Palliative care referrals in patients with pulmonary arterial hypertension: The Pulmonary Hypertension Association Registry.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a life limiting disease with substantial symptom burden and healthcare utilization. Palliative care alleviates physical and emotional symptoms for patients with serious illness, and has been underutilized for these patients. OBJECTIVE: To characterize patients with PAH referred to palliative care and identify predictors of referral. METHODS: We conducted an observational study of adult patients enrolled in the Pulmonary Hypertension Association Registry from January 2015 through June 2021, performing descriptive statistics on patient characteristics at baseline for all patients and the subset referred to palliative care. These characteristics were modeled in a backwards elimination Cox regression with time to referral to palliative care as the primary outcome. RESULTS: 92 of 1,578 patients were referred to palliative care (5.8%); 43% were referred at their last visit prior to death. Referrals were associated with increasing age per decade (hazard ratio 1.35 [95% confidence interval 1.16-1.58]), lower body mass index (hazard ratio 0.97 [95% confidence interval 0.94-0.998]), supplemental oxygen use (hazard ratio 2.01 [95% confidence interval 1.28-3.16]), parenteral prostanoid use (hazard ratio 2.88 [95% confidence interval 1.84-4.51]), and worse quality of life, measured via lower physical (hazard ratio 0.97 [95% confidence interval 0.95-0.99]) and mental (hazard ratio 0.98 [95% confidence interval 0.96-0.995]) scores on the 12-item Short Form Health Survey. CONCLUSION: Patients with PAH are infrequently referred to palliative care, even at centers of excellence. Referrals occur in sicker patients with lower quality of life scores, often close to the end of life.

Riociguat: Clinical research and evolving role in therapy.

Riociguat is a first-in-class soluble guanylate cyclase stimulator, approved for the treatment of adults with pulmonary arterial hypertension (PAH), inoperable chronic thromboembolic pulmonary hypertension (CTEPH), or persistent or recurrent CTEPH after pulmonary endarterectomy. Approval was based on the results of the phase III PATENT-1 (PAH) and CHEST-1 (CTEPH) studies, with significant improvements in the primary endpoint of 6-minute walk distance vs placebo of +36 m and +46 m, respectively, as well as improvements in secondary endpoints such as pulmonary vascular resistance and World Health Organization functional class. Riociguat acts as a stimulator of cyclic guanosine monophosphate synthesis rather than as an inhibitor of cGMP metabolism. As with other approved therapies for PAH, riociguat has antifibrotic, antiproliferative and anti-inflammatory effects, in addition to vasodilatory properties. This has led to further clinical studies in patients who do not achieve a satisfactory clinical response with phosphodiesterase type-5 inhibitors. Riociguat has also been evaluated in patients with World Health Organization group 2 and 3 pulmonary hypertension, and other conditions including diffuse cutaneous systemic sclerosis, Raynaud's phenomenon and cystic fibrosis. This review evaluates the results of the original clinical trials of riociguat for the treatment of PAH and CTEPH, and summarises the body of work that has examined the safety and efficacy of riociguat for the treatment of other types of pulmonary hypertension.

Development and Validation of the Nasal Outcome Score for Epistaxis in Hereditary Hemorrhagic Telangiectasia (NOSE HHT).

