EMERGING TRENDS IN EMERGING TRENDS IN TRANSPLANT INFECTIONSTRANSPLANT INFECTIONS

Atul HumarAtul HumarTransplant Infectious DiseasesTransplant Infectious Diseases

University of TorontoUniversity of Toronto

EMERGING TRENDS IN INFECTIONEMERGING TRENDS IN INFECTION

BacteriaFungusViruses

CHANGING OLD INFECTIONS

Respiratory virusesVector borne viruses

Blood/body fluid transmittedEnteric transmitted

NOVEL INFECTIONS

EMERGING TRENDS

KNOWN PATHOGENKNOWN PATHOGEN

More potent immunosuppression

Widespread Widespread prophylaxisprophylaxis

Modified presentation-Symptoms

-Timing-Spectrum

Drug resistance

CMV: Is it still a problem?CMV: Is it still a problem?

• Despite wide-spread use of preventative Despite wide-spread use of preventative measures, CMV infection (viremia) and disease measures, CMV infection (viremia) and disease (symptoms) continues to be common in certain (symptoms) continues to be common in certain settingssettings

• GenerallyGenerally– Decrease in incidence of disease Decrease in incidence of disease – More commonly asymptomatic or mildly symptomatic More commonly asymptomatic or mildly symptomatic

viremiaviremia– Fewer cases of severe tissue invasive diseaseFewer cases of severe tissue invasive disease

CMV

Potent Immunosuppression:SRL, campath, others

Gan, valgan, valacGan, valgan, valacprophylaxisprophylaxis

Modified presentation-Symptoms

-TimingDrug resistance

LATE CMV DISEASE: DEFINITIONLATE CMV DISEASE: DEFINITION

• CMV disease occurring >3 monthsCMV disease occurring >3 monthspost-SOTpost-SOT

• May present with atypical symptomsMay present with atypical symptoms– No fever – malaise, fatigueNo fever – malaise, fatigue– Diagnosis can be missedDiagnosis can be missed– Patient may not be followed by primary Patient may not be followed by primary

center or may not be followed as closelycenter or may not be followed as closely

Time to CMV disease up to 6 mths (n=364)Time to CMV disease up to 6 mths (n=364)

Prophylaxis period

% P

atie

nts

with

no

CM

V D

ise

ase

0

10

20

30

40

50

60

70

80

90

100

Time (days)

0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200

364 D+/R- SOT patients

Time to first CMV VIREMIA (n=364)Time to first CMV VIREMIA (n=364)

VGCV

Prophylaxis Period

GCV

% P

atie

nts

with

no

CM

V V

iral L

oad

> B

LQ

0

10

20

30

40

50

60

70

80

90

100

Time (days)0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200

HOW DO WE DEAL WITH LATE HOW DO WE DEAL WITH LATE ONSET DISEASE?ONSET DISEASE?

• OPTIONSOPTIONS– Do nothing – accept the risk of late onset Do nothing – accept the risk of late onset

disease and treat as it arisesdisease and treat as it arises– Prolong prophylaxis – Is more better?Prolong prophylaxis – Is more better?

• Not necessarily – push disease further, High NNTNot necessarily – push disease further, High NNT

– Use better prophylaxis?Use better prophylaxis?– Careful virologic monitoring of high-risk Careful virologic monitoring of high-risk

patients after completing prophylaxispatients after completing prophylaxis

HOW DO WE DEAL WITH LATE HOW DO WE DEAL WITH LATE ONSET DISEASE?ONSET DISEASE?

• What about monitoring?What about monitoring?– Molecular diagnostics e.g. quantitative PCR Molecular diagnostics e.g. quantitative PCR

testing well demonstrated as useful for pre-testing well demonstrated as useful for pre-emptive therapy in absence of prophylaxis and emptive therapy in absence of prophylaxis and early post-transplantearly post-transplant

• What happens when you apply these tests What happens when you apply these tests post-prophylaxis?post-prophylaxis?

