Chronic Thromboembolic Pulmonary Hypertension.

Chronic thromboembolic pulmonary hypertension (CTEPH), defined as precapillary pulmonary hypertension (PH) by right heart catheterization and imaging consistent with chronic thromboembolism, is a long-term complication of pulmonary embolism (PE). Pathobiological mechanisms involve pulmonary artery occlusion from organized thromboembolic material despite at least three months of uninterrupted therapeutic anticoagulation following acute PE and secondary microvasculopathy. Delay in diagnosis and management of CTEPH is associated with poor outcomes. High clinical suspicion, comprehensive assessment of residual dyspnea or exercise intolerance in the aftermath of PE and accurate interpretation of computed tomography pulmonary angiography (CTPA) are pivotal steps in the diagnosis. Ventilation-perfusion (V/Q) scan is the preferred initial radiologic screening tool as normal V/Q essentially rules out CTEPH. Any mismatched perfusion defect on the V/Q scan in the setting of PH or any finding compatible with chronic thromboembolism on CTPA should prompt referral to an expert CTEPH center. Once the diagnosis is verified, all eligible patients should be offered pulmonary thromboendarterectomy (PTE). Pulmonary vasodilators or balloon pulmonary angioplasty are safe and effective in inoperable or post-PTE persistent/recurrent CTEPH. During the course of their disease, a patient may receive a combination of treatments, at times consisting of all three strategies. Lifelong therapeutic anticoagulation is recommended for CTEPH.

Identification of a Novel EIF2AK Variant and Genetics-Assisted Approach to Diagnosis of Pulmonary Capillary Hemangiomatosis.

Pulmonary capillary hemangiomatosis (PCH) is an uncommon type of pulmonary vascular disease characterized by capillary proliferation and very poor prognosis owing to misdiagnosis and lack of effective therapeutic options. Mutations in the eukaryotic translation initiation factor 2α kinase 4 (EIF2AK4) gene have been reported in pulmonary veno-occlusive disease and PCH. In this report, we present a patient whose diagnosis of PCH was delayed by 2 ½ years despite prior surgical lung biopsy and clinical and laboratory findings suggestive of pulmonary hypertension. Genotyping revealed a novel likely pathogenic variant in the EIF2AK4 gene. Review of surgical lung biopsy performed 2 ½ years prior confirmed PCH histology along with constrictive bronchiolitis.

Donor derived hepatitis B virus infection: Analysis of the Organ Procurement & Transplantation Network/United Network for Organ Sharing Ad Hoc Disease Transmission Advisory Committee.

Hepatitis B virus (HBV) can be transmitted from organ donor to recipient, but details of transmission events are not widely published. The Disease Transmission Advisory Committee (DTAC) evaluated 105 cases of potential donor derived transmission events of HBV between 2009-2017. Proven, probable or possible transmission of HBV occurred in 25 (23.8%) cases. Recipients of liver grafts were most commonly infected (20 of 21 exposed recipients) compared to 9 of 21 exposed non-hepatic recipients. Eleven of 25 donors were HBV core antibody (HBcAb) positive/HBV surface antigen (HBsAg) negative and infected 8/20 recipients. Of the 10 liver recipients and 1 liver-kidney recipient who received organs from these donors: six were not given antiviral prophylaxis, two developed infection after antiviral prophylaxis was discontinued, two developed HBV while on lamivudine prophylaxis, one was on antiviral prophylaxis and did not develop HBV viremia or antigenemia. One recipient of a HBcAb positive/HBsAg negative kidney developed active HBV infection. Unexpected donor-derived transmission of HBV was a rare event in reports to DTAC, but was often detected in the recipient late post-transplant. Six of 11 recipients (54.5%) of a liver from a HBcAb positive donor did not receive prophylaxis; all of these were potentially preventable with the use of anti-viral prophylaxis.

Ambulatory Transition from Parenteral Prostanoid to Inhaled Treprostinil in Patients with Pulmonary Arterial Hypertension.

