LONDON S S GLOBAL UNIVERSITY. Post-transplant transplant infection: are we better prepared to face the enemy?

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1 LONDON S S GLOBAL UNIVERSITY Post-transplant transplant infection: are we better prepared to face the enemy?

2 Overview of presentation Briefly summarise viruses important after transplantation Short term and long term impact of post transplant viral infections Review current approaches to management Pre-emptive Prophylaxis Treatment Review the future of management and novel approaches

3 Viruses that can be considered Herpesviruses HSV1/2 VZV CMV EBV HHV-6/HHV-7 HHV-8 BK virus Adenoviruses influenza HIV HBV/HCV HPV West Nile

4 Viruses to be considered Herpesviruses HSV1/2 VZV CMV EBV HHV-6/HHV-7 HHV-8 BK virus Adenoviruses Influenza HIV HBV/HCV HPV West Nile

5 Immunocompetent Host: Persistent/latent virus in harmony with its host VIRUS IMMUNE SYSTEM

6 Immunocompromised host: Persistent/latent viruses has the upper hand VIRUS IMMUNE SYSTEM

7 Immunocompromised host: Subtle immune improvement can help control Persistent/latent viruses VIRUS IMMUNE SYSTEM

8 CMV Infection

9 HCMV replication in the human host Betaherpesvirus Latent in monocytes and BM progenitor cells Seroprevalence about 60% In active replication - highly dynamic Doubling time ~ 1 day Peak viral load correlates with HCMV disease after transplant In addition to peak viral loads, lower levels of persistent replication are also important for pathogenesis Don t t forget the immune system Emery VC et al (1999) J.Exp.Med. 190:177-82; Emery and Griffiths (2000) PNAS97(14): ; Regoes R Emery VC (2006) Proc. Biol. Sci.. 273:1961-7

10 Quality of the Immune response In some, but not all studies, failure to control HCMV replication n associated with sub-optimal responses in both CD4 and CD8 compartments 1,2,3 Protection against HCMV disease after heart/heart-lung transplantation associated with a CD8 IE-1 1 responses 4 Protection against HCMV replication after SCT associated with expansion of IE1 specific CD8 T-cellsT 5 Early CD4 HCMV T-cell T responses after heart transplantation protect against long term indirect effects 6 The proportion of tet+ + CD8 T-cells T producing IFNγ is an important factor in controlling high level replication 7 and progression to HCMV disease 8 Polyfunctional CD8 T-cells T against HCMV predictive of viral replication 2 Level of CD45Ra expression on HCMV CD8 T-cells T associated with duration of replication 10 1) Gerna G et al. Am J Transplant. 2006; 6: ) Nebbia G et al (2008) Am J Transplant e-pub. e 3) La Rosa et al (2007) JID 195: ) Bunde et al (2005), J.Exp.Med 201: ) Sacre et al (2008) J Virol 82: ) Tu W et al (2006) Circulation 114: ) Mattes et al (2008) Am J Transplant 8: ) Crough T et al (2007) J Virol 81: ) Cantisan et al (2010) Clin Immunol 137:

11 Effects of HCMV post solid organ transplantation Direct effects Prolonged fever Leukopenia Pneumonitis Hepatitis GI disease Retinitis myocarditis Indirect effects Acute rejection Long term graft function Atherosclerosis (CAD) Vascular disease Post transplant diabetes Bronchiolitis obliterans Opportunistic bacterial, fungal infections

12 HCMV: The Indirect effects High viral loads may not be necessary Risk factors identified include: HCMV seropositivity Low level HCMV replication (asymptomatic viremia) High level HCMV replication and HCMV disease

13 New onset diabetes mellitus in patients with asymptomatic HCMV viremia Patients with PTDM (%) /61 26% Asymptomatic HCMV infection p = /63 6% No HCMV infection Adapted from J Hjelmesæth et al. Diabetologia 2004; 47:

14 The Impact of HCMV Infection and Disease on Rejection Episodes in Renal Allograft Recipients Analysis of 477 consecutive renal allograft recipients HCMV infection and disease examined prospectively for 3 months No HCMV prophylaxis was given, and HCMV disease treated Acute rejection associated with HCMV infection (odds ratio = 1.6; p=0.02) HCMV disease (odds ratio = 2.5; p=0.01) Sagedal S. et al. Am J Transplant 2002; 2:

