1. Managing immunosuppression in the infected transplant recipient
Transplant Infectious Disease
Conference
Cancun, Mexico
Managing immunosuppression in the infected transplant recipient
Hans H Hirsch
Transplantation & Clinical Virology
Department Biomedicine (Haus Petersplatz)
Division Infection Diagnostics
University of Basel
Infectious Diseases & Hospital Epidemiology
University Hospital Basel
Switzerland

2. Transplant-centric view...
Donor
Recipient
Microbial graft
load
Anti-Donor
immunity
Microbial
replication
Over-
Immunosuppression
+++
Ideal Immunosuppression
to accommodate graft
Ideal Immunosuppression
to accommodate graft
CMV ++
EBV
BKPyV
ADV +
Under-
Immunosuppression -
Acute
rejection
Anti-Microbe
Immunity

3. Managing immunosuppression…
Increasing immunosuppression
Tailoring immunosuppression
Decreasing immunosuppression
Challenges
Reducing inflammation, SIRS, or IRIS
Managing drug-drug interactions (DDI)
Improving microbial immune control

4. Increasing Immunosuppression ?

5. Increasing Immunosuppression

6. Increasing immunosuppression
Pneumocystis breakdown products activating PAMPs, TLRs
Transplant patients are less at risk as IS dampens inflammation
Steroids prevent or delay microbe-specific immune control
Rationale for secondary prophylaxis: Duration (laboratory marker?)

7. Increasing immunosuppression
Pneumocystis jirovecii pneumonia
Severe
Reduced pO2 < 10kPa, or O2 saturation <70%
Prednisone mg/12h x 5d
Then, tapering 40mg/d x 5 d, then 20mg/d x10d
Limited evidence in transplant patients
No risk or benefit of specific IS drugs like mycophenolate, or mTORi ?
Secondary prophylaxis, but duration unclear (biomarker like CD4?)

8. Increasing Immunosuppression
Cryptococcus therapy and breakdown products activate PAMPs, TLRs, induce Th1 > Th2
Rapid reduction of immunosuppression may precipitate IRIS
Paradoxical worsening
More frequent with disseminated cryptococcosis (CNS, LN, muscle)
More frequent with tacrolimus, mycophenolate, prednisone
No RCT data available on optimal reducing immunosuppression

9. Increasing immunosuppression ?
Steroid avoidance ?
Thalidomide ?
Anti-TNFα ?
Cave M.tuberculosis
Secondary prophylaxis

10. Increasing immunosuppression
Pneumocystis jirovecii pneumonia
Severe
Reduced pO2 < 10kPa, or O2 saturation <70%
Prednisone mg/12h x 5d
Then, tapering 40mg/d x 5 d, then 20mg/d x10d
Limited evidence in transplant patients
No risk or benefit of specific IS drugs like mycophenolate, or mTORi ?
Secondary prophylaxis, but duration unclear (biomarker like CD4?)
Crypococcus sp.
No routine increase in immunosuppression
Severe presentations, at risk for IRIS (life-threatening)
Steroids 1mg/kg bw, but novel approaches needed (anti-TNFα?)
Secondary prophylaxis, duration life-long (biomarker ?)

11. Tailoring Immunosuppression ?

12. Tailoring immunosuppression ?
Pharmacokinetic interactions
Absorption, distribution, metabolism, elimination
e.g. inhibition or induction of CYP3A4 or P-glycoprotein
Pharmacodynamic interactions
Increasing or decreasing efficacy / toxicity of either drug
e.g. additive nephrotoxicity of CNI and aminoglycosides, amphotericin B, cidofovir, intravenous acyclovir, TMP/SMX
e.g. additive myelotoxicity of mycophenolate or azathioprine with ganciclovir, leflunomide

13. Tailoring immunosuppression for antimicrobial DDI
Macrolide antibiotics (Erythromycin > clarithomycin > azithromycin)
Inhibit CYP3A4,
Increased levels: cyclosporine A, tacrolimus, sirolimus, everolimus
Dose reduction, TDM
Antifungal azoles (Keto- >Posa- >Itra- >Vori-, >Fluconazole)
Inhibit CYP3A4
Increased levels cyclosporine A, tacrolimus, sirolimus, everolimus
Rifamycins
Induce CYP3A4
Decreased levels cyclosporine A, tacrolimus, sirolimus, everolimus
Dose increase, TDM
Antiretroviral HIV therapy
Boosted Pis increase CNIs, mTORi (dose reduction, TDM)
NNRTI decrease CNIs (dose increase, TDM)
Dolutegravir + NUCs, cave renal toxicity

14. Decreasing Immunosuppression

15. More than 50 genotypes with different organ tropism
Respiratory, gastrointestinal, renourinary, heart, disseminated
ADV replication frequent in the first 1 – 3 months posttransplant
Insufficient T-cell activity (quantity, quality)
Donor-Recipient sero-mismatch (Pediatric > Adult)
Depletion (Induction, rejection), lymphopenia

16. Decreasing Immunosuppression
Adjunct treatment
Cidofovir? Brincidofovir?
IVIG ?
Adoptive T-cell immunotherapy ?

17. Solid organ transplantation (SOT)
Incidence <1% to 25%; mortality 20%-80%
Hematopoietic stem cell transplantation (HSCT)
Incidence <1% to 13%; mortality 20%-80%
EBV-positive PTLD earlier (often <1 yr posttransplant)
EBV-negative PTLD later (often >1 yr posttransplant)