PURPOSE: The intravenous or subcutaneous delivery of prostanoid drugs for moderate to severe pulmonary arterial hypertension has been fraught with complications and patient dissatisfaction. Combination therapy including inhaled treprostinil is an attractive alternative in clinically stable patients. Uncertainties exist about the patient characteristics and the optimal setting (inpatient versus office/home) for transition. METHODS: Sixteen stable patients with pulmonary arterial hypertension and favorable risk profile were transitioned from parenteral prostanoid to combination therapy including inhaled treprostinil in the home setting. Nine patients were using intravenous treprostinil, two patients were using subcutaneous treprostinil, and five patients were using intravenous epoprostenol at a median dose of 80 (interquartile range, IQR 72-90), 76.5 (68 and 85), and 28 (IQR 26-30) ng/kg/min respectively. Patients were followed up for a median of 732.5 days after transition (IQR 506.5-1294 days). RESULTS: Patients tolerated the transition to inhaled treprostinil well without significant change in functional class (81.25% FC I/II before transition vs. 87.5% after), 6-min walk distance [349 m (IQR 226-461 m) to 364 m (IQR 238-565 m), p = 0.09] or NT-proBNP [149 pg/ml (IQR 71.5-383 pg/ml) to 186.5 pg/ml (IQR 83.5-444 pg/ml), p = 0.38]. Hemodynamic data, where available, showed significant improvements in mean pulmonary artery pressure and pulmonary vascular resistance from 36 mmHg (IQR 27-46.5 mmHg) and 5.2 Wood Units (WU) (IQR 3.1-5.6 WU) to 28.5 mmHg (IQR 22-35.5 mmHg) and 3.2 WU (IQR 2.4-4.2 WU) (p-values 0.022 and 0.003). More patients were on triple therapy after transition, and side effects reported were less severe. CONCLUSION: For select patients, transition from a parenteral prostanoid-based therapy to a combination regimen including inhaled treprostinil in the home setting appears safe and well tolerated.

Single-Cell Transcriptomic Analysis of Human Lung Provides Insights into the Pathobiology of Pulmonary Fibrosis.

Rationale: The contributions of diverse cell populations in the human lung to pulmonary fibrosis pathogenesis are poorly understood. Single-cell RNA sequencing can reveal changes within individual cell populations during pulmonary fibrosis that are important for disease pathogenesis. Objectives: To determine whether single-cell RNA sequencing can reveal disease-related heterogeneity within alveolar macrophages, epithelial cells, or other cell types in lung tissue from subjects with pulmonary fibrosis compared with control subjects. Methods: We performed single-cell RNA sequencing on lung tissue obtained from eight transplant donors and eight recipients with pulmonary fibrosis and on one bronchoscopic cryobiospy sample from a patient with idiopathic pulmonary fibrosis. We validated these data using in situ RNA hybridization, immunohistochemistry, and bulk RNA-sequencing on flow-sorted cells from 22 additional subjects. Measurements and Main Results: We identified a distinct, novel population of profibrotic alveolar macrophages exclusively in patients with fibrosis. Within epithelial cells, the expression of genes involved in Wnt secretion and response was restricted to nonoverlapping cells. We identified rare cell populations including airway stem cells and senescent cells emerging during pulmonary fibrosis. We developed a web-based tool to explore these data. Conclusions: We generated a single-cell atlas of pulmonary fibrosis. Using this atlas, we demonstrated heterogeneity within alveolar macrophages and epithelial cells from subjects with pulmonary fibrosis. These results support the feasibility of discovery-based approaches using next-generation sequencing technologies to identify signaling pathways for targeting in the development of personalized therapies for patients with pulmonary fibrosis.

Telomere length associates with chronological age and mortality across racially diverse pulmonary fibrosis cohorts.

Pulmonary fibrosis (PF) is characterized by profound scarring and poor survival. We investigated the association of leukocyte telomere length (LTL) with chronological age and mortality across racially diverse PF cohorts. LTL measurements among participants with PF stratified by race/ethnicity were assessed in relation to age and all-cause mortality, and compared to controls. Generalized linear models were used to evaluate the age-LTL relationship, Cox proportional hazards models were used for hazard ratio estimation, and the Cochran-Armitage test was used to assess quartiles of LTL. Standardized LTL shortened with increasing chronological age; this association in controls was strengthened in PF (R = -0.28; P < 0.0001). In PF, age- and sex-adjusted LTL below the median consistently predicted worse mortality across all racial groups (White, HR = 2.21, 95% CI = 1.79-2.72; Black, HR = 2.22, 95% CI = 1.05-4.66; Hispanic, HR = 3.40, 95% CI = 1.88-6.14; and Asian, HR = 2.11, 95% CI = 0.55-8.23). LTL associates uniformly with chronological age and is a biomarker predictive of mortality in PF across racial groups.

Comparison of sirolimus with azathioprine in a tacrolimus-based immunosuppressive regimen in lung transplantation.

