Acute lung injury associated with vinorelbine.
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Adult↗
Biomedical subjects
Edward R Garrity
Publications and source records attributed to Edward R Garrity.
Analysis of the human cytomegalovirus genomic region from UL146 through UL147A reveals sequence hypervariability, genotypic stability, and overlapping transcripts.
BACKGROUND: Although the sequence of the human cytomegalovirus (HCMV) genome is generally conserved among unrelated clinical strains, some open reading frames (ORFs) are highly variable. UL146 and UL147, which encode CXC chemokine homologues are among these variable ORFs. RESULTS: The region of the HCMV genome from UL146 through UL147A was analyzed in clinical strains for sequence variability, genotypic stability, and transcriptional expression. The UL146 sequences in clinical strains from two geographically distant sites were assigned to 12 sequence groups that differ by over 60% at the amino acid level. The same groups were generated by sequences from the UL146-UL147 intergenic region and the UL147 ORF. In contrast to the high level of sequence variability among unrelated clinical strains, the sequences of UL146 through UL147A from isolates of the same strain were highly stable after repeated passage both in vitro and in vivo. Riboprobes homologous to these ORFs detected multiple overlapping transcripts differing in temporal expression. UL146 sequences are present only on the largest transcript, which also contains all of the downstream ORFs including UL148 and UL132. The sizes and hybridization patterns of the transcripts are consistent with a common 3'-terminus downstream of the UL132 ORF. Early-late expression of the transcripts associated with UL146 and UL147 is compatible with the potential role of CXC chemokines in pathogenesis associated with viral replication. CONCLUSION: Clinical isolates from two different geographic sites cluster in the same groups based on the hypervariability of the UL146, UL147, or the intergenic sequences, which provides strong evidence for linkage and no evidence for interstrain recombination within this region. The sequence of individual strains was absolutely stable in vitro and in vivo, which indicates that sequence drift is not a mechanism for the observed sequence hypervariability. There is also no evidence of transcriptional splicing, although multiple overlapping transcripts extending into the adjacent UL148 and UL132 open reading frames were detected using gene-specific probes.
Amino Acid Sequence↗
Sequential gene expression profiling in lung transplant recipients with chronic rejection.
STUDY OBJECTIVES: Chronic allograft rejection is the leading cause of morbidity and mortality for long-term survivors of lung transplantation. Previous studies have implicated only isolated genes in the development of chronic rejection and have not examined multiple pathways in an individual concurrently. Using microarray technology, we identified and compared gene expression profiling in lung transplant recipients with and without chronic rejection, and follow sequential expression of genes differentially expressed between the two groups. DESIGN: Prospective, cohort study. SETTING: Single lung transplant center. PATIENTS OR PARTICIPANTS: Eleven transplant recipients with chronic rejection were matched with 9 control transplant recipients. INTERVENTIONS: All recipients underwent surveillance bronchoscopies at predetermined times to rule out infection and/or acute rejection. Gene expression profiling was obtained from hybridizing BAL fluid cell RNA to a 96-gene microarray. MEASUREMENTS AND RESULTS: Fifteen genes were found to be significantly differentially expressed between the two patient groups, and they are involved in inflammatory, fibrotic, and apoptotic pathways. Temporal expression of the significant genes demonstrated a change in their levels at the onset of chronic rejection, with normalization to prerejection levels as rejection continued. CONCLUSIONS: We conclude that microarray technology is valuable in studying the mechanism of chronic lung rejection, and the expression of genes in multiple pathways is elevated in patients with chronic lung rejection.
Adult↗
Donor infection: an opinion on lung donor utilization.
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Bacterial Infections↗
An update on clinical outcomes in heart and lung transplantation.
Much progress has been made in heart and lung transplantation over recent decades. The immune mechanisms that result in allograft rejection are now better understood, and the development of immunosuppressant therapies has decreased recipient mortality among transplant recipients. During the 1980s, immunosuppressant therapy primarily involved the use of corticosteroids and cyclosporine. However, while survival rates increased among transplant recipients, many patients experienced primary graft failures, acute and chronic rejection, as well as death. Until the introduction of tacrolimus in the early 1990s, all patients received the same immunosuppressant regimen, regardless of its effectiveness. Tacrolimus therapy has contributed much to the success rates of both heart and lung transplantation, and by 2001, it had become the preeminent immunosuppressant agent used in lung transplantation.