Importance: Epistaxis is the greatest cause of morbidity in patients with hereditary hemorrhagic telangiectasia (HHT); because of this, a validated epistaxis-specific quality-of-life instrument for HHT should be made available. Objective: To develop and validate an epistaxis-specific quality-of-life patient-reported outcome measure for HHT. Design, Setting, and Participants: This survey study focused on the development and validation of the Nasal Outcome Score for Epistaxis (NOSE) in HTT (NOSE HHT) outcome measure with data prospectively collected from December 10, 2019, to March 15, 2020. A total of 401 patients were recruited from within the Cure Hemorrhagic Telangiectasia online patient advocacy social media network, the Washington University HHT Center of Excellence, and a randomized clinical trial investigating an intranasal timolol gel for HHT-associated epistaxis. Main Outcomes and Measures: Face and content validity, factor analysis, internal consistency as measured through Cronbach α, construct validity, responsiveness to change, and minimal clinically important difference. Results: The NOSE HHT was developed and validated with a possible score ranging discretely from 0 to 4 for each of the 29 items and a total score ranging continuously from 0 to 4 after dividing by the total number of items answered. A total of 401 participants completed the NOSE HHT. Factor analysis identified 3 factors that matched the a priori specified subgroups of particular aspects of life affected by HHT-associated epistaxis: physical problems (mean [SD] magnitude, 1.59 [0.83]), functional limitations (mean [SD] magnitude, 1.28 [0.84]), and emotional consequences (mean [SD] magnitude, 1.95 [1.02]). The instrument had high internal consistency with an overall Cronbach α of 0.960. Convergent validity determined the total NOSE HHT score to be a strong predictor of disease severity; total NOSE HHT score can be split up into the following epistaxis severity categories: mild (0-1), moderate (1.01-2), and severe (>2). The instrument was found to be sensitive to change, and the minimal clinically important difference for the total NOSE HHT score was 0.46. Conclusions and Relevance: Evaluation of the consistency, reliability, and responsiveness of the NOSE HHT survey found it to be a valid instrument to assess severity and change in epistaxis. Study results suggest that the NOSE HHT survey is clinically applicable and useful as an outcome measure of future HHT-associated epistaxis trials.

Efficacy of Timolol in a Novel Intranasal Thermosensitive Gel for Hereditary Hemorrhagic Telangiectasia-Associated Epistaxis: A Randomized Clinical Trial.

Importance: Other than nasal moisturizers, no standard-of-care medical therapy exists for epistaxis in hereditary hemorrhagic telangiectasia (HHT). With epistaxis as the greatest cause of morbidity in patients with HHT, there is a need to identify effective topical therapies. Objective: To determine the efficacy and safety of an intranasal timolol thermosensitive gel vs placebo thermosensitive gel in treating HHT-associated epistaxis. Design, Setting, and Participants: This double-blind, placebo-controlled randomized clinical trial was conducted from October 29, 2019, to May 20, 2020, at a tertiary care center. A total of 27 patients with HHT and moderate-to-severe epistaxis were recruited and included in this prespecified analysis: 14 in the timolol group and 13 in the placebo group. Inclusion criteria included (1) age 18 years or older, (2) clinical or genetic diagnosis of HHT, (3) screening Epistaxis Severity Score (ESS) of 4 or greater and 2 or more nosebleeds cumulatively lasting at least 5 minutes per week, (4) stable epistaxis pattern over the preceding 3 months, and (5) no change in epistaxis treatment or nasal hygiene regimen in the preceding month. Exclusion criteria included (1) contraindications to systemic ß-blocker administration, (2) use of medications interacting with timolol, (3) use of antiangiogenic medications in the last month before recruitment, and (4) use of anticoagulants, antiplatelets, or fibrinolytic therapies within the last month. Interventions: Novel thermosensitive intranasal timolol (0.1%) gel vs placebo thermosensitive gel applied twice daily to each nostril for 8 weeks. Main Outcomes and Measures: The primary outcome was the median change in ESS and percentage of participants reaching the minimal clinically important difference in ESS. Secondary outcomes were changes in Clinical Global Impression-Severity and Clinical Global Impression-Improvement scores, Nasal Outcome Score for Epistaxis in Hereditary Hemorrhagic Telangiectasia, and hemoglobin level. Results: Of 27 participants randomized (median [range] age, 55 [20-76] years; 14 women [52%]; 25 White [93%]), a total of 23 patients with HHT completed the primary outcome measure. Within the timolol gel and placebo gel groups, respectively, the median change (range) in ESS was 2.32 (0.22 to 5.97) vs 1.96 (-0.91 to 5.98), and 9 of 11 (82%) vs 9 of 12 (75%) participants experienced a clinically meaningful improvement in ESS. Twenty-two of the 23 participants (96%) reported improvement via the Clinical Global Impression-Improvement score, with 81% vs 58% of participants reporting reduced severity of epistaxis in the timolol vs placebo group, respectively. Of participants completing the Nasal Outcome Score for Epistaxis in HHT at follow-up visit, 7 of 10 (70%) in the timolol group achieved a clinically important difference vs 5 of 10 (50%) in the placebo group. There was no change in hemoglobin level between or within groups. Zero participants in the placebo group and 2 of 13 (15%) in the timolol group withdrew because of adverse events. Conclusions and Relevance: Thermosensitive gel, alone or in combination with timolol, was highly effective in reducing HHT-associated epistaxis. The timolol group had greater improvement in epistaxis and quality of life than the placebo group, but effect estimates were imprecise, and no definitive conclusions on the superiority of timolol can be drawn. Physicians treating patients with HHT-associated epistaxis should consider a thermosensitive gel (with or without timolol) for their patients. Trial Registration: ClinicalTrials.gov Identifier: NCT04139018.

