Julie A. Stoner

Meta-analysis: the efficacy of strategies to prevent organ disease by cytomegalovirus in solid organ transplant recipients

Context Cytomegalovirus is a common opportunistic infection among recipients of organ transplants. Contribution This meta-analysis summarizes 17 randomized trials of antiviral therapy for recipients of liver and kidney allografts. Universal prophylaxis for all high-risk patients and preemptive treatment for patients who had the virus detected during periodic monitoring reduced cytomegalovirus organ disease and allograft rejection more than did no treatment or placebo. Only universal prophylaxis reduced bacterial and fungal infections and death. Cautions Most trials were small and were not blinded. Implications Although the authors prefer universal prophylaxis over preemptive treatment, they recommend a large confirmatory trial to directly compare the 2 strategies. The Editors Despite advances in diagnosis and therapy, cytomegalovirus (CMV) is the most common opportunistic viral infection occurring after solid organ transplantation (1, 2). It causes substantial morbidity, prolongs hospital stay, increases health care costs, and increases risk for death (3-7). It is also associated with many adverse indirect effects, such as opportunistic bacterial and fungal infections (8-15), graft rejection (16-18), atherosclerosis (19-21), and post-transplantation lymphoproliferative disorders (22, 23). Two distinct approaches, preemptive and prophylactic, are used to prevent CMV disease in solid organ transplant recipients (24). The preemptive approach involves periodic monitoring of patients for development of CMV viremia (based on detection by culture, pp65 antigen [pp65], or polymerase chain reaction [PCR]) and therapeutic intervention when the virus is detected. The prophylactic approach involves systematic administration of an antiviral drug to all patients at higher risk (based on pretransplantation CMV seropositive status of either the donor or the recipient) for CMV infection. Both approaches have been used in different transplantation centers throughout the world, and no head-to-head comparison trials have resolved which strategy is optimal for preventing disease caused by CMV. Furthermore, the efficacy of each strategy in preventing the associated adverse indirect effects of CMV infection is controversial (1, 24). More important, the potential clinical superiority of using newer drugs with the most potent in vitro activity against CMV, such as ganciclovir and valganciclovir, rather than the older and less potent agent acyclovir still needs confirmation. In this systematic review, we summarize data about the efficacy of preemptive and universal prophylaxis strategies in preventing the development of organ disease associated with CMV infection in solid organ transplant recipients. We also evaluate whether these strategies prevent adverse indirect effects associated with CMV infection and try to assess the magnitude of the preventive effect associated with individual antiviral agents. Methods Literature Search We followed QUOROM guidelines for conducting and reporting systematic reviews (25). Specifically, we searched for English-language and nonEnglish-language reports of published and unpublished trials listed in MEDLINE (1966May 2005), EMBASE (1966May 2005), Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews (2004, Issue 4), and Evidence-Based Medicine (2000May 2005). We used the following keywords in the electronic searches: cytomegalovirus, transplantation, preemptive, prophylaxis, prevention, renal, kidney, kidney-pancreas, pancreas, hepatic, liver, small bowel, cardiac, heart, lung, heart-lung, other combined transplantations, and antiviral medications. When complementary information was required, one of us contacted the original authors of the included trials. The published results of references 66 and 67 were modified after contacting the authors. We also contacted pharmaceutical companies that have manufactured or are still producing anti-CMV medications to help identify unpublished trials and reviewed the abstracts from the 2003 and 2004 meetings of the Infectious Disease Society of America, Interscience Conference on Antimicrobial Agents and Chemotherapy, and American Transplantation Congress. Study Selection Two investigators independently screened the titles and abstracts of studies to identify those that met a priori-defined inclusion criteria. We selected randomized, controlled trials that evaluated the prevention of CMV in solid organ transplant recipients. We excluded trials that 1) used less than 2 g of acyclovir per day for universal prophylaxis; 2) used less than 3 g of ganciclovir per day for universal prophylaxis; 3) gave universal prophylaxis for fewer than 60 days; 4) gave preemptive therapy for fewer than 14 days; 5) aimed to test the efficacy of immunoglobulin, alone or in combination with antiviral drugs, as the primary end point; or 6) had a control group in which an active therapy was used to