SChen Pneumocystis Infections in Renal Transplant Patients.ppt
Transcript of SChen Pneumocystis Infections in Renal Transplant Patients.ppt
Pneumocystis infections in renal transplant units: lessons from outbreaks
Sharon ChenSharon Chen
Short course in Health care infection
and controlCIDM-PH/SEIB
May 2012
Pneumocystis jirovecii
Resurgence of an “adopted” fungal infection
Today………
What’s in a name? (identity crises) � What’s in a name? (identity crises)
� Case clusters: brief story of Westmead cluster, reasonable investigation
� Lessons learned: Infection control and evaluation of prophylaxis (guidelines?)
P. jirovecii: “yew row vet zee”
Kingdom: Fungi
� Phylum: Ascomycota (Schizosaccharomyces)
� Class: Archia-ascomycetes
� Order: Pneumocystidales� Order: Pneumocystidales
� Family: Pneumocystidaceae
� Genus: Pneumocystis
Described in humans by Otto Jirovec (Czech parasitologist)
Originally a protozoan, in 1988 reclassified as fungus
(rRNA sequence analysis)
Pneumocystis Pneumonia = PCP
With permission: D. Marriott
P. jiroveci: the ABCsP. jiroveci: the ABCs
• Difficult to find in environment (non-jirovecii species in
pond water, air around apple orchards)
• Not been found in non-human hosts (P. murina: mice; P.
wakefieldiae: rats): rare for a fungus to be this host-
specific
• Absent in healthy hosts or in very low numbers
• Genetic variants are common, “type-able”
Transmission of disease
Latency vs. exogenous infection
� Airborne
� Animal model studies
� Presence of Pneumocystis DNA on filters of cages of
rats rats
� Quantitative air sampling in exhaled air from infected
patients: burden greater in samples taken < 1m from
patient
� Nosocomial outbreaks in humans
� Environmental or person-to-person?
Olsson, Scand J Infect Dis, 1996; Choukri, Clin Infect Dis 2010
PCP: kidney transplantation
PCP is a serious disease
� No prophylaxis: 2-24% patients with 49% MR
� Routine prophylaxis for 3-4 months said to be
protective…(CII/CIII level evidence)protective…(CII/CIII level evidence)
� Early cases described (sporadic)
� Acute rejection, steroid use, CMV
� Late cases reportedly rare
� Emergence case clusters last 2-5 years -risk
factors?
In the beginning …..
Patient 1: 63 yrs, male
� ESKD 2 °pauci-immune GN
� Cadaveric kidney Tx 15 yrs ago, 5/6 MM
On tacrolimus, mycophenolate, prednisone � On tacrolimus, mycophenolate, prednisone
� Serum Cr 455 µmol/l Jan 2010
� 24/3/10 presented with extreme SOB, dry cough,
fever, chest clear
Patient 1
Blood gas analysis:
pH 7.36, pO2 52, pCO2 30, HCO3 16, BE -8
Dr. Lisa Phipps, Ms. Kathy Kable, 2011
Patient 1
� Rapid respiratory failure, intubated in ICU
antibiotics, mini-BAL
� Day 2: PCR +ve for P. jirovecii on mini-BAL
Commenced high dose co-trimoxazole & hydrocortisone
MRSA blood culture bottlesMRSA blood culture bottles
� Soon after: CMV PCR +ve, Qt. << detection
� Ceased co-trimoxazole (P. jirovecii PCR “false +ve”)
� Continued with IV ganciclovir, vancomycin and azithromycin, meropenem
� Progressive difficulty ventilating, died (I mo in hospital)
A case cluster?