RATIONALE: Lung transplantation has evolved into a life-saving therapy for select patients with end-stage lung diseases. However, long-term survival remains limited because of chronic rejection. Sirolimus is beneficial in preventing cardiac rejection and may decrease rejection after lung transplantation. OBJECTIVES: To determine the potential benefit versus risk of sirolimus in lung transplantation. METHODS: We conducted a multicenter randomized, open label controlled trial comparing sirolimus (SIR) with azathioprine (AZA) in a tacrolimus-based immunosuppressive regimen in lung transplantation. The primary end point was the incidence of acute rejection at 1 year after transplantation between the two study groups. MEASUREMENTS AND MAIN RESULTS: One hundred eighty-one patients were randomized to be included in this study. At 1 year after transplantation, there was no significant difference in the incidence of grade A acute rejection between the two study groups. Similarly, the incidence of chronic rejection and graft survival was no different between the two study groups. Cytomegalovirus infection was decreased in the SIR arm compared with the AZA arm (relative risk, 0.67 [95% confidence interval, 0.55, 0.82]; P < 0.01). There was a higher rate of adverse events leading to early discontinuation of SIR (64%) compared with AZA (49%) during the course of this study. CONCLUSIONS: Sirolimus, an mTOR inhibitor, did not decrease the incidence of acute rejection at 1 year compared with azathioprine in lung transplantation. These results differ from previous results in cardiac and renal transplantation and emphasize the need for multicenter randomized controlled trials in lung transplantation. Clinical trial registered with www.clinicaltrials.gov (NCT 00321906).

Multiorgan transplant program in a nonacademic center: organizational structure and outcomes.

Given the complexity of solid organ transplantation, it is reasonable to believe that numerous factors are at play in achieving the enviable outcomes reported. The aim of this study is to examine the role of an organizational structure in maintaining the outcomes of a multiorgan transplant program at a nonacademic center. A retrospective analysis of 2378 solid organ transplants at Nazih Zuhdi Transplant Institute between March 1985 and December 2008 was performed. The 1-year and 3-year patient and graft survival rates, rate of retransplantation, and median length of hospital stay were compared with US national data released by the Scientific Registry of Transplant Recipients in January 2009. The 1-year patient survival rates were 87.5% for heart, 95.1% for kidney, 75.8% for lung, 89.6% for liver, and 100.0% for pancreas. The 3-year patient survival rates were 73.5% for heart, 89.7% for kidney, 57.8% for lung, 87.7% for liver, and 100.0% for pancreas. A well-structured transplant program along with competent medical, administrative, and ancillary support can achieve comparable patient and graft survival rates independent of volume.

Long-term results of the DelIVery for Pulmonary Arterial Hypertension trial.

BACKGROUND: The DelIVery for Pulmonary Arterial Hypertension clinical trial was a multi-center, prospective, single arm, Investigational Device Exemption study utilizing a fully implantable, programmable intravascular delivery system consisting of a pump and a catheter for intravenous treprostinil. The study met its primary endpoint and demonstrated that the intravascular delivery system significantly reduced catheter related complications at 22,000 subject-days of follow-up compared with a predefined objective performance criterion. Here we summarize the results obtained during a 6.4-year follow-up period. METHODS: Throughout study follow-up, participants had clinic visits and medication refills at least every 12 weeks (dependent on the subjects' dose). All adverse events and intravascular delivery system complications were evaluated and recorded. RESULTS: Sixty pulmonary arterial hypertension subjects were followed post device implantation for approximately 282 patient-years (range 87 days to 6.4 years). Of the 60 subjects, 14 died (1 related to intravascular delivery system pump failure), 2 withdrew after lung transplants, and 2 withdrew due to pump pocket infection. No catheter-related bloodstream infections, catheter thrombosis or occlusions, or catheter kinks occurred through 282 patient-years. Two participants had adverse events of abdominal pain, rash, due to subcutaneous treprostinil "leaks" after one catheter puncture and one catheter laceration during pump refill and replacement, respectively. Eight pump failure events occurred: seven pump motor stalls and one early replacement (faulty battery). CONCLUSION: Delivery of treprostinil with an intravascular delivery system is a safe alternative to an external delivery system, while providing enhanced life experiences. To preserve the risk-benefit ratio, treatment at specialized pulmonary arterial hypertension centers is recommended until training is disseminated at other sites.

The role of intrinsic efficacy in determining response to a beta2-agonist in acute severe asthma.