Acute Disease↗
Surrogate markers and risk factors for chronic lung allograft dysfunction.
Obliterative bronchiolitis (OB) is the histologic correlate of chronic allograft dysfunction in pulmonary transplantation. The histologic diagnosis of OB is challenging, therefore a physiologic definition, bronchiolitis obliterans syndrome (BOS) based on pulmonary function tests has been used as a surrogate marker for OB for the last decade. BOS has proven to be the best available surrogate marker for OB and is predictive of the ultimate endpoints of graft and patient survival. Multiple other clinical markers have been reported and proposed as alternates for or complements to BOS grade, but all need further evaluation and validation in large, prospective clinical trials. Lastly, given the early occurrence and high incidence of chronic allograft dysfunction, the easily measurable endpoint of BOS grade, and our lack of understanding of ways to prevent or alter the course of BOS, lung transplant recipients represent an ideal population for clinical trials targeting prevention and treatment of chronic allograft dysfunction.
Adult↗
Immunosuppressive regimens in lung transplant recipients.
A lung transplant is usually the last resort treatment for lung failure. Since the introduction of cyclosporine A, success rates after solid organ transplantation began to rise, following an incremental curve over the last decade, in which further development of biological agents and newer immunosuppressive agents has continued to improve outcomes after transplantation. Pharmacokinetic and pharmacodynamic properties, as well as efficacy and safety data from clinical trials with immunosuppressive agents and biological agents currently available, are reviewed here.
Drug Administration Schedule↗
Effect of lung volume reduction surgery on diaphragmatic neuromechanical coupling at 2 years.
STUDY OBJECTIVES: We previously reported that patients with emphysema show an increase in diaphragmatic neuromechanical coupling at 3 months after lung volume reduction surgery. Diaphragmatic neuromechanical coupling was quantified as the quotient of tidal volume (normalized to total lung capacity) to tidal change in transdiaphragmatic pressure (normalized to maximal transdiaphragmatic pressure). As such, neuromechanical coupling estimates the fraction of diaphragmatic capacity used to generate tidal breathing. The present investigation was conducted to determine whether benefit is maintained at 2 years. SUBJECTS: Fifteen patients with severe COPD, 8 of whom completed the 2-year study. METHODS: Lung volumes, exercise capacity (6-min walking distance), diaphragmatic function (maximal transdiaphragmatic pressure and twitch transdiaphragmatic pressure elicited by phrenic nerve stimulation), and diaphragmatic neuromechanical coupling were recorded before surgery, and at 3 months and 2 years after surgery. RESULTS: Two years after surgery, lung volumes deteriorated to preoperative values, but patients showed persistent improvements in 6-min walking distance (p < 0.05). Three months after surgery, maximal transdiaphragmatic pressure (p < 0.05), twitch transdiaphragmatic pressure (p < 0.01), and diaphragmatic neuromechanical coupling (p < 0.01) had increased over preoperative values. The improvements in neuromechanical coupling resulted from improvements in diaphragmatic strength and, to a lesser extent, from a decrease in transdiaphragmatic pressure required to maintain tidal breathing. The change in respiratory muscle function at 2 years varied among patients: diaphragmatic contractility was > 10% of preoperative value in half of the patients who concluded our study, and neuromechanical coupling was > 10% of preoperative value in three fourths of the patients who concluded our study. Patients who maintained their gains in neuromechanical coupling also maintained their gains in 6-min walking distance. CONCLUSION: Patients undergoing lung volume reduction surgery can maintain early gains in neuromechanical coupling and exercise capacity 2 years later.
Aged↗
Hormonal resuscitation yields more transplanted hearts, with improved early function.
