Markers of replication and immunologic responses in the

Markers of replication and immunologic responses in the prevention of viral

infections in transplant recipients

Hans H Hirsch

Transplantation & Clinical Virology

Department Biomedicine (Haus Petersplatz)

Infectious Diseases & Hospital Epidemiology

University Hospital Basel

Basel

Switzerland

Educational Workshop 008

ESGICH & ICHS

April 9, 2016 8:45 – 10:45

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Virus Pathogenicity in Immunocompromized Hosts

Insufficient immune control

– Naïve i.e. no memory

– Inherited i.e. impaired effector generation

– Depleted e.g. after anti-lymphocyte globulins, -pheresis

– Immunosuppressed e.g. rejection/GvHD prophylaxis, treatment

Donor – Recipient allo-constellation between virus-infected host

cells and available T-cells

– Virus tropism for allograft in solid organ transplantation (SOT)

– Donor T-cells in allogeneic HCT

Conducive environment: Activating virus replication

– Ischemia reperfusion, inflammation, danger signals

– Drugs, co-pathogens

Dynamics of replication

– Cytopathology

– ImmunopathologyHirsch HH ECCMID 2016 Amsterdam

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Virus

3

Virus Infection, Replication, and Disease

Time

Quantity

Limit of

Detection

IgMIgG Avidity

IgG

T-cells

Immune dysfunction

Infection

Disease

Recovery

1°Replication

2°Replication

Latent infection

Hirsch HH ECCMID 2016 Amsterdam

Reinfection

ReactivationESCMID eLibrary

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Qualitative and Quantitative Markers of

Virus - Host Balance

Virus

– Genome detection using NAT

– Quantitative, IU standards for load, plasma (not readily CSF, urine,

stools, respiratory fluids)

cave: persistence site, chromosomal integration?

Antibody

– IgG past exposure, avidity, memory response (T-cell surrogate ?)

– Quantitative, IU standards protection, seroreversion, D / R risk

cave: choice of antigen, low or negative in immunocompromised

– IgM recent antigen exposure, functional, low affinity

cave: choice of antigen, cross-reactive, routinely not quantitative?

T-cells

– Functional assays using cytokine production (IFN, TNF, IL-2,

CD107a)

– Virus antigens from cell culture, synthetic pepitopes

cave: technically demanding, standardization, commercial assays?Hirsch HH ECCMID 2016 Amsterdam

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Antiviral Strategy in Transplantation

Viral load

Viral disease

Time

Viral replication

Viral infection

Assay

sensitivity

?

Threshold

?

Dynamics?

Duration?Therapeutic

Pre-emptive

Prophylactic

Hirsch HH ECCMID 2016 AmsterdamModified slide; courtesy Per Ljungman, Stockholm,SWEESCMID eLibrary

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“ABC” of Virus Dynamics Posttransplant

Adenovirus (ADV)

BK polyomavirus (BKPyV)

Cytomegalovirus (CMV)

Diverse others

– Epstein-Barr-virus (EBV)

– Hepatitis B virus (HBV)

– Hepatitis C virus (HCV)

– Hepatitis D virus (HDV)

– Hepatitis E virus (HEV)

– Human Herpes virus 6 (HHV6)

– Human ParvoB19 virus (HPBV)

– JC polyomavirus (JCPyV)

– Varizella-Zoster virus (VZV)

Hirsch HH ECCMID 2016 AmsterdamESCMID eLibrary

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Fast Viral Dynamics Posttransplant

Funk G, Gosert R, Hirsch HH (2007) Viral Dynamics

in Transplant Patients Lancet Inf Dis 7: 460ESCMID eLibrary

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Adenovirus (ADV)



Diverse others

Hirsch HH ECCMID 2016 Amsterdamhttp://viralzone.expasy.org/viralzone/all_by_species/183.htmlESCMID eLibrary

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Human Adenovirus in Transplantation

