Martin R. Zamora

A consensus document for the selection of lung transplant candidates: 2014--an update from the Pulmonary Transplantation Council of the International Society for Heart and Lung Transplantation.

The appropriate selection of lung transplant recipients is an important determinant of outcomes. This consensus document is an update of the recipient selection guidelines published in 2006. The Pulmonary Council of the International Society for Heart and Lung Transplantation (ISHLT) organized a Writing Committee of international experts to provide consensus opinion regarding the appropriate timing of referral and listing of candidates for lung transplantation. A comprehensive search of the medical literature was conducted with the assistance of a medical librarian. Writing Committee members were assigned specific topics to research and discuss. The Chairs of the Writing Committee were responsible for evaluating the completeness of the literature search, providing editorial support for the manuscript, and organizing group discussions regarding its content. The consensus document makes specific recommendations regarding the timing of referral and of listing for lung transplantation. These recommendations include discussions not present in previous ISHLT guidelines, including lung allocation scores, bridging to transplant with mechanical circulatory and ventilator support, and expanded indications for lung transplantation. In the absence of high-grade evidence to support decision making, these consensus guidelines remain part of a continuum of expert opinion based on available studies and personal experience. Some positions are immutable. Although transplant is rightly a treatment of last resort for end-stage lung disease, early referral allows proper evaluation and thorough patient education. Subsequent waiting list activation implies a tacit agreement that transplant offers a significant individual survival advantage. It is both the challenge and the responsibility of the transplant community globally to ensure organ allocation maximizes the potential benefits of a scarce resource, thereby achieving that advantage.

DIFFUSE ALVEOLAR HEMORRHAGE AND SYSTEMIC LUPUS ERYTHEMATOSUS : CLINICAL PRESENTATION, HISTOLOGY, SURVIVAL, AND OUTCOME

Diffuse alveolar hemorrhage (DAH) complicating systemic lupus erythematosus (SLE) remains a devastating pulmonary complication of this systemic disease. We conducted this study to review the clinicopathologic presentation and the effects of prior treatment, presence of infection, and current treatment on the survival and outcome of patients with DAH and SLE. We reviewed the records of 15 SLE patients who experienced 19 episodes of DAH over a 10-year period in a single tertiary care hospital. These patients were compared with 57 previously reported cases. The 19 episodes of DAH represented 3.7% of the 510 admissions occasioned by various complications of SLE. As previously reported, the majority (66%) were women with a median age of 27 years. The onset was often abrupt: < 3 days in 12 of the episodes. In 3 patients (20%), DAH was the initial manifestation of SLE, compared with 11% in the literature series. In the other patients in the present series, DAH appeared a median of 31 months following the diagnosis of SLE, versus 35 months in the literature series. In only 42% of the episodes in the present series, compared with 66% in the literature series, was hemoptysis present at the time of admission. However, hemoptysis eventually appeared in all 19 episodes. Temperature elevation (> 38 degrees C) was another inconsistent finding, found in only 5 episodes (26%) in the present series. The most constant concurrent systemic finding was lupus nephritis (14/15 patients). This represents a significant increase when compared with the literature series (29/48 patients). In 8 of 10 patients in whom lung tissue was available, pulmonary capillaritis accompanied the DAH. This represents a marked difference in the underlying histologic pattern when compared with the literature series. In those patients, 72% (31/43 patients) had bland pulmonary hemorrhage, and capillaritis was described in only 6 patients. The overall patient mortality rate was 53% in the current series and 50% in the literature series. Factors associated with an increased mortality in the present series include the following: mechanical ventilation (62%) versus no mechanical ventilation (0%); infection (78%) versus no infection (20%); and cyclophosphamide therapy for the acute DAH episode (70%) versus no cyclophosphamide therapy (20%). The incidence of infection in DAH and SLE (9/19 episodes) is far greater than previously reported (7/ 57 episodes). One possible explanation for this difference is the increased use of outpatient immunosuppressive therapy with monthly intravenous cyclophosphamide therapy for lupus nephritis. Eighteen DAH episodes in the present series were treated with intravenous methylprednisolone. When one combines both the current and literature series experience (16 episodes), the use of plasmapheresis does not improve survival. Of the 7 patients in the present series who survived all episodes of DAH, 6 remain alive a median of 50 months post episode and without recurrence of DAH. Diffuse alveolar hemorrhage is an uncommon but lethal complication of SLE. The survival rate remains unchanged from previous reports. The absence of hemoptysis should not exclude this diagnosis, particularly in those patients who experience an acute pulmonary syndrome with new radiographic infiltrates accompanied by falling hematocrit and the presence of a hemorrhagic bronchoalveolar lavage. Evidence for lupus nephritis is present in the great majority of cases. Most cases demonstrate the histologic pattern of pulmonary capillaritis. The mortality is adversely affected by the need for mechanical ventilation, either the presence of infection at the time of admission or the development of infection in the hospital, and the use of cyclophosphamide for treatment of the acute event.

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).

