Aspergillosis: nosocomial or community acquired? Philippe Vanhems, MD, PhD, Marie-Christine Nicolle,...

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

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

?12

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

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,

demolition16

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

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

Exposure Colonization Infection (IA)

Distal date

IA = 3 stages

Proximal date

Distal date Proximal date

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Time

Exposure Colonization Infection (IA)

Distal date

IA = 3 stages

Proximal date

Distal date Proximal date

C-A

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Time

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

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

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

Exposure Colonization Infection

Distal date

IA = 3 stages

Proximal date

Distal date Proximal date

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Time

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)

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)

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)

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)

Reduction of Invasive Aspergillosis Incidence after Control of Environmental

Exposure in Immunocompromised Patients

Bénet T et al, Clin Infect Dis, 2007;45:682-686

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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