza vaccination - most effective prevention
  • Inactivated influenza vaccine (IIV) - injectable; for most groups
  • Live-attenuated influenza vaccine (LAIV) - intranasal; for healthy non-pregnant 2-49 year olds
  • Vaccine formulated annually based on WHO surveillance of circulating strains (antigenic drift necessitates yearly updates)
• Chemoprophylaxis: Oseltamivir can be used for post-exposure prophylaxis in high-risk contacts
• Jawetz Medical Microbiology, 28th Ed., p. 594-595; Sherris & Ryan's Medical Microbiology, 8th Ed., p. 336

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QUICK SUMMARY TABLE - Key Points for Exam

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• Sherris & Ryan's Medical Microbiology, 8th Edition, pp. 313-336
• Jawetz, Melnick & Adelberg's Medical Microbiology, 28th Edition, pp. 585-595