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Pandemic influenza A (2009) Clinical Controversies in Clinical Care: What worked and what did not

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Title: Pandemic influenza A (2009) Clinical Controversies in Clinical Care: What worked and what did not


1
Pandemic influenza A (2009) Clinical
Controversies in Clinical Care What worked and
what did not
  • David SC Hui
  • MBBS, MD(UNSW), FRACP, FRCP, FCCP, FHKCP, FHKAM
  • Professor, Division of Respiratory Medicine
  • Director, Stanley Ho Center for Emerging
    Infectious Diseases
  • The Chinese University of Hong Kong
  • Prince of Wales Hospital
  • HK

2
Pandemic H1N1(2009) Infection
  • Antivirals
  • Role of immuno-immudulating agents (eg systemic
    steroid, IVIg, statins, NAC)
  • Convalescent plasma, hyperimmune Ig
  • Therapeutic plasma exchange, polymyxin
    B-immobilized fiber column hemoperfusion
  • Non-invasive ventilation
  • ECMO
  • Conflict of interest nil

3
M2 Inhibitor Resistance
Virus M2 Resistance Predominant Mutation
Seasonal H1N1 Rare
Pandemic H1N1 99.7 S31N
Seasonal H3N2 100 S31N
H5N1 Clade 1 100 S31N
H5N1 Clade 2.1 80 S31N or V27A
H5N1 Clade 2.2 Rare
H5N1 Clade 2.3 Rare
Ison MG. Therapy. 2009 6 883-891.
http//cdc.gov/flu/weekly/ Accessed 5/15/10.
4
(ICU adm)
5
Jain S, et al. NEJM. 2009
6
  • When oseltamivir was initiated ? 2 days after
    symptom onset, a greater rate of decline of NPA
    viral load of treated pts vs non-treated pts was
    observed,
  • The viral load was undetectable at day 6 after
    oseltamivir initiation, which was 1 day earlier
    than that of those whose treatment was initiated
    gt2 days of symptom onset.
  • Resolution of fever was 1.4 days later in
    non-treated than treated pts ( P 0 .012).


Oselt 2d
Li IW, et al. Chest 2010
7
More observational studies suggesting that Rx
with NAI (most commonly oseltamivir) may reduce
disease severity mortality in pts hospitalized
with pH1N1
  • Among critically ill pts in Mexico, survivors
    were more likely than non-survivors to have
    received treatment with a NAI (OR 7.4, 95 CI
    1.8-31) Dominguez-Cherit G, et al. JAMA 2009.
  • Among hospitalized pts in New York City, the 28
    pts who died were less likely to have received
    oseltamivir  within 2 days of hospitalization
    than the 98 pts who survived (61 vs 96) Lee EH,
    et al. CID 2010.
  • Among pregnant women with pH1N1 in the US, those
    who began antiviral therapy gt4 days after symptom
    onset were more likely to be admitted to an ICU
    than those who began therapy lt2 days (57 vs 9
    RR 6.0, 95 CI 3.5-10.6) Siston AM, et al. JAMA
    2010.
  • Among critically ill children with pH1N1 in
    Argentina, administration of oseltamivir appeared
    to have a protective effect vs fatality when
    administered within 24 hrs after hospital adm (OR
    0.20, CI 95 0.070.54 plt0.01). Farias JA, et
    al. ICM 2010

8
pH1N1 Influenza in Hematopoietic Stem Cell
Transplant (HSCT) Recipients (n27)
  • The incidence of influenza LRTI was 52 (14/27).
    Five cases were hospital-acquired.
  • In comparison to pts with URTI (n13), those
    with LRTI were begun on antiviral therapy
    significantly later after symptom onset (3.0 days
    vs. 6.6 days after onset of symptoms, p0.03 95
    CI 0.29, 6.8).
  • Overall influenza-related 30-day mortality was
    22 (6/27) but in patients with LRTI, it was 43
    (6/14).
  • Chronic steroid use (gt/ 20 mg/day of prednisone
    equivalent) at the time of presentation was
    associated with LRTI (p 0.006) mortality (p
    0.003) on univariate analysis.
  • pH1N1 infection in HSCT often presented as
    severe illness with a high incidence of LRTI and
    high mortality.
  • Taplitz R, et al. Biol Blood Marrow Transplant.
    2010 Aug 10. Epub

