I ABTO MEETING ON TRANSPLANT INFECTIOUS DISEASES I IBEROAMERICAN MEETING ON TRANSPLANT INFECTIOUS DISEASES I ABTO MEETING ON TRANSPLANT INFECTIOUS DISEASES

I ABTO MEETING ON TRANSPLANT INFECTIOUS DISEASES

I IBEROAMERICAN MEETING ON TRANSPLANT INFECTIOUS DISEASES

I ABTO MEETING ON TRANSPLANT INFECTIOUS DISEASES

I IBEROAMERICAN MEETING ON TRANSPLANT INFECTIOUS DISEASES

Sao Paulo, Brazil- 23-24 November, 2012

José María Aguado

Hospital Universitario 12 de Octubre, Madrid, Spain

Instituto de Investigación 12 + i

The New Frontiers in Epidemiology and SurveillanceThe New Frontiers in Epidemiology and Surveillance

Tuberculosis in Solid Organ TransplantationTuberculosis in Solid Organ Transplantation

Tuberculosis is really a surprise or not so much?Tuberculosis is really a surprise or not so much?

10-1510-153.53.5

4.34.3

2.32.3

0.90.90.80.80.2-1.20.2-1.2 2.72.7

X20-74X20-74

Singh N. CID 1998 ;Aguado JM. GESITRA. Transplantation 1997. Muñoz P. Clinical Infectious Diseases 2005Singh N. CID 1998 ;Aguado JM. GESITRA. Transplantation 1997. Muñoz P. Clinical Infectious Diseases 2005

Prevalence of TB according to world regionPrevalence of TB according to world region

Type of Type of transplanttransplant FrequencyFrequency Incidence/10Incidence/1055 IC90% IC90% Odds ratioOdds ratio

HeartHeart 1/404 (0.25)1/404 (0.25) 255 (6.5-1421)255 (6.5-1421) 13.7 (1.9-97.3)13.7 (1.9-97.3)

KidneyKidney 7/2052 (0.34)7/2052 (0.34) 358 (144-728)358 (144-728) 19.0 (9.0-39.7)19.0 (9.0-39.7)

LiverLiver 8/1507 (0.53)8/1507 (0.53) 541 (269-1065)541 (269-1065) 29.5 (14.8-58.9)29.5 (14.8-58.9)

Kidney-Kidney-pancreaspancreas

1/122 (0.82)1/122 (0.82) 1204 (30.5-6710)1204 (30.5-6710) 45.5 (6.5-320.4)45.5 (6.5-320.4)

LungLung 4/303 (1.32)4/303 (1.32) 2072 (565-5306)2072 (565-5306) 73.3 (27.7-194.1)73.3 (27.7-194.1)

TotalTotal 21/4388 (0.49)21/4388 (0.49) 512 (317-783)512 (317-783) 26.6 (17.4-40.8)26.6 (17.4-40.8)

Clinical Infectious Diseases 2009; 48:1657–65

Incidence of TBC in SOT RESITRA Network (2003-2005)

Incidence of TBC in SOT RESITRA Network (2003-2005)

Reactivation, reinfection or donor transmission?Reactivation, reinfection or donor transmission?

PathogenesisPathogenesis

ReactivationReactivation

New infection Donor * New infection Donor *

91.5%91.5%

8.5%

47 TB in Kidney Tx47 TB in Kidney Tx47 TB in Kidney Tx47 TB in Kidney Tx

(*) Donor with history or TBC or + PPD with a negative Recipient

Lichtenstein IH Rev Infect Dis 1983;5:216

(*) Donor with history or TBC or + PPD with a negative Recipient

Lichtenstein IH Rev Infect Dis 1983;5:216

How important is the type of immunosuppression?How important is the type of immunosuppression?

Immunosuppressive treatmentImmunosuppressive treatment

Mean Mean doses of immunosuppressivedoses of immunosuppressive drugs in cases and controls drugs in cases and controls were were not significantly differentnot significantly different11

Rejection (56% vs. 32%, Rejection (56% vs. 32%, P=0.004; OR=2.7, CI(95%): 1.3-5.6P=0.004; OR=2.7, CI(95%): 1.3-5.6))11

OKT3 or Anti-T cell antibodies (79% vs 64%, p=0.19)OKT3 or Anti-T cell antibodies (79% vs 64%, p=0.19)22

Cyclosporine vs azathioprine first year (OR 2.5)Cyclosporine vs azathioprine first year (OR 2.5)33

Use of mycophenolate (4.5% vs 6.1%, p=NS)Use of mycophenolate (4.5% vs 6.1%, p=NS)4. 4.

