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Infectious Diseases > Viral Infections > Flashcards

Viral Infections Flashcards

1
Q

Notes on coronavirus and SARS COV 2

A

Coronaviridae

  • Pleomorphic enveloped viruses
  • Alpha, beta, gamma delta (first two infect mammals, latter two birds)

SARS COV 2

  • Beta coronavirus related to SARS & MERS
  • Droplet spread, some airborne features, also GI shedding (shedding often in pre-symptomatic phase)
  • Structure → RNA, capsid (layer that surrounds and protects the RNA, Envelope (protects RNA when not in host cells, easily disrupted by soap and water), spike glycoproteins
  • Virus binds to the ACE2 receptor on host cells
  • Incubation period of 4-5 days
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2
Q

Complications of COVID 19

A
  • ARDS
  • Myocarditis and arrhythmias
  • Encephalopathy
  • Hyponatraemia (severe) and AKI
  • Coagulopathy and DIC
    • PE
    • TIA/Stroke
    • Increased INR and features of DIC
  • Bacterial infection (rates 5-10% higher than with influenza)
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3
Q

Diagnosis of Covid 19

A
  • rt PCR
    • Expensive, sampling errors, false negative rate varies with timing of illness
  • Serology
    • IgM detected in 5 days, IgG in 10-14 days
    • Not helpful in acute setting
    • Antibodies may not indicates immunity
    • Can test for spike protein (does cross react with vaccine status and nucleocapsid antibodies)
  • RATs - fast, portable, cheaper
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4
Q

Role of sotrovimab in COVID 19 infection

A
  • Novel monoclonal antibody - provisionally approved for Rx mild to moderate covid 19
  • Reduces hospitalisation or death by 79% in adults with mild-mod covid at high risk of progression to severe disease
  • One off IV dose
  • COMET-ICE trial:
    • Adults at high risk of severe disease → diabetes (on meds), obesity, CKD, CHF, COPD, mod-severe asthma
    • Treatment within 5 days of symptom onset
    • 300 patients - treatment group 1% progressed to severe disease compared to 7% in placebo group
  • Not active against new Omicron variants → no longer in use
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5
Q

Notes on COVID virology

A
  • Spike protein interacts with cellular receptors - mainly ACE2 to facilitate fusion and uptake with the cellular or endosomal membrane -> viral contents released into cytoplasm
  • Viral RNA translated by host machinery to produce 2 polyproteins which contain all the enzymes required to produce new virus
  • Protease required to cut polyprotein into its enzymes
    • Target of nirmatrelvir in Paxlovid
  • Host machinery makes copies of proteins and viral RNA
    • Production of viral RNA requires RNA dependent RNA polymerase
      • Target of molnupiravir and remdesivir
  • Viral components assembled in cell and released from cell
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6
Q

Notes on immune response to COVID 19 infection

A
  • After contact with the virus - antigen presenting cells (mainly dendritic cells) activate antigen specific T cells
    • CD4+ Helper T cells (enhance the effects of other T cells by releasing cytokines and other stimulatory molecules)
    • CD8+ cytotoxic T cells which can immediately clear infected cells
  • Antigen specific B cells (activated following stimulation by COVID antigens) - further activated by interactions with T cells
    • Some B cells immediately produce antibodies - initially low affinity IgM antibodies, others undergo affinity maturation and class switching in secondary lymphoid tissue (spleen and lymph nodes) -> produce high amounts of IgG antibody which neutralises the virus
  • Soon after vaccination high levels of antibodies circulate -> high levels of antibodies correlate best with prevention against symptomatic infection
    • Levels will wane over months without ongoing stimulus
    • T cell response remains -> important in long term ability of vaccine to prevent severe disease even if person becomes infected with COVID
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7
Q

COVID vaccines available in Australia/NZ and class of vaccine they belong too

A
  • Pfizer/Moderna → mRNA
  • Novamax → protein subunit vaccine
  • AstraZeneca → viral vector
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8
Q

Notes on mRNA vaccines

A
  • No pre-COVID examples - first of their kind
  • Moderna/Pfizer
  • MOA
    • From the SARS-CoV-2 virus - the mRNA able to code for the spike protein of the virus is isolated and included in a lipid nano-particle (the vaccine)
    • Injected IM - attaches to host cells, injects mRNA into cytoplasm → ribosomes → translation → synthesis of spike proteins
    • Immune system produces antibodies against spike protein and Th cells produce cytokines → stimulates T cells to proliferate into memory T cells and to kill infected cells
  • Advantages:
    • Highly potent, easy to manufacture (no cell culture, no handling of infectious content)
  • Disadvantages:
    • mRNA unstable (storage -70 degrees celcius)
    • Risk pericarditis/myopericarditis
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9
Q