An international ISHLT/ATS/ERS clinical practice guideline: diagnosis and management of bronchiolitis obliterans syndrome

Bronchiolitis obliterans syndrome (BOS) is a major complication of lung transplantation that is associated with poor survival. The International Society for Heart and Lung Transplantation, American Thoracic Society, and European Respiratory Society convened a committee of international experts to describe and/or provide recommendations for 1) the definition of BOS, 2) the risk factors for developing BOS, 3) the diagnosis of BOS, and 4) the management and prevention of BOS. A pragmatic evidence synthesis was performed to identify all unique citations related to BOS published from 1980 through to March, 2013. The expert committee discussed the available research evidence upon which the updated definition of BOS, identified risk factors and recommendations are based. The committee followed the GRADE (Grading of Recommendation, Assessment, Development and Evaluation) approach to develop specific clinical recommendations. The term BOS should be used to describe a delayed allograft dysfunction with persistent decline in forced expiratory volume in 1 s that is not caused by other known and potentially reversible causes of post-transplant loss of lung function. The committee formulated specific recommendations about the use of systemic corticosteroids, cyclosporine, tacrolimus, azithromycin and about re-transplantation in patients with suspected and confirmed BOS. The diagnosis of BOS requires the careful exclusion of other post-transplant complications that can cause delayed lung allograft dysfunction, and several risk factors have been identified that have a significant association with the onset of BOS. Currently available therapies have not been proven to result in significant benefit in the prevention or treatment of BOS. Adequately designed and executed randomised controlled trials that properly measure and report all patient-important outcomes are needed to identify optimal therapies for established BOS and effective strategies for its prevention. Diagnosis of BOS requires careful exclusion of other complications that can cause delayed lung allograft dysfunction http://ow.ly/AZmbr

Following Universal Prophylaxis with Intravenous Ganciclovir and Cytomegalovirus Immune Globulin, Valganciclovir is Safe and Effective for Prevention of CMV Infection Following Lung Transplantation

We prospectively determined the safety and efficacy of valganciclovir for prevention of cytomegalovirus (CMV) in at‐risk (donor positive/recipient negative [D+/R−] or R+) lung transplant recipients. We also determined the length of prophylaxis required to significantly decrease both CMV infection and disease. Consecutive lung transplant recipients surviving >30 days (n = 90) received combination prophylaxis with intravenous (i.v.) ganciclovir (GCV) 5 mg/kg/day and cytomegalovirus immune globulin (CMV‐IVIG) followed by valganciclovir (450 mg twice‐daily) to complete 180, 270 or 365 days of prophylaxis. This group was compared to a historical group (n = 140) who received high‐dose oral acyclovir following i.v. GCV and CMV‐IVIG. CMV disease was significantly lower in patients receiving valganciclovir compared to acyclovir (2.2% vs. 20%; p < 0.0001). Freedom from CMV infection and disease was significantly greater (p < 0.02) in patients receiving 180, 270 or 365 days of prophylaxis (90%, 95% and 90%, respectively) compared to those receiving 100–179 days (64%) or <100 days (59%). No patient receiving valganciclovir died during the study. Following prophylaxis with i.v. GCV and CMV‐IVIG, valganciclovir is safe and effective for prevention of CMV infection and disease in at‐risk lung transplant recipients. The required length of prophylaxis was at least 180 days.

Cytomegalovirus and Lung Transplantation

Cytomegalovirus (CMV) infection remains a serious problem in lung transplant recipients. Development of potent oral antiviral agents, molecular techniques for the detection of infection and its response to therapy and the emergence of isolates with antiviral resistance have had significant impacts on the approach to CMV in these patients. This article discusses the following issues as part of a comprehensive CMV management strategy in lung transplant recipients: ( 1) Prevention strategies in the era of potent oral antiviral agents, ( 2) the role of new diagnostic techniques in the management of CMV, ( 3) treatment regimens for established CMV infection or disease, ( 4) the potential impact of treatment of CMV on the indirect effects on long‐term allograft function, and ( 5) the incidence, risk factors for and impact of ganciclovir resistance following lung transplantation.

Microvascular destruction identifies murine allografts that cannot be rescued from airway fibrosis

Small airway fibrosis (bronchiolitis obliterans syndrome) is the primary obstacle to long-term survival following lung transplantation. Here, we show the importance of functional microvasculature in the prevention of epithelial loss and fibrosis due to rejection and for the first time, relate allograft microvascular injury and loss of tissue perfusion to immunotherapy-resistant rejection. To explore the role of alloimmune rejection and airway ischemia in the development of fibroproliferation, we used a murine orthotopic tracheal transplant model. We determined that transplants were reperfused by connection of recipient vessels to donor vessels at the surgical anastomosis site. Microcirculation through the newly formed vascular anastomoses appeared partially dependent on VEGFR2 and CXCR2 pathways. In the absence of immunosuppression, the microvasculature in rejecting allografts exhibited vascular complement deposition, diminished endothelial CD31 expression, and absent perfusion prior to the onset of fibroproliferation. Rejecting grafts with extensive endothelial cell injury were refractory to immunotherapy. After early microvascular loss, neovascularization was eventually observed in the membranous trachea, indicating a reestablishment of graft perfusion in established fibrosis. One implication of this study is that bronchial artery revascularization at the time of lung transplantation may decrease the risk of subsequent airway fibrosis.