HAdV replication 5% - 40%

– Asymptomatic in >80%

Symptomatic HAdV replication

– Fever

HAdV end-organ disease

– Gastroenteritis

– Tonsillitis, bronchitis, pneumonia

– Hepatitis

– Nephritis, cystitis

– Kerato-konjunctivitis

– Meningo-encephalitis

Disseminated HAdV disease

Children more than adults

AlloHCT > Liver > Lung >> Kidney


Florescu DDF, Hoffmann JA, & AST IDCOP (2013) Adenovirus in Solid Organ Transplantation 13: 206

Hirsch HH, Pergam S (2016) Human Adenovirus, Polyomavirus, and Parvovirus Infections in Patients Undergoing

Hematopoietic Stem Cell Transplantation (Chapter 93) in Thomas' Hematopoietic Cell Transplantation 5th Edition

(Eds SJ Forman, RS Negrin, H Antin, FR Appelbaum, p. 1090 - 1104ESCMID eLibrary

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HAdV-specific Immunity wanes with Older Age

Hirsch HH ECCMID 2016 AmsterdamSester M, Sester U, Alarcon Salvador S, Heine G, Lipfert S, Girndt M, Gärtner B, Köhler H (2012)

Age-Related Decrease in Adenovirus-Specific T Cell Responses Transplant Infect Dis 14: 555

HAdV-specific

response

SEB-control

response

IgG level

Reflects past exposure

Size of memory compartment

HAdV-spec T-cell compartment?

Cave:

Very young age <5 years

T-cell depletion

Immunosuppression

HLA-mismatchESCMID eLibrary

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HAdV in Kidney Transplantation

11

Watcharananan SP, Avery R, Ingsathit A, Malathum K, Chantratita W, Mavichak V, Chalermsanavakorn P, Jirasiritham S, Sumethkul V (2011) Adenovirus

disease after kidney transplantation: course of infection and outcome in relation to blood viral load and immune recovery Am J Transplant 11: 1308

Adult series (n=17; 47 yrs) from Thailand in 2007 – 2010 (4.8% of 349 KTX)

Dysuria, fever, hemorrhagic cystitis at median 5 weeks ptx (75% <3 months)

HAdV load urine >6 log10 cp/mL, in 63% blood 3 log10 cp/mL (nephritis,

enteritis)

Treatment reducing immunosuppression, i.v.IG, cidofovir, outcome favorable

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HAdV in Kidney Transplantation

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Nanmoku K, Ishikawa N, Kurosawa A, Shimizu T, Kimura T, Miki A, Sakuma Y, Yagisawa T.(2016) Clinical characteristics

and outcomes of adenovirus infection of the urinary tract after renal transplantation Transplant Infect Dis [Epub ahead of print]

Adult series (n=8; 39 yrs) from Japan in 2003 – 2013 (4.7% of 170 KTX)

Dysuria, macrohematuria, fever, HAdV in urine by PCR at 1 year posttx

Hemorrhagic cystitis, pyelo-nephritis; no BKPyV; de novo HAdV infection,

Treatment reducing immunosuppression, IVIG, ganciclovir i.v.

1 death due to bacterial sepsis, but overall outcome favorable

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Comprehensive Screening in Pediatric SOT

13

Kourí V, Correa C, Martínez PA, Sanchez L et al. (2014) Prospective, comprehensive, and effective viral monitoring

in Cuban children undergoing solid organ transplantation SpringerPlus doi: 10.1186/2193-1801-3-247.

Pediatric SOT (n=34; 10 yrs); liver 23; kidney 11 (85% DD) in Cuba 2009 –

2012

CMV R+ 90%, EBV R+90%, HSV R+70%

Prospective blood and urine screening for ADV, BKPyV, CMV, EBV, HSV,

HHV6, JCPyV, VZV weekly until 3months, then monthly

- Any virus positive in 65% LiTX and in 55% KTX

(CMV>BKV>>ADV>others)

Febrile syndromes in CMV positives (10%) and in 1 ADV positive (3%)

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HAdV Screening in pediatric allogeneic HCT