Mean Mean doses of immunosuppressivedoses of immunosuppressive drugs in cases and controls drugs in cases and controls were were not significantly differentnot significantly different11

Rejection (56% vs. 32%, Rejection (56% vs. 32%, P=0.004; OR=2.7, CI(95%): 1.3-5.6P=0.004; OR=2.7, CI(95%): 1.3-5.6))11

OKT3 or Anti-T cell antibodies (79% vs 64%, p=0.19)OKT3 or Anti-T cell antibodies (79% vs 64%, p=0.19)22

Cyclosporine vs azathioprine first year (OR 2.5)Cyclosporine vs azathioprine first year (OR 2.5)33

Use of mycophenolate (4.5% vs 6.1%, p=NS)Use of mycophenolate (4.5% vs 6.1%, p=NS)4. 4.

1 1 Basiri A. Transplant Proc 2008; Singh N. Clin.Microb.Rev. 2005; 22; 3 3 John GT. Kidney Int 2001; 44Atasever A. Nephrol Dial Transplant. 2005

1 1 Basiri A. Transplant Proc 2008; Singh N. Clin.Microb.Rev. 2005; 22; 3 3 John GT. Kidney Int 2001; 44Atasever A. Nephrol Dial Transplant. 2005

Reduce immunosuppression?Reduce immunosuppression?

Controversial. Consider in severe cases in kidney TxControversial. Consider in severe cases in kidney Tx

Change immunosuppressive drugs? (imTOR)Change immunosuppressive drugs? (imTOR)

Controversial. Consider in severe cases in kidney TxControversial. Consider in severe cases in kidney Tx

Change immunosuppressive drugs? (imTOR)Change immunosuppressive drugs? (imTOR)

What are the risk factors for tuberculosis in SOT?What are the risk factors for tuberculosis in SOT?

Risk factorsRisk factors

Previous data of TBCPrevious data of TBC Underlying diseaseUnderlying disease

HemodialysisHemodialysis. Longer pre-transplant HD? . Longer pre-transplant HD? X2X2 Diabetes mellitusDiabetes mellitus ( (X2-4X2-4)) Older ageOlder age

Coexisting infectionCoexisting infection: CMV, PCP, HCV : CMV, PCP, HCV X1.6-2.3X1.6-2.3

Previous data of TBCPrevious data of TBC Underlying diseaseUnderlying disease

HemodialysisHemodialysis. Longer pre-transplant HD? . Longer pre-transplant HD? X2X2 Diabetes mellitusDiabetes mellitus ( (X2-4X2-4)) Older ageOlder age

Coexisting infectionCoexisting infection: CMV, PCP, HCV : CMV, PCP, HCV X1.6-2.3X1.6-2.3

Klote MM. Am J Transplant 2004; John GT. Kidney Int 2001; Klote MM. Am J Transplant 2004; John GT. Kidney Int 2001; Basiri A. Transplant Proc 2005. Basiri A. Basiri A. Transplant Proc 2005. Basiri A. Tranpl Infect Dis 2007; Torres J. Tranpl Infect Dis 2007; Torres J. Transpl Int. 2008.Transpl Int. 2008. Aguado JM. Clin Infect Dis 2009; 48:1657–65

Klote MM. Am J Transplant 2004; John GT. Kidney Int 2001; Klote MM. Am J Transplant 2004; John GT. Kidney Int 2001; Basiri A. Transplant Proc 2005. Basiri A. Basiri A. Transplant Proc 2005. Basiri A. Tranpl Infect Dis 2007; Torres J. Tranpl Infect Dis 2007; Torres J. Transpl Int. 2008.Transpl Int. 2008. Aguado JM. Clin Infect Dis 2009; 48:1657–65

Some clinical peculiaritiesSome clinical peculiarities?Some clinical peculiaritiesSome clinical peculiarities?

<01<01 2-32-3 4-54-5 6-76-7 8-98-9 9-129-12 13-2413-24 >24>24

Months after TxMonths after Tx

0022446688

1010121214141616

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Onset of SymptomsOnset of Symptoms

Median 9 months (60%)>24m: 40%Median 9 months (60%)>24m: 40%

AguadoJM.Transplantation.97AguadoJM.Transplantation.97

Clinical Characteristics (RESITRA cohort, 2002-2005)

Clinical Characteristics (RESITRA cohort, 2002-2005)

Early TB (< 3 mo.)Early TB (< 3 mo.) Late TB (> 3 mo.)Late TB (> 3 mo.)