Notes on viral vector vaccines

A
  • E.g. AstraZeneca, Sputnik V
  • Astrazeneca → chimpanzee adenovirus modified to include gene encoding COVID spike protein. Human immune system doesn’t recognise chimpanzee adenovirus - allows for immune response to 2nd vaccine (otherwise adenovirus would be neutralised before delivery of DNA {containing spike protein DNA} to host cells
  • Sputnik V - similar principle, uses different viral serotypes to avoid neutralisation
  • Advantages
    • Robust immune response
    • Storage 2-7 degrees celsius
  • Disadvantages
    • Vaccine induced thombotic thrombocytopaenia (young women)
    • Immunity to viral vector can develop (limits ability for repeated doses)
  • Pre-covid examples → Ebola vaccine
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10
Q

Notes on protein subunit vaccine in COVID 19

A
  • Example → Novamax
  • MOA
    • Spike protein from COVID removed, inserted into yeast/bacteria/animal cells → spike proteins produced by cells and purified → combined with other substances to boost immune response → injected
  • Novavax → protein subunit vaccine with “Matrix M” proprietary adjuvant (supposed to improve T cell response)
  • Advantages:
    • Proven platform, generally good safety profile
  • Disadvantages
    • Low immunogeneicty, need for adjuvants and/or boosters
    • Lower ability to produce cellular immune response
    • Manufacturing scalability challenging
  • Non-COVID examples
    • HBV, influenza, HPV
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11
Q

Contraindications to COVID vaccination and other considerations

A
  • If contraindication to one vaccine → can generally have another
  • General contraindications
    • Anaphylaxis/severe ADR to previous dose of the vaccine
    • Anapylaxis after exposure to any component of the vaccine
      • Pfizer = PEG
      • AZ = polysorbate 80
  • Specific contraindications
    • mRNA = myocarditis/pericarditis to a previous dose of the vaccine
    • AZ = prior thrombosis or rothrombotic syndromes
  • Vaccinate 3 months after confirmed infection
  • Vaccinate at least 3 months after COVID 19 monoclonal antibody
    • No longer using sotrovimab so less relevant. Possibly should wait longer with Evusheld
  • Vaccination recommended in pregnancy
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12
Q

Notes on vaccination and Omicron variant

A
  • 2 dose Pfizer 65% efficacy against symptomatic infection (95% with ancestral COVID), 9% at 6 months
  • 2 dose of AstraZeneca ineffective
  • Some benefit from boosters but short lived
  • Vaccines still work well in preventing severe disease but boosters required
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13
Q

General notes on use of antivirals in COVID 19 infection

A
  • Used early in disease course to prevent severe disease
  • Generally within 5 days of symptom onset (7 days for remdesivir) and not hypoxic
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14
Q

Notes on Paxlovid in COVID 19 infection

A
  • Nirmatrelvir (COVID protease inhibitor) and ritonavir (used to boost levels of nirmatrelvir, cytochrome P450 inhibitor)
  • Contraindications
    • eGFR <30, severe hepatic impairment, pregnancy, breastfeeding, attempting to conceive (men/women), note drug interactions
  • Reduces hospitalisation and death when given early in illness
  • Medications to withhold:
    • Statin, rivaroxaban, ticagrelor, salmeterol, tacrolimus, colchicine, benzodiazepines
  • Don’t prescribe Paxlovid if patient on:
    • Phenytoin, carbamazepine, rifampin, rifapentine, clopidogrel, flecainide, sildenafil, bosentan, St. john’s wort
  • Adverse effects → headache, dysgeusia, diarrhoea, vomiting
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15
Q

Notes on Molnupiravir (Lagevrio) in COVID 19 infection

A
  • Ribonucleoside analogure → incorporated into viral RNA
  • Contraindications:
    • Pregnancy, breastfeeding, attempting to conceive (men/women)
    • Used in end stage renal and liver disease, including dialysis
  • Oral
  • Adverse effects: dizziness, diarrhoea, nausea
  • Not as effective at reducing hospitalisation compared to paxlovid, significant reduction in deaths
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16
Q

Notes on remdesivir in COVID 19 infection

A
  • Ribonucleoside analogue: inhibits RNA dependent RNA polymerase
  • Contraindications
    • eGFR<30
    • Liver disease
  • IV
  • Adverse effects → deranged LFTs, renal impairment, infusion reaction
  • Reduction in hospitalisation in moderate (non-hypoxic) COVID infection, PINETREE Trial NEJM 2022 → no deaths in remdesivir or placebo arm
  • Consider use in severe disease to improve time to recovery (no effect on mortality) → 5 day course when used for this indication
17
Q

