Impact of air decontamination by use of Plasmers
on the occurrence of invasive aspergillosis in patients at risk in hematological ward
Aho Glélé LS**, Lafon I*, Ferrant M *, Barry M *, Astruc K**, Bonnin A***, Caillot D*
Hematology; ** Epidemiology and Hospital hygiene; *** MycologyDijon (France)
Denver, June 2008
Context
Aspergillosis
• Aspergillus spp. and other moulds – => Life-threatening opportunistic infections
• In immunocompromised patients
• Indoor contamination and construction work– => Liberate fungal spores
• Major source of nosocomial aspergillosis
Aspergillosis
• In immunocompromised patients– Respiratory tract colonization by Aspergillus is
associated with increased risk of invasive aspergillosis (IA)
» Wald A et al.. J Infect Dis 1997;175:1459-66
» Perfect JR et al. Clin Infect Dis 2001;33:1824-33
Aspergillosis
• Incidence rates of IA– Range from 4-26% in allogenic bone marrow
transplant patients – 5-25% in acute leukemia patients
• IA associated mortality rates – Range from 74-92%
» Denning DW.Clin Infect Dis 1998;26:781-805
» Singh N et al. Clin Microbiol Rev 2005;18:44-69
» Latge´ JP. Clin Microbiol Rev 1999;12:310-350
Previous study : Indoor fungal contamination surveillance program
• Implemented one year before building work– To establish baseline levels of contamination
• Prospective examination of air and surface fungal contamination – Following use, or not, of plasmer units – Adult and paediatric haematology units
• plasmer treated rooms – Significant reductions in overall fungal
contamination • For air and surface samples
– In both clinical units
• For A. fumigatus in the air
• plasmer units may provide an efficient method for reducing indoor fungal contamination in hospitals
» Sixt et al. J hosp Infect 2006; 65(2):156-62
Previous study : Indoor fungal contamination surveillance program
Objectives
Objectives
• To assess the impact of air decontamination
by use of Plasmers on the occurrence of invasive aspergillosis
• In patients at risk – In hematological ward
• i.e follows next study– Clinical outcome instead of environnemental
microbiologic outcome
Setting
Setting : Dijon hospital
• Tertiary care institution– Northeast France
• Hospital involved in a renovation program – Construction of two buildings adjacent to
clinical units receiving patients at high risk of fungal infection
– Hematology unit
– Infectious Diseases unit
Flow
Flow
Flow
Flow
Flow
Flow
Nurses Room 10(4)
Room 1
Nurses
Hematologyward
UniversityHospital
Dijon
« Protected » Sector
Plasmair®1 by room
Since07/20/2004
Conventional Sector
Room 10(4)
Room 10(4)
Room 1
Room 1
Room 2
Room 2 Room 1
Room 1
Room 1
Room 1
Room 1
Room 1
Room 1
Room 1
Participants
Participants
• Inclusion– Acute Myeloid leukemia (AML)– Acute Lymphoid leukemia (ALL)– See flow chart
• Non inclusion– Burkitt
• n=3
From 01/01/2000 to /12/31/2007
Proven IPA n = 17 (27%)
Probable IPA n = 41 (65%)
Possible IPA n = 5 (8%)
63 IPA(occurred in the department of hematology)
MSG & IFIG/EORTC criteria
798 episodes of aplasia at very high risk of aspergillosis
435 patients with AML or ALL
Intervention and methods
Intervention : plasmer
Mobile air-decontamination unit :
• Not based on filtration
• Destruction of airborne organisms through a three-step process – Exposure to high electric fields
• Deform and alter membrane or cell-wall
– Subsequent bombardment with positive and negative ions
• Destroy internal structures
– Electrostatic nano-filtration
Intervention: plasmer
• Electricity supply
• Three modes of activity – Correspond to increasing air-exchange capacity
and increasing noise
• Cost – One unit : about 17 000 Euros
• Maintenance needed– As for all kind of devices…
Intervention: others devices
