Aspergillosis: nosocomial or community acquired?

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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

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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
• Onset of infection gt48 hours after
  hospitalization but not always (i.e. influenza
  72 hours)
• Not in incubation at admission
• Device related ventilator associated pneumonia,
  catheter associated infection
• Invasive procedure surgical site infection
• Treatments related infections chemotherapy,
  steroids, immunosuppressive drugs,
  cyclosporin,...
• Outbreaks
• Definition more complicated
• Invasive aspergillosis (IA), MRSA community
  acquired but hospital diagnosed, hepatitis C
  viral infection, etc.

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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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Relative risk of hospital-acquired IA
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/(N1N2) RR Incidence rate in
the community N3/(N3N4) Determinants of RR?
Confounders?
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Relative risk of hospital-acquired IA
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/(N1N2) RR Incidence rate in
the community N3/(N3N4) Determinants
of RR? Confounders?
?
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Attributable risk of IA related to hospitalisation
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/(N1N2)
N3/(N3N4) Determinants? Confounders ?
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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,
  demolition

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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,
  demolition

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Environmental exposures in the hospital

• 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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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
Community Hospital
Community Hospital
Community ? Hospital
Community - Hospital
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IA 3 stages
Colonization
Infection (IA)
Exposure
Time
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IA 3 stages
Colonization
Infection (IA)
Exposure
Time
Distal date
Proximal date
Distal date
Proximal date
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IA 3 stages
Colonization
Infection (IA)
Exposure
C-A
Time
Distal date
Proximal date
Distal date
Proximal date
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IA 3 stages
Colonization
Infection (IA)
Exposure
C-A
C-A H-diag
Time
Distal date
Proximal date
Distal date
Proximal date
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IA 3 stages
Colonization
Infection (IA)
Exposure
CA
CA H-diag
C-A H-A H-diag
Time
Distal date
Proximal date
Distal date
Proximal date
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IA 3 stages
Colonization
Infection (IA)
Exposure
CA
CA H-diag
CA H-A? H-diag
H-A
Time
Distal date
Proximal date
Distal date
Proximal date
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IA 3 stages
Colonization
Exposure
Infection
Time
Distal date
Proximal date
Distal date
Proximal date
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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 lt 0.5 G/L
• 218 (93) patients with neutropenia lt 0.5 G/L

(Nicolle MC, unpublished data)
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IA and neutropenia lt 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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Onset of neutropenia (mean)
Date of IA (mean)
Onset of neutropenia Date of IA
(No patient with laminar flow)
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Community vs nosocomial IAwithout laminar flow
Community
Hospital
Colonization/ Infection
Exposure
Incubation
(Nicolle MC, unpublished data)
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Reduction of Invasive Aspergillosis Incidence
after Control of Environmental Exposure in
Immunocompromised Patients
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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 construction
• 4 rooms with laminar flux and HFPA
• 10 conventional rooms
• - Closed from september ,1er to 14
• 2005
• - Moving to new building
• 14 rooms with HFPA and positive pressure
• Units A and C, no intervention

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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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