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: 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 >2 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 >4 days after symptom onset were more likely to be admitted to an ICU than those who began therapy <2 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% 0.07–0.54; p<0.01). Farias JA, et al. ICM 2010

8. pH1N1 Influenza in Hematopoietic Stem Cell Transplant (HSCT) Recipients (n=27) • The incidence of influenza LRTI was 52% (14/27). Five cases were hospital-acquired. • In comparison to pts with URTI (n=13), those with LRTI were begun on antiviral therapy significantly later after symptom onset (3.0 days vs. 6.6 days after onset of symptoms, p=0.03; 95% CI 0.29, 6.8). • Overall influenza-related 30-day mortality was 22% (6/27) butin patients with LRTI, it was 43 % (6/14). • Chronic steroid use (>/= 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 2010;10: 521–26 Multivariate analysis for independent factorsassociated withICU admission: Delayed antiviral treatment>48 hrs (OR 3.03, 95% CI 1.24–7.39, p=0.015). Diabetesmellitus (OR 2.18, 95% CI 1.03–4.64, p=0.043).

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, p<0.01]. 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 Hodgkin’s 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 1.5–2 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 2010;50:620. 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 Caroli’s 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 detectablein 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 BMI=30 presented on 18 Aug 09 with acute dyspnea following a wk history of ILI with diarrhoea. LDH= 828, ALT=75. 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, LDH>1400, VAP, septic shock & MODS. Died on 1 Sept 09 despite ICU support umol/l Oseltamivir IV Zanamivir Oseltamivir 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; 152:687-8 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 1:40 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-γ & 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 >45 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. 2010;138:1281–8.

27. Case 1: 28 yr old male, BMI 18, SOB >1 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 2010;16:971-3.

28. 2007 Seasonal flu JID 2009 N=147, 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 1997;100:151-7. Singapore SARS cohort (n=206):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 2004;128:195-204 5 had large artery ischaemic stroke (3 had received IVIg).Umpathi T et al. J Neurol 2004;251:1227-31. IVIg - induced increase in viscosity may be consequential in pts with hypercoagulable states. Dalakas MC et al. Neurol 2003;60: 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 didn’t 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 didn’t 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.

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