Multi-drug resistant strains as etiological agents of urinary tract infections in patients after solid organ transplantation.

Introduction: Urinary tract infections (UTIs) caused by multi-drug resistant strains are a serious and growing problem in organ transplant (TX) recipients. Aim of the study: The aim of the study was to assess the prevalence and risk factors of UTIs caused by multi-drug resistant strains in hospitalized patients after kidney or liver transplantation in a large transplant center. Material and methods: 392 cases of UTIs in patients after kidney or liver TX hospitalized in 2014, 2015 and 2016 were analyzed. Among the assessed cases of UTIs, 66.07% occurred in women, 33.93% - in men, 80.1% - in kidney TX recipients and 19.9% - in liver TX recipients. The median age of the patients was 57.51 years and the median time since TX was 41.44 months. Results: Most episodes of UTIs were observed during the first year after TX - 121 (30.78%) of cases. A total of 506 pathogens were cultured: 345 Gram-negative bacteria (68.182%), 146 Gram-positive bacteria (28.854%) and 15 fungi (2.964%). More than one pathogen was found in 25.51% of urine cultures. Among bacteria (n=491), a resistance mechanism was detected in 166 (33.81%) pathogens (133 Gram-negative and 33 Gram-positive). The most common etiological agents were: E. coli ESBL- (23.72%), K. pneumoniae ESBL+ (17.19%), E. faecalis (11.27%) and E. faecium (7.71%). Diabetes was present in 129 (35.46%) of patients, and the number of UTI cases was similar in the group with and without diabetes. Conclusions: Compared to the general population, in hospitalized patients after kidney or liver transplantation UTIs occur more often in men and are more often caused by Gram-positive bacteria. In 33.81% of cases UTIs are caused by multi-drug resistant strains, predominantly Gram-negative bacteria.

Breaking Antimicrobial Resistance: High-Dose Amoxicillin with Clavulanic Acid for Urinary Tract Infections Due to Extended-Spectrum Beta-Lactamase (ESBL)-Producing Klebsiella pneumoniae.

BACKGROUND Carbapenems are the primary treatment for urinary tract infections (UTIs) caused by extended-spectrum beta-lactamase (ESBL)-producing Klebsiella pneumoniae. However, the recurrence rate is high, and patients often require rehospitalization. We present the results of an observational study on patients with recurrent UTIs who were treated in an outpatient setting with maximal therapeutic oral doses of amoxicillin with clavulanic acid. MATERIAL AND METHODS All patients had pyuria and ESBL-producing K. pneumoniae in urine culture. The starting dosage was 2875 g of amoxicillin twice daily and 125 mg of clavulanic acid twice daily. We down-titrated the doses every 7-14 days and continued prophylactic therapy with amoxicillin/clavulanic acid at 250/125 mg for up to 3 months. We defined therapeutic failure as ESBL-positive K. pneumoniae in urine culture during therapy and recurrence as positive urine culture with the same strain within 1 month after the end of treatment. RESULTS We included 9 patients: 7 kidney graft recipients, 1 liver graft recipient, and 1 patient with chronic kidney disease. We observed no therapeutic failures and no recurrences in the study group during the study period. In 1 case, the patient experienced a subsequent UTI caused by ESBL-producing K. pneumoniae 4 months after completing the therapy. CONCLUSIONS In conclusion, it is possible to break the resistance of ESBL-producing K. pneumoniae strains with high doses of oral amoxicillin with clavulanic acid. Such treatment could be an alternative to carbapenems in select cases.

An aggressive course of pyoderma gangrenosum mimicking bacterial osteomyelitis after open reduction and internal fixation of a distal radius fracture with a titanium plate.

Pyoderma gangrenosum (PG) is a rare condition characterized by the development of aseptic, non-healing skin ulcers. Any skin trauma, such as a surgical incision, can trigger an outbreak of lesions. Our case and literature review show that a physician should consider PG in every event of a non-healing, aseptic wound after surgery. The treatment of PG requires collaboration within a multidisciplinary team and immunosuppressive therapy is the first line of treatment, while surgical interventions should be avoided in the active stage of PG.

The molecular phenotypes of injury, steatohepatitis, and fibrosis in liver transplant biopsies in the INTERLIVER study.