Single centre 2003-2012,

Hannover, GER

Prospective weekly HAdV

screening (n=238)

– Mostly type A31, C1, C2

HAdV load >1000 cp/mL in

15.5%

Limited direct mortality 0.84%

HAdV load independent risk

factor for poor survival

Cidofovir i.v. treatment possibly

stabilized/decreased HAdV load

by 1 log10, but did not clear


Mynarek M, Ganzenmueller T, Mueller-Heine A, Mielke C, Gonnermann A, Beier R, Sauer M, Eiz-Vesper B, Kohstall U, Sykora KW,

Heim A, Maecker-Kolhoff B (2014) Patient, virus, and treatment-related risk factors in pediatric adenovirus infection after stem cell

transplantation: results of a routine monitoring program Biol Blood Bone Marr Transpl 20: 250ESCMID eLibrary

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HAdV Load with Cidofovir vs. T-cell Reconstitution

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Lugthart G, Oomen MA, Jol-van der Zijde CM, Ball LM, Bresters D, Kollen WJ, Smiers FJ, Vermont CL, Bredius RG, Schilham MW, van Tol MJ, Lankester AC

(2013) The effect of cidofovir on adenovirus plasma DNA levels in stem cell transplantation recipients without T cell reconstitution Biol Blood Marrow Transpl 21:

293

Children (n=36; 4.5 yrs) of 321 pediatric alloHCT in Leiden NED, 2003 – 2012

Monitoring weekly: HAdV DNA, T-cells (CD3+, CD14-), NK-cells (CD56+, CD14-

)

HAdV clearance correlated with T-cells

Cidofovir at 1mg/kg 3x/wk only stabilzes loads

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Role of Brincidofovir (CMX001) for HAdV?

16

Florescu DF, Pergam SA, Neely MN, Qiu F, Johnston C, Way S, Sande J, Lewinsohn DA, Guzman-Cottrill JA, Graham ML, Papanicolaou

G, Kurtzberg J, Rigdon J, Painter W, Mommeja-Marin H, Lanier R, Anderson M, van der Horst C (2012) Safety and efficacy of CMX001 as

salvage therapy for severe adenovirus infections in immunocompromised patients Biol Blood Marrow Transplant 18: 731

Summary of multicenter experience (n=13; 8 children; 5 adults)

HCT (n=11) with GvHD III-IV in 45%; SOT (n=1); SCID (n=1);

Renal replacement therapy at start of oral BrinCDV in 5 (38%)

Survival advantage of responders

Cave: GI intolerability; toxicity, duration, resistance (CDV pretreatement failure?)

Phase II and III studies, iv formulation?

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Role of adoptive T-cells for HAdV?

17

Single center, (n=11;) multivirus-specific T-cells (mVST) at Baylor Texas, USA,

Rapid expansion (11d) using peptide mixes for ADV (hexon, penton), BKPyV

(Ltag, Vp1), CMV (IE1, pp65), EBV (LMP2, EBNA1), HHV6 (UL11, Ul14, UL90)

10-fold expansion, >30 SPU/200‘000; 48 lines;

Infusion prohylactic, preemptive, therapeutic 0.5 – 2x107 cells

Virological and clinical response in 94%, lasting several months, safe

Papadopoulou A, Gerdemann U, Katari UL, Tzannou I, Liu H, Martinez C, Leung K, Carrum G, Gee AP, Vera JF, Krance RA, Brenner MK, Rooney CM, Heslop HE,

Leen AM (2014) Activity of broad-spectrum T cells as treatment for AdV, EBV, CMV, BKV, and HHV6 infections after HSCT Sci Transl Med 6: 242ra83ESCMID eLibrary

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Adoptive T-cell Therapy for HAdV?

