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Dual combination therapy with a phosphodiesterase-5 inhibitor (PDE5i) and endothelin receptor antagonist is recommended for most patients with intermediate-risk pulmonary arterial hypertension (PAH). The RESPITE and REPLACE studies suggest that switching from a PDE5i to a soluble guanylate cyclase (sGC) activator may provide clinical improvement in this situation. The optimal approach to escalation or transition of therapy in this or other scenarios is not well defined. We developed an expert consensus statement on the transition to sGC and other treatment escalations and transitions in PAH using a modified Delphi process. The Delphi process used a panel of 20 physicians with expertise in PAH. Panelists answered three questionnaires on the management of treatment escalations and transitions in PAH. The initial questionnaire included open-ended questions. Later questionnaires consolidated the responses into statements that panelists rated on a Likert scale from -5 ( strongly disagree ) to +5 ( strongly agree ) to determine consensus. The Delphi process produced several consensus recommendations. Escalation should be considered for patients who are at high risk or not achieving treatment goals, by adding an agent from a new class, switching from oral to parenteral prostacyclins, or increasing the dose. Switching to a new class or within a class should be considered if tolerability or other considerations unrelated to efficacy are affecting adherence. Switching from a PDE5i to an SGC activator may benefit patients with intermediate risk who are not improving on their present therapy. These consensus-based recommendations may be helpful to clinicians and beneficial for patients when evidence-based guidance is unavailable., Competing Interests: Franck F. Rahaghi reports consultation, research, and speakership honoraria from Bayer and Janssen, consultation and speakership from United Therapeutics, and consultation fees from Acceleron. Vijay P. Balasubramanian reports a research grant from United Therapeutics and serves on a speakers bureau for Bayer. Robert C. Bourge reports research grant support to my institution from United Therapeutics and Bayer, and service on a Scientific Advisory Board at United Therapeutics. Murali M. Chakinala reports grants or contracts from Actelion/Janssen, Bayer, Medtronic, NIH, Reata, Liquidia, Phase Bio, Complexa, United Therapeutics, Altavant, Trio Health Analytics, Reata, Acceleron, Arena, and Gossamer; consulting fees from Altavant, Vaderis Therapeutics, Aerovate, Reata, VWave, and Arena; honoraria from Bayer, Gilead, Simply Speaking, WebMD, and United Therapeutics; support for attending meetings and/or travel from Actelion/Janssen, United Therapeutics, Bayer, Acceleron, Reata, and Gilead; participation on a Data Safety Monitoring Board or Advisory Board for Actelion/Janssen, Express Scripts, Phase Bio, Altavant, Gossamer, United Therapeutics, Bayer, Acceleron, and Liquidia; and leadership or a fiduciary role in the Pulmonary Hypertension Association and the Cure HHT Global Research and Medical Advisory Board. Michael S. Eggert reports research contracts with United Therapeutics (BREEZE and ADVANCE Outcomes), Acceleron, and Actelion. Jean M. Elwing reports grants from Actelion, Acceleron, Reata, United Therapeutics, Liquidia, Phase Bio, Complexa, Gossamer Bio, Bayer, Arena, Eiger, Akros, Bellerophon, and Lung LLC and consulting fees from United Therapeutics, Acceleron, Liquidia, Altavant, Bayer, Gossamer Bio, Actelion, Bayer. Jeremy Feldman reports consulting and giving talks for Bayer, United Therapeutics, and Jansen. Christopher King reports personal fees from Actelion, personal fees from Genentech, United Therapeutics, and Boehringer Ingelheim; has served on advisory boards for and is on the Speakers’ Bureau of Actelion, Boehringer‐Ingelheim Pharmaceuticals, and United Therapeutics. James R. Klinger reports that his institution receives research funding from United Technologies, service on a Steering Committee and a Clinical Outcomes Committee for Bayer, and a leadership role in the Pulmonary Hypertension Association. Stephen C. Mathai reports personal fees from United Therapeutics; participation on a data safety monitoring board or advisory board from United Therapeutics, Actelion, and Bayer, and leadership or a fiduciary role in the PCORI Rare Disease Advisory Panel and the World Symposium on Pulmonary Hypertension. John Wesley McConnell reports consulting fees from Actelion, Bayer, Gossamer, Altavant, and Liquidia; honoraria from Actelion, Bayer, Simply Speaking, Impact PH, and Reata, and participation on a data safety monitoring board or advisory board for Actelion, Liquidia, Gossamer, and Altavant. Harold I. Palevsky reports honoraria for serving on scientific advisory boards for Acceleron, Actelion/Janssen, PhaseBio and United Therapeutics, and serving on a DSMB for United Therapeutics. Ricardo Restrepo‐Jaramillo reports serving on speaker's bureau for United Therapeutics, Bayer, and Actelion. Zeenat Safdar reports serving on a speakers bureau, consultation and advisory boards for Actelion, United Therapeutics, Boehringer Ingelheim, Bayer, and Roche. Jeffrey S. Sager reports personal fees from Bayer pharmaceuticals, grants and personal fees from United Therapeutics, grants and personal fees from Janssen (J and J), and grants from Reata outside the submitted work. Namita Sood reports a speaking fee from Bayer. Roxana Sulica reports research grants from Bayer, United Therapeutics, Complexa, and Reata, and serves on advisory boards for Actelion, Bayer, United Therapeutics, and Reata. R. James White reports research grants from United Therapeutics, Reata, Bayer, Merck, and Janssen and consulting fees from Merck and Bayer. Nicholas S. Hill reports honoraria from Axon Research for this study; grants to his institution from Actelion, Bayer, Gilead, and United Therapeutics; consulting fees from United Therapeutics; and participation in Data Safety Monitoring Boards for United Therapeutics and Pfizer. All authors had access to the Delphi questionnaire analysis and data and participated in the review, revision, and approval of the content of the manuscript for submission. Charles D. Burger reports no disclosures or conflicts of interest., (© 2022 The Authors. