Viral Infections Flashcards
(24 cards)
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
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)
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
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
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
- Production of viral RNA requires RNA dependent RNA polymerase
- Viral components assembled in cell and released from cell
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
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
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
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
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
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
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
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
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
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
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
- Neuraminidase inhibitors → oseltamivir 75mg PO BD
- 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
