Influenza Prevention: Clinical Trials and Their Implications

Transcription

1 Influenza Prevention: Clinical Trials and Their Implications Trish M. Perl, MD, MSc Professor of Medicine, Pathology and Epidemiology Johns Hopkins University Hospital Epidemiologist Johns Hopkins Hospital

2 Influenza Acute respiratory illness - abrupt onset of symptoms Spectrum of illness from asymptomatic to severe illness 23% HCW w/ serologic evidence of influenza 59% recalled influenza like illness 28% recalled respiratory infection Nosocomial outbreaks documented and lead to morbidity for patients & staff, increased costs for institution - Attack rates of up to 54% reported - Mortality in NICUs up to 25% - HCWs are the primary vectors Maltezou Scan Infect Dis 2010 online 1-9, 1 Stott, Occup. Med. 2002; Talbot, ICHE 2005; Elder, BMJ 1996; Lester, ICHE 2003.

3 Prevention & Control of Influenza and Other Respiratory Diseases in Healthcare Settings Risk of acquiring HIN1 was greatest in ED and among providers Generally multiple interventions and/or strategies employed simultaneously) Compliance with PPE is a challenge in healthcare settings Santos et al. Dis Med Pub Health Prep 2010:4:47

4 Impact of Interventions to Prevent & Control Influenza and Other Respiratory Diseases in Healthcare Settings Immunization in HCWs 88% (47%-97%) & 89% (14%-99%) reduction in influenza A and B respectively Hand hygiene (n=18) 21-55% (36-57%) reduction in respiratory disease Aiello et al. AJPH 2008:98; ; 81; Wilde et al. JAMA. 1999;281:908; Jefferson et al. BMJ 2008;1-9

5 Impact of Interventions to Prevent & Control Influenza and Other Respiratory Diseases in Healthcare Settings Contact avoidance Barrier precautions Gloves (n=4) 0.43 ( ) 0.65) Gowns (n=4) ( ) 0.37) Masks (n=5) 0.32 ( ) 0.4) Faceshields (limited data) Jefferson et al. BMJ 2008;1-9

6 Impact of Interventions to Prevent & Control Influenza and Other Respiratory Diseases in Healthcare Settings Contact avoidance Isolation (droplet precautions) Patient cohorting Screening Source control Screening Masking patients Antiviral prophylaxis ICHE Nov;21(11):730-2; 2; ICHE 1995;16:556-63: 63: J Pediatr 1981;99:746. Respirology Nov;8 Suppl:S41-5; Lancet 2003: 361:1519

7 Impact of Interventions to Prevent & Control Influenza and Other Respiratory Diseases in Healthcare Settings Contact avoidance Isolation (droplet precautions) Patient cohorting Screening Source control Screening Masking patients Antiviral prophylaxis Neuraminidase inhibitors: 74% reduction of ILI and 88% of influenza Amantanes: 100% reduction in flu ICHE Nov;21(11):730-2; 2; ICHE 1995;16:556-63: 63: J Pediatr 1981;99:746. Respirology Nov;8 Suppl:S41-5; Lancet 2003: 361:1519;Salgado et al. Lancet Inf Diseases 2002 :2;

8 Johnson et al. Clinical Infectious Diseases 2009; 49: 275-7

9 Which Interventions Are Most Important in Healthcare? Jefferson et al. The Cochrane library 2009; ary.com

10 PPE to prevent influenza among critical care clinicians: A survey study Daugherty et al. CCM 2009;37:

11 Daugherty et al. CCM 2009;37:

12 Studies Facemasks +/- hand hygiene Colleges Households Medical masks vs N95 in healthcare settings

13 Methodologic Issues Study design Individual RCT Cluster RCT Outcomes/proxies ILI Influenza Other respiratory viruses Serology Effect size Absolute vs. relative differences How much difference is clinically relevant Modulators Population Exposure to disease Exposures to procedures Compliance

14 Facemask and Hand Hygiene 1437 college students-dorms dorms randomized to FM vs FM + HH Reduction in ILI 35-51% 51% in weeks 4-64 Aiello et al JID 2010:201:491