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Real-world dosing and titration of parenteral (subcutaneous, SC; intravenous, IV) prostacyclin, a mainstay of pulmonary arterial hypertension (PAH) treatment, is not always consistent with prescribing information or randomized trials and has yet to be adequately characterized. The current study describes real-world outpatient dosing and titration patterns over time, in PAH patients initiated on SC or IV treprostinil. A longitudinal, cross-sectional analysis of medication shipment records from US specialty pharmacy services between 2009 and 2018 was conducted to determine dosing and titration patterns of SC or IV treprostinil in the outpatient setting beginning with the patient's first shipment. The sample for analysis included shipment records for 2647 patients (IV = 1040, SC = 1607). Although more patients were started on SC treprostinil than IV, median initial outpatient IV treprostinil dose (11 ng/kg/min at month on therapy one [MOT1]) was consistently and statistically significantly higher than initial outpatient SC dose (7.5 ng/kg/min at MOT1; p  < 0.01). However, the SC treprostinil dose acceleration rate (DAR) was more aggressive from MOT1 to MOT6, MOT12, and MOT24, leading to a higher dose achieved at later timepoints. All between-group DAR differences were statistically significant ( p  < 0.001). This study provides evidence that real-world prescribing patterns of parenteral treprostinil in the outpatient setting differs from dosing described in pivotal trials, with important differences between SC and IV administration. Although initial outpatient IV treprostinil dosing was higher, SC titration was accelerated more aggressively and a higher dose was achieved by MOT3 suggesting that factors specific to SC administration (e.g., site pain) may not limit dosing and titration as previously thought., Competing Interests: Lana Melendres‐Groves has received honoraria and/or fees for consultancy and advisory committees from United Therapeutics Corporation, outside of the submitted work; Zeenat Safdar has received honoraria and/or fees for consultancy and advisory committees from United Therapeutics Corporation, Bayer Pharmaceuticals, Actelion Pharmaceuticals, Boehringer Ingelheim, and Genentech, outside the submitted work. Margaret R. Sketch, Meredith Broderick, and Andrew C. Nelsen are employees of United Therapeutics Corporation. Dasom Lee has nothing to disclose. Vijay P. Balasubramanian has received research support, honoraria, and/or fees for consultancy and an advisory committee from United Therapeutics Corporation, speaker bureau, and advisory committee honoraria and/or fees from Bayer Pharmaceuticals, and speaker bureau honoraria and/or fees from Boehringer Ingelheim, outside the submitted work., (© 2021 The Authors. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Support group participation has been shown to be effective in many chronic medical conditions. The evidence for integrating support group into pulmonary hypertension care and its effect on quality of life, physical and psychological well-being is limited. We sought to assess the effect of support group participation on quality of life in patients diagnosed with pulmonary hypertension and their caregivers. The emPHasis-10 questionnaire (a tool validated for quality of life assessment in pulmonary hypertension) was used to evaluate the effect of support group participation. Additional demographic and health-related quality measures were examined. Results showed that 165 subjects were enrolled in the study; 122 (74.4%) were patients with pulmonary hypertension, 41 (25.0%) were their caregivers, and 2 (0.02%) did not respond. The cohort was predominantly female ( n  = 128, 78%), Caucasian ( n  = 10, 61%), and the principal self-reported classification of pulmonary hypertension was World Health Organization Group 1 ( n  = 85, 51.8%) and the self-reported New York Heart Association Functional Class was II and III ( n  = 43, 57.3%). Most participants ( n  = 118, 71.5%) attended support groups and of them, a majority ( n  = 107, 90.6%) stated it helped them. There was no difference in quality of life as assessed by emPHasis-10 scores with support group participation (median score 30 vs 32, p  = 0.387). There was self-reported improvement in understanding condition better including procedures such as right heart catheterization, medication compliance, and confidence in self-care ( p  < 0.05). Using multivariate logistic regression, baseline variables that were independently associated with emPHasis-10 scores for the entire cohort included knowledge of New York Heart Association Functional Class (odds ratio: 1.919, 95% CI: 1.004-3.67, p  = 0.04) and greater distance traveled to visit pulmonary hypertension physician (odds ratio: 1.391, 95% CI: 0.998--1.94, p  = 0.05). In conclusion, support group participation does not improve quality of life as assessed by emPHasis-10 scores but improves other meaningful health-related quality outcomes., (© The Author(s) 2021.)