Pazopanib may reduce bleeding in hereditary hemorrhagic telangiectasia.

Pazopanib (Votrient) is an orally administered tyrosine kinase inhibitor that blocks VEGF receptors potentially serving as anti-angiogenic treatment for hereditary hemorrhagic telangiectasia (HHT). We report a prospective, multi-center, open-label, dose-escalating study [50 mg, 100 mg, 200 mg, and 400 mg], designed as a proof-of-concept study to demonstrate efficacy of pazopanib on HHT-related bleeding, and to measure safety. Patients, recruited at 5 HHT Centers, required ≥ 2 Curacao criteria AND [anemia OR severe epistaxis with iron deficiency]. Co-primary outcomes, hemoglobin (Hgb) and epistaxis severity, were measured during and after treatment, and compared to baseline. Safety monitoring occurred every 1.5 weeks. Seven patients were treated with 50 mg pazopanib daily. Six/seven showed at least 50% decrease in epistaxis duration relative to baseline at some point during study; 3 showed at least 50% decrease in duration during Weeks 11 and 12. Six patients showed a decrease in ESS of > 0.71 (MID) relative to baseline at some point during study; 3/6 showed a sustained improvement. Four patients showed > 2 gm improvement in Hgb relative to baseline at one or more points during study. Health-related QOL scores improved on all SF-36 domains at Week 6 and/or Week 12, except general health (unchanged). There were 19 adverse events (AE) including one severe AE (elevated LFTs, withdrawn from dosing at 43 days); with no serious AE. In conclusion, we observed an improvement in Hgb and/or epistaxis in all treated patients. This occurred at a dose much lower than typically used for oncologic indications, with no serious AE. Further studies of pazopanib efficacy are warranted.

Effect of Topical Intranasal Therapy on Epistaxis Frequency in Patients With Hereditary Hemorrhagic Telangiectasia: A Randomized Clinical Trial.

IMPORTANCE: Epistaxis is a major factor negatively affecting quality of life in patients with hereditary hemorrhagic telangiectasia (HHT; also known as Osler-Weber-Rendu disease). Optimal treatment for HHT-related epistaxis is uncertain. OBJECTIVE: To determine whether topical therapy with any of 3 drugs with differing mechanisms of action is effective in reducing HHT-related epistaxis. DESIGN, SETTING, AND PARTICIPANTS: The North American Study of Epistaxis in HHT was a double-blind, placebo-controlled randomized clinical trial performed at 6 HHT centers of excellence. From August 2011 through March 2014, there were 121 adult patients who met the clinical criteria for HHT and had experienced HHT-related epistaxis with an Epistaxis Severity Score of at least 3.0. Follow-up was completed in September 2014. INTERVENTIONS: Patients received twice-daily nose sprays for 12 weeks with either bevacizumab 1% (4 mg/d), estriol 0.1% (0.4 mg/d), tranexamic acid 10% (40 mg/d), or placebo (0.9% saline). MAIN OUTCOMES AND MEASURES: The primary outcome was median weekly epistaxis frequency during weeks 5 through 12. Secondary outcomes included median duration of epistaxis during weeks 5 through 12, Epistaxis Severity Score, level of hemoglobin, level of ferritin, need for transfusion, emergency department visits, and treatment failure. RESULTS: Among the 121 patients who were randomized (mean age, 52.8 years [SD, 12.9 years]; 44% women with a median of 7.0 weekly episodes of epistaxis [interquartile range {IQR}, 3.0-14.0]), 106 patients completed the study duration for the primary outcome measure (43 were women [41%]). Drug therapy did not significantly reduce epistaxis frequency (P = .97). After 12 weeks of treatment, the median weekly number of bleeding episodes was 7.0 (IQR, 4.5-10.5) for patients in the bevacizumab group, 8.0 (IQR, 4.0-12.0) for the estriol group, 7.5 (IQR, 3.0-11.0) for the tranexamic acid group, and 8.0 (IQR, 3.0-14.0) for the placebo group. No drug treatment was significantly different from placebo for epistaxis duration. All groups had a significant improvement in Epistaxis Severity Score at weeks 12 and 24. There were no significant differences between groups for hemoglobin level, ferritin level, treatment failure, need for transfusion, or emergency department visits. CONCLUSIONS AND RELEVANCE: Among patients with HHT, there were no significant between-group differences in the use of topical intranasal treatment with bevacizumab vs estriol vs tranexamic acid vs placebo and epistaxis frequency. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01408030.

