Influenza Flashcards
What influenza A subtypes caused the following pandemics:
1957
1968
1977
2009
1957 = H2N2 Asian
1968 = H3N2 Hong Kong
1977 = H1N1
2009 = H1N1 (pmd2009)
Are influenza viruses RNA/DNA viruses? What type? And what is unique about their replication cycle?
Enveloped, segmented ss-RNA
Unlike most RNA viruses, they replicate in the nucleus rather than the cytoplasm
What are the reservoir hosts of influenza A, B, C and D.
A) Main reservoir is waterfowl, but IAV has human and swine reservoir and most other mammals can be infected
B) Humans only (occasion spill over into seals/pigs/ferrets)
C) Humans and pigs
D) Cattle only
What is the function of heamagglutinin and neurominidase in influenza
HA - sialic acid receptor binding site (approx 300 per virus)
NA - sialic acid cleavage allowing release of viral particles (approx 40 per virus)
How many HA and NA types are there. Which infect humans?
18 HA and 11 NA
HA 17/18 and NA 10/11 are only found in bats and do not infect humans
What is the molecular make up of H1N1pdm09?
Quadruple reassortment consisting of two swine origin viruses, one avian and one human origin virus
In relation to influenza infection which sialic acid would you find in the upper and lower respiratory tract?
a2,6-linked sialic acid is the main receptor for seasonal influenza. This is expressed by the epithelial cells in the URT
a2,3-liked sialic acid is found in duck gut epithelium and this is the target for AIVs
a2,3-liked sialic acid is also found in the LRT of humans
Risk factors for complicated flu
Underlying disease (neurological, hepatic, renal, pulmonary, cardiac)
Severe immunosuppression
Over 65 y
Pregnancy (and 2 weeks post partum)
Under 6 m
Morbid obesity
Asplenia
Learning disability
Complications of influenza
Croup, bronchiolitis, otitis media (esp in kids)
Primary viral pneumonia
Secondary bacterial pneumonia
Invasive fungal disease
Exacerbation of underlying illness
Myositis and rhabdomyelitis
Myocarditis
Encephalitis/Meningo-encephalitis
Neurological complications of flu
Encephalitis/encephalopathy
Transverse myelitis
Acute disseminated encephalomyelitis
Seizures
Less commonly GBS and Reye’s syndrome (with salicylate exposure)
Diagnostic investigation for flu CNS infection
PCR sensitivity in CSF is very low as virus may no longer be present
Intrathecal Ab may be useful
Brian biopsy may be positive
Future possible treatments for influenza
MAb to stem region of HA
Epithelial cell targets - interferon lambda and fludase
Immunomodulators - TNFa and IFNab
Etanercept - TNF inhibitors
Umifenovir - used in China and Russia, membrane fusion inhibitor with immunomodulatory effects
Nitazoxanide
Short interfering RNAs
If a patient is on zanamivir and has a poor clinical response, should you switch to oseltamivir?
No.
Zanamivir resistance strains will likely also be resistant to oseltamivir, so keep on zanamivir and request resistance testing
In which situations would you continue influenza treatment to >5 days?
Severely immunosuppressed patients on oseltamivir require 10 day course
In severe flu can extend treatment to 10+ days, but monitor for resistance
What can result in a poor clinical response to neuraminidase inhibitors?
NI resistance
Natural flu progression
Lung damage
Immune mediated damage
In which cases would you consider repeat PCR testing if patients already on neuraminidase inhibitors?
Poor clinical response at 5 days and considering extending treatment
Develops ILI whilst on NI prophylaxis
Stem cell transplant patient inadvertently given LAIV ?action
If an immunocompromised individual receives LAIV then the degree of immunosuppression should be assessed. If the patient is severely immunocompromised, antiviral prophylaxis should be considered, otherwise they should be advised to seek medical advice if they develop flu-like symptoms in the 4 days (the usual incubation period) following administration of the vaccine.
Flu reproduction cycle
Enters cells through haemaglutinin interaction with sialic acid. Then migrated to a clathrin well on the cell membrane where it is absorbed into an endosome. M2 channels pump protons into the virus envelope which decrease the pH and causes a protein change which migrates the viral envelope to the edge of the endosome. The viral genome is ejected into the nucleus where translation and transcription start following ‘cap snatching’ by the viral RNA polymerase.
Once translation and transcription has completed the viral particle is completed in the cytoplasm. This then buds out of the cell gathering the membrane as the viral envelope. Neuraminidase catalyses sialic acid at this stage and releases the viral particle into the extracellular space.