Single-center for HAdV (n=8); CMV (n=2), EBV (n=1) from Vienna

Expansion protocol 12d using pep-mix, IL15

Weekly surveillance identified 1 yr boy with AML w. fever, enteritis,

hepatitis d+34 with HAdV-C in stools, plasma, and CSF, GvHD IV


Geyeregger R, Freimüller C, Stemberger J, Artwohl M, Witt V, Lion T, Fischer G, Lawitschka A, Ritter J, Hummel M, Holter W,

Fritsch G, Matthes-Martin S (2014) First-in-man clinical results with good manufacturing practice (GMP)-compliant polypeptide-

expanded adenovirus-specific T cells after haploidentical hematopoietic stem cell transplantation Immunother 37: 245

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HAdV Nosocomial Outbreak in HCT

Dec 2011 – Mar 2012 in allogeneic HCT ward, Karolinska, SWE

9 patients with same HAdV A31 and diarrhea for 25d (4 – 94d)

Transmission via ward, outpatient and patient relative contact

7 pts with GvHD (grade2) confounding HAdV disease

5 pts with high viremia treated with cidofovir i.v.

1 pt with delayed HCT, no deaths

Hirsch HH ECCMID 2016 AmsterdamSwartling L, Allard A, Törlen J, Ljungman P, Mattsson J, Sparrelid E(2013) Prolonged outbreak of adenovirus

A31in allogeneic stem cell transplant recipients Transpl Infect Dis. 2015 Dec;17(6):785-794ESCMID eLibrary

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HAdV Nosocomial Outbreak in HCT

Hirsch HH ECCMID 2016 AmsterdamSwartling L, Allard A, Törlen J, Ljungman P, Mattsson J, Sparrelid E(2013) Prolonged outbreak of adenovirus

A31in allogeneic stem cell transplant recipients Transpl Infect Dis. 2015 Dec;17(6):785-794

Dec 2011 – Mar 2012 in allogeneic HCT ward, Karolinska, SWE

9 patients with same HAdV A31 and diarrhea for 25d (4 – 94d)

Transmission via ward, outpatient and patient relative contact

7 pts with GvHD (grade2) confounding HAdV disease

5 pts with high viremia treated with cidofovir i.v.

1 pt with postponed HCT, no deaths

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Adenovirus (ADV)

– Limited impact in SOT screening high-risk children?

– ADV-specific T-cells little explored, potential predictor of who benefits

from screening and preemptive strategy

– Significant pathogen in pediatric allogeneic HCT

– T-cell reconstitution important and clinically countered by GvHD

– Role for adoptive T-cells and for antivirals (CDV, BCDV, IVIG, others?)

– Environmental transmission (outbreaks)

– Guidelines ECIL-4 & AST IDCOP


Matthes-Martin S, Feuchtinger T, Shaw PJ, Engelhard D, Hirsch HH, Cordonnier C, Ljungman P (2012) European guidelines for diagnosis

and treatment of adenovirus infection in leukemia and stem cell transplantation: summary of ECIL-4 Transplant Infect Dis 14: 555

Florescu DF, Hoffmann JA & ASTIDCOP (2013) Adenovirus in Solid Organ Transplantation Am J Transplant 13 (suppl.4): 206ESCMID eLibrary

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Adenovirus (ADV)



Diverse others


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BKPyV is 1 of 13 human polyomaviruses (HPyV)

General population 80%-95% exposed (IgG positive)

– Transmission and primary infection undefined (oral,

respiratory?)

BKPyV persists in renourinary tract

– Asymptomatic shedding in 10% of healthy blood donors

BKPyV-associated nephropathy

– 1% - 15% of kidney transplant patients

– Rare in other immunocompromised patients incl. SOT, HCT

BKPyV-associated hemorrhagic cystitis

– 5% - 20% of allogeneic HSCT recipients

– Rare in other immunocompromised patients incl. SOT, HCT

23

Hirsch HH (2016) Human Polyoma and Papillomaviruses in

Transplant Infections (4th Edition; Editors Bowden P, Snydman D, Ljungman P) in press

BK Polyomavirus (BKPyV)

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Age and BKPyV Immunity in Healthy Donors

