서 미 선 Cytomegalovirus infection in renal transplant recipients

 Introduction  CMV infection vs disease  Prevention (prophylatic vs preemptive)  Prophylactic therapy (agents)  IV ganciclovir, Oral ganciclovir, IV → oral ganciclovir  Valganciclovir  CMV hyperimmune globulin  CMV status and prophylactic therapy  Preemptive strategy  CMV disease  Diagnosis  Treatment

Introduction  one of the m/i infections in KT recipients  exposure to virus : presence of detectable IgG anti-CMV abs in the plasma → increases with age in the general population → > 2/3 of donors & recipients prior to transplantation common for the donor and/or recipient to be CMV-positive at the time of transplantation Hematoxylin-eosin–stain typical owl-eye inclusions

CMV infection  donor recipient (blood transfusion or transplanted kidney) immunosuppressive drugs CMV disease recipient & donor are routinely tested for anti-CMV antibodies prior to transplantation

CMV : significant underlying cause of morbidity & mortality in KT  US Renal Data System  17,000 deceased donor KT recipients  multivariate analysis CMV-positive : significantly higher incidence of CMV disease, allograft loss, overall costs Am J Transplant 2003; 3: % 15.9% 9.3% 5.7% P < % 20.8% 19.4% 16.6% Am J Transplant 2003; 3: % 15.9% 9.3% 5.7% P < % 20.8% 19.4% 16.6%

 impact of CMV on overall mortality  prospective, single center study  500 patients  weekly CMV pp65 antigenemia for 100 days  f/u 66 months  CMV-antigenemia : 60% in the first 100 days Kidney Int 2004; 66:329. RR 2.9 RR 2.5 Kidney Int 2004; 66:329. RR 2.9 RR 2.5

 Introduction  CMV infection vs disease  Prevention (prophylatic vs preemptive)  Prophylactic therapy (agents)  IV ganciclovir, Oral ganciclovir, IV → oral ganciclovir  Valganciclovir  CMV hyperimmune globulin  CMV status and prophylactic therapy  Preemptive strategy  CMV disease  Diagnosis  Treatment

CMV infection vs disease  CMV infection : ≥ 1  anti-CMV IgM : seroconversion  anti-CMV IgG : four-fold ↑  detection of CMV antigens in infected cells  detection of CMV-DNAemia by molecular techniques  culture : isolation of the virus (throat, buffy coat, urine)

 CMV disease  clinical signs & symptoms  fever, leukopenia  organ involvement  hepatitis, pneumonitis, pancreatitis, colitis, meningoencephalitis, myocarditis  CMV chorioretinitis  rare in KT

Viral load  total burden of CMV viral particles → correlate with clinical evidence of disease, disease severity, response to therapy  initial CMV viral load & rate of increase of virus in the blood → correlated with the risk of developing CMV disease in renal, liver, bone marrow transplant recipients Lancet 2000; 355:2032. Lancet 2000; 355:2032.

Correlation between initial CMV load and peak CMV load (44 renal, 20 liver, 21 BM) P < Lancet 2000; 355:2032. P < Correlation between initial CMV load and peak CMV load (44 renal, 20 liver, 21 BM) Lancet 2000; 355:2032.

 Introduction  CMV infection vs disease  Prevention (prophylatic vs preemptive)  Prophylactic therapy (agents)  IV ganciclovir, Oral ganciclovir, IV → oral ganciclovir  Valganciclovir  CMV hyperimmune globulin  CMV status and prophylactic therapy  Preemptive strategy  CMV disease  Diagnosis  Treatment

Overview of prevention  CMV disease: 20 ~ 60% → 5%  two principal approaches  prophylactic strategy  antiviral agents to patients at increased risk of developing CMV infection  preemptive strategy  periodic monitoring for viremia (PCR) → prompt treatment after the detection of very early systemic infection

 It is unclear which preventive strategy is preferred  2006 systematic review  10 trials (476 solid organ recipients)  6 : preemptive Tx. vs placebo or standard Tx.  3 : preemptive Tx. vs prophylactic Tx.  1 : oral vs IV preemptive Tx. Transplantation 2006; 81:139. Transplantation 2006; 81:139.

RR 0.29 RR 1.06 RR 1.23 preemptive Tx. vs placebo or standard Tx. RR 0.29 RR 1.06 RR 1.23 preemptive Tx. vs placebo or standard Tx.

