George Moussa

Clinical Utility of Cytomegalovirus (CMV) Serology Testing in High‐risk CMV D+/R− Transplant Recipients

Late‐onset cytomegalovirus (CMV) disease is a significant problem in D+/R− solid organ transplant (SOT) patients who receive antiviral prophylaxis. We assessed the clinical utility of CMV IgG and IgM serology testing for predicting late‐onset CMV disease. We evaluated 352 D+/R− transplant recipients who participated in a trial comparing 100 days of ganciclovir versus valganciclovir prophylaxis. CMV serology was assessed on day 28, 56, 100, and 6 and 12 months post‐transplant. IgG seroconversion occurred in 26.9% of patients by day 100, and in 63.4% and 75.3% by 6 and 12 months, respectively. IgM seroconversion occurred in 8.3%, 41.8% and 54.9% by day 100, month 6 and month 12, respectively. Seroconversion by day 100 (end of prophylaxis) was not predictive of subsequent CMV disease (CMV disease 13.3% if seropositive vs. 17.8% if seronegative; p = NS). However, at 6 months post‐transplant, IgG serostatus was predictive of subsequent CMV disease between month 6 and 12 (CMV disease 1.3% if seropositive vs. 10.0% if seronegative; p = 0.002). In D+/R− patients, CMV serology testing is for the most part not clinically useful for predicting subsequent disease. However, seroconversion by 6 months may be useful for identifying patients at risk of late‐onset CMV disease.

A prospective molecular surveillance study evaluating the clinical impact of community-acquired respiratory viruses in lung transplant recipients.

Background. Community-acquired respiratory viral infections (RVIs) are common in lung transplant patients and may be associated with acute rejection and bronchiolitis obliterans syndrome (BOS). The use of sensitive molecular methods that can simultaneously detect a large panel of respiratory viruses may help better define their effects. Methods. Lung transplant recipients undergoing serial surveillance and diagnostic bronchoalveolar lavages (BALs) during a period of 3 years were enrolled. BAL samples underwent multiplex testing for a panel of 19 respiratory viral types/subtypes using the Luminex xTAG respiratory virus panel assay. Results. Demographics, symptoms, and forced expiratory volume in 1 sec were prospectively collected for 93 lung transplant recipients enrolled. Mean number of BAL samples was 6.2±3.1 per patient. A respiratory virus was isolated in 48 of 93 (51.6%) patients on at least one BAL sample. Of 81 positive samples, the viruses isolated included rhinovirus (n=46), parainfluenza 1 to 4 (n=17), coronavirus (n=11), influenza (n=4), metapneumovirus (n=4), and respiratory syncytial virus (n=2). Biopsy-proven acute rejection (≥grade 2) or decline in forced expiratory volume in 1 sec ≥20% occurred in 16 of 48 (33.3%) patients within 3 months of RVI when compared with 3 of 45 (6.7%) RVI-negative patients within a comparable time frame (P=0.001). No significant difference was seen in incidence of acute rejection between symptomatic and asymptomatic patients. Biopsy-proven obliterative bronchiolitis or BOS was diagnosed in 10 of 16 (62.5%) patients within 1 year of infection. Conclusion. Community-acquired RVIs are frequently detected in BAL samples from lung transplant patients. In a significant percentage of patients, symptomatic or asymptomatic viral infection is a trigger for acute rejection and obliterative bronchiolitis/BOS.

Clinical impact of human herpesvirus 6 infection after liver transplantation.

