Marie Budev

RNA Interference Therapy in Lung Transplant Patients Infected with Respiratory Syncytial Virus

RATIONALE Lower respiratory tract infections due to respiratory syncytial virus (RSV) are associated with development of bronchiolitis obliterans syndrome in lung transplant (LTX) recipients. ALN-RSV01 is a small interfering RNA targeting RSV replication. OBJECTIVES To determine the safety and explore the efficacy of ALN-RSV01 in RSV infection. METHODS We performed a randomized, double-blind, placebo-controlled trial in LTX recipients with RSV respiratory tract infection. Patients were permitted to receive standard of care for RSV. Aerosolized ALN-RSV01 (0.6 mg/kg) or placebo was administered daily for 3 days. Viral load was determined by quantitative reverse transcriptase-polymerase chain reaction on serial nasal swabs. Patients completed symptom score cards twice daily. Lung function, including the incidence of new-onset or progressive bronchiolitis obliterans syndrome, was recorded at Day 90. MEASUREMENTS AND MAIN RESULTS We enrolled 24 patients (ALN-RSV01, n = 16; placebo, n = 8); randomization was stratified by ribavirin use. ALN-RSV01 was well tolerated, with no drug-related serious adverse events or post-inhalation perturbations in lung function. Interpretation of viral measures was confounded by baseline differences between the two groups in viral load and time from symptom onset to first dose. Mean daily symptom scores were lower in subjects receiving ALN-RSV01, and the mean cumulative daily total symptom score was significantly lower with ALN-RSV01 (114.7 ± 63.13 vs. 189.3 ± 99.59, P = 0.035). At Day 90, incidence of new or progressive bronchiolitis obliterans syndrome was significantly reduced in ALN-RSV01 recipients compared with placebo (6.3% vs. 50%, P = 0.027). CONCLUSIONS ALN-RSV01 was safe and may have beneficial effects on long-term allograft function in LTX patients infected with RSV. Clinical trial registered with www.clinicaltrials.gov (NCT 00658086).

Should lung transplantation be performed using donation after cardiac death? The United States experience

OBJECTIVE We compared 1) survival after lung transplantation of recipients of donation after cardiac death (DCD) versus brain death donor organs in the United States and 2) recipient characteristics. METHODS Data were obtained from the United Network for Organ Sharing for lung transplantation from October 1987 to May 2007. Follow-up after DCD lung transplantation extended to 8.6 years, median 1 year. Differences among recipients of DCD versus brain death donor organs were expressed as a propensity score for use in comparing risk-adjusted survival. RESULTS A total of 14,939 transplants were performed, 36 with DCD organs (9 single, 27 double). Among the 36 patients, 3 have died after 1 day, 11 days, and 1.5 years. Unadjusted survival at 1, 6, 12, and 24 months was 94%, 94%, 94%, and 87%, respectively, for DCD donors versus 92%, 84%, 78%, and 69%, respectively, for brain death donors (P = .04). DCD recipients were more likely to undergo double lung transplantation and have diabetes, lower forced 1-second expiratory volume, and longer cold ischemic times. Once these were accounted for and propensity adjusted, survival was still better for DCD recipients, although the P value equals .06. CONCLUSION Concern about organ quality and ischemia-reperfusion injury has limited the application of lung DCD. However, DCD as practiced in the United States results in survival at least equivalent to that after brain death donation. It also demonstrates selection bias, particularly in performing double lung transplantation, making generalization regarding survival difficult. Nevertheless, the data support the expanded use of DCD.

Utility of leflunomide in the treatment of complex cytomegalovirus syndromes.

Background. Cytomegalovirus (CMV) viremia that is resistant or refractory to the standard antiviral therapy still constitutes a major threat to high-risk transplant recipients. In addition, multiple CMV recurrences may lead to neutropenia because of repeated courses of therapy with ganciclovir derivatives. Leflunomide, a drug for rheumatoid arthritis, has been reported to have anti-CMV activity. This study reports on its use in 17 transplant recipients with complex CMV syndromes who had failed or were intolerant to other therapies. Methods. Single-center, retrospective study. Clinical data were extracted from the electronic medical record. CMV DNA viral loads were performed by quantitative hybrid capture assay. Results. Leflunomide was initiated after a median of three episodes of CMV viremia, with a mean peak viral load of 245,826 copies/mL. Initial clearance of CMV viremia was observed in 14 of 17 patients (82%), and 9 of 17 (53%) patients achieved a long-term suppression of CMV recurrences. Higher peak viral load and higher viral load at the start of leflunomide therapy were associated with failure to suppress viremia. The duration of leflunomide therapy ranged from 1 to 24 months (median 3.5 months, interquartile range 2.6–7 months), and the mean time to an undetectable CMV-DNA was 1.9 months. Adverse effects included diarrhea (35%), anemia (18%), and increased liver function tests (12%). Conclusions. Leflunomide, alone or in combination, has potential utility in treatment of complex CMV syndromes and in long-term suppression of viremia. The optimal duration of therapy and the balance of risks and benefits are not yet known.