Time of onsetTime of onset 20 days (5-50 days)20 days (5-50 days) 12 months (3-30 m)12 months (3-30 m)

FrequencyFrequency 10%10% 90%90%SourceSource

Risk factorsRisk factorsTB in transplant candidate.TB in transplant candidate.

Donor transmission.Donor transmission.

Latent TB (Chest XR, PPD).Latent TB (Chest XR, PPD).

Reactivation.Reactivation.

Nosocomial.Nosocomial.

Primary infection.Primary infection.Clinical Clinical

manifestationsmanifestationsPulmonary , extrapulmonar, Pulmonary , extrapulmonar,

disseminated, FUO.disseminated, FUO.PulmonaryPulmonary

Crude mortalityCrude mortality 40%40% 15-20%15-20%Related mortalityRelated mortality 2-3%2-3% 1%1%

LUNGLUNG50-65%50-65%

EXTRAPULMONARYEXTRAPULMONARY12-16%12-16%

DISSEMINATEDDISSEMINATED25-35%25-35%

Singh N. Clin.Microb.Rev. 2005; Aguado JM. GESITRA. Transplantation. 1997Singh N. Clin.Microb.Rev. 2005; Aguado JM. GESITRA. Transplantation. 1997

Sites of infectionSites of infection

Clinical manifestationsClinical manifestations

Fever of unknown origin 11-26%Fever of unknown origin 11-26%

Constitutional symptomsConstitutional symptoms

CoughCough

Other sitesOther sites Skin and soft tissues 4%, osteoarticular 1%Skin and soft tissues 4%, osteoarticular 1% Genitourinary 0.6% Genitourinary 0.6% Liver, pancreas, larynx, adrenal glands, thyroid, eyeLiver, pancreas, larynx, adrenal glands, thyroid, eye

Fever of unknown origin 11-26%Fever of unknown origin 11-26%

Constitutional symptomsConstitutional symptoms

CoughCough

Other sitesOther sites Skin and soft tissues 4%, osteoarticular 1%Skin and soft tissues 4%, osteoarticular 1% Genitourinary 0.6% Genitourinary 0.6% Liver, pancreas, larynx, adrenal glands, thyroid, eyeLiver, pancreas, larynx, adrenal glands, thyroid, eye

John GT. 2001

Diagnostic difficulties?Diagnostic difficulties?Diagnostic difficulties?Diagnostic difficulties?

DiagnosisDiagnosis

Delayed diagnosis > mortalityDelayed diagnosis > mortality association with other infectionsassociation with other infections aggressive diagnostic techniques: FB, BX...aggressive diagnostic techniques: FB, BX...

PPD testingPPD testing Low efficacy (only 20-25% of patients are PPD+) Low efficacy (only 20-25% of patients are PPD+) Anergy skin testing???Anergy skin testing???

IGRAs: Quantiferon-TB Gold, T-SPOT.IGRAs: Quantiferon-TB Gold, T-SPOT.TBTB IFN-IFN- from sensitized L from sensitized L

Delayed diagnosis > mortalityDelayed diagnosis > mortality association with other infectionsassociation with other infections aggressive diagnostic techniques: FB, BX...aggressive diagnostic techniques: FB, BX...

PPD testingPPD testing Low efficacy (only 20-25% of patients are PPD+) Low efficacy (only 20-25% of patients are PPD+) Anergy skin testing???Anergy skin testing???

IGRAs: Quantiferon-TB Gold, T-SPOT.IGRAs: Quantiferon-TB Gold, T-SPOT.TBTB IFN-IFN- from sensitized L from sensitized L

Casas S et al. Liver Transpl 2011;17:1205-1211

Quantiferon-TB vs TSTQuantiferon-TB vs TST

European Survey TB (ESGICH)(16 European countries, 50 transplant programs)


Methods for screeningMethods for screening TST alone 41%TST alone 41% IGRAs alone 32%IGRAs alone 32% TST and IGRAs simultaneously 22%TST and IGRAs simultaneously 22% TST followed by IGRAs if TST positive 5%TST followed by IGRAs if TST positive 5%

Methods for screeningMethods for screening TST alone 41%TST alone 41% IGRAs alone 32%IGRAs alone 32% TST and IGRAs simultaneously 22%TST and IGRAs simultaneously 22% TST followed by IGRAs if TST positive 5%TST followed by IGRAs if TST positive 5%

Boillat-Blanco N, Aguado JM, Manuel O et al. ECCMID London 2012

Any therapeutic Any therapeutic difficulties?difficulties?

Any therapeutic Any therapeutic difficulties?difficulties?

