On the AMU Influenza (and pneumonia) - Dr Nick Scriven Acute Physician CHFT President Society for Acute Medicine

Influenza (    )         and pneumonia

      on the AMU
                       Dr Nick Scriven
                Acute Physician CHFT
  President Society for Acute Medicine

Influenza

   Influenza spreads around the world in yearly outbreaks
   3-5million cases of severe illness
   Approx 250,000 - 500,000 deaths
   About 20% of unvaccinated children and 10% of unvaccinated adults are infected each year.
   In the northern and southern parts of the world, outbreaks occur mainly in the ‘winter’
   Around the equator, outbreaks may occur at any time of the year.
   Death occurs mostly in the young, the old, and those with other health problems.
   Larger outbreaks known as pandemics are less frequent

What is flu?

   Influenza viruses are RNA viruses that make up four of the seven genera of the
    family Orthomyxoviridae
   Influenza virus A
        H1N1 - Spanish flu in 1918, Swine flu in 2009
        H2N2 - Asian flu in 1957
        H3N2 - Hong Kong Flu in 1968
        H5N1 - Bird Flu in 2004
   Influenza virus B – humans, seals and ferrets!
   Influenza virus C - less common, humans, pigs, dogs
   Influenza virus D – only isolated 2011, no humans yet

Pandemics
Name of pandemic       Date           Deaths         Case fatality rate   Subtype involved

                                                                           possibly H3N8
Asiatic or Russian   1889–1890       1 million             0.15%
                                                                              or H2N2
        Flu

   Spanish flu
                     1918–1920   20 to 100 million          2%                 H1N1

    Asian Flu        1957–1958    1 to 1.5 million         0.13%               H2N2
  Hong Kong Flu      1968–1969   0.75 to 1 million

Virology

Structure                                              Replication
   Virion is 80–120 nm in diameter
   Viral envelope containing 2 glycoproteins +
    central core (viral RNA genome)
   Influenza A genome - 11 genes on 8 pieces of
    RNA, encoding11 proteins inc
    haemagglutinin (HA), neuraminidase (NA),
   Haemagglutinin (HA) and neuraminidase (NA)
    are the two large glycoproteins on the outside
    of the viral particles.
   Influenza A viruses are classified into subtypes
    based on antibody responses to HA and NA.
    These different types of HA and NA form the
    basis of the H and N distinctions in, for
    example, H5N1.
   There are 18 H and 11 N subtypes known, but
    only H 1, 2 and 3, and N 1 and 2 are commonly
    found in humans.

Drift and Shift
Drift
   natural mutation over time
   can cause loss of immunity or
    vaccine inefficiency/mismatch
   occurs in Flu A and B

Shift
   two or more different strains of a virus
    combine to form a new subtype having a
    mixture of surface antigens
   only Flu A

UK DATA 2018/19

Influenza Like Illness Rates

Hospital Data 2018/19

ICU DATA
3,245 ICU admissions (1015 A(H1N1), 242 A(H3N2), 1954 A(unknown), 34 B))
317 deaths in UK this season
96 admissions to ECMO centres

Virology 2018/19

Influenza Transmission

   Usually symptoms 1-4 days after          Influenza can be spread in three
    infection but some (? 30%) could be       main ways
    asymptomatic or mild illness only             direct transmission (when an
   Transmission can start 24hrs pre               infected person sneezes mucus
    symptoms                                       directly into the eyes, nose or
                                                   mouth of another person)
   Peaks around 48hr and usually
                                                  airborne (when someone inhales
    stopped by Day 5                               the aerosols produced by an
   In elderly and                                 infected person coughing, sneezing
    immunocompromised can be                       or spitting)
    transmittable for up to 9 days (30%           hand-to-eye, hand-to-nose, or
    of elderly secreting at 7 days in 1            hand-to-mouth - contaminated
    study)                                         surfaces or from direct personal
                                                   contact such as a handshake.
   Antivirals reduce viral shedding

Flu Symptoms

   Symptoms of influenza onset 24-48
    hrs after infection
   Usually the first symptoms are chills,
    body aches, fever with body
    temperatures ranging from 38-39°C
   It can be difficult to distinguish
    between the common cold and
    influenza.
                                                Symptom:            sensitivity         specificity
   Diarrhoea is not usually a symptom of          Fever        68–86%              25–73%
    influenza in adults, although it has          Cough         84–98%              7–29%
    been seen in some human cases of
                                             Nasal congestion 68–91%                19–41%
    the H5N1 "bird flu“ and can be a
    symptom in children                      All three findings, especially fever, were less sensitive
                                             in people over 60 years of age.