• Standard Room
• Filtration and positive air-pressure– Laminar Flow– Class 104
» Federal Standard 209D
Methods
• Diagnostic– MSG & IFIG/EORTC criteria
» Ascioglu et al. Clin Infect Dis. 2002: 7-14
• Statistical analysis– Univariate analysis
• Before and after plasmers comparisons
• Classical tests, as appropriate– Fischer exact test, chi2 test
– Kruskall Wallis, T-test
Methods: multivariate analysis
• Variable to explain– Occurrence of IPA (probability of)
• Explanatory variables – Age (A)– Sex (S)– Type of leukemia (L; AML or ALL)– De novo patient (DN; Yes or No)– Duration of Leucopenia (DL; days)– Construction Work (CW; Yes or No)– Date of diagnosis (T; year)– Type of Device (TD; none, 10(4) class, plasmer,
laminar flow)
Methods: multivariate analysis
• Model– P(Occurrence of IPA) = f(TD, A, S, L, DN,
DL, CW, T, )– f: logistic link– Correlated data
• Use of GEE or mixed model – Correlation matrix = exchangeable
• Check of loglinearity
– Forced variable in the model : date of diagnosis• Non randomized study
Methods: multivariate analysis
• Time of diagnosis (T; year)– Continuous– Discrete
• Duration of leucopenia (DL; days)– Data collection not complete
• Listwise deletion
• Median imputation
• 3 classes : < Median, >= Median, « Missing »
Results
Univariate analysis
From 01/01/2000 to 07/20/2004
Probable IPA
n = 20 (80%)
Possible IPA n = 0
28 IPA (6.8%)
407 Aplasia AML/ALL(236 pts)
From 07/20/2004 to 12/31/2007
Proven IPA
n = 9 (26%)
Probable IPA
n = 21 (60%)
Possible IPA
n = 5 (14%)
35 IPA (8.7%)
391 Aplasia AML/ALL(199 pts)
Proven IPAn = 8 (20%)
Results
Baseline characteristics
Population under studyBefore Plasmairs®
After Plaismairs
®
P
Patients 236 199 -
Aplaisia 407 391 -
Age 55 (17-81) 56 (16-86) ns
AML 321 (79%) 303 (78%) ns
ALL 86 (21%) 88 (22%) ns
Laminar Flow sector
231 (57%) 197 (50%) ns
Class 104 Sector 90 (22%) 86 (22%) ns
Standart Sector
Plasmairs
86 (21%)-
-108 (28%)
--
IPA 28 (6.8%) 35 (8.7%) ns
De novo IPA 12/187 (6.4%) 17/176 (9.6%) ns
Patients’s characteristics (Aspergillosis)
BAL: BronchoAlveolar Lavage; ME: Microscopic Examination; Asperg. Ag: Aspergillus Antigen
Before Plasmairs® After Plaismairs® P
Invasive Aspergillosis (IA) 28 35 -
IPA 26/28 33/35 ns
Male vs Female 16 vs 11 20 vs 15 ns
Age 58 (27-76) 64 (22-75)
Hematol.Prog.disease 13/28 18/35 ns
Hospitalization before IA (d)
21 (8-54) 21 (10-63) ns
Neutropenia before IA (d) 17 (11-60) 18 (10-90) ns
Hospitalization after IA(d) 17 (2-85) 15 (2-40) ns
Neutropenia after IA (d) 8 (0-83) 8 (0-40) ns
BAL + (culture or ME) 9/23 5/29 ns
Asperg Ag + (in BAL) 20/23 20/29 ns
Asperg Ag + (in Sera) 20/27 21/35 ns
Pathological exam + 8 9 ns
Treatment and evolution of patients with aspergillosis
Before Plasmairs®
After Plaismairs®
P
Invasive Aspergillosis (IA) 28 35
Antifungal monotherapy 5/28 14/35 0.04
Combination antifungal therapy
23/28 21/35 0.04
Associated Surgery 3/28 3/35 ns
Aspergillosis response (CR+PR)
22/28 (79%) 29/35(83%) ns
Hematological complete response
13/28 (46%) 20/35 (57%) ns
Median survival (weeks) 31 (1-422) 34 (1-191) ns
Survival at 12 weeks 18/28 (64%) 30/35 (86%)* 0.04
Death with aspergillosis 6/28 (21%) 7/35 (20%) ns
From 01/01/2000 to 20/07/2004 (Before plasmairs®)
Laminar Flow3.9 %
9 IA / 231 Aplasia
104 Class5.6 %
5 IA / 90 Aplasia
Standard16.3 %
14 IA / 86 Aplasia
NS
Invasive aspergillosis incidence
Laminar Flow ≈ 104 Class >> Standard
P < 0.001 P = 0.03
From 07/20/2004 to 12/31/2007 (with plasmair®; without and then with construction work in the hospital)
Laminar Flow5.6 %
11 IA / 197 Aplasia
104 Class10.5 %
9 IA / 86 Aplasia
plasmair®13.8 %
15 IA / 108 Aplasia
NS
Invasive aspergillosis incidence
Laminar Flow > plasmer®
P = 0.02 NS
plasmer ® ≈ 104 Class