World Health Organization group 5 pulmonary hypertension.

World Health Organization (WHO) group 5 pulmonary hypertension (PH) entails a heterogeneous group of disorders that may cause PH by unclear and/or multiple mechanisms. In particular, group 5 includes PH caused by hematologic disorders, systemic diseases, metabolic disorders, chronic renal failure, and disorders leading to pulmonary vascular occlusion or compression. This article discusses common pathogenic mechanisms leading to group 5 PH, followed by a detailed overview of epidemiology, pathogenesis, and disease-specific management of the individual group 5 conditions. Off-label use of vasomodulatory therapies, typically indicated for pulmonary arterial hypertension (WHO group 1 PH), in group 5 conditions is also discussed.

A randomized controlled trial of tacrolimus versus cyclosporine after lung transplantation.

BACKGROUND: The optimal maintenance immunosuppressive regimen after lung transplantation is uncertain. METHODS: We conducted a randomized controlled trial of tacrolimus versus cyclosporine in combination with azathioprine and prednisone after lung transplantation. Ninety adults were randomized to tacrolimus (n = 44) or cyclosporine (n = 46). The primary end point was a composite of a cumulative acute rejection A score of 3 or higher, a cumulative lymphocytic bronchitis B score of 4 or higher, or the onset of bronchiolitis obliterans syndrome (BOS) stage 0-p. RESULTS: Recipients randomized to cyclosporine were significantly more likely to develop the primary end point than those randomized to tacrolimus. During the study period, the primary end point developed in 39 of 46 cyclosporine subjects compared with 24 of 44 tacrolimus subjects (p = 0.002); acute rejection or lymphocytic bronchitis end points developed in 29 of 46 cyclosporine subjects compared with 18 of 44 tacrolimus subjects (p = 0.036). Furthermore, BOS stage 0-p was more likely to develop in the cyclosporine group than in the tacrolimus group, but this was not statistically significant (log-rank p = 0.1). In addition, there was a trend to a higher incidence of diabetes among those in the tacrolimus group, but there was no significant difference in graft survival or the total number of infections, or in the incidence of hypertension, chronic kidney disease, or cancer between the 2 groups. CONCLUSIONS: Tacrolimus is associated with a lower burden of acute rejection and lymphocytic bronchitis and a trend to a greater freedom from BOS stage 0-p than cyclosporine after lung transplantation.

A comparison of basiliximab and anti-thymocyte globulin as induction agents after lung transplantation.

BACKGROUND: Interleukin-2 receptor antagonists have supplanted polyclonal antibody preparations as the most frequently used induction agents after lung transplantation, but the relative efficacy of these agents has not been firmly established. METHODS: We retrospectively analyzed the efficacy of basiliximab compared with antithymocyte globulin among 157 adult lung transplant recipients at our center. RESULTS: At 3, 6, and 12 months after transplantation, the median cumulative acute rejection A scores for the basiliximab group (2, 2, and 3, respectively) were significantly higher than those for the anti-thymocyte globulin group (1, 1, and 2, respectively; p = 0.003, 0.004, and 0.033, respectively). In addition, basiliximab recipients were more likely to develop acute rejection grade > or = A2 than anti-thymocyte globulin recipients; in fact, 60% of basiliximab recipients compared with 38% of anti-thymocyte globulin recipients developed their first episode of acute rejection grade > or = A2 in the first 100 days after transplantation (log-rank p = 0.04). Furthermore, basiliximab recipients were more likely to develop bronchiolitis obliterans syndrome than anti-thymocyte globulin recipients (log-rank p = 0.036). Two years after transplantation, 36% of basiliximab recipients and 26% of anti-thymocyte globulin recipients developed bronchiolitis obliterans syndrome. However, there were no significant differences in the incidences of cytomegalovirus viremia and pneumonitis between the 2 groups (p = 0.86 and 0.89, respectively). CONCLUSIONS: Induction with anti-thymocyte globulin is associated with a lower burden of acute rejection and bronchiolitis obliterans syndrome compared with basiliximab, without a significant difference in the incidence of cytomegalovirus infections.