RR 0.42 RR 0.94 RR 1.86 preemptive Tx. versus prophylactic Tx. Transplantation 2006; 81:139. preemptive Tx. versus prophylactic Tx. RR 0.42 RR 0.94 RR 1.86

 Introduction  CMV infection vs disease  Prevention (prophylatic vs preemptive)  Prophylactic therapy (agents)  IV ganciclovir, Oral ganciclovir, IV → oral ganciclovir  Valganciclovir  CMV hyperimmune globulin  CMV status and prophylactic therapy  Preemptive strategy  CMV disease  Diagnosis  Treatment

Overview of agents used for prophylactic therapy  2005 meta-analysis of 19 trials  1981 solid-organ transplant recipients  vs placebo or no treatment antiviral prophylaxis : significantly lowered the risk of CMV disease, CMV infection, mortality Lancet 2005; 365:2105. Lancet 2005; 365:2105.

Lancet 2005; 365:2105.

IV ganciclovir  low-dose prophylactic regimen  113 seropositive KT recipients  during highest risk time (antilymphocyte antibody therapy (OKT3))  randomly assigned to  no anti-CMV therapy  Ganciclovir 2.5 mg/kg qd at six months CMV infection : 14% vs 33% CMV isolation (buffy-coat) : 17% vs 35% Ann Intern Med 1995;123:18

oral ganciclovir  as effective as IV prophylaxis  poor bioavailability : relatively high doses (1000 mg TID)  prospective study  101 high-risk KT recipients  randomly assigned  to prophylactic therapy with oral ganciclovir or acyclovir  3M Tx.  significantly fewer CMV infections  donor-positive, recipient-negative : 54 vs 0%  donor-positive, recipient-positive : 43 vs 7%  donor-negative, recipient-positive : 8 vs 0% Transplantation 1998;66:168

Valganciclovir  valyl-ester prodrug of oral ganciclovir  bioavailability 70% (vs oral ganciclovir : 7%)  450 to 900 mg : serum ganciclovir levels similar to IV ganciclovir 2.5 to 5 mg/kg

 subsequent systematic review : ability to prevent posttransplant CMV disease in SOT  subsequent systematic review : ability to prevent posttransplant CMV disease in SOT  late-onset CMV disease : ganciclovir prophylaxis  D+/R- : 9%  all : 18% : valganciclovir preemptive therapy  No Am J Transplant 2008; 8:2111.

 Introduction  CMV infection vs disease  Prevention (prophylatic vs preemptive)  Prophylactic therapy (agents)  IV ganciclovir, Oral ganciclovir, IV → oral ganciclovir  Valganciclovir  CMV hyperimmune globulin  CMV status and prophylactic therapy  Preemptive strategy  CMV disease  Diagnosis  Treatment

CMV status and prophylactic therapy CMV-positive donor, CMV-negative recipient  w/o prophylactic therapy  70 – 90% : "primary" CMV infection  50 – 80% : CMV disease  30% : pneumonitis, major contributor to morbidity & mortality  mortality rate :15%  with prophylactic therapy  CMV disease : 1%

CMV status and prophylactic therapy CMV-positive donor, CMV-negative recipient  Ganciclovir or valganciclovir : TOC  Ganciclovir  Oral 1000mg TID with food  IV 5mg/kg # 2 qd, 3 weeks → oral 1000mg tid (2 – 12 weeks) Am J Transplant 2004; 4:611 m J Transplant 2004; 4:611. : Ganciclovir IV period is not necessary for prevention of CMV disease in high-risk solid organ transplant recipients

CMV status and prophylactic therapy CMV-negative donor, CMV-positive recipient  reactivation of latent CMV infection d/t the administration of immunosuppressive drugs  CMV infection and/or disease : 20%  pneumonitis : rare  lymphocyte depleting agents are used for induction therapy or treatment of rejection

CMV status and prophylactic therapy CMV-positive donor, CMV-positive recipient  both reactivation of latent virus & superinfection with a new viral strain  CMV disease risk ↑ d/t presence of multiple CMV virotypes and/or reactivation of different viruses  oral ganciclovir or valganciclovir

CMV status and prophylactic therapy CMV-negative donor, CMV-negative recipient  low prevalence of disease  no treatment with antiviral prophylaxis therapy has been recommended

Duration of prophylaxis  most institutions use three months of prophylaxis  Ganciclovir  D-R+ cases : 90 days  D+R- & D+R+ cases : 180 days J Am Soc Nephrol 2003;14:1780. J Am Soc Nephrol 2003; 14:780.

