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