BACKGROUND Reactivation of human herpesvirus 6 (HHV-6) appears to be common after transplant. Viral reactivation may result in febrile illness and may also play an immunomodulatory role that leads to indirect effects such as opportunistic infections and rejection. The objective of this study was to determine the clinical impact of HHV-6 infection after liver transplantation including both direct and indirect effects. METHODS This was a prospective single center cohort study of 200 consecutive patients undergoing liver transplantation. Systemic serial HHV-6 viral load measurements and all clinical outcomes including development of opportunistic infections, cytomegalovirus (CMV) disease, and rejection were determined. RESULTS HHV-6 infection (defined as viral load > or = 2 log10 copies/microg input DNA) occurred in 56/200 (28%) patients. Symptomatic disease attributable to HHV-6 alone occurred in 2/200 (1%) patients. Univariate analysis revealed HHV-6 infection was associated with the development of opportunistic infection and CMV disease. In a multivariate analysis designed to control for the level of immunosuppression, the risk of opportunistic infection increased by 3.68-fold in patients with HHV-6 infection (95% confidence interval [CI], 1.86-7.27; P=0.001). In a similar multivariate analysis, the risk of CMV disease increased by 3.59-fold in patients with HHV-6 infection (95% CI, 1.53-8.44; P=0.003). HHV-6 infection was not associated with rejection except in the subgroup of patients with rejection after 30 days posttransplant (odds ration 2.27; 95% CI, 1.09-4.77; P=0.029). CONCLUSIONS HHV-6 reactivation after transplant is common and is associated with the development of opportunistic infections and CMV disease and possibly with a subgroup of acute rejection episodes. HHV-6 infection likely has a significant impact in transplant recipients through indirect effects of viral replication.

Human Herpesvirus—6 Is Associated with Cytomegalovirus Reactivation in Liver Transplant Recipients

Human herpesvirus-6 (HHV-6) may be a risk factor for cytomegalovirus (CMV) disease in posttransplant patients, possibly through a direct interaction or through a general immunomodulatory effect. To examine this possibility, 88 liver transplant recipients were monitored with serial HHV-6 polymerase chain reaction (PCR), CMV antigenemia, and CMV plasma viral load. HHV-6 infection was defined by a positive PCR of peripheral blood lymphocytes. Forty-eight (54.4%) of 88 patients had at least 1 positive HHV-6 PCR. CMV recurrence was significantly more common in patients with HHV-6 infection (38/48 patients [79. 2%]), compared with recurrence in those without HHV-6 infection (18/40 patients [45%]; P=.001). Peak CMV viral load was 24, 147+/-6799 copies/mL in patients with HHV-6 infection versus 8391+/-4598 copies/mL in patients without HHV-6 infection (P=.001). Symptomatic CMV disease was more common in patients with HHV-6 infection than it was in those without infection (15/48 patients [31. 3%] vs. 4/10 patients [10.0%]; P=.013). In a multivariate analysis including other risk factors for CMV, HHV-6 infection remained an independent risk factor for CMV disease (P=.013; odds ratio, 7.26; 95% confidence interval, 1.52-34.72). HHV-6 is associated with CMV infection and disease, thus supporting an interaction between these viruses.

Interactions Between Cytomegalovirus, Human Herpesvirus‐6, and the Recurrence of Hepatitis C After Liver Transplantation

Recurrence of hepatitis C (HCV) following liver transplantation is common. Herpesvirus reactivation following transplant may have an immunomodulatory effect resulting in increased HCV replication. We studied whether cytomegalovirus (CMV) and human herpesvirus‐6 (HHV‐6) may be associated with HCV recurrence and viral load after transplant. We prospectively followed 66 HCV liver‐transplant recipients with serial viral load testing for CMV and HHV‐6. Infection and viral load were correlated with the development of biopsy‐proven HCV recurrence and HCV viral loads. Histologic recurrence of HCV occurred in 41/66 (62.1%) patients. In the primary analysis, CMV infection and disease, and HHV‐6 infection were not associated with HCV recurrence. Peak CMV and HHV‐6 viral loads were not significantly different in patients with and without recurrence. No correlation was observed between HCV viral loads at 1 and 3 months post‐transplant and peak HHV‐6 or CMV viral loads. In a subgroup analysis, HHV‐6 infection was associated with the development of more severe recurrence (hepatitis and/or fibrosis score ≥ 2) (p = 0.01). Also, fibrosis scores at last follow up were higher in patients with CMV disease (1.67 vs. 0.56; p = 0.016) and in patients with HHV‐6 infection (1.18 vs. 0.55; p = 0.031). In conclusion, HHV‐6 and CMV infection and viral load were not associated with increased overall rates of HCV recurrence or HCV viral load after liver transplantation but may be associated with more severe forms of recurrence.