Notes on Evusheld in COVID 19 infection

A
  • Combination of anti spike protein antibodies tixagevimab and cilgavimab → very long half life (3ish months)
  • Reduction in hospitalisation and death in treatment of early COVID
  • As pre-exposure prophylaxis good evidence for reduction in symptomatic infection → not currently recommended for this use, but is used in some transplant centres
  • Not advised for post-exposure prophylaxis
  • Administration → 2 x IM injections
  • Contraindications → bleeding disorders (iM injection)
  • Possible cardiac toxicity in TACKLE study - MI, CHF, arrhythmia
18
Q

Principals of drug treatment for severe COVID 19 infection

A
  • Dysregulated immune response - IL 6 major role
  • Once hypoxia develops - little/no benefit in antivirals
  • Therapies shown to improve survival:
    • Dexamethasone
    • Baricitinib
    • Tocilizumab
    • Remdesivir → reduces length of hospital stay only, not survival
19
Q

Notes on dexamethasone in severe COVID 19 infection

A
  • In hypoxic patients, some evidence dexamethasone improves mortality
    • 6mg IV/PO for 10/7
    • Use prednisone/hydrocortisone in pregnancy/breast feeding (lower foetal exposure) - if risk of preterm delivery can give dexamethasone for first 4 doses
  • Dexamethasone associated with increased mortality in non-hypoxic patients
20
Q

Role of baricitinib and tocilizumab in severe COVID 19 infection

A
  • Reduce mortality and reduce risk of requiring mechanical ventilation
  • Indication:
    • Severe/critical covid 19 (hypoxic and deteriorating)
    • Use baricitinib in most patients, tocilizumab if pregnant, or eGFR <30 or on dialysis
  • Contraindications to both:
    • Sepsis or severe non-COVID infection
    • Patient already on severe immunosuppression
  • Baracitinib → JAK 1 2 inhibitor → 4mg daily x 14/7 or until discharge. AE → VTE, cytopaenias, liver injury
  • Tocilizumab → anti IL-6 monoclonal antibody, in RECOVERY used in patients with CRP >75, AE → infection, bowel performation, liver injury
21
Q

Notes on infleunza

A
  • Entry into cell → haemagglutinin binds to sialic acid on respiratory epithelial cells for viral entry
  • Neuraminidase → allows daughter virions to be released to infect other cells
    • Neuraminidase and haemagglutinin → major antigenic proteins
  • Spread → droplet and direct contact
  • Infectious 1 day before symptom onset and 3-7 days after (PCR positive for longer)
  • Treatment:
    • Neuraminidase inhibitors → oseltamivir 75mg PO BD
      • Reduces symptoms
      • May reduce viral shedding
      • Better for Flu A than Flu B
      • More effective when started earlier in course of illness
      • Resistance increase
      • S/Es → nausea and vomiting
      • Needs dose adjustment in renal impairment
      • Can be used in pregnancy
    • Offer if: complications, ARC residents or patients being admitted to hospital, mod-high severity CAP, household contacts at higher risk of poor outcomes
  • Patients at risk of severe infection: >65 years, pregnancy, <5 years, ARC residents, homelessness, heart disease, Down syndrome, obesity, chronic illness
22
Q

Notes on antigenic drift and antigenic shift in influenza

A

Antigenic drift

  • Virus contains the enzyme RNA-dependent RNA polymerase - lacks proofreading ability
  • Accumulation of error during RNA replication - continuously evolving antigenic site to which the immune response is less effective
  • Need for annual influenza vaccine

Antigenic shift

  • Abrupt and sudden change in one of the antigenic proteins neuraminidase or haemagglutinin - results in a new subtype, to which there is very little immunity in the population and can cause a pandemic
23
Q

Notes on human monkeypox

A
  • Orthopoxvirus, zoonotic infection
  • Fever, rash, lymphadenopathy
    • Incubation period 4-21 days, prodrome 5 days prior to rash appearing
  • PCR testing of lesions, serology can support diagnosis, IgM appearing 5-56 days after rash onset
  • Suspected secondary attack rate of 8% (unvaccinated household contacts)
  • 2 strains → Central African (CFR 1-10%), West Africa (lower mortality, less virulent) → less virulent, lower mortality type responsible for current outbreak
  • Most deaths in young children and HIV
  • No current licensed treatment in NZ/Australia
    • Brincidovir (in vitro activity), tecovirimat (inhibits orthopoxvirus protein)
  • Post exposure vaccination (and pre) - modified vaccinia Ankara
24
Q

Notes on Epstein Barr Virus and Multiple Sclerosis

A
  • Recent study - followed >10 million of people in active military service in the US, checked their serology and followed up re development of MS over 20 years
    • 800 patients developed MS
    • 34 of those cases initially EBV negative, then infected with EBV before onset of MS
    • Remainder of the 800 cases (bar one) all EBV seropositive
    • Compelling data that implicates EBV as the trigger for the development of MS

Infectious Diseases (10 decks)

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