Reliability for grading acute rejection and airway inflammation after lung transplantation.

BACKGROUND: The Lung Rejection Study Group (LRSG) created a scheme for grading acute allograft rejection in 1990 and then revised it in 1996, but virtually no studies have evaluated the reliability of this formulation. This investigation assessed the reliability of the current LRSG system by determining inter- and intrareader agreement for grading transbronchial biopsy samples from lung transplant recipients. METHODS: Biopsy samples from a cohort of 204 recipients were reviewed and classified by a single pathologist who was blinded to original interpretations. The "A" and "B" rejection grades from this contemporary review were compared with original grades by the kappa statistic. RESULTS: For "A" grading, weighted kappa was 0.65 (95% confidence interval [CI] 0.60-0.70) for interreader agreement (n = 529 specimens) and 0.65 (95% CI 0.53-0.76) for intrareader agreement (n = 97 specimens). For "B" grading, weighted kappa was 0.26 (95% CI 0.14-0.39) for interreader agreement (n = 164 specimens) and 0.33 (95% CI 0.15-0.51) for intrareader agreement (n = 58 specimens). CONCLUSIONS: On the basis of the analysis of the LRSG scheme, "A" grades exhibit very good reliability, but "B" grades have only fair reliability, and steps to improve this shortcoming should be taken.

Yield of surveillance bronchoscopy for acute rejection and lymphocytic bronchitis/bronchiolitis after lung transplantation.

BACKGROUND: Better understanding of the timing and pattern of surveillance bronchoscopy findings after lung transplantation could influence the timing and frequency of surveillance bronchoscopy. We present our surveillance bronchoscopy experience and test the hypothesis that patients not encountering early acute rejection or lymphocytic bronchitis/bronchiolitis are less likely to have subsequent occult occurrences in the 1st year after lung transplantation. METHODS: We conducted a retrospective study of 204 patients who underword transplantation between 1996 and 2000. Based on contemporary biopsy-specimen grading in the first 100 days, we formed 2 groups: No Early Rejection and Early Rejection. We compared subsequent yields of surveillance bronchoscopy and the incidence of acute rejection or of lymphocytic bronchitis/bronchiolitis. RESULTS: We reviewed 645 biopsies taken from 204 recipients during the first 100 days to classify patients into a No Early Rejection Group (n=67) or an Early Rejection Group (n=137). Yield of surveillance bronchoscopy for acute rejection or lymphocytic bronchitis/bronchiolitis was 31% with the greatest yield during the first 30 days (45%), and then decreasing to 26% (p <0.001). After Day 100, 71% of occult acute rejection episodes involved minimal (A1) lesions. Yield of surveillance bronchoscopy after Day 100 was 20% in the No Early Rejection Group and was 27% in the Early Rejection Group (p=0.22). Incidence of acute rejection or lymphocytic bronchitis/bronchiolitis after Day 100 was 41% in the No Early Rejection Group and was 50% in the Early Rejection Group (p=0.17). CONCLUSION: Surveillance bronchoscopy detects occult acute rejection or lymphocytic bronchitis/bronchiolitis in approximately one-third of biopsy specimens during the 1st year, with the majority of late abnormalities being minimal (A1) rejection. The absence of acute rejection or lymphocytic bronchitis/bronchiolitis during the first 100 days does not predict freedom from such events in the remainder of the 1st year.

Respiratory viral infections are a distinct risk for bronchiolitis obliterans syndrome and death.