15 Extensive presence of HCMV DNA in Renal Biopsies Extensive infection 60% biopsies HCMV DNA positive (50% patients) ~ 80% of biopsy +ve + patients developed HCMV DNAemia HCMV DNA present in patients with and without concurrent acute rejection Some patients with HCMV in biopsy developed acute rejection subsequently Patients who developed HCMV disease had positive biopsy for HCMV Li T, Emery VC et al (2009) J Med Virol 82:85-93

16 Creatinine levels are elevated in patients with HCMV DNA in biopsy * Months post transplant No HCMV DNA HCMV DNA POS * P = 0.04 Li T, Emery VC et al (2009) J Med Virol 82:85-93

17 HCMV and long term kidney graft function In situ detection of HCMV in renal biopsies Patients with persistent intragraft HCMV had: reduced graft survival (OR=3.5; p=0.03) reduced creatinine clearance at: 1 year (OR=5.1; p=0.01) and 2 years (OR=4.3;p=0.03) post transplant In multivariable analysis HCMV was the only risk factor for lower creatinine clearance at 2 years (OR=4.9;p=0.02) Helanterä I et al.(2006) Transpl. Int. 19:

18 Therapeutic approaches to control HCMV replication Prophylaxis Universal or targeted Eliminates direct and indirect effects of HCMV Subset of patients remain at risk of late CMV infection/disease after cessation of prophylaxis Pre-emptive therapy Initiated based on virologic markers Minimises drug exposure Patients may require more than one treatment May not eliminate the indirect effects of HCMV Forum debate (2001) Rev. Med. Virol. 11:73-86 Small LN et al (2006) Clin.. Infect. Dis.43,

19 QuickTime and a decompressor are needed to see this picture. QuickTime and a decompressor are needed to see this picture. QuickTime and a decompressor are needed to see this picture. QuickTime and a decompressor are needed to see this picture. QuickTime and a decompressor are needed to see this picture. QuickTime and a decompressor are needed to see this picture. QuickTime and a decompressor are needed to see this picture. QuickTime and a decompressor are needed to see this picture. HCMV pathogenesis: a model day 0 Donor organ TNF-α, inflammation Days 7-30 Other organs HCMV Disease Days 3-7 TNF-α High level DNAemia Days Days 7-20 weeks Li, Emery et al (2009) J Med Virol 82:85-93 Acute graft dysfunction Months/years Long-term graft dysfunction

20 QuickTime and a decompressor are needed to see this picture. QuickTime and a decompressor are needed to see this picture. QuickTime and a decompressor are needed to see this picture. QuickTime and a decompressor are needed to see this picture. QuickTime and a decompressor are needed to see this picture. QuickTime and a decompressor are needed to see this picture. QuickTime and a decompressor are needed to see this picture. QuickTime and a decompressor are needed to see this picture. HCMV pathogenesis: Pre-emptive emptive therapy day 0 Donor organ TNF-α, inflammation Days 7-30 Other organs HCMV Disease Days 3-7 TNF-α High level DNAemia Days Days 7-20 weeks Acute graft dysfunction Months/years Long-term graft dysfunction

21 QuickTime and a decompressor are needed to see this picture. QuickTime and a decompressor are needed to see this picture. QuickTime and a decompressor are needed to see this picture. QuickTime and a decompressor are needed to see this picture. QuickTime and a decompressor are needed to see this picture. QuickTime and a decompressor are needed to see this picture. QuickTime and a decompressor are needed to see this picture. QuickTime and a decompressor are needed to see this picture. HCMV pathogenesis: prophylaxis day 0 Donor organ TNF-α, inflammation Days 7-30 Other organs HCMV Disease Days 3-7 TNF-α High level DNAemia Days Days 7-20 weeks Acute graft dysfunction Months/years Long-term graft dysfunction

22 Guidelines for the management of HCMV following transplantation National guidelines (out of date) UK guidelines (2002) Australian and American guidelines (2004) Canadian guidelines (2005) KDIGO guidelines (2009) TTS consensus guidelines published in 2010 * British Transplantation Society Guidelines. Published by the British Transplantation Society, The CARI Guidelines. Nephrology 2004; 9 (Issue s3):s Am J Transplant 2004; 4 (Suppl.10):51-8. Preiksaitis JK et al. Am J Transplant 2005; 5: *Cotton K et al Transplantation 89:779-95