prevent CMV infections. Study Quality and Data Extraction We independently evaluated the quality of the trials with the Jadad scale, which includes yes-or-no items for scoring the reported method and concealment of randomization, the reported blinding of patients and investigators to the allocation of the intervention, and the reporting of patients who dropped out or withdrew from the study (26). We defined CMV organ disease as CMV viremia (defined by positive culture, pp65, or PCR) plus clinical or histologic involvement of an organ due to the same infection. Recognizing that CMV syndrome (symptomatic viremia with no end-organ involvement) and CMV organ disease are distinct entities with different rates of associated morbidity and mortality, we included only patients with CMV organ disease in the case definition. We disagreed in only 1 case definition and resolved the disagreement through consensus. (Of note, the sample size of each trial remained the same because patients with CMV syndrome were included in the sample without CMV disease.) We also abstracted data regarding the following secondary end points: allograft rejection, allograft loss, bacterial and fungal infections, non-CMV viral infections, time to CMV organ disease, CMV recurrence, CMV resistance, and death. Statistical Analysis We pooled data by using both the MantelHaenszel fixed-effects model (27) and the random-effects model of DerSimonian and Laird (28). In the absence of statistically significant heterogeneity (P< 0.10), we reported the results of the fixed-effects model. For studies with no outcome events (that is, no incidence of CMV organ disease) in 1 group, 0.50 was added to all cells. Because of the asymptotic approximation used with the aforementioned methods, we also examined the data by using the exact method, version 6 (StatXact, Cytel Software, Cambridge, Massachusetts). The results from the exact methods were similar to those from the asymptotic methods, and therefore, only the results from the asymptotic tests are presented. We used the BreslowDay method to assess statistical heterogeneity (29) and I2 analysis to detect the magnitude of variation attributable to heterogeneity rather than to chance (30). To estimate possible publication bias, we used the Egger regression approach (31). We planned a priori stratified analyses in the following subgroups: CMV serology mismatch (positive in donors and negative in recipients), type of allograft, type of CMV diagnostic method, type of immunosuppression regimen, type of drug used to prevent CMV, and length of follow-up. We also did several post hoc sensitivity analyses that excluded data from certain studies. We found that participants in one good-quality trial involving heart transplant recipients had been given universal prophylaxis for fewer than 60 days (32). We found 2 trials that met inclusion criteria that had different characteristics from those reported in most of the selected studies; 1 of these trials only included patients with donor-positive/recipient-negative CMV serostatus (33), and the other had used an acyclovir dosage of 2 g/d (34). Finally, we found 3 trials that met inclusion criteria whose authors could not be contacted for clarifications about discrimination between CMV syndrome and organ disease (35-37). Analyses were done with SAS, version 9.1 (SAS Institute, Inc., Cary, North Carolina), and Forest plots were built with Comprehensive Meta-Analysis, version 2 (BioStat, Englewood, New Jersey). Role of the Funding Source No funding was received in support of this study. Results The process of study selection is shown in Figure 1. Two studies (38, 39) met exclusion criterion 1, 1 study (40) met exclusion criterion 2, 4 studies (41-44) met exclusion criterion 3, and 14 studies (45-58) met exclusion criterion 6. A list of studies that met exclusion criterion 5 is available from the authors on request. Eleven trials involving 1582 patients (14, 32-37, 59-62) were selected for the universal prophylaxis analysis, and 6 trials involving 398 patients (63-68) were selected for the preemptive therapy analysis. One of the 11 universal prophylaxis trials only administered prophylaxis for 28 days (32). Three trials were double-blind (32, 35, 59), and 6 trials were placebo-controlled (14, 32, 35, 37, 59, 62). Allocation concealment was adequate in 5 trials (14, 32, 35, 59, 62) and was unclear or inadequate in the remaining trials. We assessed the length of follow-up as adequate in 7 trials (14, 33, 35, 59, 63-65) but noted that most trials did not report the exact timing of outcome events. Figure 1. Study selection. The characteristics of selected trials are shown in the Table. The median number of patients enrolled per trial was 73 (range, 32 to 616) for the universal prophylaxis analysis and 64 (range, 36 to 113) for the preemptive analysis. The proportion of patients with donor-positive/recipient-negative CMV serostatus and recipient-positive CMV serostatus (higher risk for CMV infection) were, respectively, 11.6% and 86.2%