Treatment

   Prevention – Vaccination
   Cure or symptomatic?
        Simple measure
        Amantidine – resistance ~100% in A, no use in B
        Neuraminidase inhibitors- Oseltamiver/Zanamivir

UK Vaccinations 2018/19

3 vaccines used:
   Adjuvanted trivalent flu vaccine (aTIV) - people aged >65
   Quadrivalent vaccine (QIV) - children aged from 6 months to 2 years and in
    adults ages 18 -65 who are at increased risk because of a long term health
    condition.
   Live attenuated influenza vaccine (LAIV) (nasal spray).The age groups
    targeted in England for this vaccine in 2018/19 were 2-3year olds (through
    their GP surgery) and school aged children in reception - Year 5 (schools).

Vaccination data (May 2019)
   Proportions of people in England who had received the 2018/19 influenza vaccine in targeted
    groups
        48.0% in under 65 years in a clinical risk group
        45.2% in pregnant women
        72.0% in 65+ year olds.
        43.8% in 2 year olds and 45.9% in 3 year olds.
   Influenza vaccine uptake by frontline healthcare workers show 70.3% were vaccinated by 28
    February 2019,

Vaccine Effectiveness (All FLU A)

   For 6 months to end Jan 2019 from 6 European studies
   In primary care settings among all ages, VE against confirmed influenza A
    ranged - 32-43%
        Patients aged 18–64 years ranged from 32% (EU-PC) to 55% (DK-PC).
        In children aged 2–17 years in UK-PC, the VE of LAIV4 was 80%
        Among target groups for influenza vaccination, VE was 59%
   VE against laboratory-confirmed hospitalised influenza A among all ages was
    38%

Vaccine Effectiveness (A(H1N1))

   In the primary care studies, VE against confirmed influenza A(H1N1)pdm09 -
    all ages – 45 - 71%
   In UK-PC, the VE of LAIV4 among children aged 2–17 years – 87%
   In hospital-based studies among patients aged >65 years VE was 29-37%. VE
    among those aged 18–64 years was 49%.

    To date, all A(H1N1)pdm09 viruses characterised in Europe were
    antigenically similar to the vaccine virus

Cochrane Review (2014) and NIHR (2016)

   Oseltamivir and zanamivir have non-specific effects on reducing the time to
    alleviation of influenza symptoms in adults (not in asthmatic children) —
     oseltamivir reduced the time by 16.8 hours
   Treatment of adults with oseltamivir had no significant effect on
    hospitalisations.
   Prophylaxis with either oseltamivir or zanamivir may reduce symptomatic
    influenza in individuals and in households
   Oseltamivir increases the risk of adverse effects, such as nausea, vomiting,
    psychiatric effects and renal events in adults and children — oseltamivir in
    the treatment of adults increased the risk of nausea (NNTH = 28 ) and
    vomiting (NNTH = 22)

Oseltamivir treatment for influenza in adults:
a meta-analysis of randomised controlled trials
Joanna Dobson, MSc, Prof Richard J Whitley, MD, Prof Stuart Pocock, PhD, Prof Arnold S Monto, MD
Lancet 2015

In the intention-to-treat infected population
         21% shorter time to alleviation of all symptoms
         The median times to alleviation were 97·5 h for oseltamivir and 122·7 h for placebo
         Fewer lower respiratory tract complications requiring antibiotics >48h after randomisation
         Fewer admittances to hospital for any cause
         Oseltamivir increased the risk of nausea and vomiting
         No recorded effect on neurological or psychiatric disorders or serious adverse events.

Complicated influenza:
   Influenza requiring hospital admission and/or with symptoms and signs of lrti, cns
    involvement and/or a significant exacerbation of an underlying medical condition.

   Risk factors for complicated influenza:
        a. Neurological, hepatic, renal, pulmonary and chronic cardiac disease.
        b. Diabetes mellitus
        c. Severe immunosuppression.
        d. Age over 65 years.
        e. Pregnancy (including up to two weeks post partum).
        f. Children under 6 months of age.
        g. Morbid obesity (BMI ≥40).

