CMV infection in the organ transplant recipient

CMV infection in the organ transplant recipient Dr BH Tan Head, Dept of Infectious Diseases Singapore General Hospital

CMV Disease in Renal Transplant Recipients • Ubiquitous • Propensity for reactivation when host defenses compromised • Ability to disseminate to many organs • Hence prominent role in transplantation, but not well understood • RV of post renal tx active CMV disease Minnesota Health Sciences centre (Oct ’77 – Nov ’78) Peterson PK et al. Medicine 1980;59:283

CMV in Renal Tx – Minnesota ’77-’78 Causes of fever

No. (%) of episodes

Virus as sole cause CMV disease Zoster EBV infection Hep B (chronic active) Influenza Virus + others CMV + rejection CMV + systemic infection Bacteria as sole cause E. coli bacteremia (UTI) S. marcescens (toe gangrene) Salmonella bacteremia Gp A Strep bacteremia Pneumonia (undertermined bug0 Pulmonary cryptococcosis Rejection (ac/chr) Anti-lymphocyte globulins Drug fever Retroperitoneal hematoma

35 30 2 1 1 1 24 17 7 12 2 1 1 1 2 1 12 2 2 1

(38)

(26) (13)

(13) (2) (2) (1) Peterson PK et al. Medicine 1980;59:283

Peterson PK et al. Medicine 1980;59:283

Severity of CMV disease • Diffuse pulm infiltrates – lethal in 12 of 25 patients

• GI bleeding – lethal in 8 of 12 patients • Pancreatitis – lethal in all 4 patients • “Other infections” developed in 12 pts with CMV disease (PCP [2], P. aeruginosa bacteremia [1], C. tropicalis fungemia [1], disseminated C. albicans disease [2] etc) • Graft nephrectomy – required in 11 patients (19%) (CMV disease  cessation of aza, decrease in steroids  elevation of Cr; occurred more often in those with lethal disease) Peterson PK et al. Medicine 1980;59:283

Significance of CMV disease • Overt CMV disease was commonest cause of fever in 1st post-tx yr • Overt CMV disease in 1st 4 mths after tx was significantly a/w incidence of post-tx nephrectomy and death

Ample evidence that CMV exerts profound influence on renal transplantation Peterson PK et al. Medicine 1980;59:283

CMV pneumonitis after heart tx • RV of 171 heart tx pts transplanted at RushPresbyterian from 1977 – 1988 • 27 cases identified • Higher likelihood of CMV pneumonia in D+ • Mean onset 2.9 ± 1.6 mth post-tx • Bilat hazy opacities in 70% of cases • Respiratory failure 52% • Death 44% Schulman LL et al. Arch Intern Med 1991;151:1118

CMV - a success Successful infectious agent  causes widespread infection without killing host 2 properties that render it particularly successful  latency  association

Transplanted kidney - source of CMV Primary infection developed in 83% of sero-negative recipients who received kidneys from sero-positive donors

D+R- 10/12 infected D-R- 3/10 infected (p = 0.017) Infection: isolation of CMV from urine or blood culture; seroconversion Virology: demonstration of virus identity when two organs shared a common donor Ho M. NEJM 1975;293:1109

Pathogenesis of CMV disease in transplantation

Pathogenesis of CMV disease • Association between CMV activity, graft rejection and anti-rejection therapy well known • What is exact sequence of events? • RV of clinical data in 1990’s in German hospital • 225 pts transplanted at U of Ulm (’93 – ’98) • No prophylaxis Von Muller L et al. J Med Virol 2006;78:394

Rejection & CMV – which is 1st? • Rejection treatment with steroid bolus or anti-lymphocyte therapy was strongly a/w active CMV infection • Rejection and anti-Tcell treatment occurred before CMV disease (18.8 ± 1.5d) vs 35 ± 2.9d) • Only 2pts developed active CMV disease before rejection therapy Von Muller L et al. J Med Virol 2006;78:394

TNF reactivates CMV • Assayed bld of RTx recipients for TNF, IL-6, IL-8; followed them up for CMV antigens • 79% of RTx recipients admitted for acute rejection had elevated levels of cytokines • 4% (only 1 out of 25) pts without an immunological complication had any elevation of cytokines • Administration of anti-rejection therapy (OKT3, ATG) raised cytokine levels further (by factor of 2 – 10) • Elevated peak plasma TNF levels correlates with subsequent CMV reactivation (within 2 weeks) Fietze E. et al. Transplantation 1994;58:675

TNF reactivates CMV Patient group

Peak plasma TNF (pg/ml)

I II

100

CMV Ag + (%)**

6% 32% 88%

**developing within 2 weeks p values chi2 test: I vs II