A Systematic Review of the Frequency of Neurocyticercosis with a Focus on People with Epilepsy

Background The objective of this study is to conduct a systematic review of studies reporting the frequency of neurocysticercosis (NCC) worldwide. Methods/Principal Findings PubMed, Commonwealth Agricultural Bureau (CAB) abstracts and 23 international databases were systematically searched for articles published from January 1, 1990 to June 1, 2008. Articles were evaluated for inclusion by at least two researchers focusing on study design and methods. Data were extracted independently using standardized forms. A random-effects binomial model was used to estimate the proportion of NCC among people with epilepsy (PWE). Overall, 565 articles were retrieved and 290 (51%) selected for further analysis. After a second analytic phase, only 4.5% of articles, all of which used neuroimaging for the diagnosis of NCC, were reviewed. Only two studies, both from the US, estimated an incidence rate of NCC using hospital discharge data. The prevalence of NCC in a random sample of village residents was reported from one study where 9.1% of the population harboured brain lesions of NCC. The proportion of NCC among different study populations varied widely. However, the proportion of NCC in PWE was a lot more consistent. The pooled estimate for this population was 29.0% (95%CI: 22.9%–35.5%). These results were not sensitive to the inclusion or exclusion of any particular study. Conclusion/Significance Only one study has estimated the prevalence of NCC in a random sample of all residents. Hence, the prevalence of NCC worldwide remains unknown. However, the pooled estimate for the proportion of NCC among PWE was very robust and could be used, in conjunction with estimates of the prevalence and incidence of epilepsy, to estimate this component of the burden of NCC in endemic areas. The previously recommended guidelines for the diagnostic process and for declaring NCC an international reportable disease would improve the knowledge on the global frequency of NCC.

All-digital image capture and whole-field analysis of ciliary beat frequency

We hypothesized that a high‐speed all‐digital video imaging system, with computerized analysis, would precisely capture and measure ciliary beat frequency (CBF) and would shorten the time from data capture to data analysis. We compared a conventional analog video system with a new high‐speed digital system we developed for CBF analysis. Using ciliated primary bovine bronchial epithelial cells we made simultaneous analog and digital CBF measurements of the same region of interest (ROI) while temperature was varied. This yielded nearly identical data over a wide range of frequencies (7–15 Hz) using either system. Unlike the digital system however, the analog system did not accurately detect CBF above 15 Hz (temperatures higher than 30 °C). We also compared ROI analysis with a new analysis algorithm we have named whole‐field analysis (WFA). WFA measurement of CBF agreed with ROI and reduced operator time required to analyse data by more than 90% compared with the analog system. We conclude that all‐digital computerized CBF analysis correlates closely with standard video methods, markedly speeds up data analysis and provides new ways, including WFA, to analyse entire fields of motile cilia simultaneously. We have termed this system ‘Sisson–Ammons Video Analysis’ (SAVA).

Vincristine, Actinomycin, and Cyclophosphamide Compared With Vincristine, Actinomycin, and Cyclophosphamide Alternating With Vincristine, Topotecan, and Cyclophosphamide for Intermediate-Risk Rhabdomyosarcoma: Children's Oncology Group Study D9803