Schmidt T, Adam C, Hirsch HH, Janssen M, Wolf M, Kardas P, Ahlenstiel T, Pape L, Rohrer T, Flieser, Sester M, Sester U (2014) BK Polyoma

Virus-specific cellular immune responses are age-dependent and strongly correlate with phases of virus replication Am J Transplant 14: 1334

Antibody level

CD4 T-cells

BKPyV-specific CD4+ T-cell responses > CD8+ T-cells in blood

BKPyV-specific IgG and CD4+ T-cell activity decreases with age decade

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BK viremia and PyVAN in Kidney Transplantation

Non-modifiable risk factors

Older recipients

Male recipient

Donor BK antibody high or pos /

Recipient BK antibody low or

neg

Donor shedding

HLA mismatches

Acute rejection, and steroid

therapy

ABO-incompatibility

Pediatric recipient

Re-transplantation

Modifiable risk factors

Induction

Maintenance immunosuppression

– Tacrolimus - mycophenolate

Stents

1. Schold et al.Transpl Internat 2009

2. Dharnidharka et al. Transplantation 2009

3. Hirsch et al. N Engl J Med 2002

4. Schmitt et al. J Clin Virol 2014; Verghese et al. Transplant 2015

5. Bohl et al. Am J Transplant 2005

6. Ramos et al. J Am Soc Nephrol 2002

7. Theodoropoulos et al. Am J Transplant 2013

8. Hirsch et al. Am J Transplant 2013

9. Sood et al. Transplantation 2013

10. Sharif et al. Clin J Am Soc Nephrol 2012

11. Ginevri et al. Am J Transplant 2007

12. Hirsch & Ramos Am J Transplant 2005

13. Dharnidharka et al. Am J Transplant 2010

14. Brennan et al. Am J Transplant 2005

15. Hirsch et al. Am J Transplant 2016

Common surrogate to all these factors

BK virema 3

✔

✔

✔

✔

✔

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High-level BK viruria and viremia precede proven disease

Hirsch HH, Knowles W, Dickenmann M, Passweg J, Klimkait T, Mihatsch MJ, Steiger J (2002) Prospective Study of

Polyomavirus type BK Replication and Nephropathy in Renal Transplant Recipients N Engl J Med 2002; 347: 488ESCMID eLibrary

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BKPyV Plasma Viral Loads

Renal allograft nephrectomy associated with rapid plasma BKPyV

load decline (R0 < 0.2) and t1/2 of <2 h

Steady-state R0 = 1, represents substantial cytopathology

Funk G, Gosert R, Hirsch HH (2007) Viral Dynamics

in Transplant Patients Lancet Inf Dis 7: 460ESCMID eLibrary

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BK Load Dynamics after reduced Immunosuppression

Funk GA, Steiger J, Hirsch HH (2006) Rapid dynamics of polyomavirus

type BK in renal transplant recipients J Infect Dis 193:80

Funk, G.A., Gosert, R., Comoli, P., Ginevri, F., Hirsch, H.H (2008) Polyomavirus BK replication dynamics in vivo

and in silico to predict cytopathology and viral clearance in kidney transplants Am J Transpl 8: 2368

Changing and decreasing maintenance immunosuppression results

in declining viral loads with average efficacy R0 of 0.8

Plasma BKPyV 100’000 cp/mL 7 weeks for clearance

Plasma BKPyV 10’000’000 cp/mL 13 weeks for clearance

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Proven

PyVAN

(n=13)

Presumptive

PyVAN

(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 clearance8.8

(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) 8 (100) 0.001

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

Steps and Time to Clearance of BK Viremia

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Rising

viremia

Clearin

g

viremia

Rising

viremia

Clearin

g

viremia

Non-structural proteins

LTag

Structural proteins

Vp1

Binggeli S, Egli A, Schaub S, Binet I, Mayr M, Steiger J, Hirsch HH

(2007) Polyomavirus BK-Specific Cellular Immune Response to VP1 and

Large T-Antigen in Kidney Transplant Recipients Am J Transplant 7:

1131

Cioni M, Leboeuf C, Comoli P, Ginevri F, Hirsch HH (2016)

Characterization of Immuno-dominant BK Polyomavirus 9mer

Epitope T- Cell Responses Am J Transplant 16: 1193

CD107a

HL

A-B

*07

02 9

m1

27

Str

ep

tam

er

BKPyV 9m127 Other BKPyV 9m

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Adenovirus (ADV)


– Persistent challenge in kidney and allogeneic HCT

– Blood viral loads and dynamics reflect degree of organ involvement

– Surveillance indicated in kidney transplants, HCT ?

