206.1 🎓 醫孞生版

206.1.0.1 📌 䞀頁重點

  • Virus: ssRNA, Orthomyxoviridae, segmented genome (8 segments → reassortment)
  • Types:
    • Influenza A: animal reservoirs (waterfowl, swine, etc.) + humans; pandemic potential through antigenic shift
    • Influenza B: 人 only; less variable; 2 lineages (Victoria, Yamagata — Yamagata now extinct post-COVID)
    • Influenza C: rare mild disease
    • Influenza D: cattle (no human disease)
  • Hemagglutinin (HA) + Neuraminidase (NA) = antigens; HA = entry, NA = exit
  • Antigenic drift: minor mutations → annual seasonal variation; basis for annual vaccine update
  • Antigenic shift: major genetic reassortment between human + animal strains → pandemic (only Flu A)
  • Clinical:
    • Acute febrile illness: fever ≥ 39°C + cough + sore throat + headache + myalgia + fatigue + chills
    • “Knocks you flat” — acute incapacitation distinguishes from common cold
    • Self-limited 5-7d typical
    • Severe: high-risk populations
  • High-risk groups for severe disease:
    • ≥ 65 yr
    • < 2 yr (especially < 6 mo)
    • Pregnant (3rd trimester especially)
    • Chronic disease (cardiopulmonary, DM, CKD, immunocompromise)
    • Obesity (BMI ≥ 40)
    • Native American populations
  • Complications:
    • Primary viral pneumonia (severe ARDS)
    • Secondary bacterial pneumonia — S. pneumoniae, S. aureus (post-flu necrotizing!), GAS, H. influenzae
    • Myocarditis, pericarditis
    • Encephalitis / Encephalopathy (especially pediatric — IAE)
    • Myositis / Rhabdomyolysis
    • Reye’s syndrome with aspirin (children)
  • Diagnosis:
    • Rapid antigen test — quick but lower sens
    • RT-PCR — gold standard, multiplex panels
    • Multiplex respiratory PCR includes flu A subtypes (H1, H3) + B
  • Treatment:
    • Oseltamivir (Tamiflu) 75 mg PO bid × 5d within 48 hr onset (preferred)
    • Baloxavir (Xofluza) single dose for outpatient
    • Peramivir IV for hospitalized / inability to tolerate PO
    • Zanamivir inhaled alternative
    • Empirical for hospitalized + suspected flu — start within hours
  • Vaccines (2024-2025):
    • IIV3 / IIV4 (inactivated, quadrivalent (Yamagata removed 2024 — now trivalent))
    • RIV (recombinant — Flublok)
    • LAIV (live attenuated, nasal — children + healthy adults)
    • High-dose IIV3 (≥ 65 yr — Fluzone HD)
    • Adjuvanted IIV3 (≥ 65 yr — Fluad)
    • Universal annual recommendation for all ≥ 6 mo
  • 2024-2025 Threats:
    • H5N1 avian spread to USA dairy cattle 2024 + farmworker infections + first human death (Louisiana Jan 2025) — pandemic preparedness alert
    • H7N9 sporadic in China

206.1.0.2 1⃣ Virology

206.1.0.2.1 Genome + Structure
  • Segmented ssRNA (8 segments for Flu A + B)
  • HA + NA on surface
  • 18 HA + 11 NA subtypes (only some infect humans)
  • Pandemic strains: H1, H2, H3 historic human; H5, H7, H9 zoonotic concern
206.1.0.2.2 Antigenic Variation
206.1.0.2.2.1 Antigenic Drift
  • Minor point mutations in HA + NA
  • Annual seasonal variation
  • Basis for annual vaccine reformulation
  • Both Flu A + B
206.1.0.2.2.2 Antigenic Shift
  • Major reassortment between animal + human strains
  • Only Flu A (segmented genome enables reassortment)
  • Creates pandemic potential
  • Examples:
    • 2009 H1N1 (pdm09) — swine-origin
    • 1968 H3N2 — Hong Kong flu
    • 1957 H2N2 — Asian flu
    • 1918 H1N1 — Spanish flu (50-100M deaths)
    • Future: H5N1, H7N9 concerns
206.1.0.2.3 Cell Entry
  • HA binds sialic acid (different α-2,3 vs α-2,6 species tropism)
  • α-2,6 = human upper respiratory
  • α-2,3 = avian (lower respiratory in human, conjunctiva)
  • Avian flu strains binding α-2,3 → severe LRTI but limited human-to-human transmission
206.1.0.2.4 Lifecycle
  • Endocytosis → uncoating → RNA replication in nucleus
  • Assembly + budding (NA cleaves sialic acid for release)
  • Neuraminidase inhibitors (oseltamivir, zanamivir) block NA
206.1.0.2.5 Resistance Mechanisms
  • NA mutations: H275Y for oseltamivir resistance in N1
  • PA mutations: I38 for baloxavir resistance (~ 10% post-treatment)
  • M2 channel mutations: amantadine/rimantadine R (universal — no longer used)