Bronchiolitis obliterans syndrome (BOS) is the major obstacle to long-term survival after lung transplantation, in part because its pathogenesis is poorly understood and treatment options are limited. To identify unique risk factors for BOS and death, we performed a retrospective cohort study on 259 consecutive adult lung transplant recipients over a 5-year period. The demographic and clinical characteristics of this population were analyzed for an association between BOS or death and potential risk factors, including community-acquired respiratory viral (CARV) infections, acute rejection, and cytomegalovirus pneumonitis. Respiratory syncytial virus, parainfluenza, influenza, and adenovirus accounted for 21 CARV infections. Univariate and multivariate time-dependent Cox regression analyses demonstrated that this CARV group was more likely to develop BOS, death, and death from BOS. Furthermore, these trends were more pronounced in patients with evidence of lower respiratory tract-CARV (lower-CARV) infections. Notably, the CARV and lower-CARV infections were risk factors for BOS, death, and death from BOS distinct from the risk attributable to acute rejection. Identification of CARV and lower-CARV infections as BOS and mortality risk factors has important clinical implications and may provide insight into disease pathogenesis and accelerate the development of novel treatment strategies to modify post-CARV BOS.

Abdominal-pelvic lymphoproliferative disease after lung transplantation: presentation and outcome.

BACKGROUND: Lymphoproliferative disease (LPD) is a well-recognized complication after lung transplantation. However, its presentation in the abdomen and pelvis has not been previously detailed. METHODS: We retrospectively identified cases of abdominal-pelvic LPD in lung transplant recipients. The cases were characterized clinically, and the outcomes were analyzed. RESULTS: Abdominal-pelvic LPD was identified in 19 of 603 adult patients who underwent lung or heart-lung transplantation at Barnes-Jewish Hospital between July 1, 1988 and December 31, 2001. The median time from transplantation to the onset of LPD was 5.8 years. Three cases presented early after transplantation (median, 175 days), and 16 cases presented late (median, 2,255 days). The time to diagnosis of LPD was significantly shorter for Epstein-Barr virus (EBV)-seronegative than for EBV-seropositive recipients (median, 175 vs. 2255 days; log-rank, P<0.001). Seventeen cases were non-Hodgkin's lymphomas, one was a Burkitt's lymphoma, and one was an atypical lymphoid proliferation. Among the 19 cases, 12 involved the gastrointestinal tract and 7 occurred in other sites. Immunosuppressive therapy was decreased in all patients. Eleven underwent surgical resection, and nine received chemotherapy. Sixteen patients have died, and 14 deaths were attributable to LPD. The median time from the diagnosis of LPD to death was 68 days. CONCLUSIONS: Abdominal-pelvic LPD is typically a late complication after lung transplantation; however, when it occurs early, it may be related to a primary EBV infection. This form of LPD is most frequently a non-Hodgkin's lymphoma, and despite aggressive therapy, the prognosis is poor.

Community acquired respiratory viral infections after lung transplantation: clinical features and long-term consequences.

Community acquired respiratory viruses (CARVs) are increasingly recognized as serious threats to lung transplant recipients. While CARVs such as respiratory syncytial virus, parainfluenza, influenza, and adenovirus usually cause self-limited illnesses in immunocompetent subjects, infections in the transplant recipient can be dramatic. As transplant recipients live longer and diagnostic methods improve, the burden of CARVs will undoubtedly increase. Because of limited therapeutic options, some patients may succumb to CARV infections, while many survivors develop chronic allograft dysfunction. Recognition of this latter phenomenon has implicated CARVs in the pathogenesis of bronchiolitis obliterans.

Acute allograft rejection after lung transplantation: diagnosis and therapy.

Acute rejection remains a significant problem after lung transplantation. While it generally is a treatable condition, significant resources and therapies are directed toward its prevention and resolution. Its larger significance undoubtedly rests in its contribution to the pathogenesis of BOS. Significant questions regarding the origins of AR, the role of LBB, alternative histologic appearances of acute allograft injury, and optimal therapy remain. Controversy regarding the utility of surveillance bronchoscopy and preemptive treatment of occult AR persists because of lack of conclusive evidence. Future investigations might resolve these matters and provide more efficacious and less toxic therapies that will hopefully reduce the impact of chronic rejection and improve long-term outcomes.