aspergillosis: nosocomial or community acquired? philippe vanhems, md, phd, marie-christine nicolle,...
TRANSCRIPT
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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
Hôpitaux de Lyon
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No conflict of interest for every author regarding the topic of the presentation
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Aspergillosis: nosocomial or community acquired? … Some
answers but many epidemiological questions are
unresolved
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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 admission3. Device related : ventilator associated pneumonia,
catheter associated infection4. Invasive procedure : surgical site infection5. 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
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Definition : community acquired
…. exposure outside health-care setting and infection not related to care.
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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
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Epidemiological issues for IA • Environmental exposure documented in
the community
• Environmental exposure documented in the hospital
• Where are the most important sources of infections?
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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
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Epidemiological issues for IA
• What is the incubation period ?
• Is a definition based on the interval time between hospitalization and onset a valid definition?
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Risk calculation of IA• Relative risk
• Attributable risk
• Theoretical interest
• But faisability questionnable
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Invasive Aspergillosis +
Invasive Aspergillosis -
Hospital exposure
N1 N2
Community exposure
N3 N4
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
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Invasive Aspergillosis +
Invasive Aspergillosis -
Hospital exposure
N1 N2
Community exposure
N3 N4
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
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Invasive Aspergillosis +
Invasive Aspergillosis -
Hospital exposure
N1 N2
Community exposure
N3 N4
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
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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
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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,
demolition15
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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,
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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)
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Environmental exposures in the hospital
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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,…
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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
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Natural history
CommunityHospital
CommunityHospital
Community ?Hospital ++
Community -Hospital +++
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Exposure Colonization Infection (IA)
IA = 3 stages
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Time
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Exposure Colonization Infection (IA)
Distal date
IA = 3 stages
Proximal date
Distal date Proximal date
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Time
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Exposure Colonization Infection (IA)
Distal date
IA = 3 stages
Proximal date
Distal date Proximal date
C-A
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Time
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Exposure Colonization Infection (IA)
Distal date
IA = 3 stages
Proximal date
Distal date Proximal date
C-A
C-AH-diag
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Time
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Exposure Colonization Infection (IA)
Distal date
IA = 3 stages
Proximal date
Distal date Proximal date
CA
CAH-diag
C-AH-AH-diag
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Time
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Exposure Colonization Infection (IA)
Distal date
IA = 3 stages
Proximal date
Distal date Proximal date
CA
CAH-diag
CAH-A?H-diag
H-A
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Time
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Exposure Colonization Infection
Distal date
IA = 3 stages
Proximal date
Distal date Proximal date
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Time
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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)
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IA and neutropenia < 0.5 G/L
Median Min ; Max
Delay between admission and neutropenia onset
5 days -3 ; 56
Delay between admission and IA 20 days 0 ; 185
Delay between neutropenia onset and IA
14 days -15 ; 198
(Nicolle MC, unpublished data)
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0 20 40 60 80
02
04
06
08
0
Time since admission (days)
Pa
tien
ts
++++ ++ ++ ++ + ++++
++ +++ + + ++
+ + ++ + ++ ++ ++ + ++ ++ +++ ++ ++ +++ ++ ++ + ++ ++++ + + ++++
+++ ++ ++ + ++ +++ +++ ++ +
******* * **
**** ****
** ******
***** **
* ***
* * ** * ** ***** * ** ** ***
** *
*****
* ****
** * ***
* Onset of neutropenia+ Date of IA
Date of IA (mean)Onset of neutropenia (mean)
(No patient with laminar flow)
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0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
0
10
20
30
40
50
60
70
80
90
100
110
-56 -49 -42 -35 -28 -21 -14 -7 0 7 14 21 28 35 42 49 56 63 70 77 84
Num
ber o
f IA
Num
ber o
f pati
ents
with
neu
trop
enia
< 0
,5 G
/L
Time since admission (days)
Neutropenia < 0.5 G/L
Invasive aspergillosis
Community vs nosocomial IAwithout laminar flow
Community Hospital
Exposure Incubation
Colonization/Infection
(Nicolle MC, unpublished data)
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Reduction of Invasive Aspergillosis Incidence after Control of Environmental
Exposure in Immunocompromised Patients
Bénet T et al, Clin Infect Dis, 2007;45:682-686
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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
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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
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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
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Méthodes (3)• Intervention, B unit
- Before construction4 rooms with laminar flux and HFPA 10 conventional rooms
- Closed from september ,1er to 14 2005
- Moving to new building14 rooms with HFPA and positive pressure
• Units A and C, no intervention
Hôpitaux de Lyon
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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)
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/ 100 hosp. stays / 1000 patient-days
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• Straightforward association between environmental modification and decreased IA incidence
• Emphasized the utility of an environmental strategy, including high-efficiency air filtration, in IA prevention
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Conclusion
« Despite the breadth of studies of Aspergillus pathogenesis, there are few well-defined factors that contribute to A. fumigatus-related IA » (Dagenais, 2009)
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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
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• 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.
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• 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.
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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)
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