Update and review: state-of-the-art management of cytomegalovirus infection and disease following thoracic organ transplantation.

PURPOSE Cytomegalovirus (CMV) is among the most important viral pathogens affecting solid organ recipients. The direct effects of CMV (eg, infection and its sequela; tissue invasive disease) are responsible for significant morbidity and mortality. In addition, CMV is associated with numerous indirect effects, including immunomodulatory effects, acute and chronic rejection, and opportunistic infections. Due to the potentially devastating effects of CMV, transplant surgeons and physicians have been challenged to fully understand this infectious complication and find the best ways to prevent and treat it to ensure optimal patient outcomes. SUMMARY Lung, heart, and heart-lung recipients are at considerably high risk of CMV infection. Both direct and indirect effects of CMV in these populations have potentially lethal consequences. The use of available treatment options depend on the level of risk of each patient population for CMV infection and disease. Those at the highest risk are CMV negative recipients of CMV positive organs (D+/R-), followed by D+/R+, and D-/R+. More than 1 guideline exists delineating prevention and treatment options for CMV, and new guidelines are being developed. It is hoped that new treatment algorithms will provide further guidance to the transplantation community. The first part describes the overall effects of CMV, both direct and indirect; risk factors for CMV infection and disease; methods of diagnosis; and currently available therapies for prevention and treatment. Part 2 similarly addresses antiviral-resistant CMV, summarizing incidence, risk factors, methods of diagnosis, and treatment options. Parts 3 and 4 present cases to illustrate issues surrounding CMV in heart and lung transplantation, respectively. Part 3 discusses the possible mechanisms by which CMV can cause damage to the coronary allograft and potential techniques of avoiding such damage, with emphasis on fostering strong CMV-specific immunity. Part 4 highlights the increased incidence of CMV infection and disease among lung transplant recipients and its detrimental effect on survival. The possible benefits of extended-duration anti-CMV prophylaxis are explored, as are those of combination prophylaxis with valganciclovir and CMVIG. CONCLUSION Through improved utilization of information regarding optimized antiviral therapy for heart and lung transplant recipients to prevent and treat CMV infection and disease and through increased understanding of clinical strategies to assess, treat, and monitor patients at high risk for CMV recurrence and resistance, the health care team will be able to provide the coordinated effort needed to improve patient outcomes.

The value of polymerase chain reaction for the diagnosis of viral respiratory tract infections in lung transplant recipients.

BACKGROUND Respiratory viruses cause severe infections in lung transplant recipients, which require rapid and accurate diagnosis for appropriate management. OBJECTIVES To evaluate the added benefit of a multiplex PCR for respiratory viruses (influenza [FLU] A and B, respiratory syncytial virus [RSV] A and B and parainfluenza virus [PIV] 1, 2, and 3) complementing rapid respiratory viral culture (RRV) and FLU-A antigen detection (EIA) in this transplant population. RESULTS Over 6 months, 116 nasal washes and bronchoalveolar lavages, obtained from 72 lung transplant recipients with symptoms of upper or lower respiratory tract infections, were tested in real time by RRV and FLU-A EIA, and batched frozen by PCR. One or more methods recognized a respiratory virus in 31 (27%) specimens, including 15 FLU-A, nine RSV and seven PIV. PCR identified 26 of 31 positive samples demonstrating a sensitivity of 84%, higher than RRV (67%) or EIA (54%). PCR, RRV and EIA detected 60, 80 and 54%, respectively, FLU-A samples. PCR and RRV were equivalent for RSV-A, PIV-2 and 3, but PCR found a significantly higher number of RSV-B and PIV-1. CONCLUSIONS These data indicate that routine use of PCR will enhance the number and speed with which viral respiratory tract infections are diagnosed in lung transplant recipients.

Antibody-mediated rejection of the lung: A consensus report of the International Society for Heart and Lung Transplantation

Antibody-mediated rejection (AMR) is a recognized cause of allograft dysfunction in lung transplant recipients. Unlike AMR in other solid-organ transplant recipients, there are no standardized diagnostic criteria or an agreed-upon definition. Hence, a working group was created by the International Society for Heart and Lung Transplantation with the aim of determining criteria for pulmonary AMR and establishing a definition. Diagnostic criteria and a working consensus definition were established. Key diagnostic criteria include the presence of antibodies directed toward donor human leukocyte antigens and characteristic lung histology with or without evidence of complement 4d within the graft. Exclusion of other causes of allograft dysfunction increases confidence in the diagnosis but is not essential. Pulmonary AMR may be clinical (allograft dysfunction which can be asymptomatic) or sub-clinical (normal allograft function). This consensus definition will have clinical, therapeutic and research implications.