Interactions with Antituberculous drugsInteractions with Antituberculous drugs

IsoniazidRifampinRifabutinPirazinamideEtambutolMoxifloxacinCicloserin

IsoniazidRifampinRifabutinPirazinamideEtambutolMoxifloxacinCicloserin

CyA

- --*

FK

- ----

MMF

-----

SRL

- ----

* Increase the levels of antituberculous drugs* Increase the levels of antituberculous drugs

Impact of rifampin based anti-tuberculosis regimens on outcomes in SOT recipients

Impact of rifampin based anti-tuberculosis regimens on outcomes in SOT recipients

63 SOT recipients with TB: 63 SOT recipients with TB: RIF 26RIF 26, , non-RIF 37non-RIF 37

Rejection rate and death Rejection rate and death at 1 year wereat 1 year were similar similar in both in both groups.groups.

Immune Reconstitution Syndrome (IRS) more frequent Immune Reconstitution Syndrome (IRS) more frequent in RIF in RIF than in non-RIFthan in non-RIF (27% vs 5,4%, p=.04) (27% vs 5,4%, p=.04)

MortalityMortality at 1 y: at 1 y: 33%33% with IRSwith IRS, 14% without IRS , 14% without IRS (p = 0.15)(p = 0.15)

63 SOT recipients with TB: 63 SOT recipients with TB: RIF 26RIF 26, , non-RIF 37non-RIF 37

Rejection rate and death Rejection rate and death at 1 year wereat 1 year were similar similar in both in both groups.groups.

Immune Reconstitution Syndrome (IRS) more frequent Immune Reconstitution Syndrome (IRS) more frequent in RIF in RIF than in non-RIFthan in non-RIF (27% vs 5,4%, p=.04) (27% vs 5,4%, p=.04)

MortalityMortality at 1 y: at 1 y: 33%33% with IRSwith IRS, 14% without IRS , 14% without IRS (p = 0.15)(p = 0.15)

Sun HY et al. ICAAC 2012. Singh N et al. ICAAC 2011

Aguado JM et al. Clinical Infectious Diseases 2009; 48:1276–84

Guidelines. RESITRA-Spanish Society of Infectious DiseasesGuidelines. RESITRA-Spanish Society of Infectious Diseases



Treatment with rifamycins in TBTreatment with rifamycins in TB Non-severe TB 61%Non-severe TB 61% Severe disseminated TB 95%Severe disseminated TB 95%

Treatment with rifamycins in TBTreatment with rifamycins in TB Non-severe TB 61%Non-severe TB 61% Severe disseminated TB 95%Severe disseminated TB 95%


Crude mortality 19%.

Attributable mortality 9.5%

Crude mortality 19%.

Attributable mortality 9.5%

RESITRA Network dataRESITRA Network data


Tuberculosis in SOT: current situation in Spain

Tuberculosis in SOT: current situation in Spain

Prophylaxis: who, what, Prophylaxis: who, what, when, when, how long?how long?

Prophylaxis: who, what, Prophylaxis: who, what, when, when, how long?how long?

Exclude active infection and give prophylaxis if the recipient:

Exclude active infection and give prophylaxis if the recipient:

TST >5mm (initial of after “booster”)TST >5mm (initial of after “booster”)

TST negative andTST negative and Compatible Compatible lung residual lesions (RR 1.05-3.4)lung residual lesions (RR 1.05-3.4) History of untreated TB History of untreated TB (RR 1.2-48) (RR 1.2-48) or TB contact or TB contact Donor with possible TBDonor with possible TB

TST >5mm (initial of after “booster”)TST >5mm (initial of after “booster”)

TST negative andTST negative and Compatible Compatible lung residual lesions (RR 1.05-3.4)lung residual lesions (RR 1.05-3.4) History of untreated TB History of untreated TB (RR 1.2-48) (RR 1.2-48) or TB contact or TB contact Donor with possible TBDonor with possible TB

GESITRA. Consensus Document. Clinical Infectious Diseases 2009; 48:1276–84GESITRA. Consensus Document. Clinical Infectious Diseases 2009; 48:1276–84

…or if the donor…or if the donor

Live kidney donor TST+ Live kidney donor TST+ : 3 months of INH beforeTx: 3 months of INH beforeTx Death donor Death donor consider prophylaxis ifconsider prophylaxis if

History of tuberculosisHistory of tuberculosis PPD (+) with normal Chest-X rayPPD (+) with normal Chest-X ray Residual lung lesions Residual lung lesions

(contraindication for lung Tx)(contraindication for lung Tx) Lymph nodes found during surgeryLymph nodes found during surgery

Live kidney donor TST+ Live kidney donor TST+ : 3 months of INH beforeTx: 3 months of INH beforeTx Death donor Death donor consider prophylaxis ifconsider prophylaxis if