To extend previous molecular analyses of rejection in liver transplant biopsies in the INTERLIVER study (ClinicalTrials.gov #NCT03193151), the present study aimed to define the gene expression selective for parenchymal injury, fibrosis, and steatohepatitis. We analyzed genome-wide microarray measurements from 337 liver transplant biopsies from 13 centers. We examined expression of genes previously annotated as increased in injury and fibrosis using principal component analysis (PCA). PC1 reflected parenchymal injury and related inflammation in the early posttransplant period, slowly regressing over many months. PC2 separated early injury from late fibrosis. Positive PC3 identified a distinct mildly inflamed state correlating with histologic steatohepatitis. Injury PCs correlated with liver function and histologic abnormalities. A classifier trained on histologic steatohepatitis predicted histologic steatohepatitis with cross-validated AUC = 0.83, and was associated with pathways reflecting metabolic abnormalities distinct from fibrosis. PC2 predicted histologic fibrosis (AUC = 0.80), as did a molecular fibrosis classifier (AUC = 0.74). The fibrosis classifier correlated with matrix remodeling pathways with minimal overlap with those selective for steatohepatitis, although some biopsies had both. Genome-wide assessment of liver transplant biopsies can not only detect molecular changes induced by rejection but also those correlating with parenchymal injury, steatohepatitis, and fibrosis, offering potential insights into disease mechanisms for primary diseases.

Assessment of the Banff Working Group classification of definitive BK polyomavirus nephropathy.

Polyomavirus associated nephropathy (PyVAN) continues to be a burden in renal transplantation leading to allograft insufficiency or graft failure. A presumptive diagnosis of PyVAN is made based on the presence of BK polyomavirus in patients' plasma; however, kidney biopsy remains the gold standard to establish a definitive diagnosis. The Banff Working Group on PyVAN proposed a novel classification of definitive PyVAN based on polyomavirus replication/load level and the extent of interstitial fibrosis. The aim of our study was to test the newly defined classes of PyVAN using independent cohorts of 124 kidney transplant patients with PyVAN with respect to the initial presentation and outcome, and to compare our analysis to that previously reported. Detailed analysis of our cohort revealed that the proposed classification of PyVAN did not stratify or identify patients at increased risk of allograft failure. Specifically, while class 3 was associated with the worst prognosis, there was no significant difference between the outcomes in classes 1 and 2. We also found that the timing post-transplantation and inflammation in areas of interstitial fibrosis and tubular atrophy might be additional factors contributing to an unfavorable allograft outcome in patients with PyVAN.

Shear Wave Elastography Performance in Noninvasive Assessment of Liver Cirrhosis in Liver Transplant Recipients With the Recurrence of Hepatitis C Infection.

BACKGROUND: The recurrence of hepatitis C (HCV) after liver transplant (LTX) leads to graft fibrosis and cirrhosis. Liver biopsy remains the criterion standard for their diagnosis and monitoring. Our objective was evaluation of shear wave elastography (SWE) in patients with HCV recurrence after LTX and its comparison with histopathologic fibrosis assessment scoring systems. METHODS: A total of 101 LTX recipients with HCV recurrence (42 women [41.6%] and 59 men [58.4%]) were evaluated by graft biopsy specimens (Ishak, Scheurer, and meta-analysis of histologic data in viral hepatitis [Metavir] score) and SWE (liver stiffness). Median age of patients was 59.4 years; median time from LTX was 84.9 months. The study protocol conforms with the Declaration of Helsinki. RESULTS: Median liver stiffness was 21.3 kPa. To differentiate between liver fibrosis and cirrhosis, patients were divided into 2 subgroups: Ishak score fibrosis (1-4 [85.2%]) and cirrhosis (5-6 [13.9%]); Scheurer score fibrosis (0-3 [85.2%]) and cirrhosis (4 [12.9%]); Metavir score fibrosis (0-3 [85.2%]) and cirrhosis (4 [14.9%]). We have observed statistically significant differences between liver fibrosis and liver cirrhosis groups defined on the basis of Ishak, Scheurer, and Metavir scoring systems: 20.8 kPa vs 29.6 kPa (P = .001), 20.7 kPa vs 30.3 kPa (P = .0005), and 20.7 kPa vs 28.8 kPa (P = .002), respectively. CONCLUSIONS: Our results indicate that SWE may be useful in differentiating patients with advanced cirrhosis from those with fibrosis and may be helpful in the noninvasive diagnosis and monitoring of HCV recurrence after LTX.

