BREEZE: Open-label clinical study to evaluate the safety and tolerability of treprostinil inhalation powder as Tyvaso DPI™ in patients with pulmonary arterial hypertension.

Inhaled treprostinil is an approved therapy for pulmonary arterial hypertension (PAH) and pulmonary hypertension associated with interstitial lung disease in the United States. Studies have confirmed the robust benefits and safety of nebulized inhaled treprostinil, but it requires a time investment for nebulizer preparation, maintenance, and treatment. A small, portable treprostinil dry powder inhaler has been developed for the treatment of PAH. The primary objective of this study was to evaluate the safety and tolerability of treprostinil inhalation powder (TreT) in patients currently treated with treprostinil inhalation solution. Fifty-one patients on a stable dose of treprostinil inhalation solution enrolled and transitioned to TreT at a corresponding dose. Six-minute walk distance (6MWD), device preference and satisfaction (Preference Questionnaire for Inhaled Treprostinil Devices [PQ-ITD]), PAH Symptoms and Impact (PAH-SYMPACT®) questionnaire, and systemic exposure and pharmacokinetics for up to 5 h were assessed at baseline for treprostinil inhalation solution and at Week 3 for TreT. Adverse events (AEs) were consistent with studies of inhaled treprostinil in patients with PAH, and there were no study drug-related serious AEs. Statistically significant improvements occurred in 6MWD, PQ-ITD, and PAH-SYMPACT. Forty-nine patients completed the 3-week treatment phase and all elected to participate in an optional extension phase. These results demonstrate that, in patients with PAH, transition from treprostinil inhalation solution to TreT is safe, well-tolerated, and accompanied by statistically significant improvements in key clinical assessments and patient-reported outcomes with comparable systemic exposure between the two formulations at evaluated doses (trial registration: clinicaltrials.gov identifier: NCT03950739).

Efficacy of Inhaled Treprostinil on Multiple Disease Progression Events in Patients with Pulmonary Hypertension due to Parenchymal Lung Disease in the INCREASE Trial.

Rationale: The INCREASE study of inhaled treprostinil met its primary endpoint of change in 6-minute-walk distance at Week 16. In addition, there were significantly fewer clinical worsening events in patients receiving inhaled treprostinil. However, the incidence of multiple events in the same patient is unknown. Objectives: This post hoc analysis evaluated the effect of continued treatment with inhaled treprostinil on the frequency and impact of multiple disease progression events. Methods: Patients enrolled in INCREASE were analyzed for disease progression events, defined as at least 15% decline in 6-minute-walk distance, exacerbation of underlying lung disease, cardiopulmonary hospitalization, lung transplantation, at least 10% decline in forced vital capacity, or death during the duration of the 16-week study. Measurements and Main Results: In total, 147 disease progression events occurred in the inhaled treprostinil group (89/163 patients, 55%) compared with 215 events (109/163 patients, 67%) in the placebo group (P = 0.018). There was a lower incidence of each disease progression component in the inhaled treprostinil group: 6-minute-walk distance decline (45 vs. 64 events), lung disease exacerbation (48 vs. 72 events), FVC decline (19 vs. 33), cardiopulmonary hospitalization (23 vs. 33 events), and death (10 vs. 12). Fewer patients receiving inhaled treprostinil had multiple progression events compared with those receiving the placebo (35 vs. 58, 22% vs. 36%; P = 0.005). Conclusions: Patients who received inhaled treprostinil were significantly less likely to experience further disease progression events after an initial event compared with patients receiving placebo. These results support the continuation of inhaled treprostinil despite the occurrence of disease progression in clinical practice.

Mavrilimumab in patients with severe COVID-19 pneumonia and systemic hyperinflammation (MASH-COVID): an investigator initiated, multicentre, double-blind, randomised, placebo-controlled trial.

BACKGROUND: In patients with COVID-19, granulocyte-macrophage colony stimulating factor (GM-CSF) might be a mediator of the hyperactive inflammatory response associated with respiratory failure and death. We aimed to evaluate whether mavrilimumab, a monoclonal antibody to the GM-CSF receptor, would improve outcomes in patients with COVID-19 pneumonia and systemic hyperinflammation. METHODS: This investigator-initiated, multicentre, double-blind, randomised trial was done at seven hospitals in the USA. Inclusion required hospitalisation, COVID-19 pneumonia, hypoxaemia, and a C-reactive protein concentration of more than 5 mg/dL. Patients were excluded if they required mechanical ventilation. Patients were randomly assigned (1:1) centrally, with stratification by hospital site, to receive mavrilimumab 6 mg/kg as a single intravenous infusion, or placebo. Participants and all clinical and research personnel were masked to treatment assignment. The primary endpoint was the proportion of patients alive and off supplemental oxygen therapy at day 14. The primary outcome and safety were analysed in the intention-to-treat population. This trial is registered at ClinicalTrials.gov, NCT04399980, NCT04463004, and NCT04492514. FINDINGS: Between May 28 and Sept 15, 2020, 40 patients were enrolled and randomly assigned to mavrilimumab (n=21) or placebo (n=19). A trial of 60 patients was planned, but given slow enrolment, the study was stopped early to inform the natural history and potential treatment effect. At day 14, 12 (57%) patients in the mavrilimumab group were alive and off supplemental oxygen therapy compared with nine (47%) patients in the placebo group (odds ratio 1·48 [95% CI 0·43-5·16]; p=0·76). There were no treatment-related deaths, and adverse events were similar between groups. INTERPRETATION: There was no significant difference in the proportion of patients alive and off oxygen therapy at day 14, although benefit or harm of mavrilimumab therapy in this patient population remains possible given the wide confidence intervals, and larger trials should be completed. FUNDING: Kiniksa Pharmaceuticals.