364 D+/R- patients364 D+/R- patients

3 Months of Antiviral Prophylaxis3 Months of Antiviral Prophylaxis

1- YEARF/U

AnalysisAnalysis

• CMV viral load quantified by Roche CMV viral load quantified by Roche Amplicor Amplicor PCR PCR (Detection limit: 400 copies/mL) (Detection limit: 400 copies/mL) – At baseline, every two weeks until day 100, and then at 4, 4.5, 5,

6, 8 and 12 months post-transplant

• Relationship between viral load measurement and Relationship between viral load measurement and subsequent CMV disease investigatedsubsequent CMV disease investigated

Sensitivity (%)

Specificity (%)

PPV (%)

NPV (%)

All time points

38 60 17 82

At Day 100 4 96 14 84

At 4 months 18 85 19 84

Monitoring: PREDICTIVE VALUEMonitoring: PREDICTIVE VALUE• Incidence of CMV disease was 64/364 (17.6%) Incidence of CMV disease was 64/364 (17.6%)

mostly after day 100. mostly after day 100. For prediction of For prediction of subsequent disease, viral load had a:subsequent disease, viral load had a:

Humar et al AJT 2004Humar et al AJT 2004

Results: Predicting CMV Disease Results: Predicting CMV Disease by Viral Loadby Viral Load

• Sensitivity 38%Sensitivity 38%– Only 24 of 64 patients with CMV disease Only 24 of 64 patients with CMV disease

had a positive viral load at some time prior had a positive viral load at some time prior to onset of CMVto onset of CMV

• Positive Predictive Value 17%Positive Predictive Value 17%– If positive viral load, then 17% chance of If positive viral load, then 17% chance of

developing subsequent CMV disease developing subsequent CMV disease (majority of patients with viremia do not (majority of patients with viremia do not develop disease)develop disease)

What about host response?What about host response?

• CMI (CD8, CD4) responses critical for CMI (CD8, CD4) responses critical for control of CMVcontrol of CMV– Number of relatively complicated methods Number of relatively complicated methods

to assess thisto assess this– Elispot, HLA tetramers, CFC, ICS, Elispot, HLA tetramers, CFC, ICS,

• Can a more simple test like Can a more simple test like seroconversion in a D+/R- patient predict seroconversion in a D+/R- patient predict immunity and risk of disease?immunity and risk of disease?

CMV IgM and IgG seroconversionCMV IgM and IgG seroconversion

1.6 2.68.3

41.8

54.9

16.219.6

26.9

63.4

75.3

0

20

40

60

80

Day 28 Day 56 Day 100 Month 6 Month 12

Patients (%)

IgM IgG

Predictive value of IgG seroconversionPredictive value of IgG seroconversionfor CMV diseasefor CMV disease

0

4

8

12

16

20

Seropositive Seronegative Seropositive Seronegative

Pat

ien

ts w

ith

su

bse

qu

ent

CM

V d

isea

se (

%)

End of prophylaxis(day 100)

Month 6

13.2

17.8

1.3

10.0

P=0.34

P=0.002

Humar et al AJT 2005Humar et al AJT 2005

GANCICLOVIR RESISTANCEGANCICLOVIR RESISTANCE

• Are we shooting ourselves in the foot by Are we shooting ourselves in the foot by over use of antiviral for CMV preventionover use of antiviral for CMV prevention– Will emergence of ganciclovir resistance lead Will emergence of ganciclovir resistance lead

to more harm than good in the long run?to more harm than good in the long run?

• Risk factorsRisk factors11::– D+/R- patientsD+/R- patients– Prolonged oral ganciclovir therapyProlonged oral ganciclovir therapy– More potent immunosuppressionMore potent immunosuppression

(Limaye et al. Lancet 2000)(Limaye et al. Lancet 2000)

ExtracellularIntracellular

GCV GCV-MP GCV-DP GCV-TP

CellularEnzymes

Inhibits Viral DNA Polymerase (UL54)

MECHANISM OF ACTIONMECHANISM OF ACTION

ViralProtein Kinase

(UL97)

RESISTANCE : The Good NewsRESISTANCE : The Good News VGCV OR GCV

(n=301 D+/R- patients)

Number of mutations: 7(2.3%)

- ganciclovir resistance 2 (0.7%)

- wild-type variant 2 (0.7%)

- unknown significance* 3 (1.0%)

*Evidence suggests these are unlikely to be resistance mutations

Kidney, liver, heartKidney, liver, heart

2/88 (2.3%) in pts with CMV disease2/88 (2.3%) in pts with CMV disease

Boivin et al. JID, 2004Boivin et al. JID, 2004

Resistance: The bad news!Resistance: The bad news!