Platelets level variability during the first year after liver transplantation in the risk prediction model for recipients mortality.

INTRODUCTION AND OBJECTIVES: Many scoring systems in liver diseases use static values of liver function parameters. These parameters may change significantly in liver transplant (LTx) recipients over time due to various processes. The study was aimed at building a new model for survival prediction after LTx based on variability of selected parameters. MATERIALS AND METHODS: The study included 450 LTx recipients who survived a minimum one year after transplantation. We analyzed liver enzymes and hematology parameters static values and their variability during the first year after transplantation. Modeling patients' survival was performed using Cox regression. Various sets of parameters (both static and variability and trends values) were tested to predict survival in our study group. Models' performance was measured using the concordance index. RESULTS: The single predictors of the patients survival were the static values of AST with C-index 0.706 (0.5883-0.7494), ALT 0.6102 (0.4843-0.6857) and bilirubin 0.6224 (0.5537-0.6695). High prediction scores were observed for variability in creatinine 0.6023 (0.5409-0.6451), PLT 0.6350 (0.5491-0.7043), RBC 0.5689 (0.5065-0.6213) and WBC 0.6506 (0.5095-0.7124). Our best-fitted and proposed model for patients survival after LTx has C-index 0.8273 (IQR 0.7767-0.8649). The model uses the following indicators for mortality prediction: the static value of AST, variability measure of PLT and trend measures of WBC and PLT. CONCLUSIONS: Adding variability and trend measures increases predictive accuracy in modeling patients survival after LTx. We propose a high-accuracy survival model in which variability and trend of PLT measures in the first year after transplantation are strong predictors of long-term mortality.

Hepatocellular Carcinoma Is a Negative Predictor of Sustained Viral Response in Liver Transplant Recipients With Hepatitis C Treated With Direct-Acting Antivirals.

INTRODUCTION: Treatment with direct-acting antivirals (DAA) for hepatitis C (HCV) in liver transplant (LTX) recipients is very effective, but some studies showed that the treatment effectiveness might be impaired in patients with hepatocellular carcinoma (HCC). The study aimed to evaluate the predictors of DAA treatment failure in LTX recipients. METHODS: Liver biopsy was done before the treatment in 107 of the 120 patients included. All patients had an abdominal ultrasound and liver elastography performed before and after the therapy. Blood HCV polymerase chain reaction was done before; during; and at 4, 12, and 24 weeks after the treatment. RESULTS: Overall sustained viral response 24 weeks after treatment (SVR24) was 96%. There were 2 patients with HCC at the start of the DAA treatment and 3 cases of HCC recurrence during a 1-year follow-up. Treatment failure was observed in 1/115 (0.9%) patients without HCC and 4/5 (80%) with active HCC (P = .0001). Liver fibrosis and previous interferon treatment had no impact on treatment efficacy. Time to viremia elimination on treatment was shorter in the responder versus nonresponder group (28 vs 58 days, P = .03). CONCLUSIONS: HCC is a negative predictor of DAA therapy success in LTX recipients.

Long-Term Follow-up of Liver Transplant Recipients Treated With Direct-Acting Antiviral Agents for Hepatitis C Recurrence After Transplantation.

BACKGROUND: Treatment of hepatitis C virus (HCV) recurrence after liver transplantation (LTX) with direct-acting antiviral agents (DAA) is effective and leads to sustained viral response (SVR) in most cases. Long-term effect of HCV elimination on LTX function is not clear. The aim of the study was to evaluate the long-term influence of DAA with HCV on the liver function in LTX recipients. METHODS: The study included 120 LTX patients with HCV recurrence. Before starting DAA therapy, all patients underwent liver biopsy and elastography. Biochemical tests and HCV viremia were assessed at baseline, 4, 12, and 24 weeks and 24 months after the end of treatment (EOT). The study protocol conformed with the Declaration of Helsinki. RESULTS: In the HCV genotype 1 (G1) group, 106 patients were treated with ledipasvir/sofosbuvir with ribavirin (RBV), and 3 patients received paritaprevir/ritonavir/ombitasvir/dasabuvir/RBV. All HCV genotype 3 (G3) patients were treated with sofosbuvir/RBV; all HCV genotype 4 (G4) patients were treated with paritaprevir/ombitasvir/RBV. The efficacy of the treatment defined as SVR at week 12 after EOT (SVR12) was 97.3% in G1 group, 75% in G3, and 100% in G4 group. Median alanine (ALT) and aspartate (AST) transaminase before therapy were 44.0 IU/mL and 42.5 IU/mL, respectively. Median ALT and AST at 24 months after EOT were 17 IU/mL and 22 IU/mL, respectively. The lack of transaminases normalization was observed in 10 patients 24 months after EOT. CONCLUSION: The efficacy of DAA therapy of HCV recurrence after LTX is as high as that reported in randomized clinical trials. It is also associated with the improvement of liver function tests during long-term follow-up.