Severe immunosuppression:
   a. Severe primary immunodeficiency.
   b. Current (within six months) chemotherapy or radiotherapy
   c. Solid organ transplant recipients on immunosuppressive therapy.
   d. Bone marrow transplant recipients currently, or within 12 months of receiving
    immunosuppression.
   e. Patients with current graft-versus-host disease.
   f. Patients currently receiving high dose systemic corticosteroids (equivalent to ≥40 mg
    prednisolone per day for >1 week) and for at least three months after treatment has stopped.
   g. HIV infected patients with severe immunosuppression (CD4

Treatment Notes
    At risk population - including pregnant women:
      Oseltamivir (PO). Do not wait for laboratory confirmation. Treatment should be started as soon as possible, ideally
 within 48 hours of onset.
    Severely immunosuppressed patients:
       Some influenza subtypes are associated with a greater risk of developing oseltamivir resistance, and the selection
 of first line antivirals in severely immunosuppressed individuals should take account of the dominant circulating strain
 of influenza.
       Oseltamivir PO is the first line treatment, unless the dominant circulating strain is influenza A(H1N1), in which
 case use zanamivir (INH).
      Treatment should start as soon as possible
      If clinical condition does not improve take a specimen for resistance testing and consider other possible causes.
      When oseltamivir is indicated based on the above advice use 75mg PO twice daily for 10 days
    Suspected or confirmed oseltamivir resistant influenza in a patient who requires treatment:
       Zanamivir (INH). Treatment should be started as soon as possible
    Management of patients for whom zanamivir is indicated, who are unable to self-administer inhaled zanamivir:
       Patients who are severely immunosuppressed and cannot take inhaled zanamivir should receive oseltamivir PO.
 Patients who have suspected or confirmed oseltamivir resistant infection and cannot take inhaled zanamivir should be
 considered for nebulised aqueous zanamivir.

Viral susceptibility to standard
treatment
   990 influenza A(H1N1) viruses have been tested for oseltamivir susceptibility-
    968 were fully susceptible and 22 were resistant
        (all susceptible zanamivir)
   238 and 223 influenza A(H3N2) viruses have been tested for oseltamivir and
    zanamivir susceptibility - all were susceptible.
   Three influenza B viruses have been tested for both oseltamivir and zanamivir
    and all were susceptible

Complications of Influenza

   Pulmonary
   Extrapulmonary

                     Sam Ghebrehewet et al. BMJ 2016;355:bmj.i6258

Pulmonary Complication

   Primary influenza pneumonia
   Secondary bacterial pneumonia – Strep , Staph, Haem
   Superadded infection with unusual pathogens – Chlamydia, Legionella,
    Aspergillus
   Exacerbation underlying lung disease
   ARDS

Pneumonia drug susceptibility (2019)
   Proportion of all lower respiratory tract isolates of Streptococcus pneumoniae, Haemophilus
    influenza, Staphylococcus aureus, MRSA and MSSA tested and susceptible to antibiotics.

Extrapulmonary complications

   Pericarditis/myocarditis – 1 study 50% of hospitalised flu patients had abn ECG (2005
    clin inf dis)

   Myocardial infarction
   Myositis
   Encephalopathy (Reye’s Syn)
   Encephalomyelitis/transverse myelitis
   Aseptic meningitis
   Guillain- Barre
   Rhabdomyositis
   AKI

   Encephalitis lethargica (historical)

Other ‘Bugs’ we worry about
Avian Influenza                                      Middle East respiratory
     (February - April 2019)
                                                     syndrome coronavirus (MERS-
                                                     CoV)
   Influenza A(H5) viruses
                                                        Since September 2012 WHO has been notified
        no new laboratory-confirmed human               of 2,419 laboratory-confirmed cases of
         cases of influenza A(H5) virus infections       infection with MERS-CoV (836 deaths).
         were reported to WHO.
                                                        In UK to May 2019, 5 cases of MERS-CoV, (3
   Influenza A(H7N9)                                    imported, 2 linked cases)
        1 new laboratory-confirmed human case          Since September 2012, 1,515 suspected cases
         of influenza A(H7N9) virus infection            in the UK that have tested negative.
         were reported to WHO from China
                                                        From March - April 2019, Saudi Arabia
   Influenza A(H9N2)                                    reported 45 additional cases of MERS-CoV
                                                         infection (13 deaths). Of these 9 cases,
        1 new laboratory-confirmed case of              including 1 death, were linked to the
         influenza A(H9N2) virus infection was           outbreak in Wadi Aldwasir city.
         reported to WHO from China. Avian
         influenza A(H9N2) viruses are enzootic         The latest ECDC MERS-CoV risk assessment
         in poultry in China.                            highlighted that risk of widespread
                                                         transmission of MERS-CoV remains very low.

And now the bad news……..

In conclusion

Have outlined
    last year’s data
    Current treatment guide
    Virology/Vaccine
    Some gloom and doom

Have not talked about CAP as there’s nothing new!