– BKPyV-specific T-cells need research and assays

– Antiviral still needed (BCDV in HCT?)

– Guidelines ECIL-6, AST-IDCOP, ESGICH

Cesaro S, Dalianis T, Rinaldo CH, Koskenvuo M, Einsele H, Hirsch HH (2016) ECIL 6 - Guidelines for the Prevention, Diagnosis, and Treatment of BK

Polyomavirus Disease in Stem Cell Transplant Patients (in prep) https://www.ebmt.org/Contents/Resources/Library/ECIL/Pages/ECIL.aspx

Hirsch HH, Randhawa P & ASTIDCOP (2013) BK polyomavirus in Solid Organ Transplantation Am J Transplant 13 (suppl 4): 179

Hirsch HH, Babel N, Comoli P, Friman V, Ginevri F, Jardine A, Lautenschlager I, Legendre C, Midtvedt K, Muñoz P, Randhawa P, Rinaldo CH, Wieszek A

(2014) European perspective on human polyomavirus infection, replication and disease in solid organ transplantation Clin Microbiol Infect 20 (Suppl 7): 74ESCMID eLibrary

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Adenovirus (ADV)



Diverse others

– Epstein-Barr-virus (EBV)

– Hepatitis B virus (HBV)

– Varizella-Zoster virus (VZV)


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CMV Serostatus predicts graft and patient survival

Opelz et al. (2004) Am J Transplant 13

Boeckh & Nichols (2004) Blood 103

Kidney transplantation Allogeneic HSCT

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CMV replication dynamics and host immunity

Emery V, Hassan-Walker Burroughs AK, Griffiths PD (2002) Human cytomegalovirus (HCMV) replication

dynamics in HCMV-naive and -experienced immunocompromised hosts J Infect Dis 185: 1723ESCMID eLibrary

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CMV Replication Dynamics linked to Failure?

Tx patients Viremiaa Antiviral tx CMV syndromeEnd-organ

disease

Liver (n = 321) 136 (42%) 63 (20%) 18 (5.6%) 5 (1.6%)

Kidney (n = 368) 158 (43%) 79 (22%) 18 (4.9%) 3 (0.8%)

Total (n = 689) 294 (43%) 142 (21%) 36 (5.2%) 8 (1.2%)

P < 0.0001 (log-rank test)

Atabani SF et al.(2012) Am J Transplant 12:2457–64

7.2%

5.7%

6.4%

Total

50%

10%

100%

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High CMV-specific T-cells Predict Immune Control

Above threshold:

Positive predictive value = protected

Above threshold:

Negative predictive value = at risk

If immunosuppression is not changed

Egli A, Binet I, Binggeli S, Jaeger C, Dumoulin A, Schaub S, Steiger J, Sester U, Sester M, Hirsch HH (2008)

Cytomegalovirus-specific T-cell responses and viral replication in kidney transplant recipients J Transl Med 6: 29 Hirsch HH ECCMID 2016 Amsterdam

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Multicentre SOT D+/R- patients (n=127)

Synthetic CMV epitopes (n=22) for CD8+ T-cells (pos IFN- >0.1 IU/mL)

CMV-specific T-cells Response: Risk or Protection?