9
Kumar D,
et al. Lancet ID 201010 52126
Multivariate analysis for independent factors
associated with ICU admission Delayed antiviral
treatment gt48 hrs (OR 3.03, 95 CI 1.247.39,
p0.015). Diabetes mellitus (OR 2.18, 95 CI
1.034.64, p0.043).
10
Patients with severe pH1N1 pneumonia exhibited
slow viral clearance with oseltamivir treatment,
esp in the lower respir tract duration of
RNA-positivity after antiviral initiation,
median(IQR) NPFS, 6.0(3.0-8.0) days tracheal
aspirate, 11.0(7.8-14.3) days vs milder-illness
group NPFS, 2.0(1.0-3.0) days, plt0.01. Lee N,
et al. AVT 2010 (in press)
11
PLoS ONE 2010
12
Respir Failure caused by pH1N1 in a 40 yo lady
with BMI 31.8 HSCT for myeloma Detection of
pH1N1 RNA (plasma, BAL fluid stool) on D7-9
despite triple antiviral combo IVIg. IV
Peramivir 600mg/d for 10 days from
D13. Extubated D24 home D47.
Campbell AP, et al.
Cf. Nguyen JT, et al. Triple combo of amantadine,
ribavirin, oseltamivir is highly active
synergistic against drug resistant influenza
virus strains in vitro. PLoS One. 2010
5(2)e9332. Rowe T, et al. In vivo ribavirin
activity against severe pH1N1 influenza A in a
mouse model. J Gen Virol. 2010 Aug 25. Epub
13
22-yr-old woman, neutropenic after chemotherapy
for Hodgkins disease, was referred to ICU with 3
days of increasing dyspnea, bilateral chest
infiltrates, lab-confirmed pH1N1 2009 infection
not responding to oseltamivir 75 mg bd
broad-spectrum antimicrobials.
Other ref for IV ZNV Gaur AH. NEJM 09. Harter
G. CID 2010 Dulek DE. CID 2010
14
Fatal Respiratory Events Caused by Zanamivir
Nebulization
  • Expiratory filter obstruction caused by nebulized
    zanamivir (20mg lactose powder formulation
    dissolved in normal saline) resulted in severe
    hypoxemia bilateral pneumothoraces that led to
    fatality in a 26-yr old pregnant lady with severe
    pH1N1 on D8 of admission (used 3 ventilators) in
    Thailand. Exam of the removed filter demonstrated
    inside-blockade caused by sticky material.
  • A simulation was performed by connecting the
    ventilator to a test lung a pressure manometer
  • From the 6th dose of neb zanamivir,
    significant retardation of expiratory flow noted
    with 1.52 cm H2O elevation of PEEP airway
    pressure. Severe ventilator occlusion occurred
    during the 8th dose became persistent at the
    9th dose of nebulization, during which the
    ventilator automatically opened its safety valve
    switched to a low respir rate, a low airway
    pressure, a zero PEEP ventilation. Further
    ventilator reset failed to recover its previous
    function.
  • Kiatboonsri S, et al. CID 201050620.
  • FDA MedWatch 9 Oct 2009 - Zanamivir Inhalation
    Powder must NOT be reconstituted in liquid
    formulation or used in any nebulizer or
    mechanical ventilator !

15
2003
Zanamivir supplied by GSK as an IV formulation
for this study
2007
16
  • 2 yr old child received cadaveric liver
    transplant for Carolis dis. On cyclosporin A
    (CSA) prednisolone. Developed ARDS 4 days after
    transplant tracheal aspirate for pH1N1. Rx
    Oseltamivir (30 mg/day bd) immediately after p
    H1N1 results noted at D3 after onset of respir
    symptoms.
  • As respir failure further deteriorated, IV
    zanamivir (2x260 mg/day) started for 5 days from
    D10 to 15 after transplantation. Rx course
    neither led to negative p H1N1 PCR nor to respir
    improvement. CSA was discontinued, prednisone
    was reduced to 10 mg/m2 at D11 after
    transplantation.
  • During IV zanamivir Rx,
  • ? of AST ALT up to 628 U/L and 193 U/L,
    respectively. Liver US revealed an unexplained
    retrograde flow of the portal vein but no
    evidence of portal vein thrombosis. Rejection
    ruled out pH1N1 RNA not detectable in liver
    biopsy. Portal vein flow normalized 10 days after
    stopping zanamivir.
  • serum creatinine ? from 0.36mg/dL to a max of
    0.68mg/ dL. Kidney function normalized with
    termination of zanamivir.
  • Oseltamivir was continued for another 10 days.
    The patient improved slowly was weaned off
    mechanical ventilation after 25 days. pH1N1 RNA
    in tracheal aspirate negative 22 days after first
    detection.

  • Dohna-Schwake C, et al. Transplantation 2010
    90(2)223-4.