18. Epstein-Barr virus and immunosuppression
Preemptive
(EBV load)
Therapeutic
(PTLD)

19. Decreasing immunosuppression

20. Cytomegalovirus and Immunosuppression

23. Prospective studies on preemptive IS reduction
Hirsch HH, Babel N, Comoli P, Friman V, Ginevri F, Jardine A, Lautenschlager I, Legendre C, Midtvedt K, Munoz P, Randhawa P, Rinaldo CH, Wieszek A, ES GICH (2015) European Perspective on Human Polyomavirus Infection, Replication and Disease in Solid Organ Transplantation Clin Microb Infect 20 (s7): 72

24. Steps and Time to BK Viremia Clearance
Proven
PyVAN
(n=13)
Presumptive
(n=17)
Low BK viremia
(<4 log10)
(n=18)
P value
Clearance of BK viremia, n (%)
12 (92)
15 (88)
8 (100)
0.60
Months from first BK viremia
to BK clearance
8.8
(2.8–18.5)
4.6
(1.2–23.3)
2.9
(0.9–4.6)
0.001
Reduction of immunosuppression
to achieve BK clearance, n (%)
Step 1
2 (17)
8 (53)
Step 2
6 (50)
7 (47)
Step 3
4 (33) ‒
Schaub S, Hirsch HH, Dickenmann M, Steiger J, Mihatsch MJ, Hopfer H, Mayr M (2010) Reducing immunosuppression
preserves allograft function in presumptive and definitive polyomavirus-associated nephropathy Am J Transplant 10: 2615

25. BKPyV-specific T-cell Responses in Kidney Transplant Patients
Egli, Köhli, Dickenmann, Hirsch (2009) Transplantation 88: 1161

26. CNI inhibit CMV or BKPyV-specific T-cell responses in healthy blood donors
Egli, Köhli, Dickenmann, Hirsch (2009) Transplantation 88: 1161

27. Antiproliferative drugs do not inhibit signal-1 response on CMV or BKPyV-specific T-cell
Positive control
CMV-pp65
BKV-LT
Egli, Köhli, Dickenmann, Hirsch (2009) Transplantation 88: 1161

28. mTOR inhibitors reduce BKPyV events
EVR 3–8ng/mL
N=274
EVR 6–12ng/mL
N=278
MPA 1.44g
N=273
Rejection (%)
19.9
15.1
19.1
EVR, everolimus; MPA, mycophenolic acid;
Tedesco Silva et al (2010) Am J Transplant 10: 1401

29. mTOR inhibitors block BKPyV replication in vitro
Hirsch HH, Yakontova K, Lu M, Manzetti J (2015) BK Polyomavirus Replication in Renal Tubular Epithelial Cells is
inhibited by Sirolimus, but activated by Tacrolimus through a Pathway involving FKBP-12 Am J Transplant (in press)

30. Tacrolimus increases – Cyclosporine decreases BKPyV replication in primary human kidney cells
Hirsch HH, Yakontova K, Lu M, Manzetti J (2015) BK Polyomavirus Replication in Renal Tubular Epithelial Cells is
inhibited by Sirolimus, but activated by Tacrolimus through a Pathway involving FKBP-12 Am J Transplant (in press)

31. Summary
Immunosuppression is primarily targeting the known or perceived immunologic risk of “not accomodating” the transplant
Increasing immunosuppression
considered to mitigate microbe-intrinsic inflammation and IRIS
Tailoring immunosuppression
needed to manage drug-drug interactions
Decreasing immunosuppression
used when lacking specific/efficient antimicrobial therapies
Obvious for BKPyV, EBV, ADV, less obvious for CMV
Evidence is largely derived from observational cohorts, case series, expert opinion, but hardly ever from RCT
Not all immunosuppressive drugs are created equal

32. Thank you ! Swiss Transplant Cohort Study Nicolas Müller
Christian van Delden
Oriol Manuel
Pascal Meylan
Maja Weisser
...
Transplantation & Clinical Virology
Elvis Ajuh
Tobias Bethge
Vroni DelZenero
Michela Cioni
Andrea Glaser
Rainer Gosert
Celine Leboeuf
Julia Manzetti
Gunhild Unterstab
Marion Wernli
Fabian Weissbach
Past members Alexis Dumoulin
Adrian Egli
Georg Funk
Helen Hachemi
Nina Khanna
Min-Ji Lu
Sabrina Köhli
Ksenia Yakhontova
David Leuenberger
Nephrology USB
Jürg Steiger
Stefan Schaub
Michael Dickenmann
Michael Mayr
Pathology Basel
Michael Mihatsch
Helmut Hopfer
Infectious Diseases Basel
Manuel Battegay
Nina Khanna & Team
San Matteo Pavia, Italy
Patrizia Comoli
Medizin Hochschule Hannover
Lars Pape
University Hospital North Norway
Christine H. Rinaldo
Stian Henrikson
Garth Tylden
Universitäts-Kinderklinik Heidelberg
Burkhard Tönshoff
University of Helsinki
Irmeli Lautenschlager
Minna Koskenvuo
Istituto Gaslini Genua, Italy
Fabrizio Ginevri
UMTC Baltimore, Md, USA
Cinthia Drachenberg
Emilio Ramos
Universitätsklinikum Homburg
Martina Sester
Urban Sester