Adapted from Manuel O et al. (2013) Assessment of Cytomegalovirus-Specific Cell-Mediated Immunity for the Prediction

of Cytomegalovirus Disease in High-Risk Solid-Organ Transplant Recipients: A Multicenter Cohort Study Clin Infect Dis 56: 817

Kaplan-Meier curves of the incidence of cytomegalovirus (CMV) disease according to the result of an ELISA CMV test. A,

Positive vs negative vs indeterminate result of the assay (long-rank test, P<.001. B, Positive vs nonreactive result of the

assay (log-rank test, P=.024). Abbreviation: CMV, cytomegalovirus.


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Single-centre adult allogeneic HCT R+ patients (n=63)

CMV IE-1 and pp65 15mer IFN- ELISPOT (T-SPOT.CMV test)

preHCT, d+30; d+60; d+100

75,000 – 250,000 PBMCs per well; correction for background and cell count

CMV-specific T-cells Predict Risk or Protection?

IE-1 <50 SFU per 250,000

or

pp65 <100 SFU per 250,000

Nesher et al. (2016) Utility of the Enzyme-Linked Immunospot Interferon-γ– Release Assay to Predict the

Risk of Cytomegalovirus Infection in Hematopoietic Cell Transplant Recipients J Infect Dis Feb 11. pii: jiw064. [Epub ahead of print] Hirsch HH ECCMID 2016 Amsterdam

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Adenovirus (ADV)



– Persistent challenge in all SOT and allogeneic HCT

– Blood viral loads and dynamics reflect degree of organ involvement

– Effective antiviral drugs available for prophylactic and preemptive therapy

– Strategy failure in 1% - 10% of patients

– New antivirals in phase III trials (BCDV, Letermovir)

– Viral load dynamics and T-cell responses ready for clinical application

– Guidelines ECIL-4, TTS, ESGICH


Kotton CKumar D, Caliendo AM, Asberg A, Chou S, Danziger-Isakov L, Humar A & TTS

consenus group (2013) Updated international consensus guidelines on the management of

cytomegalovirus in solid-organ transplantation Transplantation 98: 333

Lumbreras C, Manuel O, Len O, ten Berge IJ, Sgarabotto D, Hirsch HH (2014)

Cytomegalovirus infection in solid organ transplant recipients Clin Microbiol Infect (Suppl

7):19

Ljungman P, de la Camara R, Einsele H, Engelhard D, Reusser P, Styczynski J, Ward K

(2011) Updated guidelines for CMV and HHV6

https://www.ebmt.org/Contents/Resources/Library/ECIL/Pages/ECIL.aspx

Sester M, Leboeuf C, Schmidt T, Hirsch HH (2016) The “ABC” of virus-specific

T-cell immunity in solid organ transplantation Am J Transplant 16 : 817ESCMID eLibrary

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Thank You!

Transplantation & Clinical Virology

Elvis Ajuh

Francesca Compagno

Vroni DelZenero

Michela Cioni

Andrea Glaser

Rainer Gosert

Celine Leboeuf

Julia Manzetti

Gunhild Unterstab

Marion Wernli

Fabian Weissbach

Nephrology USB

Jürg Steiger

Stefan Schaub

Michael Dickenmann

Kim Ming Jeong

Pathology USB

Michael Mihatsch

Helmut Hopfer

Istituto Gaslini Genua, Italy

Fabrizio Ginevri

University Hospital North Norway

Christine H. Rinaldo

UMTC Baltimore, Md, USA

Cinthia Drachenberg

Emilio Ramos

San Matteo Pavia, Italy

Patrizia Comoli

Swiss Transplant Cohort Study

Basel, Bern, Geneva,

Lausanne,

Zurich,

St Gallen

University of Helsinki

Irmeli Lautenschlager

Ilkka Helanterä

Minna Koskenvuo

DBM

Giulio Spagnoli

Paul Zaja

Pascal Lorentz

Universitätsklinikum Homburg

Martina Sester

Urban Sester

Medizinische Hochschlule Hannover

Lars Pape

Jean Tinguely

Hematology USB

Jakob Passweg

Jörg Halter

Dominik Heim

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Markers of replication and immunologic responses in the