� More diagnoses PCP (n=14; Mar 10 – Jan 11)� September 2010 – Sydney West PHU contacted� Definition of possible case cluster:
“2 or > diagnosed cases linked by locality and proximity in time (generally +/- 6 months) for which there is strong epidemiological evidence of a common source of infection, +/- microbiological evidence”
Sydney West PHU in
action
� Confirmed case::symptoms, other clinical and
radiological features of PCP with +ve P. jirovecii
PCR
� Probable case:: symptoms, clinical and radiological
Case Definitions
� Probable case:: symptoms, clinical and radiological
features of PCP, responding to cotrimoxazole but
where specimens not available for PCR
� Definitions vary in literature
Direct microscopy not routinely performed at ICPMR
Response
� Confirmation of cases: review of clinical status, radiological investigations, additional laboratory tests – Ag staining of archived BALs and induced sputa
� Contact Tracing� Contact Tracing
� Blanket prophylaxis with co-trimoxzazole
� Case-control study to identify risks for PJP
� Cost-Benefit Analysis of Blanket prophylaxis
� Laboratory epidemiology – genotyping of PCR extracts; air sampling, staff sampling
Contact Tracing
� Review of dates of all outpatient visits,
hospitalisations and other potential contact:
points identified co-localisation of 12 patients
in transplant outpatient clinic (location 1)
Patient
number
Site Contact Specimen tested PCR +ve Death
Confirmed cases (mean: 6.3 yrs after transplant +/- 5.3) 1 Location 1 BAL, induced sputum Yes Yes
2 Locations 1 and 2 BAL, induced sputum Yes No
3 Location 1 Induced sputum Yes No
6 Location 1 BAL, induced sputum Yes Yes
7 Location 2 only BAL Yes No
8 Location 1 and 3 BAL Yes No
9 Location 1 BAL, induced sputum Yes Yes9 Location 1 BAL, induced sputum Yes Yes
11 Location 1 BAL Yes No
12 Location 3 Induced sputum Yes No
13 Location 1 Induced sputum Yes Yes
14 Locations 1 and 3 Induced sputum Yes No
Probable cases (similar mean duration after transplant)
4 Location 1 Nil ND No
5 Location 1 and 3 Nil ND No
10 Location 1 Nil ND No
Transmission Map: Cases, Contacts.
2*
1 Index
3
(4)
(5)
6
7*
Cases
Key: (bracket) suspected case
2nd genotype * F graft fail & dialysis
died
(F )
F
F
F
F
Jan Feb Mar Apr May Jun Jul Aug Sept Oct Nov Dec Jan Feb
2010 2011
8
(9)
10
11
12
13
14
Dec
blanket co-trimoxazole
F
F
B.Nankivell, 2011
MLST (stored extracts, 11 unrelated “control DNA” same period)
Four genetic loci:β-tubulin
ITS1/2 region**
DHPS
mtLSU
ST1
ST2
Carolina Firacative, Wieland Meyer
Contemporaneous
patients, Sydney
Infection Control questions
� Human-to-human most plausible
� Single room, droplet precautions
� Selected staff: oral rinses – negative by PCR
� Air sampling?? – attempted solid support set up � Air sampling?? – attempted solid support set up
(all negative by PCR) but need liquid support
system
� Sample patients? (ethics)
Risk Analysis in kidney transplants
Case control study
14 PCP cases vs. 326 ‘unaffected’ controls
attending clinic during outbreak period
� Risk factors for PJP: Univariate analysis
� Significant risk factors then evaluated via
multivariate logistic regression analysis
� No patient was co-infected with CMV
Phipps et al, Transplantation 2011
PCP Controls p values
Numbers 14 324
Age
Sex (n, % males)
Deceased donors (n, %)
Years after transplant
HLA Mismatch (out of 6)
Prior rejections (numbers)
Anti-lymphocyte preparations (n, %)
Recent pulse steroids
PJP prophylaxis
46.6 +/- 13.3
10 (36%)
10 (71%)
6.3 +/- 5.3
3.8 +/- 1.9
0.5 +/- 0.5
3 (21.4%)