MOA
- Oseltamivir/Zanamivir
- Baloxivir
- Amantadine
Neuraminidase inhibitors
- Cap dependent endonuclease inhibitor
- M2 protein channel blocker
Treatment dose oseltamivir/zanamivir in adults
- dose
- route
- duration
Oseltamivir
- 75mg BD PO for 5 days (10 if severe disease or immunosuppressed)
Zanamivir
- 10mg BD Inh for 5 days (can be IV if inhaler not available and oseltamivir not suitable).
What is the make up of H1N1pdm09?
Quadruple reassortant
1) Eurasian swine
2) Classic swine H1N1
3) Human H3N2
4) Avian
What are the receptors for HA?
a2,6-linked sialic acid in URT
a2,3-linked sialic acid in LRT and duck gut epithelium
What are the risk factors for complicated flu?
Underlying disease - hepatic, cardiac, neurological, renal, pulmonary
Severe immunosuppression
Over 65 years
Under 6 months
Pregnancy
Morbid obesity
Diabetes
Asplenia/splenic dysfunction
Learning disability
When do neurological symptoms occur in relation to flu infection, and what neurological disorders can occur?
Shortly after onset of symptoms, more commonly in children.
Encephalopathy
Encephalitis
Transverse myelitis
ADEM
Seizures
GBS
Reye’s syndrome (with salicylate exposure)
What supportive care is available in flu infection?
Hydration
Pain killers
Treating exacerbation of underlying conditions
Oxygen
Antibiotics
Options for flu positive mum in labour
Treat mum
Baby
1) prophylax with oral oseltamivir suspension
2) separation until after 5 days symptom onset
3) monitor
How long post partum are pregnant woman still at risk of severe influenza?
2 weeks
Treatments of:
- Uncomplicated flu in previously healthy patient
- Uncomplicated flu in at risk group, not severely immunosuppressed
- Complicated flu, not severely immunosuppressed
- Uncomplicated flu in severely immunosuppressed
- Complicated flu in severely immunosuppressed
- No treatment (unless at risk of complications)
- Oseltamivir 5d
- Oseltamivir 5d (second line zanamivir)
- Oseltamivir if H3 or IBV. Zanamivir if H1
- Oseltamivir if H3 or IBV, second line Zanamivir if poor clinical response, gastro dysfunction. Zanamivir if H1
What influenza vaccine and schedule is recommended in the following patients:
1) 18 month old in clinical risk category, never had flu vaccine previously
2) 18 month old in clinical risk category, previously had one flu vaccine
3) 5 y old in clinical risk category, never had flu vaccine previously
4) 5 y old in clinical risk category, previously had one flu vaccine
1) 2 doses of QIVc 4 weeks apart (Aged 6-24 m in clinical risk category)
2) 1x doses of QIVc (Aged 6-24 m in clinical risk category having had at least previous flu vaccine dose)
3) 2 doses of LAIV 4 weeks apart (Aged 5-9 in clinical risk category)
4) 1 dose of LAIV (Aged 5-9 in clinical risk category, and in >9 y in clinical risk group)
What are the benefits of cell based influenza vaccines over egg based?
Overcome issues with lower vaccine effectiveness due to egg adaptions
Which groups get influenza vaccine?
All at risk patients aged 6 month + in clinical risk groups
All patients aged 65y +
Children aged 2-17
Pregnant women
Carers
Household contacts of the immunosuppressed
Care home residents
Healthcare workers
People working in the avian industry
Which type of flu vaccine does JCVI recommend for the following groups:
1)18-59 years eligible groups
2) 60-64 y eligible groups
3) >65 y
1) QIVc
2) QIVc or QIV-HD
3) aQIV or QIV-HD
Which type of flu vaccine does JCVI recommend for the following groups:
1) At risk 6m-2y
2) 2-18 y
1) QIVc
2) LAIV (unless contraindicated then use QIVc)
Are the LAIV and inactivated flu vaccines trivalent or quadravalent?
LAIV is trivalent
All inactivated vaccines are quadravalent
When can you give NIs before/after LAIV?
Do not vaccinate until after 48 h after finishing antivirals
If given antivirals within 2 weeks of LAIV then revaccinate
Future influenza vaccines
Universal flu vaccine is the goal!
Viral like particles
mRNA vaccines
Recombinant HA vaccine using baculovirus expression system
Targeting HA stalk domain
PPE for staff and visitors within 2 m of flu patient
Plastic apron, gloves, face mask and eye protection
PPE for AGP in flu
FFP3 face mask, fluid repellent gown, gloves, eye protection
How long should patients with flu be isolated for?
Until 24 h after resolution of symptoms