 Introduction  CMV infection vs disease  Prevention (prophylatic vs preemptive)  Prophylactic therapy (agents)  IV ganciclovir, Oral ganciclovir, IV → oral ganciclovir  Valganciclovir  CMV hyperimmune globulin  CMV status and prophylactic therapy  Preemptive strategy  CMV disease  Diagnosis  Treatment

Preemptyive strategy monitor whole blood quantitative CMV-PCR weekly for 12 to 16 weeks post-surgery CMV-PCR (+) : > 2000 copies/mL antimetabolite ( azathioprine or MMF) stop until viremia clears weekly quantitative PCRs If the quantitative PCR level does not decrease by 50 percent in two weeks : suspect viral resistance or recipient immunocompetence

dose of valganciclovir ↑ or switched to IV ganciclovir treatment should continue for one week beyond the finding of a negative quantitative CMV asymptomatic or only mild disease valganciclovir for ≥ 21 days invasive disease IV ganciclovir

 Introduction  CMV infection vs disease  Prevention (prophylatic vs preemptive)  Prophylactic therapy (agents)  IV ganciclovir, Oral ganciclovir, IV → oral ganciclovir  Valganciclovir  CMV hyperimmune globulin  CMV status and prophylactic therapy  Preemptive strategy  CMV disease  Diagnosis  Treatment

CMV Disease  1-4 M after transplantation if prophylaxis is not used  1-4 M after discontinuation of prophylaxis  the risk of reactivation  ↑ seropositive recipients treated with OKT3 or other forms of antilymphocyte serum.

CMV disease - Clinical presentation  mononucleosis-like syndrome with fever, malaise, myalgias, arthralgias  m/c  usually associated with leukopenia & mild (5 to 10 %) atypical lymphocytosis  mild elevation in serum aminotransferase  MMF : invasive CMV disease can occur in the absence of fever & leukopenia  Interstitial pneumonitis, ulcerations in the esophagus & colon  major morbidity  G-I bleeding is commonly caused by erosions d/t CMV  invasive disease is usually confirmed with endoscopic biopsy  encephalopathy & chorioretinitis  unusual in KT

 Introduction  CMV infection vs disease  Prevention (prophylatic vs preemptive)  Prophylactic therapy (agents)  IV ganciclovir, Oral ganciclovir, IV → oral ganciclovir  Valganciclovir  CMV hyperimmune globulin  CMV status and prophylactic therapy  Preemptive strategy  CMV disease  Diagnosis  Treatment

1. Serology  indirect evidence of recent CMV infection : changes in antibody titers at different time points  detection of CMV-specific IgM antibodies  recent seroconversion  fourfold increase in CMV-specific IgG titers : in paired specimens obtained at least 2-4 weeks apart CMV disease - Diagnosis

 Helpful  past exposure to CMV infection  management of immunosuppressed hosts at risk for CMV reactivation syndromes  risk of acquisition of infection  seronegative patient is not at risk for CMV reactivation  Limitation  requirement for paired serum samples  IgM antibody can also persist for several months

2. Cultures  blood, urine, throat washings, cerebrospinal fluid, bronchial washings, biopsy specimens  Limitations  CMV grows slowly in cell culture (1-6 weeks)  presence of the virus, not confirm active disease  shed from the urine and throat for several months after acute CMV infection  isolation of CMV from the blood → not diagnostic  Useful  presence of drug resistance

3. Early antigen detection (shell vial cultures)  detect CMV in culture before the development of characteristic cytopathic effects → accelerating the time to diagnosis  centrifugation of clinical samples (virus absorption ↑)  cell monolayers are exposed to monoclonal antibodies  binding of antibodies → "early" CMV replication within the cells  available within 2-3 days CMV early antigen detection in cultured cells ("shell vials")

4. CMV antigenemia assays  rapid detection of CMV proteins in peripheral blood leukocytes  tagged monoclonal antibodies specific to the pp65 lower matrix protein of CMV  Positive results : number of cells with staining per total number of cells  available within 24 hours  useful marker of symptomatic cytomegalovirus infection after renal [Transplantation 1989; 48:991.]  antigenemia correlate with viremia [J Clin Microbiol 1988; 26:2531.]

 40 patients, suspected CMV mononucleosis-like syndrome  two-year period  10/40 : CMV infection confirm ( 9/10 : positive CMV antigenemia )  7/9 : low level antigenemia (< 20 positive cells)  Sensitivity 90%, specificity 96% Infect Dis 1998;26:646 J Am Soc Nephrol 2003; 14:780.

4. Molecular amplification  COBAS Amplicor test  PCR assay  amplifies a 365 base pair region of the CMV polymerase gene  ,000 copies/mL  plasma, leukocyte, whole blood specimens  Hybrid Capture System CMV DNA test  signal amplification method using an RNA probe  targets 17 percent of the CMV genome  target is detected employing antibodies that specifically bind RNA:DNA hybrids  1400 to 600,000 copies/mL  whole blood specimens.