The molecular diagnosis of rejection in liver transplant biopsies: First results of the INTERLIVER study.

Molecular diagnosis of rejection is emerging in kidney, heart, and lung transplant biopsies and could offer insights for liver transplant biopsies. We measured gene expression by microarrays in 235 liver transplant biopsies from 10 centers. Unsupervised archetypal analysis based on expression of previously annotated rejection-related transcripts identified 4 groups: normal "R1normal " (N = 129), T cell-mediated rejection (TCMR) "R2TCMR " (N = 37), early injury "R3injury " (N = 61), and fibrosis "R4late " (N = 8). Groups differed in median time posttransplant, for example, R3injury 99 days vs R4late 3117 days. R2TCMR biopsies expressed typical TCMR-related transcripts, for example, intense IFNG-induced effects. R3injury displayed increased expression of parenchymal injury transcripts (eg, hypoxia-inducible factor EGLN1). R4late biopsies showed immunoglobulin transcripts and injury-related transcripts. R2TCMR correlated with histologic rejection although with many discrepancies, and R4late with fibrosis. R2TCMR , R3injury , and R4late correlated with liver function abnormalities. Supervised classifiers trained on histologic rejection showed less agreement with histology than unsupervised R2TCMR scores. No confirmed cases of clinical antibody-mediated rejection (ABMR) were present in the population, and strategies that previously revealed ABMR in kidney and heart transplants failed to reveal a liver ABMR phenotype. In conclusion, molecular analysis of liver transplant biopsies detects rejection, has the potential to resolve ambiguities, and could assist with immunosuppressive management.

Incidence of end-stage renal disease after heart transplantation and effect of its treatment on survival.

AIMS: Many heart transplant recipients will develop end-stage renal disease in the post-operative course. The aim of this study was to identify the long-term incidence of end-stage renal disease, determine its risk factors, and investigate what subsequent therapy was associated with the best survival. METHODS AND RESULTS: A retrospective, single-centre study was performed in all adult heart transplant patients from 1984 to 2016. Risk factors for end-stage renal disease were analysed by means of multivariable regression analysis and survival by means of Kaplan-Meier. Of 685 heart transplant recipients, 71 were excluded: 64 were under 18 years of age and seven were re-transplantations. During a median follow-up of 8.6 years, 121 (19.7%) patients developed end-stage renal disease: 22 received conservative therapy, 80 were treated with dialysis (46 haemodialysis and 34 peritoneal dialysis), and 19 received a kidney transplant. Development of end-stage renal disease (examined as a time-dependent variable) inferred a hazard ratio of 6.45 (95% confidence interval 4.87-8.54, P < 0.001) for mortality. Tacrolimus-based therapy decreased, and acute kidney injury requiring renal replacement therapy increased the risk for end-stage renal disease development (hazard ratio 0.40, 95% confidence interval 0.26-0.62, P < 0.001, and hazard ratio 4.18, 95% confidence interval 2.30-7.59, P < 0.001, respectively). Kidney transplantation was associated with the best median survival compared with dialysis or conservative therapy: 6.4 vs. 2.2 vs. 0.3 years (P < 0.0001), respectively, after end-stage renal disease development. CONCLUSIONS: End-stage renal disease is a frequent complication after heart transplant and is associated with poor survival. Kidney transplantation resulted in the longest survival of patients with end-stage renal disease.

Viruses in transplantology.