PURPOSE The purpose of this study was to compare the outcome of patients with intermediate-risk rhabdomyosarcoma (RMS) treated with standard VAC (vincristine, dactinomycin, and cyclophosphamide) chemotherapy to that of patients treated with VAC alternating with vincristine, topotecan, and cyclophosphamide (VAC/VTC). PATIENTS AND METHODS Patients were randomly assigned to 39 weeks of VAC versus VAC/VTC; local therapy began after week 12. Patients with parameningeal RMS with intracranial extension (PME) were treated with VAC and immediate x-ray therapy. The primary study end point was failure-free survival (FFS). The study was designed with 80% power (5% two-sided alpha level) to detect an increase in 5-year FFS from 64% to 75% with VAC/VTC. RESULTS A total of 617 eligible patients were entered onto the study: 264 were randomly assigned to VAC and 252 to VAC/VTC; 101 PME patients were nonrandomly treated with VAC. Treatment strata were embryonal RMS, stage 2/3, group III (33%); embryonal RMS, group IV, less than age 10 years (7%); alveolar RMS or undifferentiated sarcoma (UDS), stage 1 or group I (17%); alveolar RMS/UDS (27%); and PME (16%). At a median follow-up of 4.3 years, 4-year FFS was 73% with VAC and 68% with VAC/VTC (P = .3). There was no difference in effect of VAC versus VAC/VTC across risk groups. The frequency of second malignancies was similar between the two treatment groups. CONCLUSION For intermediate-risk RMS, VAC/VTC does not significantly improve FFS compared with VAC.

Clinical Manifestations Associated with Neurocysticercosis: A Systematic Review

Background The clinical manifestations of neurocysticercosis (NCC) are poorly understood. This systematic review aims to estimate the frequencies of different manifestations, complications and disabilities associated with NCC. Methods A systematic search of the literature published from January 1, 1990, to June 1, 2008, in 24 different electronic databases and 8 languages was conducted. Meta-analyses were conducted when appropriate. Results A total of 1569 documents were identified, and 21 included in the analysis. Among patients seen in neurology clinics, seizures/epilepsy were the most common manifestations (78.8%, 95%CI: 65.1%–89.7%) followed by headaches (37.9%, 95%CI: 23.3%–53.7%), focal deficits (16.0%, 95%CI: 9.7%–23.6%) and signs of increased intracranial pressure (11.7%, 95%CI: 6.0%–18.9%). All other manifestations occurred in less than 10% of symptomatic NCC patients. Only four studies reported on the mortality rate of NCC. Conclusions NCC is a pleomorphic disease linked to a range of manifestations. Although definitions of manifestations were very rarely provided, and varied from study to study, the proportion of NCC cases with seizures/epilepsy and the proportion of headaches were consistent across studies. These estimates are only applicable to patients who are ill enough to seek care in neurology clinics and likely over estimate the frequency of manifestations among all NCC cases.

Multicenter Experience with Upper Gastrointestinal Polyps in Pediatric Patients with Familial Adenomatous Polyposis

BACKGROUND:Familial adenomatous polyposis (FAP) is a hereditary cancer syndrome that includes gastro-duodenal involvement, polyposis, and a propensity to adenocarcinoma necessitating endoscopic surveillance. There are few data describing pediatric upper gastrointestinal FAP resulting in conflicting screening recommendations.OBJECTIVES:To characterize pediatric gastroduodenal FAP and to investigate the association between symptoms at endoscopy and APC mutation analysis with endoscopic-histologic findings warranting surveillance.METHOD:A retrospective chart review was performed, including all children with FAP who underwent upper endoscopy (EGD) at two institutions; (UNMC: 1992–2002, JHH: 1983–2002), all biopsies were reviewed and the APC mutations present in the cohort of patients were correlated to the pattern of severity of endoscopic findings and the frequency of APC mutations identified through commercially available testing for FAP (Labcorp: 1998–2002).RESULTS:Twenty-four patients from 21 families underwent 49 EGDs. Eighty-three percent were asymptomatic at the time of endoscopy. The most common finding was fundic gland polyposis (FGP) (51%), of which 42% and 15% harbored dysplasia and changes indefinite for dysplasia, respectively. Periampullary duodenal adenomata were present in 41% of patients with one patient necessitating ampullectomy. Symptoms at endoscopy were not predictive of premalignant changes. In 15 patients where the APC mutation was known patients with dysplastic FGP, gastric, or duodenal adenoma were more likely to harbor a mutation between codons 1225–1694 than the reference population (p = 0.006).CONCLUSIONS:All pediatric patients with FAP warrant upper gastrointestinal screening and surveillance endoscopy from the time of initial colonoscopy irrespective of referable symptoms. Patients with APC mutation between codon 1225–1694 may be more susceptible to aggressive gastroduodenal involvement in FAP.