A Surveillance Study of Adenovirus Infection in Adult Solid Organ Transplant Recipients

Little is known about adenovirus infections in adult organ transplant recipients. We prospectively assessed adenovirus infection in 263 transplant recipients using polymerase chain reaction (PCR) on plasma samples at regular intervals post‐transplant. Adenovirus DNA was detected in 19 of 263 patients (7.2%). Viremia by transplant type was: liver (n = 10 of 121 [8.3%]), kidney (n = 6 of 92 [6.5%]) and heart (n = 3 of 45 [6.7%]). Time to viremia onset was within 10 days post‐transplant (n = 4), on day 28 (n = 1), on day 100 (n = 7) and between months 6 and 12 (n = 7). At the time of viremia, 11 of 19 (58%) patients had no symptoms, 2 of 19 (10.5%) had gastrointestinal (GI) symptoms, 2 of 19 (10.5%) had respiratory symptoms and 4 patients (21%) had vague/non‐specific symptoms. All patients recovered spontaneously. Only 1 of 19 (5%) patients had subsequent acute rejection. Adenovirus viremia is relatively common in adult liver, kidney and heart transplant recipients and most infections are asymptomatic, transient and self‐limited. No serious clinical sequelae or effects on subsequent acute rejection were observed.

A Prospective Assessment of Valganciclovir for the Treatment of Cytomegalovirus Infection and Disease in Transplant Recipients

We assessed valganciclovir for the treatment of cytomegalovirus (CMV) in organ-transplant recipients. Virologic and clinical outcomes were compared with those in matched historical control individuals. Thirty-two patients (23 with symptomatic disease) received valganciclovir, and 32 patients received intravenous (iv) ganciclovir. The rate of virologic clearance by day 21 of therapy was similar in the valganciclovir arm (50.0%) and the ganciclovir arm (46.9%) (P value not significant). The change from baseline viral load by day 7 and day 14 of therapy was similar in both arms. Two patients treated with valganciclovir required a switch to iv ganciclovir, because of a lack of response. Valganciclovir is useful for the treatment of CMV infection and disease in selected organ-transplant recipients.

Lack of Association Between ß-herpesvirus Infection and Bronchiolitis Obliterans Syndrome in Lung Transplant Recipients in the Era of Antiviral Prophylaxis

Background. Cytomegalovirus (CMV), human herpesvirus-6 and -7 (HHV-6 and -7) are &bgr;-herpesviruses that commonly reactivate and have been proposed to trigger acute rejection and chronic allograft injury. We assessed the contribution of these viruses in the development of bronchiolitis obliterans syndrome (BOS) after lung transplantation. Methods. Quantitative real-time polymerase chain reaction of bronchoalveolar lavage samples were performed for CMV, HHV-6 and -7 in a prospective cohort of lung transplant recipients. A time-dependent Cox regression analysis was used to correlate the risk of BOS and acute rejection in patients with and without &bgr;-herpesviruses infection. Results. Ninety-three patients were included in the study over a period of 3 years. A total of 581 samples from bronchoalveolar lavage were obtained. Sixty-one patients (65.6%) had at least one positive result for one of the &bgr;-herpesviruses: 48 patients (51.6%) for CMV and 19 patients (20.4%) for both HHV-6 and -7. Median peak viral load was 3419 copies/mL for CMV, 258 copies/mL for HHV-6, and 665 copies/mL for HHV-7. Acute rejection (≥grade 2) occurred in 46.2% and BOS (≥stage 1) in 19.4% of the patients. In the Cox regression model the relative risk of acute rejection or BOS was not increased in patients with any &bgr;-herpesviruses reactivation. Acute rejection was the only independently associated risk factor for BOS. Conclusions. In lung transplant recipients receiving prolonged antiviral prophylaxis, reactivation of &bgr;-herpesviruses within the allograft was common. However, despite high viral loads in many patients, virus replication was not associated with the development of rejection or BOS.