The 3 leading causes of death in patients after solid organ transplantation (SOT) include cardiovascular diseases, malignancies, and infections. According to our current understanding, the latter play the key role in the pathogenesis of atherosclerosis. Similarly, infections (mainly viral) are implicated in the pathogenesis of at least 20% of known neoplasms. In other words, the implications of acute and chronic infectious diseases in modern medicine, not only transplantology, are significant and ever­increasing. Immunosuppressive treatment impairs the immune function, which renders the patient more susceptible to infections. Furthermore, treatment of infections in immunocompromised patients poses a challenge and SOT. The current publication provides a brief summary of the key information provided in 20 lectures on viral infections in patients after SOT delivered during the 9th Practical Transplantology Course in Warsaw, Poland on September 15-16, 2017.

Long-term outcome of renal transplantation: a 10-year follow-up of 765 recipients.

INTRODUCTION: Renal transplantation is a treatment of choice for patients with end­stage renal disease. The main goal of transplant care is to achieve the best long­term patient survival (PS) and graft survival (GS). OBJECTIVES: We aimed to assess the impact of various immunosuppression (IS) protocols on PS and GS following renal transplantation. PATIENTS AND METHODS: This was a retrospective single­center cohort study including a total of 765 consecutive adult renal transplant recipients (RTRs) who underwent transplantation between 1998 and 2003. The primary endpoints included PS and GS. The secondary endpoints were graft function determined by estimated glomerular filtration rate and hospitalization length per patient per year. RESULTS: Ten­year PS and GS rates were 88.6% and 78.7%, respectively. The intent­to­treat (ITT) group received IS that was later changed, whereas in the group on randomized therapy (ORT), the same IS protocol was maintained during follow­up. The ITT group had significantly better PS and GS than the ORT group. In the ITT group, patients treated with a combination of tacrolimus (TAC) and azathioprine (AZA), cyclosporine (CSA) and AZA, or CSA and mycophenolic acid metabolites (MPAs) had significantly better PS than those treated with TAC and MPA. The ORT group receiving AZA in any combination also had significantly better PS than MPA­treated individuals. CONCLUSIONS: The effect of IS protocols on long­term outcomes varies depending on patient subpopulations. Immunosuppressive therapy solves rejection­related problems but does not address the increasing mortality of RTRs due to cardiovascular diseases, malignancies, or infections. Therefore, treatment recommendations should be individualized and posttransplant care, provided mainly by internists, should be carefully structured to improve long­term outcomes of renal transplantation.

Successful transplantation of kidneys from deceased donors with terminal acute kidney injury.

BACKGROUND: There are many doubts with regards to accepting deceased kidneys with acute kidney injury (AKI) for transplantation. PURPOSE: The aim of this study was to present the 5-years outcome of kidney transplantation cases where deceased donors developed AKI before organ procurement. METHODS: Two hundred twenty-six deceased renal transplants were analyzed. Data regarding donors and recipients were collected. Terminal AKI was defined as terminal serum creatinine concentration higher than 1.99 mg/dL and 66 such cases were diagnosed. All kidney transplant recipients were followed for 60 months. RESULTS: AKI group presented more episodes of delayed graft function (DGF) compared to the non-AKI group (56% vs 35%, p < .05). No differences were observed between the groups in the rate of acute rejection episodes, kidney function as well as patient and graft survival. CONCLUSIONS: Transplants with AKI present more often DGF and comparable graft survival to transplants without AKI. Kidneys with AKI can be a valuable source of organs provided attentive selection and appropriate care of deceased donors.

Killer Immunoglobulin-Like Receptor 2DS2 (KIR2DS2), KIR2DL2-HLA-C1, and KIR2DL3 as Genetic Markers for Stratifying the Risk of Cytomegalovirus Infection in Kidney Transplant Recipients.