Clinical outcomes and nephrotoxicity associated with vancomycin trough concentrations during treatment of deep-seated infections

Objective: Higher vancomycin concentrations are thought necessary for treatment of deep-seated methicillin-resistant Staphylococcus aureus (MRSA) infection, yet this may result in greater risk of nephrotoxicity. We evaluated the relationship of serum vancomycin trough concentration with clinical outcomes and nephrotoxicity for patients with deep-seated MRSA infection. Methods: A retrospective cohort study evaluated adults with MRSA pneumonia, endocarditis or osteomyelitis who received vancomycin for ≥ 5 days from June 2005 to June 2007. Patients were stratified by mean vancomycin trough level [low (< 15 mg/l), high (≥ 15 mg/l)]. Outcomes were clinical response, mortality, length of stay (LOS) and nephrotoxicity. Three definitions of nephrotoxicity were used: i) rise in serum creatinine (SCr) ≥ 0.5 mg/dl; ii) 50% increase in SCr; and iii) 25% decrease in estimated creatinine clearance. Results: Fifty-five patients experiencing MRSA pneumonia (n = 28), endocarditis (n = 9), osteomyelitis (n = 20) and multiple infections (n = 2) were stratified into low (n = 39) and high (n = 16) groups. High group patients were more likely to be septic (p = 0.01) and have a higher APACHE II score (p = 0.01). After adjustment for APACHE II score, clinical response rates among survivors did not differ significantly. Risk of death was not significantly different between the high (19%) and low (5%) group patients (p = 0.1). LOS did not differ significantly between groups (p = 0.7). Nephrotoxicity occurred in the low and high groups, respectively, for 10 and 31% (p = 0.04) with definition 1, 10 and 31% (p = 0.04) with definition 2, and 13 and 25% (p = 0.1) with definition 3. After adjustment for APACHE II score, odds of nephrotoxicity based on definitions 1 or 2 were increased among the high versus low groups (OR = 3.27, 95% CI: 0.7 – 15.25, p = 0.1), although not statistically significant. Conclusions: Clinical outcomes did not differ significantly between high and low trough groups for deep-seated MRSA infections. Nephrotoxicity was consistently higher in the high trough group, regardless of the definition used.

Macrophage proteomic fingerprinting predicts HIV-1-associated cognitive impairment

Background: Specific proteins produced from monocytes may be linked to the pathogenesis and aid in the diagnosis of HIV-1–associated dementia (HAD). Objective: The authors assessed whether a diagnostic phenomic protein profile could be obtained from monocyte-derived macrophages (MDM) from HIV-1–infected patients with cognitive impairment. Methods: Twenty-one HIV-1–infected Hispanic women and 10 seronegative controls matched by age and sex were followed at the University of Puerto Rico Medical Sciences Campus, where neuropsychological, immune, and viral parameters were tested. Monocytes were recovered by Percoll gradient centrifugation from peripheral blood mononuclear cells. MDM lysates were prepared after 7 days of cultivation and protein profiles analyzed by surface enhanced laser desorption/ionization (SELDI)–time of flight (TOF) ProteinChip tests. Classification trees were prepared for statistical analyses. Results: A total of 177 protein peaks from 2 to 80 kDa were evaluated in 31 patient MDM lysates by SELDI-TOF ProteinChip assays. Select protein peaks, at 5028 and 4320 Da, separated HIV-1–infected from HIV-1–seronegative subjects with a sensitivity of 100% and a specificity of 80%. Thirty-eight peaks were used to differentiate HIV-1–infected subjects with and without cognitive impairment. A 4348 Da protein separated the two groups with a sensitivity of 100% and a specificity of 75%. Conclusions: The identification of unique phenomic MDM profiles from cognitively impaired HIV-1–infected patients supports the hypothesis that changes in monocyte function parallel the development of HAD.