17

50 yr.old male driver with BMI30 presented on 18
Aug 09 with acute dyspnea following a wk history
of ILI with diarrhoea. LDH 828, ALT75. IMV from
19 Aug 09.
Oseltamivir
Oseltamivir
Zanamivir iv
Data source Dr KW Choi, AHNH. Paul Chan, CUHK
18
Complicated by ARF after IV ZNV requiring CVVH,
LDHgt1400, VAP, septic shock MODS. Died on 1
Sept 09 despite ICU support
umol/l
Oseltamivir
Oseltamivir
IV Zanamivir
simvastatin
Data source Dr KW Choi, AHNH
IVIg
N-acetylcysteine
19
High plasma levels of IL-6, IL-8, MCP-1 sTNFR-1
were observed, which correlated with the extent
progression of pH1N1 pneumonia in hospital. Lee
N, et al. AVT 2010, in press.


Other ref To KK, et al. CID 2010
20
Hypercytokinemia with 2009 pH1N1 influenza
successfully treated with polymyxin B-immobilized
fiber column hemoperfusion. Takeda S, et al.
Intens Care Med. 2010 36(5)906-7.
(an inhibitor of human neutrophil elastase)
16 yr old girl not responsive to Zanamivir 10mg
bd initially
high-mobility group box-1
21
Lai KY, et al. Annals Intern Med 2010 152687-8
A 48 yr old lady, previously healthy, presented
with severe pneumonia septic shock. Rx NG
oseltamivir, 75 mg bd, IV antibiotics on D1.
Oseltamivir ? to 150 mg bd from D2 started
high-dose NAC at 100 mg/kg continuous IV infusion
daily for 3 days then oral NAC 600mg bd but
worse. High dose NAC restarted D10.
Oselt 75mg bd then 150mg bd?
Oral NAC ?
Home on D20
22
Geiler J, et al. Biochem Pharmacol 2009
NAC at conc from 5-15mM ? H5N1-induced
cytopathogenic effects, virus-induced apoptosis
and infectious viral loads 24 hrs post infection.
NAC ? production of pro-inflam molecules in
H5N1-infected lung epithelial (A549) cells The
antiviral and anti-inflam mechanisms of NAC
include inhibition of activation of oxidant
sensitive pathways including transcription factor
NFKB and mitogen activated protein kinase p38.
23
Patel P, et al. Pediatr Crit Care Med. 2010 Jun
18. Epub
Age, yrs 8 11 17
This case series suggest there may be a role for
therapeutic plasma exchange as a strategy for
cytokine attenuation in severe shock and acute
lung injury related to pH1N1 that has not
responded to traditional therapy.
24
90 of the 881 convalescent donors had
seroprotective titer of ?140
The convalescent NAT correlated well with the
initial viral load was independently associated
with severity of the viral illness, including
pneumonia. The findings provide some markers for
identifying potential convalescent plasma donors
with high serum NAT, which can be used to produce
hyperimmune IVIg in a randomized treatment trial
for pts with severe pH1N1 infection.
Hung I, et al.
25
Statins have anti-inflammatory
immuno-modulatory effects (eg by repressing
induction of MHC-II by IFN-? subsequent
T-lymphocyte activation). A potential role for
treatment prophylaxis of pandemic influenza
based on observational studies showing the
survival benefits in patients receiving statins
who developed bacteremia, sepsis or pneumonia.
Fedson DS. Lancet ID 08/ EID 09
Thomsen RW, et al.
26
Data from anonymized electronic medical records
of persons aged gt45 yrs were examined for statin
use, chronic morbidity, respiratory Dx,
vaccination procedures, immune suppression. A
total of 329,881 person-year observations
included 18 statin users 46 influenza
vaccinees.
Conclusion No benefit in respiratory infection
outcomes attributable to statin use, although
uniformly higher ORs in non-vaccinated statin
users might suggest synergism between statins
influenza vaccination. Fleming DM,
et al. Epidemiol. Infect. 201013812818.
27
Case 1 28 yr old male, BMI 18, SOB gt1 wk before
adm. IMV for severe pH1N1 pneumonia. Received
high-dose methylpred (1 mg/kg/day) for ARDS for
28 days. Pneumothoraces bronchopleural fistula.
A. fumigatus isolated from sputum, bronchoscopy,
pleural fluid cultures. Died D70. Case 2 51
yr old male office worker, BMI 24.5. Fever
bilat lung infiltrates. IMV from day 2. ARDS
prompted administration of methylpred (1
mg/kg/day for 3 days). A. fumigatus isolated from
bronchoscopy on D12. Died on D21 with fungal
abscesses consistent with Aspergillus spp. in the
lung, thyroid gland, liver.
No antiviral therapy given in both cases as pH1N1
Dx beyond 48 hrs from symptom onset. Both
received high dose systemic steroid for ARDS.
EID 201016971-3.
28
2007 Seasonal flu
JID 2009
N147, H3N2
29
  • CROSS-REACTIVE NEUTRALIZING ANTIBODY AGAINST p
    H1N1 2009 INFLUENZA A VIRUS IN INTRAVENOUS
    IMMUNOGLOBULIN PREPARATIONS.
  • Hong DK, et al. Pediatr Infect Dis J. 2010 Aug
    18. Epub
  • Prepandemic IVIG sera from Kawasaki disease
    pts treated with this IVIG were analyzed for 2009
    H1N1-specific micro-neutralization
    hemagglutination inhibition antibodies.
  • All 6 different IVIG preparations tested had
    significant levels of cross-reactive-specific
    antibody at a concentration of 2.0 g/dL of
    immunoglobulin.
  • Sera from 18 of 19 Kawasaki disease pts had
    significant increases of cross-reactive-specific
    antibody after 2.0 g/kg of prepandemic IVIG.
  • These results suggest a role for adjunctive IVIG
    therapy for severe and/or drug-resistant 2009
    H1N1 virus other highly antigenically drifted
    influenza strains, esp in the immuno-compromised.