BACKGROUND: Brain death results in cardiovascular instability and poor organ perfusion in many brain-dead donors. Hormonal resuscitation stabilizes certain brain-dead donors and is associated with significant increases in the numbers of organs transplanted per donor. The goal of this study was to examine the quality of hearts recovered from donors treated with hormonal resuscitation. METHODS: A retrospective analysis of 4,543 recipients of hearts recovered from brain-dead donors, reported to the United Network for Organ Sharing/Organ Procurement and Transplantation Network database between November 1, 1999, and December 31, 2001, was conducted. Hormonal resuscitation consisted of a methylprednisolone bolus and infusions of vasopressin and either triiodothyronine or l-thyroxine. Univariate and multivariate analyses were used to evaluate the quality of hearts from donors who received three-drug hormonal resuscitation (3HR) treatment versus donors who did not receive all three drugs (non-3HR). Death within 30 days and early graft dysfunction were used as endpoints. RESULTS: Hearts from 3HR donors demonstrated a 1-month survival rate of 96.2%, compared with a 92.1% survival rate for non-3HR donor hearts (P<0.01). Early graft dysfunction occurred in 5.6% of 3HR donor hearts and 11.6% of non-3HR donor hearts (P<0.01). Multivariate results demonstrated a 46% reduced odds of death within 30 days and a 48% reduced odds of early graft dysfunction. Steroids alone and steroids plus triiodothyronine/l-thyroxine also significantly reduced prolonged graft dysfunction. CONCLUSIONS: This study suggests that 3HR treatment of brain-dead donors results in increased numbers of transplanted hearts, with improved short-term graft function.
Adult↗
Aggressive pharmacologic donor management results in more transplanted organs.
BACKGROUND: Brain death results in adverse pathophysiologic effects in many cadaveric donors, resulting in cardiovascular instability and poor organ perfusion. Hormonal resuscitation (HR) has been reported to stabilize and improve cardiac function in brain-dead donors. The goal of this study was to examine the effect of HR on the brain-dead donor on the number of organs transplanted per donor. METHODS: A retrospective analysis of all brain-dead donors recovered in the United States from January 1, 2000, to September 30, 2001, was conducted. HR consisted of a methylprednisolone bolus and infusions of vasopressin and either triiodothyronine or L-thyroxine. Univariate analyses and multivariate logistic regression analyses were used to detect differences between the HR group and those donors who did not receive HR. RESULTS: Of 10,292 consecutive brain-dead donors analyzed, 701 received three-drug HR. Univariate analysis showed the mean number of organs from HR donors (3.8) was 22.5% greater than that from nonhormonal resuscitation donors (3.1) (P <0.001). Multivariate analyses showed that HR was associated with the following statistically significant increased probabilities of an organ being transplanted from a donor: kidney 7.3%, heart 4.7%, liver 4.9%, lung 2.8%, and pancreas 6.0%. Extrapolation of these probabilities to the 5,921 brain-dead donors recovered in 2001 was calculated to yield a total increase of 2,053 organs. CONCLUSION: HR stabilizes certain brain-dead donors and is associated with significant increases in organs transplanted per donor.
Adult↗
Lung transplantation. Recipient selection.
Since international recommendations for lung transplant recipients were made in 1998, newer tools for predicting mortality in patients who have end-stage lung disease have been investigated. This article reviews studies for predicting mortality in obstructive, restrictive, pulmonary vascular, and suppurative/bronchiectatic lung disease. Newer considerations for alternative treatments, postoperative risks, and contraindications are also examined. The article aims to provide more accurate data for selecting patients who will benefit from lung transplantation.
Health Care Rationing↗
Comparison of three tacrolimus-based immunosuppressive regimens in lung transplantation.
Immunosuppressive therapy for solid organ transplantation has significantly evolved over the past decade. While these therapies have been found to be beneficial in abdominal organ transplantation, the efficacy of these therapies remains unclear in lung transplantation. We retrospectively compared three potent immunosuppressive regimens in our lung transplant population: Group 1 (tacrolimus/azathioprine/prednisone), Group 2 (tacrolimus/azathioprine/prednisone/daclizumab) and Group 3 (tacrolimus/mycophenolate mofetil/prednisone/daclizumab). We compared these three groups with respect to 3-year rates of acute rejection, chronic rejection, infection and survival. A total of 109 patients was followed during the course of this study. There were 32 patients in Group 1, 49 patients in Group 2 and 28 patients in Group 3. Freedom from acute rejection at 1 and 3 years were higher in Group 3 compared with Group 1 (p < 0.05). The overall incidence of infection up to 3 years after transplantation was comparable among all three groups. Freedom from chronic rejection and survival at 1 and 3 years did not differ among the three groups. In conclusion, we determined the safety and efficacy of three potent immunosuppressive regimens in lung transplantation. Addition of daclizumab and MMF to a tacrolimus-based immunosuppressive regimen decreased the incidence of acute rejection episodes without increasing any adverse events in our lung transplantation population.