BACKGROUND: Current guidelines recommend repeated doses of albuterol for the emergency treatment of acute asthma. However, approximately one-third of patients show little or no initial response to this partial beta(2)-agonist. METHODS: We conducted a randomized, double-blind, proof-of-concept study to investigate whether a full beta(2)-agonist, isoproterenol, offers a therapeutic advantage in adults presenting with acute severe asthma (FEV(1)<50%) who fail to respond to an initial treatment of the partial beta(2)-agonist, albuterol. Study subjects were randomized to receive a 2-h continuous nebulization of either albuterol (7.5mg/h) (n=10, mean FEV(1)=37% predicted) or isoproterenol (7.5mg/h) (n=9, mean FEV(1)=33% predicted). Respiratory symptoms, vital signs and pulmonary function measures were collected. RESULTS: Subjects from both treatment groups had similar baseline characteristics. The percent improvements from baseline FEV(1) at 60 and 120min were significantly higher in subjects receiving isoproterenol than those receiving albuterol (44 vs. 17% and 63 vs. 24%, respectively, P<0.05). The change in symptoms measured by the modified Borg score was also significantly greater in subjects receiving isoproterenol (P<0.01). Both treatments were well tolerated, though the mean increase in pulse rate at 60 and 120min (21 vs. 1 and 23 vs. 6beats/min, respectively, P<0.05) and the mean change in serum potassium at 120min (-0.52 vs. -0.07meq/L, P<0.05) from baseline were significantly greater in the isoproterenol group. CONCLUSIONS: Our data suggest that in subjects presenting with acute severe asthma who fail to show an initial response to albuterol, the use of a beta(2)-agonist of higher intrinsic efficacy can be more effective in improving lung function and symptoms.

Comprehensive Care of the Lung Transplant Patient.

Lung transplantation has evolved into a life-saving treatment with improved quality of life for patients with end-stage respiratory failure unresponsive to other medical or surgical interventions. With improving survival rates, the number of lung transplant recipients with preexisting and posttransplant comorbidities that require attention continues to increase. A partnership between transplant and nontransplant care providers is necessary to deliver comprehensive and optimal care for transplant candidates and recipients. The goals of this partnership include timely referral and assistance with transplant evaluation, optimization of comorbidities and preparation for transplantation, management of common posttransplant medical comorbidities, immunization, screening for malignancy, and counseling for a healthy lifestyle to maximize the likelihood of a good outcome. We aim to provide an outline of the main aspects of the care of candidates for and recipients of lung transplants for nontransplant physicians and other care providers.

Serum KL-6 as a marker for bronchiolitis obliterans syndrome after lung transplantation.

Bronchiolitis obliterans (BO) is the pathologic manifestation of chronic allograft rejection in lung transplant recipients and specific diagnosis requires invasive tests. BO causes progressive obstruction of the small airways. The term bronchiolitis obliterans syndrome (BOS) is a clinical surrogate for the histopathologic diagnosis of BO and is measured by lung function testing. KL-6 is a glycoprotein expressed on pulmonary epithelial cells and it is present in the serum of normal individuals in small amounts. Serum KL-6 has been shown to be a useful marker of disease activity in interstitial lung diseases. We demonstrated that serum levels of KL-6 are elevated in lung transplant recipients with BOS when compared with those without BOS and healthy controls. Our results indicate that serum KL-6 measurement has the potential to serve as a noninvasive diagnostic test for the detection of BO in lung transplant recipients.

Severe gastroparesis causing splenic rupture: a unique, early complication after heart-lung transplantation.

Several weeks or even months after heart-lung transplantation, gastroparesis-or delayed gastric emptying-commonly presents with cough, early satiety, and bloating. As it progresses, gastroparesis can cause substantial malnutrition and impair drug absorption. Gastroparesis after heart-lung transplantation can be attributed to bilateral vagus nerve injury, which probably occurs just above the level of the carina, where the recipient's trachea is resected. We report a highly unusual case wherein gastroparesis presented early after heart-lung transplantation and was managed conservatively. However, 19 days postoperatively, the patient developed acute abdominal pain and hypotension. Laparotomy revealed a massively dilated stomach and total avulsion of the splenic capsule with hemorrhage. The patient was fed via jejunostomy tubes until the gastroparesis resolved spontaneously. This case illustrates an important sequela of heart-lung transplantation. In order to decrease the morbidity from gastroparesis in these fragile patients, a drainage procedure should be considered as an adjunct to heart-lung transplantation.

An immune basis for lung parenchymal destruction in chronic obstructive pulmonary disease and emphysema.