23 Prophylaxis and preemptive strategies both reduce the development of CMV disease Odds ratio (95% CI) Overall effect of preemptive trials Overall effect of universal prophylaxis trials Favors Treatment Favors Control Bacterial and fungal infections and death statistically reduced by universal prophylaxis, but not by preemptive therapy Kalil AC et al. Ann Intern Med 2005; 143:

24 HCMV load cut-offs to initiate pre-emptive emptive therapy In the absence of a universal standard difficult to compare between laboratories At our centre we use 3000 ge/ml blood Other studies have used antigenemia > 50 +ve + cells/400,000 leukocytes in renal patients 1 Equivalent to ~ 8,600 ge/ml blood RCT of DNAemia (>300,000 ge/ml) vs Agemia (>100 +ve + cells) in SOT patients 2 reported that: 23/99 patients treated in the DNAemia arm compared to 42/101 patients in the Antigenemia arm (p=0.01) 4 cases of disease Universal HCMV DNA standard required 1.Kim et al (2007) Transplant Proc 39, ; 2.Gerna G (2007) Antiviral Therapy 12:63-72

25 Prospective randomised trial comparing preemptive therapy with prophylaxis Study aims: To determine if CMV prophylaxis with oral ganciclovir is superior compared to IV preemptive therapy Oral prophylaxis prevents graft exposure to CMV Effects of both treatments on long-term graft survival Kliem V et al. Am J Transplant 2008; 8:

26 Prophylaxis prolongs time to first CMV infection Freedom from CMV Infection (%) Prophylaxis period Oral prophylaxis IV preemptive therapy p value (Log rank test) < Time after transplantation (days) Kliem V et al. Am J Transplant 2008; 8:

27 HCMV prophylaxis is associated with improved long-term graft survival Freedom from graft loss (uncensored for death; %) Oral prophylaxis IV preemptive therapy p value (Log rank test) = Time after transplantation (years) Kliem V et al. Am J Transplant 2008; 8:

28 Treatment of HCMV Disease - What do current guidelines say? Intravenous ganciclovir (5mg/kg bid) or valganciclovir (900mg bid) Severe life threatening disease should be treated with iv GCV Treatment should continue until eradication of viraemia and secondary prophylaxis may be considered Both formulations require dose adjustment for renal function Cotton K et al Transplantation 89:

29 Treatment of HCMV disease: VICTOR study Oral valganciclovir Intravenous ganciclovir Cumulative probability of persistant viraemia DNAemia Cumulative probability of persistant active CMV disease Disease Days of observation Days of observation Asberg et al. Am J Transplant 2007;7:

30 Long term outcomes from VICTOR In the VICTOR study recurrence of clinical and virological endpoints was 15.1% and 30% Major risk for recurrence was failure to eradicate HCMV plasma DNA by day 21 Clinical endpoints OR 3.4; p=0.012 Virologic endpoint OR 5.6; p< GCV resistance developed in 8 patients No differences in long term outcomes between treatment arms Asberg A et al (2009) Am J Transplant 9;

31 Failure to Eradicate at D21 Predicts Recurrence cumulative probability of persistance in remission success P=0.004 Odds ratio: 6.23 p=0.008 failure days of observation Asberg et al Am J Transplant. 9: , 1213, 2009

32 Optimal duration of prophylaxis - What do current guidelines say? 3 months - 6 months prophylaxis should be used in D+R- patients Decision based on immunosuppression and type of transplant Dosing should be optimal Minimum of 6 months for lung and small intestine receipients Preiksaitis JK et al. (2005) Am J Transplant 5: Cotton K et al (2010) Transplantation 89:

33 Study Design - IMPACT (D+R- Renal transplant patients) Humar A et al (2010) Am J Transplant 10:

34 Confirmed CMV Disease Humar A et al (2010) Am J Transplant 10:

35 Incidence of Viremia Humar A et al (2010) Am J Transplant 10:

36 Two loci involved UL97 UL54 GCV resistance Relatively small number of mutations in UL97 associated with GCV r M460, L595, A594, H520, E596, C603, C607 Resistance at UL54 locus more complex but usually occurs after UL97 mutations in GCV resistance Frequency of GCV r relatively low in transplant setting but promoted by: Sub-optimal therapy Very long term therapy especially in patients with ongoing DNAemia Suspect GCV r if persistent high HCMV loads or progression of clinical disease 1 Cotton K et al (2010). Transplantation 89:779-95