Antibodies, Monoclonal↗
Analysis and characterization of antiviral drug-resistant cytomegalovirus isolates from solid organ transplant recipients.
The development of cytomegalovirus (CMV) disease and subsequent emergence of drug-resistant strains was examined in a large group of solid organ transplant recipients; drug-resistant CMV was detected in a total of 30 transplant recipients (20 lung, 5 kidney, 4 heart, and 1 liver). Drug resistance was confirmed both phenotypically and genotypically. The sequences of drug-resistant CMV strains from the same patient differed from drug-susceptible baseline sequences only at single sites previously confirmed to confer drug resistance. At least 1 isolate from each patient had a mutation in the UL97 phosphotransferase coding sequence. Mutations in the DNA polymerase gene were found in 6 of 38 sequenced strains. Lung transplant recipients had the highest incidence of drug-resistant virus: of the 30 patients, 28 were CMV-seronegative transplant recipients of CMV-seropositive organs, which strongly supports the premise that drug resistance is most prevalent in that transplant population.
Antiviral Agents↗
Emergence of ganciclovir-resistant cytomegalovirus in lung transplant recipients.
BACKGROUND: Since ganciclovir-resistant cytomegalovirus (CMV) disease was initially described in a patient with acquired immunodeficiency syndrome (AIDS) in 1986, the incidence of ganciclovir-resistant CMV disease appears to be increasing in immunocompromised patients. More recently, there have been sporadic reports of ganciclovir-resistant CMV disease in solid organ transplantation. METHODS: We retrospectively assessed the incidence of ganciclovir-resistant CMV disease in all lung transplant recipients transplanted between 6/93 and 6/01 at Loyola University Medical Center. All patients underwent routine CMV blood culture, shell vial assay as well as phenotypic and genotypic anti-viral susceptibility testing according to a pre-determined schedule. The number of CMV episodes, intravenous ganciclovir use, acute and chronic rejection and survival data were documented for all patients. RESULTS: Twelve of 212 (6%) transplant recipients developed ganciclovir-resistant CMV disease. Ganciclovir resistance was associated with a higher number of CMV episodes (3.4 +/- 2.3 episodes/patient vs 1.7 +/- 0.7 episodes/patient [p < 0.05]) and an increased exposure to cumulative intravenous ganciclovir in the primary CMV-mismatched (D(+)R(-)) population (22 +/- 10 vs 13 +/- 7 days [p < 0.05]) compared with patients who did not develop ganciclovir resistance. In addition, the use of daclizumab therapy was associated with a 7-fold greater likelihood of developing ganciclovir resistance (p < 0.0001). The presence of ganciclovir-resistant CMV disease in our population was associated with a decreased survival that could be attributed to CMV disease itself (p < 0.05). CONCLUSIONS: By screening all lung transplant recipients with CMV disease for ganciclovir resistance, we were able to detect a higher incidence of ganciclovir-resistant CMV disease (6%) than previously seen in solid organ transplantation. High-risk patients (D(+)R(-) CMV serostatus) who receive anti-lymphocytic therapy should be monitored aggressively and treated to prevent the development of ganciclovir resistance and avert a negative outcome.
Adult↗
Report of the Crystal City meeting to maximize the use of organs recovered from the cadaver donor.
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Humans↗
Increased transplanted organs from the use of a standardized donor management protocol.
The organ shortage has resulted in increasing recipient waiting lists and waiting-list deaths. The increased use of expanded donors has been associated with increased discarding of procured organs because of poor organ function. A structured donor management algorithm or critical pathway was tested to determine its effect on the donor management and procurement process. A pilot study examined donors from 88 critical care units in 10 organ procurement organizations managed under the critical pathway and compared them to retrospective data collected at those same pilot sites. The total number of organs both procured and transplanted per 100 donors was significantly greater (p <0.01) in the critical pathway group when compared to the control group. There was no significant difference in 1-year graft survival for any of the organs recovered, and no significant difference in the rate of delayed graft function in the kidneys transplanted. Use of a structured donor management algorithm results in significant increases in organs procured and organs transplanted without any reduction in the quality of the organs being transplanted.
Clinical Protocols↗