• In certain subpopulations, resistance rates In certain subpopulations, resistance rates of up to 10% described in some studiesof up to 10% described in some studies– Especially lung TransplantEspecially lung Transplant

• Bharade et al JHLT 2002, Limaye et al. JID 2002Bharade et al JHLT 2002, Limaye et al. JID 2002• D+/R- lung recipients at highest risk D+/R- lung recipients at highest risk

• The two alternative therapies are The two alternative therapies are – Foscarnet and cidofovirFoscarnet and cidofovir– Both have significant toxicities. Both have significant toxicities.

WHAT DOES THE FUTURE WHAT DOES THE FUTURE HOLDHOLD

• Use of translational research to establish better Use of translational research to establish better predictive toolspredictive tools– Host response – CD8, CD4 responses to specific Host response – CD8, CD4 responses to specific

herpesvirus antigensherpesvirus antigens– Viral factors – immune evasion gene expressionViral factors – immune evasion gene expression– Understand the impact of herpesvirus interactionsUnderstand the impact of herpesvirus interactions

• Novel targets – tailored drug therapy, selective Novel targets – tailored drug therapy, selective immunosuppression, immunosuppression with immunosuppression, immunosuppression with co-existing antiviral activityco-existing antiviral activity

• Novel preventative strategiesNovel preventative strategies– Vaccine strategies- DNA vaccine, multi-epitope vaccinesVaccine strategies- DNA vaccine, multi-epitope vaccines– Cell Mediated therapeutic modalitiesCell Mediated therapeutic modalities

NOVEL INFECTIONS & NOVEL INFECTIONS & TRANSPLANTATIONTRANSPLANTATION

HHV-6/7adenovirus

Old pathogensPreviously unrecognized

BKVANWest Nile virus

Old PathogensNew disease

(in transplant pts)

SARSXenotransplantion

New PathogenNew disease

Emerging Infections

Prevalence of significant HHV-7 Prevalence of significant HHV-7 DNAemia (DNAemia (1000 copies/ml)*1000 copies/ml)*

0

1

2

3

4

5

6

7

Day 7 Day

14

Day 4

2

Day 7

0

Day 1

00

Month

4

Month

4.5

Month

6

Month

8

Month

12

Prophylaxis

*Data for valganciclovir and ganciclovir recipients combined (n = 263)

Patients (%)with HHV-7DNAemia

In press JIDIn press JID

Adenovirus viremia (n=263) Adenovirus viremia (n=263)

0

2

4

6

8

10

Liver kidney Heart kidney-pancreas

Transplant type

Incidence of

viremia (%)

8.3

6.5 6.7

0

Humar et al AJT in pressHumar et al AJT in press

Clinical reactivation

Sub-clinical reactivation

CASE PRESENTATIONCASE PRESENTATION

• 58 y.o. female kidney 2 years ago58 y.o. female kidney 2 years ago• Well since transplant; On neoral and MMF.Well since transplant; On neoral and MMF.• Not working; ++ outdoor activity / recent cottage Not working; ++ outdoor activity / recent cottage

visit (no protection measures). visit (no protection measures). • Fever and chills then confusion and a headache. Fever and chills then confusion and a headache. • LP: WBC 58 mil/L and elevated protein (0.6 g/L). LP: WBC 58 mil/L and elevated protein (0.6 g/L). • WNV serology negative initially – positive 1 WNV serology negative initially – positive 1

month later month later

DWIDWI ADCADCFLAIRFLAIR

Hospital day 6

Hospital day 65

WEST NILE VIRUS

Neurotropic ssRNA virusNeurotropic ssRNA virus

USA WNV Meningoencephalitis 2002USA WNV Meningoencephalitis 2002

CANADA – first ever WNV in 2002 – large epidemic in the Toronto Area (~400 cases of mostly meningoencephalitis)