30
IVIg
  • Immuno-modulatory properties may down-regulate
    cytokine expression. Ballow M. JACI
    1997100151-7.
  • Singapore SARS cohort (n206) 11 and 7 episodes
    of DVT and PE reported respectively among 46
    critically ill SARS pts at TTSH despite LMWH. Lew
    TW et al. JAMA 2003.
  • 4/8 postmortem cases had evidence of PE. Chong PY
    et al. Arch Pathol Lab Med 2004128195-204

  • 5 had large artery ischaemic stroke (3 had
    received IVIg). Umpathi T et al. J Neurol
    20042511227-31.
  • IVIg - induced increase in viscosity may be
    consequential in pts with hypercoagulable states.
    Dalakas MC et al. Neurol 200360 1736-7.
  • Renal impairment esp on conservative fluid
    balance for ARDS

31
Non-invasive ventilation (NIV)
  • NIV for hypoxemic respiratory failure is
    controversial.
  • NIV does not decrease the need for intubation,
    there is not enough evidence to support its use
    in ARDS. Agarwal R, et al. Respir Med 2006
  • 25 to 30 of pH1N1 pts were non-invasively
    ventilated on admission, but 70 to 85 of these
    pts required subsequent intubation invasive
    ventilation. (Rello J, Crit Care 2009 Ramsey CD,
    et al CCM 2010 Rodriguez A,et al. Arch
    Bronchoneumol 2010 Farias JA, et al. ICM 2010)
  • NIV useful in reversing hypercapnia in pts with
    AECOPD without pneumonia (Hui DS, Chest 2010).
  • As a general rule, NIV not recommended as an
    alternative to invasive ventilation in pts
    affected by pH1N1 (Conti G, et al. ERS ESICM
    guidelines).

32
Norfolk SG, et al. Crit Care Med. 2010 Aug 12.
Epub Rescue therapy in adult and pediatric
patients with pH1N1 influenza infection A
tertiary center intensive care unit experience
from April to October 2009. In critically ill
adult and pediatric patients with pH1N1 infection
severe lung injury, the use of high-frequency
oscillatory ventilation extracorporeal
membranous oxygenation can result in significant
improvements in Pao2/Fio2 ratio, oxygenation
index, and Fio2. However, the impact on mortality
is less certain.
33
Pandemic H1N1 influenza A (2009) Clinical
Controversies in Clinical Care
What worked

What didnt work
Adamantane Nebulized /inhaled zanamivir (lactose
formulation) for severe disease High dose
systemic steroid NIV for pH1N1 ARDS in general
Neuraminidase inhibitors if initiated early ECMO
as rescue therapy (in highly resourced centers)
34
Pandemic H1N1 influenza A (2009) Clinical
Controversies in Clinical Care
What worked What might work
(inadequate data) What didnt work
Adamantane Nebulized /inhaled zanamivir (lactose
formulation) for severe disease High dose
systemic steroid NIV for pH1N1 ARDS in general
Neuraminidase inhibitors if initiated early
ECMO as rescue therapy (in highly resourced
centers)
Combo antiviral Convalescent plasma, hyperimmune
Ig Statins NAC Plasma exchange Hemoperfusion
  • No adequate data from head-to-head randomized,
    controlled trials directly comparing the efficacy
    of one antiviral agent vs another (need more data
    oral vs IV, dosage, timing duration Rx for
    severe disease/immunocompromised, survival).
  • Difficult to interpret effects of other Rx
    modality added on top of antiviral uncontrolled
    with small sample size.

35
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