1. Aspergillosis: nosocomial or community acquired? Philippe Vanhems, MD, PhD, Marie-Christine Nicolle, MD, Nicolas Voirin, PhD, Thomas Bénet, MD, MSc Infection Control Unit Edouard Herriot University Hospital Lyon, France 1

2. No conflict of interest for every author regarding the topic of the presentation 2

3. Aspergillosis: nosocomial or community acquired? … Some answers but many epidemiological questions are unresolved 3

4. Definition : nosocomial (hospital- acquired) infections Usual definition 1.Onset of infection >48 hours after hospitalization but not always (i.e. influenza : 72 hours) 2.Not in incubation at admission 3.Device related : ventilator associated pneumonia, catheter associated infection 4.Invasive procedure : surgical site infection 5.Treatments related infections : chemotherapy, steroids, immunosuppressive drugs, cyclosporin,... 6.Outbreaks Definition more complicated Invasive aspergillosis (IA), MRSA community acquired but hospital diagnosed, hepatitis C viral infection, etc. 4

5. Definition : community acquired …. exposure outside health-care setting and infection not related to care. 5

6. Aspergillosis Invasive Aspergillosis (IA) : a severe disease in immunocompromised persons and often fatal –« Disease IA »: dysfunction of host defense in combination with Aspergillus survival and growth (Dagenais, 2009) Asthm and allergenic manisfestions in immunocompetent persons 6

7. Epidemiological issues for IA Environmental exposure documented in the community Environmental exposure documented in the hospital Where are the most important sources of infections? 7

8. Epidemiological issues for IA Environmental exposure documented in the community Environmental exposure documented in the hospital Where are the most important sources of infections? Impact of inoculum size on colonization/infection is unknown in humans Patients at risk inside the hospital Patients at risk outside the hospital 8

9. Epidemiological issues for IA What is the incubation period ? Is a definition based on the interval time between hospitalization and onset a valid definition? 9

10. Risk calculation of IA Relative risk Attributable risk Theoretical interest But faisability questionnable 10

11. Invasive Aspergillosis + Invasive Aspergillosis - Hospital exposure N1N2 Community exposure N3N4 RR (OR) of hospital exposure vs community exposure? Incidence rate in the hospital N1/(N1+N2) RR = = Incidence rate in the community N3/(N3+N4) Determinants of RR? Confounders? Relative risk of hospital-acquired IA 11

12. Invasive Aspergillosis + Invasive Aspergillosis - Hospital exposure N1N2 Community exposure N3N4 RR (OR) of hospital exposure vs community exposure? Incidence rate in the hospital N1/(N1+N2) RR = = Incidence rate in the community N3/(N3+N4) Determinants of RR? Confounders? Relative risk of hospital-acquired IA ? 12

13. Invasive Aspergillosis + Invasive Aspergillosis - Hospital exposure N1N2 Community exposure N3N4 The attributable exposure to hospital regarding the risk of IA? Or % of prevented cases if hospital exposure was eliminated compared to the community : AR =N1/(N1+N2) – N3/(N3+N4) Determinants? Confounders ? Attributable risk of IA related to hospitalisation 13

14. Exposures in the community Air, soil, water Ubiquitous Common spores inhalation (200 Asp conidia/day (Dagenais, 2009) Colonization before IA but after IA could also occurred Impact of underlying diseases 14

15. Environmental exposures in the hospital Sources of Aspergillus spores in the hospital air (VandenBergh, 1999): –Inadequate filtration of outside air or malfunctionning of ventilation (High-efficiency particulate air filtration, LAF) –Dust and places infrequently cleaned –Vacuum cleaning –Plants, flowers, etc. –Periods of hospital constructions, renovations, demolition 15

16. Environmental exposures in the hospital Sources of Aspergillus spores in the hospital air (VandenBergh, 1999): –Inadequate filtration of outside air or malfunctionning of ventilation (High-efficiency particulate air filtration, LAF) –Dust and places infrequently cleaned –Vacuum cleaning –Plants, flowers, etc. –Periods of hospital constructions, renovations, demolition 16

17. Correlation between concentration of Aspergillus spores in the air and the risk of human infection (IA) is difficult to calculate Baseline measurements are needed (i.e. before renovation) 17 Environmental exposures in the hospital

18. Individual risk factors Diseases with major impact on immunity –Related to treatments as chemotherapy : HSCT, GVHD, solid transplantation, –Neutropenia : degree and duration –Acquired immunosuppression : AIDS, granulomatosis diseases Host predisposition (Bochud, 2008) Drugs: steroids,… 18

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20. Incubation(s) of IA ? At least 12 days of neutropenia (Denning, 1999) Cases observed for short periods (1 week after hospitalization) (Carter, 1997) Cases observed 3-6 months after HSCT (McWhinney, 1993) Unknown delays : –From exposure to colonization –From colonization to disease –Migration from sup airways to the lungs –Impact of duration and severity of neutropenia on disease incubation 20

