PPT Grossi "Tuberculosis and transplants", Symposium on TB, 15 October, V Session (Physicians & surgeons), Monza, Italy.

1. Clinica delle Malattie Infettive e Tropicali
Università degli Studi dell’Insubria –
Ospedale di Circolo e Fondazione Macchi, Varese
“Second Opinion” Infettivologica
Centro Nazionale Trapianti, ISS, Roma
Tubercolosi e trapianti
Paolo Grossi
TUBERCOLOSI: UNA MALATTIA COMPLESSA
Monza 14-15 Ottobre, 2011

3. Post-transplant tuberculosis
20-70 times higher incidence
Prevalence mimics endemic prevalence (0.35-15%)
High morbidity and mortality (13-40%)
TB contributes to graft dysfunction
High incidence of extrapulmonary involvement and
atypical presentation
Complex management/drug-interactions
 Importance of preventive measures
Singh&Paterson Clin Infect Dis (1998) 27: 1266; Munoz et al Clin Infect Dis (2005) 40: 581

4. M. tuberculosis Infection in Recipients of Solid Organ Transplants
CLINICAL
MANIFESTATIONS
511 transplant patients with tuberculosis
Singh N, Paterson DL. Clin Infect Dis 1998; 27:1266–77.
33 lung involvement
disseminated
51%
16
extrapulmonary
OVERALL MORTALITY RATE 29%
Major predictors of mortality
- disseminated infection (P = .0003),
- prior rejection (P = .006),
- receipt of OKT3 or anti-T cell antibodies (P = .0013)
Università degli Studi di Udine – Clinica di Malattie Infettive

5. M. tuberculosis Infection in Recipients of Solid Organ Transplants
EPIDEMIOLOGY Munoz P, Rodriguez C, Bouza E, Clin Infect Dis 2005; 40:581–7
% 15
6,5
2,3 2,5 2
1 1,5
0,7 0,5 0,23 0,79
adult liver pediatric liver kidney heart lung bone
marrow
min max
Università degli Studi di Udine – Clinica di Malattie Infettive

6. Frequency of Tuberculosis
in solid-organ transplant recipients
Transplanted Organ
Prevalence, % Overall Lung Kidney Liver Heart Kidney-
pancreas
Literature 1.2-15 2-6.5 0.5-15 0.7-2.3 1-1.5 …
GESITRA 0.45 1.15 0.35 0.47 0.26 0.85
(Spain, from
2008)
Incidence 512 2012 358 541 255 1204
Higher risk of TB among SOT recipients when
(Cases per 105 (317-783) (565- (144-728) (269- (6.5- compared
(30.5-6710)
popul/year; 5306) 1065) 1421)
GESITRA) with the general population
Aguado JM et al, CID 2009; 48:1276-84

7. Risk factors for tuberculosis after transplantation
Aguado JM, et al. Clinical Infectious Diseases 2009; 48:1276–84

8. Screening pre-trapianto
Esame Se positivo Se negativo
Intradermoreazione alla Escludere malattia
tubercolina (PPD) tubercolare in atto
Test IGRA
Valutazione malattia tubercolare
Anamnesi e esame Esami di laboratorio Esami strumentali
clinico
(in tutti i candidati)
Storia di TBC Ricerca micobatteri Rx torace (protocollo
Fattori di rischio e (diretto, PCR e colturale) su standard)
contatti espettorato, urine e sangue Ecografia addome
(almeno 3 campioni) completo
Eventuali terapie Eventuale ricerca su altri Eventuale TC Torace
pregresse campioni
Adeguatezza delle
terapie
Valutazione clinica Altro

9. Immunodiagnosis of
latent M. tuberculosis infection
antigens/
peptides APC
IGRA
IFN- release assay
PPD
ESAT-6/CFP-10/TB7.7 T cell
activation/
cytokine cytokine cytokine cytokine
induction induction induction induction
Skin test ELISA ELISPOT assay Flow-cytometry
activation marker
QuantiFERON TB gold T-SPOT.TB cytokine