Long-Term Follow-up of a Cohort of HIV-Infected Patients Who Discontinued Maintenance Therapy for Cytomegalovirus Retinitis

Abstract Purpose: To determine the long-term safety of discontinuation of maintenance therapy for cytomegalovirus retinitis (CMVR) and to identify predictors for relapse. Method: This was a prospective cohort study. Patients with treated CMVR who responded to HAART were followed by ophthalmologic assessment, markers for CMV replication (blood and urine cultures, CMV antigenemia, CMV DNA by PCR), and in vitro lymphoproliferative responses to CMV and other antigens after discontinuation of CMVR maintenance therapy. Results: 23 patients were followed a median of 34 (range, 5-61) months. Median CD4 count was 321/mm3 at enrollment and 395/mm3 at last follow-up. HIV RNA was <50 copies/mL in 78% of patients at enrollment and 65% at last follow-up. One CMVR reactivation occurred at 12 months at a CD4 count of 395/mm3 (21%) and HIV RNA <50 copies/mL. Urine cultures were a poor predictive marker for reactivation. Other CMV replication markers had good negative predictive value. 96% of patients had a good lymphoproliferative response to CMV antigen in vitro. Conclusion: Maintenance therapy for CMVR can safely be discontinued in patients who have responded to HAART. Combining our results with the published literature, the risk of reactivation is estimated at 0.016 per person year of follow-up. Markers to predict relapse and the need for re-initiation of maintenance therapy are not yet identified.

Utility of a monitoring strategy for human herpesviruses 6 and 7 viremia after liver transplantation: a randomized clinical trial.

Background Reactivation of human herpesvirus (HHV)-6 and HHV-7 has been linked to various posttransplant adverse events through immunomodulatory effects. The potential utility of monitoring for HHV-6 and HHV-7 viremia remains unclear. Methods In this clinical trial, 129 liver transplant recipients were randomized to be monitored in real-time for HHV-6 and HHV-7 viremia by polymerase chain reaction at regular intervals from 0 to 12 weeks after transplantation (“monitoring” group) or to undergo usual care (“no-monitoring” group). Therapeutic intervention for a positive polymerase chain reaction result included reduction in immunosuppression and preemptive antiviral therapy, at the discretion of the attending team. The primary outcome was a composite of adverse events indirectly attributable to viral reactivation (including opportunistic infection, graft rejection and severe hepatitis C virus recurrence). Results In the “monitoring” group, HHV-6 and HHV-7 viremia occurred in 23 of 64 patients (35.9%) and 21 of 64 patients (32.8%) patients, respectively. We found no cases of symptomatic HHV-6 and HHV-7 disease. Some therapeutic interventions were performed in 59.1% of viremic episodes. There were no differences in cumulative incidence of the primary outcome between the “monitoring” and “no-monitoring” groups at 1 year (58.7% vs. 52.3%; odds ratio, 0.77; 95% confidence interval, 0.38-1.55) or at 5 years after transplantation (79.0% vs. 70.3%; odds ratio, 0.63; 95% confidence interval, 0.28-1.42). However, we found a trend toward a lower incidence of graft rejection at year 1 in the “monitoring” group (30.2% vs. 44.6%; P=0.091). Conclusion In this first trial, no benefit could be demonstrated from routine monitoring of HHV-6 and HHV-7 viremia in graft or patient outcome after liver transplantation.