206.1.0.3 2⃣ Seasonal Influenza

206.1.0.3.1 Epidemiology
  • N hemisphere: Oct-May (peak Jan-Feb)
  • S hemisphere: May-Sep
  • Tropical: year-round + bi-modal peaks
  • Annual epidemics: 3-5M severe + 290,000-650,000 deaths globally
  • Post-COVID changes:
    • Yamagata lineage of Flu B appears extinct (last detected April 2020 globally)
    • 2024 trivalent vaccines (vs prior quadrivalent)
    • Co-circulation with COVID + RSV
206.1.0.3.2 Transmission
  • Respiratory droplets + aerosol
  • Contact (less)
  • Highly transmissible
  • 1-2 day incubation
  • Shedding 1-2 days before to 5-7 days after onset (longer in pediatric, immunocompromise)
206.1.0.3.3 Clinical (Adult)
  • Abrupt onset
  • Fever ≥ 39°C + chills + headache + myalgia + fatigue
  • Dry cough + sore throat
  • Substernal soreness
  • Rhinorrhea common but not dominant
  • 5-7d typical duration
  • “Knocks you flat” — bedridden 2-4 days
  • Cough may persist 2-4 weeks (post-influenza bronchial hyperreactivity)
206.1.0.3.4 Pediatric Clinical
  • Higher fever
  • More GI symptoms (vomiting, diarrhea)
  • More febrile seizures
  • IAE (influenza-associated encephalopathy) — Japanese term, severe necrotizing encephalopathy
206.1.0.3.5 Differential from Common Cold
Feature Influenza Common Cold (Rhinovirus)
Fever High ≥ 39 Low / none
Onset Abrupt Gradual
Headache Severe Mild
Myalgia Severe Mild
Fatigue Profound Mild
Runny nose Sometimes Common
Sore throat Sometimes Common
Duration 5-7 days 7-10 days

206.1.0.4 3⃣ Complications

206.1.0.4.1 A. Primary Viral Pneumonia
  • 倚 ARDS in severe
  • Diffuse alveolar damage
  • Hypoxia
  • High mortality
  • 2009 H1N1 pandemic prominent
  • ICU + ventilation + ECMO + oseltamivir / baloxavir
206.1.0.4.2 B. Secondary Bacterial Pneumonia
  • 1 week after acute flu
  • S. pneumoniae #1
  • S. aureus (including MRSA) — necrotizing pneumonia (post-influenza classic; Panton-Valentine leukocidin PVL strains particularly severe)
  • GAS
  • H. influenzae
  • Treatment: ceftriaxone + macrolide / FQ; add vancomycin if S. aureus risk
206.1.0.4.3 C. Cardiovascular
  • Myocarditis (rare, 1-5%)
  • Myopericarditis
  • Acute coronary events ↑ in 7-30 days post-flu (5-7× MI risk acutely; vaccination reduces)
  • Heart failure exacerbation
206.1.0.4.4 D. Neurological
  • IAE (Influenza-Associated Encephalopathy) — pediatric, Japanese clinical entity
  • Acute necrotizing encephalopathy
  • Reye’s syndrome with aspirin (children)
  • GBS post-influenza
  • Transverse myelitis rare
  • Encephalitis
206.1.0.4.5 E. Myositis + Rhabdomyolysis
  • Children + adults
  • CK ↑
  • AKI risk
206.1.0.4.6 F. Otitis Media + Sinusitis
  • Common bacterial superinfection sites
206.1.0.4.7 G. Pregnancy
  • Increased severity (3rd trimester)
  • Preterm labor risk
  • Vertical transmission rare
  • Maternal vaccination protects mother + infant (via transplacental Ab)

206.1.0.5 4⃣ Diagnosis

206.1.0.5.1 Rapid Antigen Test
  • POC, 15-30 min
  • Sensitivity 50-80%
  • Specificity high
  • Useful for outpatient triage
206.1.0.5.2 RT-PCR (Gold Standard)
  • Sensitivity 95%+
  • Multiplex panels (BioFire) — flu + RSV + COVID + others
  • 1-3 hr turnaround
  • Subtype identification (H1, H3, B)
206.1.0.5.3 Direct Fluorescent Ab
  • Older, less used now
206.1.0.5.4 Viral Culture
  • Reference, slow
206.1.0.5.5 CXR
  • May show consolidation in pneumonia
  • Hospitalized + severe cases