WNV in TransplantationWNV in Transplantation

• Transplant patients can acquire WNV Transplant patients can acquire WNV in 3 ways:in 3 ways:

Transfusion-transmitted

Organ transmitted Community-

acquired

WNV: Transfusion TransmittedWNV: Transfusion Transmitted

• In the U.S. 23 cases of TTWNV (2002)In the U.S. 23 cases of TTWNV (2002)• 13/23 developed meningoencephalitis13/23 developed meningoencephalitis

– 10 patients Immunocompromised 10 patients Immunocompromised (cancer,transplant,others)(cancer,transplant,others)

– Mortality of TTWNV 29%Mortality of TTWNV 29%• ? Immunocompromised patients may have a higher ? Immunocompromised patients may have a higher

risk of severe diseaserisk of severe disease

Pealer et al. NEJM, 2003

RISK OF Transfusion RISK OF Transfusion Transmitted InfectionsTransmitted Infections

HIV (AIDS VIRUS): 1 in 4,000,000HIV (AIDS VIRUS): 1 in 4,000,000

Hepatitis C: 1 in 3,000,000Hepatitis C: 1 in 3,000,000

Hepatitis B: 1 in 275,000-1,000,000Hepatitis B: 1 in 275,000-1,000,000

HTLV 1: in 2,000,000HTLV 1: in 2,000,000

West Nile Virus: 1 in 30,000*West Nile Virus: 1 in 30,000*

•Across US; Much higher in areas with Across US; Much higher in areas with epidemic (possibly as high as 1:1000). epidemic (possibly as high as 1:1000). PCR screening now done to reduce riskPCR screening now done to reduce risk

WNV Blood ScreeningWNV Blood Screening

• Blood productsBlood products– Screened by minipool (6 donor samples)Screened by minipool (6 donor samples)– This screening was performed on This screening was performed on

approximately 6 million units during June-Dec approximately 6 million units during June-Dec 20032003

– 818 viremic blood donations removed from the 818 viremic blood donations removed from the blood supply. blood supply.

– 6 cases of TTWNV (low level donor viremia)6 cases of TTWNV (low level donor viremia)

ORGAN DONOR ORGAN DONOR TRANSMITTED WNVTRANSMITTED WNV

• Of the 23 cases of TTWNVOf the 23 cases of TTWNV• One of these patient went on to donate 4 One of these patient went on to donate 4

organs organs • 3 / 4 recipients meningoencephalitis,3 / 4 recipients meningoencephalitis,

– 1 WNV fever 1 WNV fever – 7-17 days post-transplant7-17 days post-transplant

Iwamoto et al., NEJM, 2003

To Screen or not to screenTo Screen or not to screen

• Decision to screen must be based on numerous Decision to screen must be based on numerous factors factors

• Sensitivity/Specificity of testSensitivity/Specificity of test– A recent medical decision analysis suggested A recent medical decision analysis suggested

that screening would result in a net loss of 452 that screening would result in a net loss of 452 life years due to false positive testslife years due to false positive tests

• Other issues include local WNV activity, Other issues include local WNV activity, availability of rapid turnaround time and medico-availability of rapid turnaround time and medico-legal concernslegal concerns

Kiberd et al. (AJT 2004)Kiberd et al. (AJT 2004)

http://www.cdc.gov/ncidod/dvbid/westnile/surv&control04Maps_PrinterFriendly.htm

Case #Case # TxTx SerologySerology PresentationPresentation ExposureExposure

11 LiverLiver IgM/IgG IgM/IgG positive positive but but delayeddelayed

EncephalitisEncephalitis Cottage visitCottage visit

22 KidneyKidney IgM/IgG IgM/IgG positivepositive

EncephalitisEncephalitis Outdoor Outdoor occupationoccupation

33 HeartHeart IgM/IgG IgM/IgG positivepositive

MeningitisMeningitis Outdoor Outdoor occupationoccupation

44 KidneyKidney IgM/IgG IgM/IgG positivepositive

Encephalitis/Encephalitis/

Flaccid Flaccid paralysisparalysis

Cottage visitCottage visit

WNV and Organ TransplantWNV and Organ Transplant

Kumar et al. Transplantation, 2004

:

Community Acquired WNVCommunity Acquired WNV

• Seroprevalence study of 816 organ transplant patients following the 2002 epidemic

• All patients enrolled in Oct 2002; outpatients only

• IgG, IgM testing

• Questionnaire on knowledge and behavior patterns– This followed specific educational attempts by the

transplant program in August and September

:

Community Acquired WNVCommunity Acquired WNV

• The seroprevalence of IgM antibody to West Nile was 2/816 (0.25%;95%CI 0.03-0.88%)

• Both these patient recalled a febrile illness

• Based on application of the seroprevalence data to our population of ~ 2500 transplant patients, and using data from hospital based surveillance of meningoencephalitis…

:

Community Acquired WNVCommunity Acquired WNV

• The estimated risk of meningoencephalitis in transplant patient infected with WNV is 40% (95%CI 16-80%).

• MUCH HIGHER RATE OF SEVERE DISEASE VS. GENERAL POPULATION (< 1%)

Knowledge / BehaviorsKnowledge / Behaviors Variable

Number of patients (%)

Had heard of West Nile virus

Yes 679/757 (89.7) No 78/757 (10.3)

Knew at least one protective measure

Yes 428/757 (56.5) No 335/757 (44.3)

Acted on at least one protective measure

Yes 342/757 (45.2) No 422/757 (55.7)

Used insect repellent when outdoor

Sometimes or often: 250/752 (33.2) Never: 502/752 (66.8)

““BIRD FLU”BIRD FLU”

• How do novel viral RTIs impact transplant How do novel viral RTIs impact transplant patients?patients?– Avian InfluenzaAvian Influenza– pandemic influenzapandemic influenza

RTI IN A TRANSPLANT PATIENTRTI IN A TRANSPLANT PATIENT

1.1. Given contact with Health care setting high Given contact with Health care setting high risk for exposurerisk for exposure

2.2. Once exposed, more rapidly progressive Once exposed, more rapidly progressive lethal diseaselethal disease

3.3. Higher viral shedding - Increased infectivity – Higher viral shedding - Increased infectivity – “Super-spreaders”“Super-spreaders”

4.4. Potential for donor transmissionPotential for donor transmission

SARS CoV TISSUE VIRAL LOADS (x10SARS CoV TISSUE VIRAL LOADS (x1033 copies/gram)copies/gram)

TissueTissue Lung Lung TransplantTransplant

Non-transplant Non-transplant (n=21)(n=21)

LungLung 8,760,000 360360

HeartHeart 28,000 3232

KidneyKidney 740 4848

LiverLiver 1600 1818

SpleenSpleen 140 4848

Lymph NodeLymph Node 890,000 710710

Large BowelLarge Bowel 370,000 130130

Small BowelSmall Bowel 240,000 270270Kumar et al. AJT, 2004 [ABS]

CONCLUSIONSCONCLUSIONS

• Infections complications continually Infections complications continually evolve in transplant patientsevolve in transplant patients– Understand the spectrumUnderstand the spectrum– Research in to the sequelaeResearch in to the sequelae– Build prospective monitoring in Build prospective monitoring in

immunosuppressive trials immunosuppressive trials

AcknowledgmentsAcknowledgments

• University of Toronto- D Kumar, G University of Toronto- D Kumar, G Levy, U Allen, T MazzulliLevy, U Allen, T Mazzulli

• PV16000 Study Group - C Paya, R PV16000 Study Group - C Paya, R Razonable, M Pescovitz, RocheRazonable, M Pescovitz, Roche

• National Microbiology Lab of Canada- National Microbiology Lab of Canada- M Drebot, H Artsob, P BuckM Drebot, H Artsob, P Buck

• Laval University – Guy BoivinLaval University – Guy Boivin• CDC -D ErdmanCDC -D Erdman• CIHR, PSI foundationCIHR, PSI foundation