10. Test characteristics
Skin-test ELISA ELISPOT
Sensitivity 77 % 78 % 90 %
Specificity
59-97 % 96 % 93 %
Low risk controls
Pai et al Ann Intern Med (2008) 149: 177

11. Treatment for Latent TB Infection
• Treating LTBI reduces the risk that M.
tuberculosis infection will develop into TB
disease
• Certain groups have higher risk for developing
TB disease after infection; should be treated
• Before beginning treatment for LTBI
– Exclude diagnosis of TB
– Ensure patient has no history of adverse
reactions resulting from prior LTBI treatment

12. Treatment Regiments for LTBI
Months of Minimum
Drugs Interval
Duration Doses
Daily 270
INH 9*
2x wkly 76
Daily 180
INH 6
2x wkly 52
RIF 4 Daily 120
*Preferred
INH=isoniazid; RIF=rifampin

13. Diagnosis of active tuberculosis
Patient history
Chest X-ray
Culture
Acid-fast bacilli staining
Nucleic acid amplification testing

14. Poor specificity for distinction
of active and latent infection
Skin-test ELISA ELISPOT
Sensitivity 77 % / 65 % 78 % / 80 % 90 % / 81 %
Specificity 59-97 % 96 % 93 %
Low risk controls
Specificity 75 % 79 % 59 %
TB suspects
Sester et al Eur Respir J (2011) 37: 100 Pai et al Ann Intern Med (2008) 149: 177

15. IFN-γ and IL-2 cytokine profiles of antigen-specific T cells
measured by flow-cytometry ex vivo might correlate with TB
disease activity in vivo.
Receiver operator characteristics (ROC) analysis revealed that
frequencies of PPD specific IFN- γ /IL-2 dual-positive T cells
below 56% were an accurate marker for active TB (specificity
100%, sensitivity 70%) enabling effective discrimination from
non-active states.
In conclusion, a frequency lower than 56% IFN- γ /IL-2 dual
positive PPD-specific circulating CD4 T-cells is strongly
indicative of active TB.
Sester M, et al. PLoS ONE 2011;6:

16. Case – donor-derived tuberculosis
Deceased donor •CNS disease
not recognized as having active TB •CSF was AFB negative
•48 years, male •29 years, male •30 years, male
•TB 8 weeks post-Tx •TB 3 months post-Tx •ATG treatment
•BAL/Bone marrow AFB+ •Hepatic abscess AFB+ •TB 3 weeks post-Tx
•Patient survived •Patient survived •Bone marrow AFB+
•Patient died
Edathodu et al Int J Tuberc Lung Dis (2010) 14: 1493

17. Donor‘s Risk factors for TB transmission
Active TB
History of untreated/improperly treated TB
Positive TST/IGRA, in particular recent conversion
Abnormal chest X-ray
Recent close contact to TB case
Birth/residence in a high prevalence country
TB disease
Highest risk donors
Latency Live bacilli?
Latency Bacterium extinguished? Singh&Paterson Clin Infect Dis (1998) 27: 1266
Munoz et al Clin Infect Dis (2005) 40: 581

18. Management – Donor screening
Grouped by living or deceased donor
Categorized
• Active TB vs latent infection
• Active TB
- History of active disease or currently active
- Treated adequately > 2 years ago or not
- Same site of organ being transplanted or distant
site (except lung)
• Microbiologic or pathologic diagnosis
Donor-Derived Consensus Conference TB – Morris et al in preparation

19. Problems with diagnostics
in deceased donors
Results often only obtained after
transplantation
Clinical history often not reliable
Skin testing not feasible
IGRAs not validated

20. Summary
Donor risk assessment
Need for increased awareness
Identification of who may have greatest risk for
transmission or reactivation of M. tuberculosis
Application of recommendations likely to vary from
country to country and even region to region
Consult infectious disease specialist
Communication among transplant centers

21. Major areas for future studies
Use of IGRAs in deceased donors
Evaluation of nucleic acid based testing on
body fluids of high risk donors
Prospective evaluation and outcomes of
recipients receiving organs from donors with
high risk for latent infection
Donor-Derived Consensus Conference TB – Morris et al in preparation