Incidence, Duration, and Prevalence of Escherichia coli O157: H7 Fecal Shedding by Feedlot Cattle during the Finishing Period

The objective was to describe variability in prevalence, incidence, and duration of fecal shedding of naturally occurring E. coli O157:H7 by a group of feedlot cattle over time. One hundred steers, randomly assigned to 10 pens, were fed a high-concentrate finishing diet for 136 days (19 weeks). Rectal feces from each animal were tested for E. coli O157:H7 every week for 19 weeks. E. coli O157:H7 was recovered from each animal that completed the study and was detected from at least one animal every week. Average pen prevalence of cattle shedding E. coli O157:H7 varied significantly over time (P < 0.0001) and across pens (P < 0.0001), ranging from 1 to 80%. Pairwise comparisons of mean pen prevalence of E. coli O157:H7 between weeks and estimation of the predicted probability of an incident case of E. coli O157:H7 over time allowed the definition of three distinct phases--namely, the preepidemic, epidemic, and postepidemic periods. Average pen prevalence varied significantly over time (P < 0.01) and across pens (P < 0.001) for all time periods. The odds of an incident case were significantly greater during epidemic and postepidemic periods relative to the preepidemic period (P = 0.0002 and P = 0.03, respectively). Duration of infection was significantly longer for first or second infections that began during epidemic or postepidemic periods relative to the preepidemic period (P < 0.001). Both incidence and duration of shedding peaked during the epidemic period. Pen-level prevalence of cattle shedding E. coli O157:H7 was affected by both incidence and duration of shedding and could be explained by time- or pen-dependent risk factors, or both.

Valganciclovir for Cytomegalovirus Prevention in Solid Organ Transplant Patients: An Evidence-Based Reassessment of Safety and Efficacy

Background Several anti-viral drugs have demonstrated efficacy in preventing Cytomegalovirus (CMV) infections in solid organ transplant (SOT) patients. The recently approved valganciclovir is the most commonly used and most expensive drug for CMV prevention. The safety and efficacy data have been drawn from a single trial. We hypothesized that valganciclovir may not be as safe as nor more effective than other therapies for CMV prevention. Methods All experimental and analytical studies that compared valganciclovir with other therapies for prevention of CMV infection after SOT were selected. Based on meta-analytic and multivariate regression methodologies we critically analyzed all available evidence. Findings Nine studies were included (N = 1,831). In trials comparing valganciclovir with ganciclovir, the risk for CMV disease is 0.98 (95% Confidence Interval (95%CI) 0.67 to 1.43; P = 0.92; I2 = 0%). Valganciclovir was significantly associated with the risk of absolute neutropenia (<1,500/mm3) compared with all therapies (Odds Ratio (OR) 3.63 95%CI 1.75 to 7.53; P = 0.001; I2 = 0%); with ganciclovir only (OR 2.88, 95%CI 1.27 to 6.53; P = 0.01; I2 = 0%); or with non-ganciclovir therapies (OR 8.30, 95%CI 1.51 to 45.58; P = 0.01; I2 = 10%). For a neutropenia cut-off of <1,000/mm3, the risk remained elevated (OR 1.97, 95%CI 1.03 to 3.67; P = 0.04; I2 = 0%). For every 24 patients who receive valganciclovir prophylaxis, one more will develop neutropenia compared to other therapies. The risk of late-onset CMV disease with valganciclovir was similar to ganciclovir and higher than those with non-ganciclovir therapies (OR 8.95, 95%CI 1.07 to 74.83; P = 0.04; I2 = 0%]. One more patient will develop late-onset CMV disease for every 25 who receive valganciclovir compared to treatment with non-ganciclovir therapies. The risk of CMV tissue-invasive disease in liver recipients receiving valganciclovir was 4.5 times the risk seen with ganciclovir [95%CI 1.00 to 20.14] (p = 0.04). All results remained consistent across different study designs, valganciclovir doses, and CMV serostatus. Conclusions Valganciclovir shows no superior efficacy and significantly higher risk of absolute neutropenia, CMV late-onset disease, and CMV tissue-invasive disease compared to other standard therapies. Due to the availability of efficacious, safer, and lower cost drugs (high-dose acyclovir, valacyclovir, ganciclovir), our results do not favor the use of valganciclovir as a first-line agent for CMV preemptive or universal prophylaxis in SOT patients.