37 Are we better prepared for CMV? Not bad! Better understanding of pathogenesis and immune control Prophylaxis in high risk patients Pre-emptive emptive therapy Availability of oral valganciclovir Drug resistance not a major problem Encouraging data from vaccine studies Remaining issues Identifying patients at high risk of infection and its long term consequence Management of post prophylaxis infection/disease Very few new drugs on the horizon (maribavir failed phase 3 studies)

38 BK Viral Infections

39 BK Virus Ubiquitous virus member of the polyomaviruses Natural virus infection occurs in childhood Latent in kidney epithelium Serological prevalence 90% and stable since virus discovery in the 1970s Immuncompetent adults intermittent reactivation 5-10% at viral loads about 3,000 ge/ml urine Active infection more common in immunocompromised 20-60% with much higher viral loads Incidence of BKV nephropathy (PVAN) following transplantation 2-8% 45% of biopsy positive patients will loose graft Mutations in the non-coding control region 1 associated with: 20-fold increase in plasma viral load More extensive inflammation Higher replication capacity 1. Gosert et al (2008) J Exp Med 205:841-52

40 Immune control of BKV BKV neutralising antibodies target the VP1 capsid protein Accelerate BKV clearance during primary infection Protect agianst BK viraemia weak role in resolving disease In patients with haemorrhagic cystitis, T-cell proliferation occurs and may drive pathology In the case of PVAN evidence supports a key role for CD8 T- cells in resolving infection/disease CD8 T-cells target a range of proteins including large T, small t and VP1,2,3 Frequency of IFN gamma CD8 T-cells is relatively low for both VP1 and large T (~0.3%) Threshold levels of BKV large T-antigen cells may be important in protection against BKV replication Reviewed by Comoli et al (2008) Curr Opinion in Org Transplant 13:569-74

41 Diagnosis of BK virus and PVAN Primary screening usually by urine cytology (every 3 months) Presence of decoy cells triggers more frequent surveillance and/or biopsy Biopsy provides a picture of PVAN Various patterns can be observed and staining with anti SV40 LT Ag antibodies definitive Screening with real time PCR of urine and blood has become more common Very high loads in urine BK viraemia is associated with PVAN Key message is that early diagnosis and pre-emptive emptive therapy is key to minimise graft loss

42 Acute rejection vs PVAN Tubulitis with Lymphocytic infiltrates QuickTime and a decompressor are needed to see this picture. Nuclear staining with antibodies to SV40 LT-Ag Taken from Ramos et al (2009) Transplantation 87:621-30

43 Biopsy sampling and PVAN Ab SV40 LT Ab SV40 LT QuickTime and a decompressor are needed to see this picture. Ab SV40 LT Taken from Ramos et al (2009) Transplantation 87:621-30

44 Efficacy of quantitative BKV monitoring BK load (real time PCR) in: Urine,plasma, kidney biopsies Patients with asymptomatic viruria, BKVAN, and resolved BKVAN BKVAN associated with: BK viremia > 5 x 10 3 ge/ml BK viruria > 1 x 10 7 ge/ml Resolved BKVAN associated with lower viral loads in urine Randhawa et al (2004) J Clin Micro 42;

45 Urine BKV loads higher in patients with BKV plasma viraemia QuickTime and a decompressor are needed to see this picture. Funk et al (2008) Am J Transplant 8:

46 Natural History of BKV/PVAN QuickTime and a decompressor are needed to see this picture. Taken from Ramos et al (2009) Transplantation 87:621-30

47 Incidence and treatment of PVAN Two large series published OPTN analysis included 48,292 RTx patients from National SRTR database (also derived from the OPTN included 48,838 patients 2 Treated BKV infection rising in recent years (OR 1.69) Kaplan Meier estimates for treated BK virus were: Between % at 6 months Between % 2.8% at 12 months 6.6% at 5 years Graft survival estimates at 6 months were: 90% in patients with no BKV 79% in patients with BKV 1. Dharnidharka et al (2009) 87: ; 2. Schold et al (2009) Transplant International 22:626-34

48 Patient and graft survival with or without BKV QuickTime and a decompressor are needed to see this picture. Schold et al (2009) Transplant International 22:626-34