Ovarian hyperstimulation syndrome

Objective:Ovarian hyperstimulation syndrome (OHSS) is a rare iatrogenic complication of ovarian stimulation usually occurring during the luteal phase or during the early part of pregnancy. OHSS is a potential complication of ovarian induction by almost every agent used for ovarian stimulation. Today, due to aggressive treatment protocols including the development of in vitro fertilization and cryopreservation with the goal of obtaining sufficient numbers of oocytes and embryos, an increased risk of developing OHSS is present. OHSS is now becoming increasingly more recognized due to the higher number of women undergoing assisted reproductive techniques. Design:Review of the literature regarding ovarian hyperstimulation syndrome. Methods:A review of the epidemiology, pathophysiology, risk factors, classification, clinical features, and treatment and prevention of OHSS. Conclusion:OHSS can be thought of as the loss of control over the hyperstimulation of the ovaries. Although the prevalence of the severe form of OHSS is small, it is important to remember that OHSS is usually an iatrogenic complication of a nonvital treatment that has the potential for a fatal outcome. Therefore, critical care physicians play an integral part in the care of these patients and therefore should be familiar with and recognize the various clinical manifestations and potential outcomes of this entity.

Early Experience With Lung Transplantation Using Donors After Cardiac Death

Lung transplantations that utilize donor organs after cardiac death (DCD) can substantially increase the number of available allografts for waiting recipients. Unfortunately, reported clinical outcomes are limited and widespread acceptance is slow. To further examine the potential of this modality, the results of 4 patients transplanted with DCD organs, implementing a protocol of controlled organ retrieval (Maastricht Classification III), were reviewed. There were no operative deaths; extracorporeal membrane oxygenation was required in 1 patient secondary to severe primary graft dysfunction. Three patients are alive and well at 4, 15 and 21 months; 1 patient died at 34 months with bronchiolitis obliterans syndrome, in part attributable to medication non-compliance.

Effects of influenza immunization on humoral and cellular alloreactivity in humans

Background. Alloreactive T cells and anti-human leukocyte antigen antibodies mediate transplant injury. Environmental exposures, including vaccinations, may activate the alloimmune repertoire leading to accelerated allograft injury. To test whether vaccination impacts human alloimmunity, we analyzed humoral and cellular immune reactivity in subjects undergoing influenza vaccination. Methods. We serially obtained blood samples from 30 healthy subjects and 8 kidney and 9 lung transplant recipients who received influenza vaccination, and from 20 healthy unvaccinated controls. We measured cellular and humoral anti-influenza responses, anti-human leukocyte antigen antibodies, and alloreactive T-cell immunity (interferon-&ggr; ELISPOT) at 0, 2, 4, and 12 weeks after vaccination. Results. Vaccination induced influenza-reactive humoral and cellular responses in control subjects and in transplant recipients. Only two of 30 vaccinated volunteers developed new alloantibodies, but none of the transplant patients. Vaccination also specifically and significantly augmented cellular alloimmunity based on reactivity to a panel of stimulators in both healthy subjects and in transplant recipients within 4 weeks of vaccination. The enhanced cellular alloresponse waned toward prevaccine levels by week 12. Conclusion. Our findings newly demonstrate that influenza vaccination can have a significant impact on the potency of the alloimmune repertoire. Because the strength of the alloresponse influences long-term graft function, our results suggest that further investigation of alloimmune monitoring after vaccination is needed.

Growing Single-Center Experience With Lung Transplantation Using Donation After Cardiac Death

BACKGROUND Early experience with lung transplantation (LTx) using organs from donors after cardiac death (DCD) has been promising, although widespread adoption has been slow because of the perception of diminished organ quality. Some centers have even suggested that use of DCD lungs is high risk and have recommended ex vivo evaluation before transplantation. We analyzed our growing single-center experience with DCD lungs procured and transplanted using protocols established for brain-dead donors. METHODS From August 2004 to July 2011, 605 patients underwent LTx, 32 (4.9%) with DCD organs. Standardized donor selection, procurement, and preservation protocols established for brain-dead donors were applied to DCD organs. Measured outcomes were Kaplan-Meier survival, early graft function measured by arterial partial pressure of oxygen/fraction of inspired oxygen (PO2/FIO2 ratio [P/F ratio]), airway complications, spirometry, and development of bronchiolitis obliterans syndrome (BOS). RESULTS Survival was 97% at 30 days, 91% at 1 year, 91% at 2 years, and 71% at 3 and 4 years. Mean P/F ratio at 6 hours and 24 hours was 305 and 332, respectively. One airway complication required intervention. Median time to extubation, intensive care unit (ICU), and total hospital lengths of stay were 1, 4, and 14 days, respectively. At median follow-up of 2.8 years, median forced expiratory volume in 1 second, percent of predicted (FEV1%) of the survivors was 59% (range, 27%-113%), with 16% (5/32) having BOS. CONCLUSIONS This growing experience suggests that recipient survival and early graft function using DCD lungs is excellent and has occurred without significant adjustment of procurement, preservation, or implantation protocols. Concerns over diminished organ quality are unfounded, and use of DCD lungs should be expanded.