21. Natural history Community Hospital Community Hospital Community ? Hospital ++ Community - Hospital +++ 21

22. Exposure ColonizationInfection (IA) IA = 3 stages 22 Time

23. Exposure ColonizationInfection (IA) Distal date IA = 3 stages Proximal date Distal date Proximal date 23 Time

24. Exposure ColonizationInfection (IA) Distal date IA = 3 stages Proximal date Distal date Proximal date C-A 24 Time

25. Exposure ColonizationInfection (IA) Distal date IA = 3 stages Proximal date Distal date Proximal date C-A H-diag 25 Time

26. Exposure ColonizationInfection (IA) Distal date IA = 3 stages Proximal date Distal date Proximal date CA H-diag C-A H-A H-diag 26 Time

27. Exposure ColonizationInfection (IA) Distal date IA = 3 stages Proximal date Distal date Proximal date CA H-diag CA H-A? H-diag H-A 27 Time

28. Exposure Colonization Infection Distal date IA = 3 stages Proximal date Distal date Proximal date 28 Time

29. IA at Edouard Herriot hospital Prospective surveillance of IA in patients hospitalized in a department of haematology N = 235 IA –17 (7%) patients without neutropenia < 0.5 G/L –218 (93%) patients with neutropenia < 0.5 G/L (Nicolle MC, unpublished data)

30. IA and neutropenia < 0.5 G/L MedianMin ; Max Delay between admission and neutropenia onset 5 days-3 ; 56 Delay between admission and IA20 days0 ; 185 Delay between neutropenia onset and IA 14 days-15 ; 198 (Nicolle MC, unpublished data)

31. * Onset of neutropenia + Date of IA Date of IA (mean) Onset of neutropenia (mean) (No patient with laminar flow)

32. Community vs nosocomial IA without laminar flow CommunityHospital ExposureIncubation Colonization/ Infection (Nicolle MC, unpublished data)

33. Reduction of Invasive Aspergillosis Incidence after Control of Environmental Exposure in Immunocompromised Patients Bénet T et al, Clin Infect Dis, 2007;45:682-686

34. Background Controversial impact of environmental control invasive aspergillosis (IA) Most studies evaluating environmental intervention were conducted retrospectively without control group Objective: to assess the impact of the relocation of an adult hematological intensive care unit on IA incidence 34

35. Methods (1) Study design –Quasi-experimental –With control group –Pre-test and post-test evaluation Setting –3 adult hematological intensive care units –Each composed of 14 single rooms in a university hospital Patients –Hospitalised 48 hours –Period 1 (pre-test) : 14/04/2005 – 01/09/2005 –Period 2 (post-test) : 14/09/2005 – 01/02/2006 35

36. Methods (3) Intervention –Relocation of a unit from the main building to an adjoining modular construction –4 rooms equipped with laminar air flow before relocation –All rooms were equipped with positive pressure isolation after relocation Control group: –The 2 other units –Each containing 8 rooms with laminar air flow –No environmental modification 36

37. Méthodes (3) Intervention, B unit - Before construction 4 rooms with laminar flux and HFPA 10 conventional rooms - Closed from september,1 er to 14 2005 - Moving to new building 14 rooms with HFPA and positive pressure Units A and C, no intervention 37

38. Results 356 hospitalized patients included 7 027 patient-days 21 IA diagnosed –18 nosocomial –3 of undetermined origin Delay between hospitalisation and IA diagnosis –Median: 22 days (15-26) 38

39. / 100 hosp. stays / 1000 patient-days 39

40. Straightforward association between environmental modification and decreased IA incidence Emphasized the utility of an environmental strategy, including high-efficiency air filtration, in IA prevention 40

41. Conclusion « Despite the breadth of studies of Aspergillus pathogenesis, there are few well-defined factors that contribute to A. fumigatus-related IA » (Dagenais, 2009) 41

42. Epidemiology of IA : some open questions and expectations Factors associated with colonization and portage? But difficult to assess in the community. Factors associated with colonization to disease in the hospital. –Environmental data –Virulence and Aspergillus dependent –Iatrogenic/ treatment/ diseases dependant –Predisposing genetic factors –Other factors 42

43. Epidemiological studies for a detailled description of the sequence of the events from exposure before hospital admission, exposure after admission and the diagnosis of IA Modelisation of incubations using for exemple parametric and non-parametric survival models « Cohort of cohorts » of patients with documented data on exposure could be helpfull for incubation calculations. 43

44. Molecular typing : –additional studies are needed which compared environmental and clinical isolates –determinants associated with similiarities and lack of similarities between environmental and clinical isolates Repeated measurements of fungal exposure outside and inside the hospital. 44

45. Aknowledgments Dr MC Nicolle, Dr T Bénet, N Voirin Pr M. Michallet, Dr A. Thiébaut, and colleagues (Hematology department, Edouard Herriot University Hospital, Lyon) Department of mycology (Pr S Picot, Dr MA Piens, & colleagues, Lyon) 45

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