Infection with cytomegalovirus (CMV) remains a major problem in kidney transplant recipients, resulting in serious infectious complications and occasionally mortality. Accumulating evidence indicates that natural killer cell immunoglobulin-like receptors (KIRs) and their ligands affect the susceptibility to various diseases, including viral infections (e.g., CMV infection). We investigated whether KIR genes and their ligands affect the occurrence of CMV infection in a group of 138 kidney transplant recipients who were observed for 720 days posttransplantation. We typed the recipients for the presence of KIR genes (human leukocyte antigen C1 [HLA-C1], HLA-C2, HLA-A, HLA-B, and HLA-DR1) by polymerase chain reaction with sequence-specific primers. The multivariate analysis revealed that the lack of KIR2DS2 (p = 0.035), the presence of KIR2DL3 (p = 0.075), and the presence of KIR2DL2⁻HLA-C1 (p = 0.044) were risk factors for posttransplant CMV infection. We also found that a lower estimated glomerular filtration rate (p = 0.036), an earlier time of antiviral prophylaxis initiation (p = 0.025), lymphocytopenia (p = 0.012), and pretransplant serostatus (donor-positive/recipient-negative; p = 0.042) were independent risk factors for posttransplant CMV infection. In conclusion, our findings confirm that the KIR/HLA genotype plays a significant role in anti-CMV immunity and suggest the contribution of both environmental and genetic factors to the incidence of CMV infection after kidney transplantation.

Modulation of the Immune System in Chronic Hepatitis C and During Antiviral Interferon-Free Therapy.

The treatment of patients with chronic hepatitis C virus (HCV) infection has changed tremendously over the past 2 years, with an increasing variety of all-oral direct-acting antiviral (DAA) treatment regimens available for different HCV genotypes and distinct clinical settings. These treatments have significantly improved safety in patients with advanced liver disease compared with interferon (IFN)-based regimens. HCV modifies the human immune system to escape immunosurveillance via several mechanisms. One of the basic mechanisms of HCV is the ability to "switch" the immune response by reducing the activity of cells responsible for the elimination of virus-infected cells. IFN-free DAA treatment regimens provide a unique opportunity to assess the effect of HCV elimination on the immune system. Abrupt changes in the immune system can in some cases be responsible for two alarming processes: viral reactivation in patients with chronic hepatitis B and recurrence of hepatocellular carcinoma in patients with previous successful cancer treatment.

Diagnostic utility of monitoring cytomegalovirus-specific immunity by QuantiFERON-cytomegalovirus assay in kidney transplant recipients.

BACKGROUND: Despite universal prophylaxis, late cytomegalovirus (CMV) infection occurs in a high proportion of kidney transplant recipients. We evaluated whether a specific viral T-cell response allows for the better identification of recipients who are at high risk of CMV infection after prophylaxis withdrawal. METHODS: We conducted a prospective study in 19 pretransplant anti-CMV seronegative kidney graft recipients R- (18 from seropositive donors [D+] and one from a seronegative donor [D-]) and 67 seropositive recipients R(+) (59 from seropositive donors and eight from seronegative donors) who received antiviral prophylaxis with valganciclovir. The QuantiFERON-CMV (QF-CMV) assay was performed within the first and third months after transplantation. Blood samples were monitored for CMV DNAemia using a commercial quantitative nucleic acid amplification test (QNAT) that was calibrated to the World Health Organization International Standard. RESULTS: Twenty-one of the 86 patients (24%) developed CMV viremia after prophylaxis withdrawal within 12 months posttransplantation. In the CMV R(+) group, the QF-CMV assay yielded reactive results (QF-CMV[+]) in 51 of 67 patients (76%) compared with 7 of 19 patients (37%) in the CMV R(-) group (p = 0.001). In the CMV R(+) group, infection occurred in seven of 16 recipients (44%) who were QF-CMV(-) and eight of 51 recipients (16%) who were QF-CMV(+). In the CMV R(-) group, infection evolved in five of 12 recipients (42%) who were QF-CMV(-) and one of 7 recipients (14%) who were QF-CMV(+). No difference was found in the incidence of CMV infection stratified according to the QF-CMV results with regard to the recipients' pretransplant CMV IgG serology (p = 0.985). Cytomegalovirus infection occurred in 15 of 36 patients (42%) with hypogammaglobulinemia (HGG) 90 days posttransplantation compared with two of 34 patients (6%) without HGG (p = 0.0004). Cytomegalovirus infection occurred in seven of 13 patients (54%) with lymphocytopenia compared with 14 of 70 patients (20%) without lymphocytopenia (p = 0.015). The multivariate analysis revealed that the nonreactive QuantiFERON-CMV assay was an independent risk factor for postprophylaxis CMV infection. CONCLUSIONS: In kidney transplant recipients who received posttransplantation prophylaxis, negative QF-CMV results better defined the risk of CMV infection than initial CMV IgG status after prophylaxis withdrawal. Hypogammaglobulinemia and lymphocytopenia were risk factors for CMV infection.