49 Risk Factors for PVAN A number of risk factors identified although one of the most important is the quantity of immunosppression Factors increasing risk include: MMF and Tacrolimus based regimens Induction therapy especially with thymoglobulin Male gender Acute rejection episode in 1st 6 months HLA mismatch Donor age and peadiatric recipients

50 Management of PVAN Mainstay has been reduction in immunosuppresion When and by how much? Reconstitution of the immune response against BKV takes 4-12 weeks so start early Reduced immunosuppression can lead to AR but if reduction occurs early then AR may be 10-15% Several protocols (Maryland): Step 1: reduce MMF by 50% after diagnosis Step 2: 50% decrease in target trough levels of tacrolimus if decpy cells persist Step 3: eliminate MMF at 6 months if decoy cells persist Maintenance immunosuppression with low dose tacrolimus and prednisone (not exceeding mg/week)

51 Antiviral therapy for PVAN No agents approved by the FDA A range of agents used including: Cidofovir,, immunoglobulin,leflunomide leflunomide No prospective trials undertaken and all reports also reduce immunosuppression Very few studies combine high quality virological, clinical and immune monitoring post intervention Doses of cidofovir and leflunomide required to inhibit BKV replication in vitro are much higher than those achieved in vivo using current dosing regimens No new agents in the pipeline

52 Case 1 42 year old female with prior history of familial pancreatitis, diabetes mellitus Underwent partial pancreatectomy and splenectomy at age 23/25 years Full splenectomy at age 37 Kidney-pancreas transplant 2007 Good course for 1st year on Tacrolimus and MMF Day 405 admitted with MRSA and increasing creatinine levels Renal ultrasound normal

53 Next steps? A) perform renal biopsy B) analyse urine for BK virus inclusions C) perform BKV PCR on blood D) all of the above

54 Case 1: progress Renal biopsy shows features of BKV infection although no chronic damage Urine viral inclusions present BKV PCR of blood shows a viral load of 26,000 genomes/ml

55 Patient Management decision A) BKV nephropathy stop MMF B) BKV nephropathy so initiate cidofovir therapy C) BKV nephropathy so stop MMF and initiate cidofovir therapy D) wait and see if creatinine levels stabilise

56 Case 1: progress MMF stopped Creatinine levels stabilise for 1 month Day 441 admitted for rising creatinine Biopsy confirms severe BKV infection, No rejection BKV DNA in blood 110,000 ge/ml

57 Case 1: progress Placed on cidofovir BKV levels reduce on cidofovir over the next 4 weeks At day 500 admitted with high creatinine Tacrolimus reduced to 2mg bd At day 530 rising creatinine but BKV DNA level in blood 50 ge/ml Cidofovir re-started 15mg iv fortnightly BKV load in blood at day 565 at 30,000 ge/ml Re-admitted at day 572 with lethargy and rising creatinine Renal biopsy shows persistent BKV infection but no rejection

58 Case 1 -options A) Continue cidofovir therapy B) Stop cidofovir and Tacrolimus and initiate leflunomide therapy C) Remove kidney

59 Are we better prepared for BKV? Not really! Reduction in immunosuppression is first line approach Earlier is better Lack of data on efficacy of antivirals No new drugs in the pipeline

60 EBV Infection

61 EBV Infection High seroprevalence,, member of the gammaherpesvirus family 173kB genome EBV can infect B and T lymphocytes, squamous epithelial cells of the oro- and nasopharynx,, glandular epithelial cells and SMCs and DCs EBV linked to a range of benign and neoplastic human diseases: NPC and PTLD (>95% EBV) Hodgkins lymphoma and NHL (5-95% EBV) Oral hairy leukoplakia (>95%) EBV specific CD8 T-cells T control EBV transformed cells during primary infection Virus undergoes frequent reactivation in the immunocompetent host without causing pathology Reductions in CD8 T-cell T control results in high levels of EBV replication including infection of bystander cells and leads to pathological consequences

62 EBV Infection after transplantation Active EBV infection relatively common Closely linked to degree of immunosuppression Subset of patients at risk of developing pathological consequences of EBV in particular PTLD Viral replication can be reduced by antiviral prophylaxis with ACV,VACV,GCV and VGCV Antiviral agents have no effect against latently infected or transformed B-cellsB

63 Incidence of EBV infection after transplantation Transplant type * Liver (n=121) Heart (n=45) Renal (n=92) Overall (n=263) EBV DNAemia ** 72 (59.5%) 22 (48.9%) 52 (56.5%) 148 (56.3%) *Patients received oral GCV or valganciclovir prophylaxis ** Baseline incidence of EBV DNAemia was 16.8% Razonable R et al (2005) J. Infect. Dis. 192,

