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Mechanistic Deep Dive
Influenza Replication
- Hemagglutinin (HA): binds sialic acid receptors
- Neuraminidase (NA): release of virions
- Targets for oseltamivir (NA inhibitor) + zanamivir + peramivir
- Baloxavir: polymerase (cap-dependent endonuclease) inhibitor
SARS-CoV-2 Entry
- Spike protein â ACE2 receptor
- Furin cleavage site
- Endocytosis vs membrane fusion
- Receptor in lungs, GI, vessels
- Multi-organ tropism
COVID-19 Inflammation Cascade
- Cytokine storm (IL-6, IL-1β, TNF-α)
- Endothelial dysfunction
- Coagulation activation
- Anti-inflammatory therapies target this
Recent Trials & Updates
EPIC-HR (2022) â Paxlovid
- Outpatient COVID-19, high-risk
- 89% reduction in hospitalization
- FDA approval
CAP-IT (2023) â Baloxavir for Influenza
- Comparable to oseltamivir
- Single dose advantage
RECOVERY (2020-2024) â Multiple COVID Therapies
- Dexamethasone, tocilizumab (positive)
- Hydroxychloroquine, lopinavir/ritonavir, azithromycin, ivermectin (negative)
- Practice-defining trial
COV-BARRIER (2021) â Baricitinib
- JAK inhibitor in severe COVID
- â Mortality
MOVe-OUT (2022) â Molnupiravir
- Outpatient COVID
- Less effective than initial trials (vs Omicron)
Universal Influenza Vaccine
- mRNA-based, multi-strain (Moderna mRNA-1010)
- Phase 1-2 trials
- Hope for less frequent boosters
Long COVID Trials
- RECOVER (NIH)
- Various symptomatic therapies
- Underway with mixed results
High-Yield Specialist Points
Paxlovid Drug Interactions
- Ritonavir = strong CYP3A4 inhibitor
- Many drugs require dose adjustment or temporary hold
- Statins (simvastatin, lovastatin contraindicated)
- DOAC adjustments
- Calcineurin inhibitors
- Pharmacist consultation valuable
COVID-19 + Anticoagulation
- INSPIRATION: prophylactic dosing for ICU patients (less benefit than higher dose)
- ATTACC + ACTIV-4a: therapeutic dose for moderate (non-ICU) â reduces organ failure
- ICU patients: prophylactic preferred (less bleeding)
RSV Severity in Immunocompromised
- Stem cell transplant recipients
- Lung transplant
- Hematologic malignancy
- Severe pneumonia + high mortality
- Ribavirin sometimes given
Influenza Vaccine Strain Selection
- Annual WHO recommendations
- Northern + Southern hemisphere separate
- Standard: trivalent / quadrivalent
- High-dose for elderly (Fluzone HD): more immunogenic
- Adjuvanted: FLUAD for elderly
- Cell-based + recombinant: avoid egg
Adenovirus in Hematopoietic Stem Cell Transplant
- Severe disseminated infection
- Cidofovir / brincidofovir
- Monitor adenovirus PCR
Measles + Pneumonia
- Vitamin A supplementation
- Giant cell pneumonia in immunocompromised
- Severe in pregnant + young children
- Vaccine-preventable (MMR)
Varicella Pneumonia
- Adults with primary varicella infection
- Severe, hemorrhagic
- Acyclovir + supportive
- Vaccine-preventable
Hantavirus Workflow
- Rodent exposure (Southwest US)
- Phase: prodrome â cardiopulmonary (rapid) â diuretic â convalescent
- High mortality early
- Supportive (ECMO for refractory)
- No specific antiviral
Cidofovir + Adenovirus
- Off-label
- Renal toxicity
- HSCT patients
- Combination strategies
Future Directions
- Universal influenza vaccine (mRNA)
- COVID-19 next-generation vaccines (intranasal, etc.)
- RSV vaccines expanding
- Long COVID treatments
Pearls
- Influenza: oseltamivir within 48 hr; baloxavir single dose alternative
- Post-flu pneumonia: S. aureus + S. pneumoniae; vancomycin + standard CAP
- RSV vaccines (2023): Arexvy + Abrysvo for adults ⥠60
- Nirsevimab (2023): long-acting mAb for infants
- COVID outpatient: Paxlovid (within 5 d, high-risk)
- COVID hospitalized: dexamethasone + remdesivir
- COVID severe: + tocilizumab or baricitinib
- Long COVID: 10-30% of survivors; multidisciplinary
- Annual influenza + COVID + RSV ⥠60 + pneumococcal for prevention