Oral versus inhaled ribavirin therapy for respiratory syncytial virus infection after lung transplantation

BACKGROUND Respiratory syncytial virus (RSV) is a significant contributor to morbidity in adult lung transplant recipients. Multiple modes of ribavirin administration have been described in the literature. This study investigated outcomes related to delivery route. METHODS We performed a retrospective analysis of adult lung transplant patients infected with RSV (2006-2010). RSV severity was graded according to clinical symptoms and bronchiolitis obliterans syndrome (BOS) status on International Society for Heart and Lung Transplantation (ISHLT) criteria. Relationships between route of ribavirin delivery and RSV severity, BOS progression at 6 months after RSV infection, and overall survival were assessed. Of 30 RSV-positive patients identified, 9 were ultimately excluded. RESULTS The 21 study patients were a mean age of 49 ± 17 years (range, 17-72 years) at transplant. Six received oral and 15 received inhaled ribavirin per clinician preference. No significant differences were observed between the groups by age, sex, or ethnicity. Mean time from transplant to RSV was 26 ± 29 months (range, 1-100 months). Infections were mild in 2 of 6 patients in the oral compared with 11 of 15 in the inhaled group (p = 0.17). None of the oral group and 3 of the inhaled group exhibited BOS 1 at time of infection (p = 0.53); 2 (inhaled) had new onset/progression of BOS at 6 months after RSV (p > 0.99). No difference in overall survival (p = 0.41) was observed between the 2 groups. CONCLUSIONS This retrospective study demonstrates no significant differences in 6-month outcomes between oral and inhaled ribavirin therapy for RSV infection after lung transplantation.

An Emerging Population: Kidney Transplant Candidates Who Are Placed on the Waiting List after Liver, Heart, and Lung Transplantation

BACKGROUND AND OBJECTIVES ESRD has an adverse impact on patients who have had previous nonrenal solid-organ transplants (NRTxs; liver, heart, lung) and may be referred for a kidney transplant (KTx). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Using Scientific Registry of Transplant Recipients data for all KTx candidates who had NRTx and were listed between 1995 and 2008, incidence of NRTx listings were compared with trends in KTx without NRTX. The efficacy of kidney transplantation relative to dialysis was measured in time-dependent Cox models that incorporated candidates with the applicable previous organ transplant as a reference group. RESULTS Overall, 4904 NRTx candidates were listed during the study period, growing from <1% of candidates before 1995 to 3.3% in 2008. A total of 38% of NRTx candidates were listed preemptively versus 21% of other candidates. NRTx candidates had dramatically shorter half-lives (≤ 4 years) after listing compared with previous KTx recipients (9.2 years). KTx demonstrated a survival advantage for each type of NRTx candidate relative to maintenance dialysis. Listing for expanded-criteria donor kidneys averaged 47% and did not differ significantly by previous transplant category. CONCLUSIONS KTx candidates who are placed on the waiting list after NRTx constitute a significant and more rapidly growing cohort compared with the general KTx candidate population. NRTx candidates are frequently listed preemptively but have rapid decline once placed on the waiting list. Targeted use of expanded-criteria donor and living-donor transplants in the NRTx population may be particularly important given their high mortality on the waiting list.

Spirometry After Transplantation: How Much Better Are Two Lungs Than One?

BACKGROUND The purpose of this study was to determine how much double lung transplantation improves lung function over single lung transplantation and to identify predictors of lung function after transplantation. METHODS From February 1990 to November 2005, 463 adults underwent lung transplantation. Among 379 of these patients (82%), 6372 evaluations of postoperative normalized forced expiratory volume in 1 second (FEV(1)) and forced vital capacity (FVC) were analyzed using longitudinal temporal decomposition methods for repeated continuous measurements. We characterized the time course of postoperative spirometry, compared it between double and single lung transplantation, and identified its modulators. RESULTS FEV(1) (% of predicted) was only somewhat better after double than single lung transplantation (65%, 58%, and 59% vs 51%, 43%, and 40% at 1, 3, and 5 years, p = 0.03), as was FVC (% of predicted) (67%, 68%, and 66% vs 62%, 56%, and 51%, p < 0.0001). Both FEV1% and FVC% increased sharply to 1 year. For double lung transplantation, these values persisted, with minimal decline to 5 years; but for single lung transplantation, they continuously declined to 5 years. Values for double lung transplantation remained higher than for single lung transplantation at all time points but never approached twice the value. Patients undergoing double lung transplantation for emphysema had the highest postoperative FEV1% and FVC%, but also the lowest values for single lung transplantation; the benefit of double lung transplantation was between these values for other diagnoses. CONCLUSIONS Spirometry weakly favors double lung over single lung transplantation. The advantage of spirometry values alone may not justify double lung transplantation.