From 07/20/2004 to 12/31/2006 (with plasmair®; without construction work in the hospital)
Laminar Flow5.7 %
8 IA / 141 Aplasia
104 Class8.5 %
5 IA / 59 Aplasia
plasmair®12.8 %
10 IA / 78 Aplasia
NS
Invasive aspergillosis incidence
Laminar Flow > ≈ plasmer®
P = 0.06 NS
plasmer ® ≈ 104 Class
From 01/01/2007 to 12/31/2007 (with plasmair®; with construction work in the hospital)
Laminar Flow5.3 %
3 IA / 56 Aplasia
104 Class14.8 %
4 IA / 27 Aplasia
plasmair®16.7 %
5 IA / 30 Aplasia
P = NS
Invasive aspergillosis incidence
Laminar Flow > = plasmer®
P = 0.08 P = NS
plasmer ® ≈ 104 Class
Laminar Flow5.7 %
8 IA / 141 Aplasia
104 Class8.5 %
5 IA / 59 Aplasia
plasmairs®12.8 %
10 IA / 78 Aplasia
All sectors8.3 %
23 IA / 278 Aplasia
From 07/20/2004 to 12/31/2006 From 01/01/2007 to 12/31/2007
Impact of construction work in the university hospitalDuring construction With plasmairs®
Laminar Flow5.3 %
3 IA / 56 Aplasia
104 Class14.8 %
4 IA / 27 Aplasia
plasmairs®16.7 %
5 IA / 30 Aplasia
All sectors10.6 %
12 IA / 113 Aplasia
P = NS
P = NS
P = NS
P = NS
Results
Multivariate analysis
Methods: multivariate analysis
• Duration of leucopenia (DL; days)– 7.43 % « missing data » (1-(735/794))– Missing At Random
• Sex, Type of device, API, Time, Construction Work
Results of the model
Significant
– Age (A)
– Duration of Leucopenia (DL; days)
– Time of diagnosis (T; year)
– Type of Device (TD; none, 10(4) class, plasmer, laminar flow)
Not significant
– Sex (S)
– Type of leukemia (L; AML or ALL)
– de novo patient
(DN; Yes or No)
– Construction Work (CW; Yes or No)
Model 1 (Time continuous; logit)
Variables Odds Ratio (OR)
p
Duration of leucopenia 1.053 0.0001
Age 1.022 0.031
Time (continuous) 1.099 0.270
Type of deviceNoneplasmer Class 10(4)Laminar Flow
Ref.3469.2015.1569
-----0.0560.00010.0001
Model 2 (Time discrete; GEE)
Variables Coefficient p
Duration of leucopenia 0.0067 0.001
Age 0.0014 0.012
Time (discrete) -- 0.18
Type of deviceNoneplasmer Class 10(4)Laminar Flow
ref-0.0834-0.1495-0.1552
ref0.0600.00010.0001
Model 3 (Time discrete and duration of leucopenia with median substitution; GEE)
Variables Coefficient p
Duration of leucopenia(Median substitution)
0.0068 0.0001
Age 0.0012 0.013
Time (discrete) - 0.367
Type of device
None
plasmer
Class 10(4)
Laminar Flow
ref
-0.075
-0.1280
-0.1371
ref
0.066
0.0001
0.0001
Model 4 (Time continuous and duration of leucopenia with 3 classes; GEE)
Variables Coefficient p
Duration of leucopenia(reference : < median)
0.0578 0.0001
Age 0.00138 0.011
Time (continuous) 0.01034 0.022
Type of device
None
plasmer
Class 10(4)
Laminar Flow
ref
-0.0833
-0.1340
-0.1429
ref
0.045
0.0001
0.0001
Discussion
Discussion
Multivariate analysis
• Duration of leucopenia– Major risk factor– Missing values
• Effect of Plamairs remains significant under sensitivity analysis
Discussion
What about others devices ?
• Example Photoclean®– http://www.photocleanquartz.com/– Under evaluation in medical area
Discussion
Limits of the study
• Randomization– It would be better for internal validity
• But, no randomized study available for the reference device (Laminar flow)
» Humphreys H. J Hosp Infect 2004.56:93-100
• Power– Sample size not determined a priori
• IPA is a rare disease– Multicentric study needed ?
Discussion
Limits of the study
• Outcome measure– Plan to take into account time to event – « Missing » values for duration of leucopenia– Only simple imputation methods used
• No multiple imputation or Maximum likelihood-based procedures
– = > Recover the data !
Conclusion
Conclusion
• plasmers seems to prevent IPA
• Results must be confirmed– « Missing values » for duration of leucopenia– Taking into account time to event
Thank you for your attention