22. Dati anamnestici
 CS, maschio, 44 in 60^ giornata post-tx co-infezione
Dimesso aa, ex-tossicodipendente,
HIV-HCVdimissione:
Esami alla Terapia immunosoppressiva:
 DM tipo 1, IRC da nefropatia diabeticamg/sett
- creatinina= 1,1mg/dL - Tacrolimus 0,5 in emodialisi dal
2000
- glicemia= 80mg/dL - Micofenolato mofetile
 Valutazione pre-tx: Anamnesi per TB e PPD negative
- Metilprednisolone (sospeso a 3
Nell’aprile 2007 trapianto mesi dal tx)
di combinato di rene-pancreas
Terapia antiretrovirale:
Ottima ripresa della Lamivudina/Abacavir
- funzionalità dei graft
ComplicanzeFosamprenavir/ritonavir
- chirurgiche:
 1°gg sanguinamento dal corpo del pancreas e dall’anastomosi
arteria renale.
 26°gg deiscenza della ferita con eviscerazione, colecistite
gangrenosa e ascesso pelvico; colecistectomia e toilette
chirurgica

23. .... 36 mesi post-tx
Comparsa sintomi aspecifici: astenia, febbricola, sudorazioni notturne
Lieve incremento degli indici di flogosi (VES=45, PCR=27)
Funzionalità renale e pancreatica nella norma
HIV-RNA undetectable; Linfociti T CD4= 307/mmc
Tra i vari esami effettuati:
Intradermoreazione alla tubercolina: positiva
QuantiFERON-TB Gold: positivo
BAL:
•Esame microscopico pos per micobatteri
• Esame molecolare (PCR) pos per Mycobacterium tuberculosis
• Esame colturale + antibiogramma: Mycobacterium tuberculosis sensibile
a streptomicina, isoniazide, rifampicina, etambutolo, pirazinamide

24. Terapia
NO Rifampicina
Isoniazide 300 mg/die
Livelli FK, CyA,
Etambutolo 1600 mg/die
Rapamicina, Inibitori
Moxifloxacina 400 mg/die Protesi
Pirazinamide 1500 mg/die (sospesa dopo 2 mesi)
Vit B 6
Lieve aumento delle transaminasi (2vv)
Aumento dell’uricemia
Dispepsia
Tacrolimus
Acido micofenolico
Abacavir/lamivudina
Fosamprenavir
Ritonavir
Allopurinolo
Acido acetilsalicilico

25. TB treatment options in solid organ transplant
recipients (GESITRA)
Aguado JM. Clinical Infectious Diseases 2009; 48:1276–84

26. Quali sono le problematiche correlate alla
terapia della tubercolosi nel paziente
immunocompromesso per trapianto?
 Interazione tra i farmaci
 Maggior Tossicità
 Compliance
 Durata della terapia

27. Drug Interactions
• Relatively few drug interactions substantially
change concentrations of antituberculosis
drugs
• Antituberculosis drugs sometimes change
concentrations of other drugs
– Rifamycins can decrease serum concentrations
of many drugs, (e.g., most of
immunosuppressive drugs, the HIV-1 protease
inhibitors and many others), to subtherapeutic
levels
– Isoniazid increases concentrations of some
drugs (e.g., phenytoin) to toxic levels

28. Conclusioni
• La Tubercolosi rappresenta una grave complicanza nel post-
tx dovuta nella maggior parte dei casi a riattivazione di TB
latente, raramente da trasmissione dal donatore, ma anche
come infezione primaria comunitaria
• E’ fondamentale un’approfondita valutazione pre-tx
(anamnesi, clinica, PPD o Test IGRA) non solo per
diagnosticare un’eventuale TB latente, ma anche per
acquisire un dato di negatività che può rivelarsi utile nel
post-tx
• Le indagini colturali vanno sempre eseguite anche alla luce
dell’emergenza di MDR
• Il trattamento deve possibilmente escludere l’utilizzo di
rifamicine, potenti induttori del CYP450; se utilizzate,
stretto monitoraggio dei livelli degli immunosoppressori
• La durata della terapia deve proseguire per almeno 12-18
mesi