Micro 4 goodness me Flashcards
Why do influenza cause respiratory diseases
Influenza virus in humans causes respiratory disease because the virus requires activation by host cell proteases that are only expressed in the respiratory tract
Past influenza pandemics
There have been FOUR big pandemics in the 20th and 21st centuries
o 1918 - Spanish Flu (50 million deaths)
o 1957 - Asian Flu (2 million deaths)
o 1968 - Hong Kong Flu (1 million deaths)
o 2009 - Swine Flu (200,000 deaths)
Features of a pandemic flu virus
- A pandemic virus will have novel antigenicity.
- A pandemic virus will replicate efficiently in human airway.
- A pandemic virus will transmit efficiently between people.
What strains are the influenza vaccinations based on?
3 antigenically different flus tend to affect humans each year
1. Influenza A (H1) (peaks beginning of January)
2. Influenza A (H1N1) (peaks end of December)
3. Influenza B (peaks March)
– Trivalent vaccine in targeted pop’s = purified fraction with HA + NA of inactivated virus
What is the resevoir of influenza A
Natural reservoir of Influenza A is ducks
Human > human transmission of bird flu (H5N1) difficult as virus does not replicate very well at cold temperatures of upper airways (32OC).
Better in deeper lung tissue (still not ideal – 41.5OC) and from here it is difficult to escape.
What is the differenece between antigenic shift and drift
Antigenic Drift = Mutation occur to HA/NA to give new strains of the virus
Antigenic Shift = Complete change of HA/NA
Can only occur with influenza A
There is trading of RNA segments between human and animal strains
What is the role of haemolguttinin in viral pathogenesis
The virus attach to cells via sialic acid receptors. The virus enter the cell in a vesicle called the endosome. The haemaglutinin (HA) protein must be cleaved for the virus to be able to fuse with the endosome membrane and release its genome into the host cells
• Human airway tryptase in the lung lining is capable of cleaving HA, however, this enzyme is not present in other parts of the body
NOTE: there are some mutated forms of influenza which do NOT require HA to be cleaved to be able to enter host cells (this is a particularly virulent form of influenza)
o H5N8 is an example of a very deadly bird flu but it does not cross into humans
What is the significance of PB2 627K
• One of the key factors that allows animal influenza to cross into humans is a mutation in the polymerase protein (PB2 627K)
• The appropriate genes can be incorporated into a virus due to reassortment
o This is when a single cells is infected by both a human virus and a bird virus
o They then shuffle their RNA resulting in the production of a bird virus with the capability of infecting a human
o This is a quick way of acquiring the ability to infect humans and becoming a pandemic
o This is an example of antigenic shift
What happens once the virus breaks free of the endosome membrane?
They enter through endosomes. The acidity of the endosome triggers a fusion event by which it releases its genome into the cell
The genome then travels to the nucleus and takes over host factors to drive transcription and translation
New viral products are produced (proteins and genome)
They will assemble at the surface of the cell and bud off to produce hundreds of copies of the virus
Barriers to viral entry
- Mucus is difficult for viruses to get through
- Human viruses have evolved the ability to chop through the mucus to reach the cells
- They need to be able to recogise sialic acid in order to enter the cell.
- There may be intermediate hosts in whom only a couple of the changes need to be made to be able to infect them (e.g. pigs)
What are the complications of flu?