BACKGROUND: Chronic obstructive pulmonary disease and emphysema are a frequent result of long-term smoking, but the exact mechanisms, specifically which types of cells are associated with the lung destruction, are unclear. METHODS AND FINDINGS: We studied different subsets of lymphocytes taken from portions of human lungs removed surgically to find out which lymphocytes were the most frequent, which cell-surface markers these lymphocytes expressed, and whether the lymphocytes secreted any specific factors that could be associated with disease. We found that loss of lung function in patients with chronic obstructive pulmonary disease and emphysema was associated with a high percentage of CD4+ and CD8+ T lymphocytes that expressed chemokine receptors CCR5 and CXCR3 (both markers of T helper 1 cells), but not CCR3 or CCR4 (markers of T helper 2 cells). Lung lymphocytes in patients with chronic obstructive pulmonary disease and emphysema secrete more interferon gamma--often associated with T helper 1 cells--and interferon-inducible protein 10 and monokine induced by interferon, both of which bind to CXCR3 and are involved in attracting T helper 1 cells. In response to interferon-inducible protein 10 and monokine induced by interferon, but not interferon gamma, lung macrophages secreted macrophage metalloelastase (matrix metalloproteinase-12), a potent elastin-degrading enzyme that causes tissue destruction and which has been linked to emphysema. CONCLUSIONS: These data suggest that Th1 lymphoctytes in the lungs of people with smoking-related damage drive progression of emphysema through CXCR3 ligands, interferon-inducible protein 10, and monokine induced by interferon.

Interobserver variability in grading transbronchial lung biopsy specimens after lung transplantation.

BACKGROUND: Acute rejection remains a major source of morbidity after lung transplantation. Given the importance of this diagnosis, an international grading system was developed to standardize the diagnosis of acute lung-allograft rejection. The reliability of this grading system has not been adequately assessed by previous studies. METHODS: We examined the level of agreement in grading transbronchial biopsy specimens obtained from a large multicenter study (AIRSAC [Comparison of a Tacrolimus/Sirolimus/Prednisone Regimen vs Tacrolimus/Azathioprine/Prednisone Immunosuppressive Regimen in Lung Transplantation] trial). Biopsy specimens were initially graded for acute rejection and lymphocytic bronchiolitis by the site pathologist and subsequently graded by a central pathologist. Reliability of interobserver grading was evaluated using Cohen κ coefficients. RESULTS: A total of 481 transbronchial biopsy specimens were graded by both the site and central pathologists. The overall concordance rates were 74% and 89% for grade A and grade B biopsy specimens, respectively. When samples from biopsies performed at different time points after transplantation were assessed, there was a higher level of agreement early (≤ 6 weeks) after transplant compared with later time points for acute rejection. However, there was still only moderate agreement for both grade A (κ score 0.479; 95% CI, 0.29-0.67) and grade B (κ score 0.465; 95% CI, 0.08-0.85) rejection. CONCLUSIONS: These results expand upon previous reports of interobserver variability in grading transbronchial biopsy specimens after lung transplantation. Given the variability in grading these specimens, we advocate further education of the histopathologic findings in lung transplant biopsy specimens, as well as revisiting the current criteria for grading transbronchial biopsy specimens to improve concordance among lung transplant pathologists. TRIAL REGISTRY: ClinicalTrials.gov; No. NCT00321906; URL: www.clinicaltrials.gov.

Decreased incidence of cytomegalovirus infection with sirolimus in a post hoc randomized, multicenter study in lung transplantation.

BACKGROUND: Cytomegalovirus (CMV) is the most common opportunistic infection in lung transplantation. A recent multicenter, randomized trial (the AIRSAC study) comparing sirolimus to azathioprine in lung transplant recipients showed a decreased incidence of CMV events in the sirolimus cohort. To better characterize this relationship of decreased incidence of CMV events with sirolimus, we examined known risk factors and characteristics of CMV events from the AIRSAC database. METHODS: The AIRSAC database included 181 lung transplant patients from 8 U.S.-based lung transplant centers that were randomized to sirolimus or azathioprine at 3 months post-transplantation. CMV incidence, prophylaxis, diagnosis and treatment data were all prospectively collected. Prophylaxis and treatment of CMV were at the discretion of each institution. RESULTS: The overall incidence of any CMV event was decreased in the sirolimus arm when compared with the azathioprine arm at 1 year after lung transplantation (relative risk [RR] = 0.67, confidence interval [CI] 0.55 to 0.82, p < 0.01). This decreased incidence of CMV events with sirolimus remained significant after adjusting for confounding factors of CMV serostatus and CMV prophylaxis. CONCLUSIONS: These data support results from other solid-organ transplantation studies and suggest further investigation of this agent in the treatment of lung transplant recipients at high risk for CMV events.