15 Hand Hygiene and Respiratory Protection 3 interventions (1:1:1 block randomization) of at least 2 members of households within 48 hours of sx onset in index case Control vs hand hygiene vs mask + hand hygiene 65-75% were randomized within 12 hours of diagnosis (distributed equally among groups) 11-17% 17% were vaccinated (flu); 22-28% 28% received antivirals 2ndary attack ratio for lab confirmed flu (within 48 hours of index case Sx): 11% overall; 6% in hand hygiene group and 4% in mask group Cowling et al. AIM 2009:151:437

16 Hand Hygiene and Respiratory Protection 49-59% of disease developed in those < 15 yrs Risk of influenza was 0.57 ( ) in hand hygiene group, 0.77 ( ) in mask group Cowling et al. AIM 2009:151:437

17 Compliance to Hand Hygiene and Respiratory Protection Cowling et al. AIM 2009:151:437

18 Medical Masks vs. P2 Masks in Households Parents of ill children approached-256 individuals in 145 households Adherence self measured; no information about hand hygiene practices and influenza vaccination Adherence with any mask use decreased the risk of ILI and influenza MacIntyre et al. EID 2009:15:233

19 Hand Hygiene and Respiratory Protection Contacts could have been incubating at time index case was enrolled Illness was not tracked in children < 2years Use of antiviral agents may decrease shedding and blunted the impact of both hand hygiene and masks Adherence was less than 50% in mask intervention arm and masks were used in other arms. Adherence was self-reported Cowling et al. AIM 2009:151:437; MacIntyre et al. EID 2009:15:233

20 RTC: medical mask vs N95 in healthcare Individual randomization of nurses on Medicine, Pediatrics, ED units In 8 hospitals 11 season RNs wore masks while in contact with patients with suspected influenza 30% of enrolled vaccinated Non inferiority trial (9% difference between N95 and medical mask) Assumes a 20% event rate Audits performed for 1 week during study Loeb et al. JAMA published online Oct 1, 2009

21 RTC: medical mask vs N95 Loeb et al. JAMA published online Oct 1, 2009

22 RTC: Medical Mask vs N95 Serology only performed on non vaccinated participants Loeb et al. JAMA published online Oct 1, 2009

23 RTC: Medical Mask vs N95 Loeb et al. JAMA published online Oct 1, 2009

24 Commentary Lower attack rate than anticipated Trial aborted because of a change in Ontario Infection Control Policy Compliance measured intermittently and in a limited fashion and only in Medicine and Pediatric units (not ED) Loeb et al online JAMA October 1

25 Cluster RTC: Medical Mask vs N95 15 hospitals (1441 HCWs) - Bejing, China 3 Arms: Medical masks vs fit tested N95 vs N95 1 season Masks worn for entire shift Adherence monitored by nurse managers/supervisors Outcomes: clinical respiratory infections, ILI, PCR for 8 viruses Based on presentation at IDSA 2009, Philadelphia, PA

26 Singapore H1N1 Experience: April- June 2009 No HCW caring for a patient with nh1n1 developed subsequent nh1n1 Ang et al. CID 2010:50;1011-3

27 Commentary RTC trials in the community suggest that hand hygiene and medical masks decrease transmission of respiratory disease and perhaps influenza in households. Adherence with any type mask was associated with decrease acquisition. Compliance with both mask use and hand hygiene is suboptimal and complicates measure of impact RTC in healthcare settings have not demonstrated superiority of N95 mask to medical masks although compliance with mask use has been suboptimal and other strategies (hand hygiene) not considered.

28 Research Agenda Epidemiology & Disease Burden How do we best determine the incidence and disease attributable to occupational settings? What is the contribution of contact, droplet or airborne transmission in healthcare Impact on specific settings Which settings and procedures are associated with increased transmission? How do HVAC systems, pressure relationships contribute to circumstances of transmission

29 Research Agenda Options for prevention & control What are the incremental benefits of hand hygiene, masks, type of mask, other barriers (gloves, gowns and face shields) need to be delinated. What innovations can improve wearability of masks? Does improved comfort improve adherence? What are the barriers to improved adherence? Clinical trials to evaluate respiratory PPE are needed and must be adequately powered to detect clinically relevant differences in masks/respirators and use relevant outcomes.