Secondary bacterial pneumonia/Mutant virus/Co morbidity/Cytokine storm
Antivirals for flu
- Amantadine (Influenza A only) – Targets M2 ion channel. BUT single AA mutation in M2 (S31N) = resistance (now in many ‘flu A strains incl. H1N1)
Therefore not effective against: influenza B, pH1N1 or seasonal H3N2 - Neuraminidase inhibitors: Oseltamivir (Tamiflu), Zanamivir (Relenza), Sialic acid – Effective only if given <48hrs after infection
• Relenza (zanamivir) - inhaled or IV
• Peramivir - IV
HSV Treatment
Encephalitis - Emergency IV aciclovir 10mg/kg tds for 21 days do not wait for test results
Meningitis - self limiting, treat only if IC with IV or 2-3d then oral for 10 days
VZV Treatment
Aciclovir PO/IV. Or valciclovir (prodrug) PO, famcliclovir. 2nd line is foscarnet but toxic. Only treat VZV if: neonatae chickenpox adult chickenpox shingles >50 underlying lung or eye problem
CMV treatment
IV Gancliclovir but BM hepatic and renal toxic so if CI or neurtopenic-»>
Foscarnet
If I/C, 3rd line is cidofovir
CMV strategy for transplant patients
TREAT established disease once it has been developed (high mortality in bone marrow transplant patients)
PROPHYLAXIS for organ TPs with ganciclovir or valganciclovir Side-effects: bone marrow toxicity
PRE-EMPTIVE THERAPY (for bone marrow transplant patients) Starting ganciclovir, valganciclovir or foscarnet when the viral load reaches a certain threshold, monitoring for the appearance of CMV on PCR in the blood.
Maribavir
- Inhibits viral kinase
- Effective in vitro against CMV and EBV (but no others)
- Does not cause bone or renal toxicity
- On going clinical trials (but they have been disappointing)
EBV MX
In post transplant, pts are at risk of lymphoproliferative disease. (LPD)
• DIAGNOSIS: EBV viral load in blood
• TREATMENT
• Reduce immunosuppression
• Rituximab - anti-CD20 monoclonal antibody
Influenza Treatment
The TWO main surface proteins are haemaglutinin (HA) and neuraminidase (NA)
- HA mediated virus binding and entry into the target cell
- NA allows release of progeny virus particles from the host cell
o NA is the target of the current generation of anti-influenza drugs
o Neuraminidase Inhibitors
• Examples:
• Oselatmivir (Tamiflu) - ORAL
• Zanamivir (Relenza) - Dry Powder
• Effective against influenza A and B
Indicated for all patients who are unwell enough to be admitted to hospital with an influenza virus-related respiratory disease. NEEDS TO BE WITHIN 48 HOURS OF SX ONSET. (36 for zana)
RSV Mx
1st line is outpatient care
If they have asthma, you can give prednisolone
If they are at risk of severe disease in highly seletive situations you can give inhaled ribvarin ±IVIG
IVIG - Derived from pooled donors. Often used as an adjunct to treatment of viral pneumonitis in the immunocompromised
Palivizumab- Monoclonal antibody against RSV
Used prophylactically in the winter months for the prevention of serious lower respiratory tract disease caused by RSV in high risk infants (e.g. preterm, heart or lung disease, SCID)
BK Virus Mx
• Treatment of BK Haemorrhagic Cystitis o Bladder washouts o Reduce immunosuppression o Cidofovir IV • May consider intravesical cidofovir • Treatment of BK Nephropathy o Reduce immunosuppression o IVIG o NOTE: cidofovir cannot be used because it is nephrotoxic
Adenovirus Mx
• Issue in paediatric transplant patients
• Can cause severe multi-organ involvement
• Treatment
o Cidofovir IV
o IVIG
HSV Drug Resistance
o Majority are due to mutation in viral thymidine kinase
o Most of these will show cross-resistance with ganciclovir
o Nearly always occur in immunocompromised patients
o Diagnosed using viral culture and plaque reduction assays (although genotypic assays are also becoming available)
o TREATMENT: foscarnet or cidofovir
CMV Drug resistance
o Most commonly caused by mutations in protein kinase gene (UL97)
o More likely to occur in the context of prolonged therapy in immunocompromised patients
o TREATMENT: foscarnet or cidofovir
How do vaccinations work
- An antigen is delivered by the vaccine which is then taken up by the antigen-presenting cell
- The APC will present the antigen to a naïve T helper cell which becomes activated
- This, in turn, results in activation of B cells
- A proportion of these activated B cells will mature into plasma cells
- The plasma cells will produce antibodies specific for the vaccine antigen
- Antibodies will then bind to the antigen leading to:
o Neutralisation of infectivity
o Antibody-dependent cellular cytotoxicity
NB If an attenuated virus vaccine is used, the T cell response is very important in destroying infected cells