64 Post transplant lymphoproliferative disease (PTLD) Common tumour in transplant patients Associated with latency type III EBNAs 1,2,3A,3B,3C, LP, LMP1,LMP2 and EBERs Incidence varies between different transplant groups and greatest in peadiatric transplantation >90% tumours are associated with EBV Clinically and morphologically diverse Highest incidence in the first years Relapses common and mortality high (>50%)

65 Incidence of PTLD Type of Transplant Renal Liver Heart Heart-lung Lung Small bowel Incidence (%) Adult Children % NA Reviewed by Taylor et al (2005) Critical Reviews in Oncology/Haematology 56,

66 Risk factors for PTLD development Degree of immunosuppression (IS) Type of Transplant Donor-recipient HLA-mismatch (liver, heart &/or lung) Repeated episodes of rejection Re-transplantation Bone marrow/hsct T cell depletion (Incidence up to 24%) Unrelated or HLA-mismatched donors Use of ATG or anti-cd3 monoclonal Ab (OKT3)

67 Risk factors for PTLD development Epstein-Barr Virus EBV seronegativity at transplant Primary EBV infection following transplantation Mostly children Organ donor is EBV seropositive Reactivation of pre-existing existing EBV infection Usually in adults

68 Clinical presentations of PTLD Infectious mono-like illness: Primary EBV infection in previously seronegative patients, mostly children Fever, sore throat, lymphadenopathy,, enlarged liver & spleen, diarrhoea, weight loss, anaemia Nodal and/or extranodal: EBV seropositive Single or multiple sites Common in transplanted organ, bowel, CNS

69 Role of EBV load monitoring in predicting PTLD EBV loads are elevated at the time of PTLD However, role of sequential EBV load measures to identify patients at risk of PTLD more controversial Differences in analyte also important Whole blood Plasma/serum

70 Treatment of PTLD Reduction of immunosuppression Antivirals (aciclovir, ganciclovir) Chemotherapy Surgery Radiotherapy Rituximab, mab against CD20 expressed on B cell surface EBV-specific cytotoxic T lymphocytes (CTL)

71 Antiviral prophylaxis and EBV replication >1000 >2000 >5000 EBV load ge/ml whole blood oral GCV ValGCV Valganciclovir achieves higher levels of GCV better control of high level EBV replication (p=0.03) Razonable R et al (2005) J. Infect. Dis. 192,

72 Rituximab to control PTLD Rituximab results in a profound long-lasting lasting depletion of B lymphocytes Three clinical trials reported in SOT 4 weekly injections of rituximab (375 mg/m 2 ) Response rate between 44.2% and 64.0% Survival rates ~67% Relapse rate in one study was 22% Ortel S et al (2005) AJT 5, Blaes A et al (2005) Cancer 104, Choquet S et al (2006) Blood 107,

73 Control of EBV replication by adoptive Immunotherapy Expand EBV specific CD8 T-cells T (and CD4 T-cells) T ex vivo and then re-infuse them into patients with high level EBV or patients with PTLD Pioneered in HSCT setting and now being applied in SOT Autologous CTLs reduce EBV load, expand in vivo and result in regression of PTLD Cells can be expanded from EBV seropositive recipients but seronegative recipients require cells expanded from allogeneic donors

74 CTL trial: Outcome at 6 months Complete response: 14/28 pts (50%) Tumour regressed Graft function improved EBV load decreased 13 patients remain well and 1 relapsed Partial response: 3/28 pts (11%) No response: 11/28 pts (39%) Mortality 6 mo: 2/28 (7%) 2 years: 6/28 (21%) Haque T et al, Transplantation 2001; Haque et al, Lancet 2002; Haque et al (2007) Blood 110:

75 Are we better prepared against EBV Some progress Quantitative genome measurement available but predictive value uncertain Anti-herpesviral prophylaxis reduces incidence of EBV infection/ptld Recent advances in therapy Rituximab Adoptive T-cell T therapy

76 QuickTime and a None decompressor are needed to see this picture. Thank You

77 There does not exist a category of science to which one can give the name applied science. There are science and the applications of science, bound together as the fruit of the tree which bears it Louis Pasteur