 Nucleic acid sequence-based amplification (NASBA)  detect both immediate-early gene UL123 (IE1) and late gene expression (pp67)  whole blood samples  30 renal transplant recipients : Sensitivity100%, specificity 76% [Clin Microbiol Infect 2001; 7:254]

 Introduction  CMV infection vs disease  Prevention (prophylatic vs preemptive)  Prophylactic therapy (agents)  IV ganciclovir, Oral ganciclovir, IV → oral ganciclovir  Valganciclovir  CMV hyperimmune globulin  CMV status and prophylactic therapy  Preemptive strategy  CMV disease  Diagnosis  Treatment

Treatment  varies with the severity of the clinical manifestations  mononucleosis-like syndrome  may resolve without the administration of antiviral drugs  reduction in the overall level of immunotherapy is often recommended  OKT3 (or other antilymphocyte serum) : discontinue  azathioprine or MMF : dosage reduction or discontinue  cyclosporine or tacrolimus : not discontinue unless there is evidence of life- threatening  corticosteroids : continue (to prevent possible adrenal insufficiency)

ganciclovir  action mechanism  GCV to GCV-triphosphate → competes with dGTP  inhibit viral DNA polymerase  incorporated into viral DNA → slows & stops DNA chain elongation  route  IV : preferred  oral : 6% bioavailability; high pill burden  dosage with normal renal function  Induction therapy  5 mg/kg IV q 12 h  maintenance therapy  5 mg/kg IV daily  1 g orally q 8 h with food

 adverse effects  frequent: bone marrow toxicity, reversible neutropenia, thrombocytopenia  occasional: anemia, fever, rash, change in mental status, headache, liver toxicity

hyperimmune globulin (Cytogam)  pool of CMV IgG antibody  route : IV only  prophylaxis  150 mg/kg within 72 h → 2, 4, 6, 8 weeks  100 mg/kg at 12, 16 weeks after transplantation  treatment  for severe CMV pneumonia  400 mg/kg on days 1, 2, 7 or 8 → 200 mg/kg on days 14, 21 Code : A-Megal Human anti-CMV Ig. 1ml = 100mg 10ml = 1000mg 1-2ml/kg q 2 days (5 회 ) 주입속도 : 1ml/min, NS mix

 Indication  CMV disease refractory to ganciclovir in renal transplantation [ Transplant Proc 1995;27:46]  CMV prophylaxis (licensed in 1987)  heart or lung recipients at high risk of infection (CMV-seronegative recipients, CMV-seropositive donors) [Transplantation 2005; 80:545]  CMV severe disease [Ann Intern Med 1988; 109:777–82]  rescue therapy for invasive disease in SOT recipients it remains unclear whether the addition of CMVIG to antiviral drugs will improve clinical outcomes or whether it could help in the management of infection due to ganciclovir-resistant CMV [CID 2008:47;702-11], [Transplant Proc 1993; 25:22–4]

 adverse effects  occasional : fever, chills, nausea, flushing, volume overload  rare : renal failure, hemolysis, anaphylaxis, aseptic meningitis, pulmonary edema

Valganciclovir  excellent bioavailability & pharmacokinetics  VICTOR study  noninferiority trial  321 solid organ recipients (74% KT) with CMV disease  randomly assigned to  oral valganciclovir (900 mg twice daily for 21 days)  IV ganciclovir (5 mg/kg twice daily for 21 days) → valganciclovir (900 mg daily until day 49) Am J Transplant 2007; 7:2106. Am J Transplant 2009; 9:1205. Am J Transplant 2007; 7:2106. Am J Transplant 2009; 9:1205.

similarly effective in suppressing viremia at 21 days (77% vs 80%) at 49 days (85% vs 84%) Side effects were also comparable Follow-up at one year also found that outcomes were similar Am J Transplant 2007; 7:2106. Am J Transplant 2009; 9:1205. similarly effective in suppressing viremia at 21 days (77% vs 80%) at 49 days (85% vs 84%) Side effects were also comparable Follow-up at one year also found that outcomes were similar Am J Transplant 2007; 7:2106. Am J Transplant 2009; 9:1205.

 symptomatic patients with high viral loads & tissue-invasive disease : initially with IV ganciclovir until a response to therapy has been documented (by clinical improvement & a decrease in viral load ) because of the risk of relatively resistant CMV Am J Transplant 2008; 8:1297 Am J Transplant 2007; 7:2062 Am J Transplant 2008; 8:1297 Am J Transplant 2007; 7:2062