History of tuberculosisHistory of tuberculosis PPD (+) with normal Chest-X rayPPD (+) with normal Chest-X ray Residual lung lesions Residual lung lesions

(contraindication for lung Tx)(contraindication for lung Tx) Lymph nodes found during surgeryLymph nodes found during surgery



Limitations for the Control of TBC RESITRA Network

Limitations for the Control of TBC RESITRA Network



Screening of TB in SOT candidatesScreening of TB in SOT candidates systematically 61%systematically 61% only in patients with risk factors 30%only in patients with risk factors 30% no screening 9%no screening 9%

Treatment of latent TB (Prophylaxis)Treatment of latent TB (Prophylaxis) prior to liver TX 41% prior to liver TX 41% no prophylaxis at all 5%-17%no prophylaxis at all 5%-17% (depending on the organ) (depending on the organ) considered a temporary contraindication for TX 32%considered a temporary contraindication for TX 32%

Screening of TB in SOT candidatesScreening of TB in SOT candidates systematically 61%systematically 61% only in patients with risk factors 30%only in patients with risk factors 30% no screening 9%no screening 9%

Treatment of latent TB (Prophylaxis)Treatment of latent TB (Prophylaxis) prior to liver TX 41% prior to liver TX 41% no prophylaxis at all 5%-17%no prophylaxis at all 5%-17% (depending on the organ) (depending on the organ) considered a temporary contraindication for TX 32%considered a temporary contraindication for TX 32%


Toxicity of prophylaxisToxicity of prophylaxis

Toxicity: 2.7% KT, 4% HTx, 2-20% LT

Individualize in liver recipientsIndividualize in liver recipients If stable consider prophylaxis before TxIf stable consider prophylaxis before Tx If not, wait till transplantation has been doneIf not, wait till transplantation has been done

Toxicity: 2.7% KT, 4% HTx, 2-20% LT

Individualize in liver recipientsIndividualize in liver recipients If stable consider prophylaxis before TxIf stable consider prophylaxis before Tx If not, wait till transplantation has been doneIf not, wait till transplantation has been done


Efficacy and Safety of Levofloxacin vs. Isoniazid for the Treatment of Latent Tuberculosis Infection in Liver

Transplant Recipients

Efficacy and Safety of Levofloxacin vs. Isoniazid for the Treatment of Latent Tuberculosis Infection in Liver

Transplant Recipients

Phase III stuy, multicentric, prospective, randomized, and openCandidates for liver transplantation. FLISH Study.

Phase III stuy, multicentric, prospective, randomized, and openCandidates for liver transplantation. FLISH Study.

Group A (usual practice): isoniazid 300 mg / day for 9 months beginning after the transplant, when the "liver function is stable" and not before 3 months and after 6 months.

Group A (usual practice): isoniazid 300 mg / day for 9 months beginning after the transplant, when the "liver function is stable" and not before 3 months and after 6 months.

Group B (experimental): levofloxacin 500 mg daily for 9 months (commencing on the waiting list).Group B (experimental): levofloxacin 500 mg daily for 9 months (commencing on the waiting list).

Primary endpoint: difference in the incidence of TBC in both groups at 18 months of follow-up after transplantation.

Sample size: n = 870 patients. 16 centers in Spain

Conclusions........Conclusions........

- Incidence > general population- Incidence > general population

- Reactivation- Reactivation

- Mortality > 30%- Mortality > 30%

- Clinical presentation: atypical and diverse- Clinical presentation: atypical and diverse

- Treatment requires control of interactions- Treatment requires control of interactions

- Prophylaxis is complicated because of:- Prophylaxis is complicated because of:

- Difficulty in identifying pts at risk- Difficulty in identifying pts at risk

- Toxicity of therapy. - Toxicity of therapy.

- Incidence > general population- Incidence > general population

- Reactivation- Reactivation

- Mortality > 30%- Mortality > 30%

- Clinical presentation: atypical and diverse- Clinical presentation: atypical and diverse

- Treatment requires control of interactions- Treatment requires control of interactions

- Prophylaxis is complicated because of:- Prophylaxis is complicated because of:

- Difficulty in identifying pts at risk- Difficulty in identifying pts at risk

- Toxicity of therapy. - Toxicity of therapy.

Thanks God, he finished

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I ABTO MEETING ON TRANSPLANT INFECTIOUS DISEASES I IBEROAMERICAN MEETING ON TRANSPLANT INFECTIOUS DISEASES I ABTO MEETING ON TRANSPLANT INFECTIOUS DISEASES