206.1.0.6 5⃣ Treatment

206.1.0.6.1 A. Antiviral Drug Choices
206.1.0.6.1.1 Oseltamivir (Tamiflu)
  • Most commonly used
  • 75 mg PO bid × 5d (adult)
  • Pediatric weight-based
  • Within 48 hr onset best efficacy
  • Indications:
    • Hospitalized influenza
    • Outpatient high-risk
    • Outpatient < 48 hr onset (any age)
  • Pregnancy: safe + recommended
  • Side effects: GI (nausea, vomiting), rare neuropsych pediatric Japan
206.1.0.6.1.2 Baloxavir (Xofluza)
  • Single oral dose 40-80 mg
  • Cap-dependent endonuclease inhibitor (PA subunit)
  • Convenient adherence
  • Resistance: I38 mutation post-treatment (~ 10%)
  • Cost concern
206.1.0.6.1.3 Zanamivir Inhaled
  • 10 mg twice daily × 5d
  • Alternative; bronchospasm in asthma/COPD avoid
206.1.0.6.1.4 Peramivir IV
  • Single dose 600 mg
  • Hospitalized + cannot tolerate PO
206.1.0.6.1.5 Amantadine + Rimantadine
  • No longer recommended — universal resistance
206.1.0.6.2 B. Adjunctive Therapy
  • Acetaminophen / NSAID for fever / aches (no aspirin in children → Reye’s)
  • IV fluids
  • Oxygen + ventilation for severe
  • Steroid for ARDS (controversial; not standard)
206.1.0.6.3 C. Empirical Strategy
  • Hospitalized + suspected flu: start oseltamivir within hours, before lab results
  • Outpatient < 48 hr + symptoms: consider oseltamivir or baloxavir
  • PEP for high-risk + exposure: oseltamivir 75 mg qd × 7-10d post-exposure

206.1.0.7 6⃣ Vaccines

206.1.0.7.1 Annual Vaccine Update
  • WHO reviews circulating strains twice yearly (Feb for N hemisphere, Sep for S)
  • Selects 3-4 strains for inclusion in next season’s vaccine
  • 2024-2025: Trivalent (Yamagata lineage extinct, dropped)
  • Influenza A H1N1 + H3N2 + Flu B Victoria
206.1.0.7.2 Vaccine Types
206.1.0.7.2.1 IIV3 (Trivalent Inactivated)
  • Standard injectable
  • 3 strains
  • All ages ≥ 6 mo
  • 60-70% efficacy in younger, 30-50% in elderly
206.1.0.7.2.2 RIV (Recombinant)
  • Flublok — recombinant HA produced in insect cells (no eggs)
  • Egg-allergic patients OK
  • Adult only
206.1.0.7.2.3 LAIV (Live Attenuated)
  • Nasal spray, 2-49 yr healthy
  • 䞍 immunocompromise / pregnant
  • AAP + ACIP recommend
206.1.0.7.2.4 High-Dose IIV3
  • Fluzone HD — 4× antigen for ≥ 65 yr
  • Better elderly response
206.1.0.7.2.5 Adjuvanted IIV3
  • Fluad — MF59 adjuvant for ≥ 65 yr
  • Improved immune response
206.1.0.7.3 Universal Recommendation
  • All ≥ 6 mo (ACIP, WHO, etc.)
  • Updated annually
  • Especially high-risk + healthcare workers
  • Co-administration with COVID, RSV, pneumococcal allowed
206.1.0.7.4 Efficacy
  • Varies by season, age, vaccine type
  • Reduces severe disease + hospitalization + death
  • Pediatric: severe disease reduction 60-80%
  • Elderly: more variable

206.1.0.8 7⃣ 2024-2025 H5N1 Avian Influenza

206.1.0.8.1 Background
  • H5N1 highly pathogenic avian influenza (HPAI)
  • Endemic in poultry many regions
  • Sporadic human cases (conjunctivitis, mild URI to severe pneumonia)
  • Pre-2024: low human-to-human transmission (binds α-2,3 sialic acid — avian-type)
206.1.0.8.2 2024 USA Dairy Cattle Outbreak
  • First detected March 2024 (Texas)
  • Now > 700 dairy herds affected in 15+ states
  • Cattle infection unprecedented
  • Cattle don’t show severe illness but shed in milk
  • Farmworker infections (mostly mild conjunctivitis + URI)
  • Cooked / pasteurized dairy safe (heat inactivates)
206.1.0.8.3 Human Cases
  • 2024 USA: ~ 60 farmworker cases (mostly mild)
  • First USA death January 2025 (Louisiana) — older patient, comorbidities
  • Egypt, Cambodia, Vietnam ongoing avian flu human cases
  • Pandemic preparedness alert (WHO + CDC monitoring closely)
206.1.0.8.4 Pandemic Concerns
  • Genetic adaptation if H5N1 acquires α-2,6 binding (human-type) + maintained transmissibility
  • Mutations of concern monitored: PB2 627K, HA Q226L, etc.
  • WHO + CDC stockpile vaccines (egg-based + cell-based)
  • H5N1 vaccines in development (mRNA candidates)
206.1.0.8.5 Treatment
  • Oseltamivir + baloxavir effective in vitro for H5N1
  • Higher dose / longer course considered for severe avian flu
206.1.0.8.6 Prevention
  • Farmworker PPE
  • Surveillance
  • Pasteurization of dairy
  • Avoid raw milk
  • Cull infected poultry
  • Vaccinate farmworkers (limited deployment)