Pharmacokinetic studies with oral treprostinil demonstrate that three times daily (TID) dosing reduces peak-to-trough plasma trepostinil fluctuations compared with twice daily (BID) dosing. TID dosing may allow for faster titration, higher total daily doses, and potentially improve the tolerability of oral trepostinil. This analysis, which looks at the real-world dosing of oral treprostinil, supports the utility of TID dosing.

In patients treated with macitentan (Opsumit®, Actelion Pharmaceuticals Ltd., Basel, Switzerland) for pulmonary arterial hypertension (PAH), prevention and/or effective management of treatment-related adverse events may improve adherence. However, management of these adverse events can be challenging and the base of evidence and clinical experience for macitentan is limited. In the absence of evidence, consensus recommendations from physicians experienced in using macitentan to treat PAH may benefit patients and physicians who are using macitentan. Consensus recommendations were developed by a panel of physicians experienced with macitentan and PAH using a modified Delphi process. Over three iterations, panelists developed and refined a series of statements on the use of macitentan in PAH and rated their agreement with each statement on a Likert scale. The panel of 18 physicians participated and developed a total of 118 statements on special populations, add-on therapy, drug-drug interactions, warnings and precautions, hospitalization and functional class, and adverse event management. The resulting consensus recommendations are intended to provide practical guidance on real-world issues in using macitentan to treat patients with PAH.

Oral treprostinil was recently labeled for treatment of pulmonary arterial hypertension. Similar to the period immediately after parenteral treprostinil was approved, there is a significant knowledge gap for practicing physicians who might prescribe oral treprostinil. Despite its oral route of delivery, use of the drug is challenging because of the requirement for careful titration and management of drug-related adverse effects. We aimed to create a consensus document combining available evidence with expert opinion to provide guidance for use of oral treprostinil. Following a methodology commonly used in business and social sciences (the 'Delphi Process'), two investigators from the oral treprostinil (Freedom) studies created a series of statements based on available evidence and the package insert. The set of 'best practice' statements was circulated to nine other Freedom trial investigators. Their comments were incorporated into the document as new line items for further vote and comment. The subsequent document was put to vote line by line (scale of -5 to +5) and a final statement was drafted. Consensus recommendations include initial therapy with 0.125 mg for treatment naÿ patients, three times daily dosing, aggressive use of antidiarrheal medication, and a strong preference for use of the drug in combination with other approved PAH therapies. This process was particularly valuable in providing guidance for the management of adverse events (where essentially no data is available). The Delphi process was useful to codify investigator experience and subsequently develop investigator consensus about practical issues for physicians who may wish to prescribe oral treprostinil.

Pneumocystis carinii pneumonia (PCP) is a life-threatening opportunistic infection that occurs in immunocompromised hosts, especially patients with the acquired immunodeficiency syndrome (AIDS). However, this infection is increasing in frequency in other immunosuppressed patients, including organ transplant recipients and those with malignancy who are treated with chemotherapeutic regimens. It carries a relatively high mortality in the non-human immunodeficiency virus (HIV) population. Pleural involvement is rare with PCP; all reported cases in the literature are associated with HIV disease and characterized as small effusions. We report a case of a renal transplant recipient with PCP and moderate-sized pleural effusion with pneumocystis cysts.