Influenza

Question 1

What influenza A subtypes caused the following pandemics:

1957
1968
1977
2009

Answer 1

1957 = H2N2 Asian
1968 = H3N2 Hong Kong
1977 = H1N1
2009 = H1N1 (pmd2009)

Question 2

Are influenza viruses RNA/DNA viruses? What type? And what is unique about their replication cycle?

Answer 2

Enveloped, segmented ss-RNA

Unlike most RNA viruses, they replicate in the nucleus rather than the cytoplasm

Question 3

What are the reservoir hosts of influenza A, B, C and D.

Answer 3

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

Question 4

What is the function of heamagglutinin and neurominidase in influenza

Answer 4

HA - sialic acid receptor binding site (approx 300 per virus)

NA - sialic acid cleavage allowing release of viral particles (approx 40 per virus)

Question 5

How many HA and NA types are there. Which infect humans?

Answer 5

18 HA and 11 NA

HA 17/18 and NA 10/11 are only found in bats and do not infect humans

Question 6

What is the molecular make up of H1N1pdm09?

Answer 6

Quadruple reassortment consisting of two swine origin viruses, one avian and one human origin virus

Question 7

In relation to influenza infection which sialic acid would you find in the upper and lower respiratory tract?

Answer 7

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

Question 8

Risk factors for complicated flu

Answer 8

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

Question 9

Complications of influenza

Answer 9

Croup, brinchiolitis, otitis media (esp in kids)

Primary viral pneumonia

Secondary bacterial pneumonia

Invasive fungal disease

Exacerbation of underlying illness

Myositis and rhabdomyelitis

Myocarditis

Question 10

Neurological complications of flu

Answer 10

Encephalitis/encephalopathy

Transverse myelitis

Acute disseminated encephalomyelitis

Seizures

Less commonly GBS and Reye’s syndrome (with salicylate exposure)

Question 11

Diagnostic investigation for flu CNS infection

Answer 11

PCR sensitivity in CSF is very low as virus may no longer be present

Intrathecal Ab may be useful

Brian biopsy may be positive

Question 12

Future possible treatments for influenza

Answer 12

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 interferring RNAs

Question 13

If a patient is on zanamavir and has a poor clinical response, should you switch to oseltamivir?

Answer 13

No.

Zanamivir resistance strains will likely also be resistant to oseltamivir, so keep on zanamivir and request resistance testing

Question 14

In which situations would you continue influenza treatment to >5 days?

Answer 14

Severely immunosuppressed patients on oseltamivir require 10 day course

In severe flu can extend treatment to 10+ days, but monitor for resistance

Question 15

What can result in a poor clinical response to neuraminidase inhibitors?

Answer 15

NI resistance

Natural flu progression

Lung damage

Immune mediated damage

Question 16

In which cases would you consider repeat PCR testing if patients already on neuraminidase inhibitors?

Answer 16

Poor clinical response at 5 days and considering extending treatment

Develops ILI whilst on NI prophylaxis

Question 17

Stem cell transplant patient inadvertently given LAIV ?action

Answer 17

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.

Question 18

Flu reproduction cycle

Answer 18

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. Neuaraminidase catalyses sialic acid at this stage and releases the viral particle into the extracellular space.

Question 19

MOA
- Oseltamivir/Zanamivir
- Baloxivir
- Amantadine

Answer 19

• Neuraminidase inhibitors
• Cap dependent endonuclease inhibitor
• M2 protein channel blocker

Question 20

Treatment dose oseltamivir/zanamivir in adults
- dose
- route
- duration

Answer 20

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).