0 (0%)
13 (93%)
46.0 +/- 13.4
193 (59.6%)
204 (62.9%)
5.5 +/- 6.1
3.5 +/- 1.9
0.6 +/- 1.0
50 (15.4%)
36 (11%)
302 (93%)
NS
NS (0.08)
NS
NS
NS
NS
NS
NS
NS
Tacrolimus Dose (mg/day)
Tacrolimus Levels (ng/day)
4.0 +/- 2.3
6.7 +/- 1.8
5.4 +/- 3.5
7.5 +/- 3.8
NS
NSTacrolimus Levels (ng/day)
MMF Dose (g/day)
Prednisolone Dose (mg/day)
6.7 +/- 1.8
1.6 +/- 0.5
8.9 +/- 2.5
7.5 +/- 3.8
1.7 +/- 0.6
11.3 +/- 5.9
NS
NS
NS
Serum creatinine (umol/L)
eGFR (mls/min/1.73m2)
Prior CMV disease
Pulmonary Disease
Former Smoker
267 +/- 193
31+/- 23
4 (28.6%)
4 (28.6%)
4 (28.6%)
144 +/- 94
52 +/- 20
2 (0.6%)
10 (3.1%)
128 (49.5%)
< 0.01
< 0.001
< 0.001
< 0.001
NS
*Multivariate: sig risk factors for PCP - underlying lung disease (OR10.1), previous CMV infection (OR 65.9), impaired eGFR (OR1.61 /10mls/min/1.732)
Follow up 6-12 months on
� Missed
patients X 2:
PCP
� RPAH (7)
ST1
� RPAH (7)
� RNSH (3)
� Genotyping
results
� Transplant
games: “point
of contact”
ST2
Clusters in kidney transplants
Systematic review
� 16 outbreaks, 15 articles (since then >10 abstracts + 2 pubs, 2011)
� Median 12 cases (up to 28 cases) � Median 12 cases (up to 28 cases)
� Median time diagnosis after Tx 12 mo (IQR 7-21 mo) vs. 6.3 yrs this outbreak
� Preceding prevalence low (<2%)
� 12/15 studies reported no chemoprophylaxis;
� No patient cohorting !
De Boer MJ, et al, Med Mycol 2011; 49: 673
PCP outbreaks: 1980-2011Year Location n Durn. (mo) % <1 y Tx MR (%)
1984
1988
USA
P. Rico
14
11
12
14
86 21.4
45.5
1988 Norway 14 2 100 50
1995
1996
France
Germany
7
7
6
6
86 42.9
0
2001 Sweden 12 10 10
2004 France 10 29 50
2007
2008
Holland
Germany
22
16
13
8
50
94
4.5
25
2009
2009
2009
Japan
Japan
Switz
27
9
20
22
7
18
41
44
55
3.7
33.3
15
2011
2011
England
Australia
27
14
24
10 0
21.5
28.6
Genotyping
� Seven studies performed MLST or ITS1/2 sequencing
� In n=3, identical strains;
� In further n=3, varying results
� n=1 Australian study (pred. strain)
� Acquisition of Pneumocystis
� Search for environmental source without result but methods are limited
� Via other patients? Via carriers?
Are colonized patients the
source?
� ITS genotyping, Brest University, France
� 18 renal transplants, 22 unlinked controls ,69
contemporaneous patients (some with PCP,
some colonized, some healthy) some colonized, some healthy)
� “Type Eg” most frequent in PCP patients and
those colonized
� Index patients identified to be colonized
(transmission map)
Le Gal et al. Clin Infect Dis 2012;54:e62
Lessons Learned
Westmead Outbreak
� Late infection can occur (no prophylaxis)
� Acute presentation, respiratory failure, hypoxia
� MR 28%
� Low threshold for bronchoscopy � Low threshold for bronchoscopy
� Pre-emptive strategy
- early cluster recognition
- prompt blanket prophylaxis - effective
- Contact tracing is effective
Lessons to learn
Why is this occurring?
� Larger number of renal transplants
� Immuno-suppression status
� Regular FU, high rate of encounters
� Absence of prophylaxis in some units: � Absence of prophylaxis in some units: consistency and practice review?
� Duration – extend beyond 4/6 months:
� Recent outbreaks challenge presumption that risk of PCP is greatest early on – consensus needed?
� Who to offer prophylaxis to?
Acknowledgments
� Renal Unit: Lisa Phipps, Kathy Kable, Brian
Nankivell, Jeremy Chapman, Phil O’Connell
� CIDMLS: Catriona Halliday, Sue Sleiman,
Sharon ChenSharon Chen
� Molecular Mycology Research Laboratory:
Wieland Meyer, Carolina Firacative
� Infection Control: Jo Tallon, Kathy Dempsey
� SWAHS PHU: Vicky Sheppeard