Urgent Creation of a Palliative Care Team in a Small Hospital During the COVID Crisis.

The COVID-19 pandemic created a global health emergency that has changed the practice of medicine and has shown the need for palliative care as an essential element of hospital care. In our small South Florida hospital, a palliative care service was created to support the frontline caregivers. Thanks to the hospital support, our team was formed rapidly. It consisted of 3 advanced care practitioners, a pulmonary physician with palliative care experience and the cooperation of community resources such as hospice and religious support. We were able to support patients and their families facilitating communication as visitation was not allowed. We also addressed goals of care, providing comfort care transition when appropriate, and facilitating allocation of scarce resources to patients who were most likely to benefit from them. With this article we describe a simplified framework to replicate the creation of a Palliative Care Team for other hospitals that are experiencing this need.

Reducing rates of readmission and development of an outpatient management plan in pulmonary hypertension: lessons from congestive heart failure management.

Pulmonary hypertension currently has minimal guidelines for outpatient disease management. Congestive heart failure studies, however, have shown effectiveness of disease management plans in reducing all-cause mortality and all-cause and congestive heart failure-related hospital readmissions. Heart failure exacerbation is a common reason for readmission in both pulmonary hypertension and congestive heart failure. Our aim was to review individual studies and comprehensive meta-analyses to identify effective congestive heart failure interventions that can be used to develop similar disease management plans for pulmonary hypertension. A comprehensive literature review from 1993 to 2019 included original articles, systematic reviews, and meta-analyses. We reviewed topics of outpatient congestive heart failure interventions to decrease congestive heart failure mortality and readmission and patient management strategies in congestive heart failure. The most studied interventions included case management, multidisciplinary intervention, structured telephone strategy, and tele-monitoring. Case management showed decreased all-cause mortality at 12 months, all-cause readmission at 12 months, and congestive heart failure readmission at 6 and 12 months. Multidisciplinary intervention resulted in decreased all-cause readmission and congestive heart failure readmission. There was some discrepancy on effectiveness of tele-monitoring programs in individual studies; however, meta-analyses suggest tele-monitoring provided reduced all-cause mortality and risk of congestive heart failure hospitalization. Structured telephone strategy had similar results to tele-monitoring including decreased risk of congestive heart failure hospitalization, without effect on mortality. Extrapolating from congestive heart failure data, it seems strategies to improve the health of pulmonary hypertension patients and development of comprehensive care programs should include structured telephone strategy and/or tele-monitoring, case management strategies, and multidisciplinary interventions.

Current Understanding of COVID-19 Clinical Course and Investigational Treatments.

Importance: Currently, there is no unified framework linking disease progression to established viral levels, clinical tests, inflammatory markers, and investigational treatment options. Objective: It may take many weeks or months to establish a standard treatment approach. Given the growing morbidity and mortality with respect to COVID-19, this systemic review presents a treatment approach based on a thorough review of scholarly articles and clinical reports. Our focus is on staged progression, clinical algorithms, and individualized treatment. Evidence Review: We followed the protocol for a quality review article proposed by Heyn et al. (1). A literature search was conducted to find all relevant studies related to COVID-19. The search was conducted between April 1, 2020, and April 13, 2020, using the following electronic databases: PubMed (1809 to present); Google Scholar (1900 to present); MEDLINE (1946 to present), CINAHL (1937 to present); and Embase (1980 to present). The keywords used included COVID-19, 2019-nCov, SARS-CoV-2, SARS-CoV, and MERS-CoV, with terms such as efficacy, seroconversion, microbiology, pathophysiology, viral levels, inflammation, survivability, and treatment and pharmacology. No language restriction was placed on the search. Reference lists were manually scanned for additional studies. Findings: Of the articles found in the literature search, 70 were selected for inclusion in this study (67 cited in the body of the manuscript and 3 additional unique references in the Figures). The articles represent work from China, Japan, Taiwan, Vietnam, Rwanda, Israel, France, the United Kingdom, the Netherlands, Canada, and the United States. Most of the articles were cohort or case studies, but we also drew upon other information, including guidelines from hospitals and clinics instructing their staff on procedures to follow. In addition, we based some decisions on data collected by organizations such as the CDC, FDA, IHME, IDSA, and Worldometer. None of the case studies or cohort studies used a large number of participants. The largest group of participants numbered <500 and some case studies had fewer than 30 patients. However, the review of the literature revealed the need for individualized treatment protocols due to the variability of patient clinical presentation and survivability. A number of factors appear to influence mortality: the stage at which the patient first presented for care, pre-existing health conditions, age, and the viral load the patient carried. Conclusion and Relevance: COVID-19 can be divided into three distinct stages, beginning at the time of infection (Stage I), sometimes progressing to pulmonary involvement (Stage II, with or without hypoxemia), and less frequently to systemic inflammation (Stage III). In addition to modeling the stages of disease progression along with diagnostic testing, we have also created a treatment algorithm that considers age, comorbidities, clinical presentation, and disease progression to suggest drug classes or treatment modalities. This paper presents the first evidence-based recommendations for individualized treatment for COVID-19.

Are Chest Radiographs Routinely Indicated After Chest Tubes Placed for Non-Surgical Reasons Are Removed?

Background The insertion and subsequent removal of chest tubes are frequently performed procedures for the management of pneumothoraces, pleural effusions, and cardio-thoracic surgical interventions. A chest radiograph is commonly obtained after the removal of a chest tube to rule out the interval development of a pneumothorax. This practice has been questioned in various retrospective and prospective studies conducted on surgical patient populations, showing little to no benefits in performing routine chest X-rays (CXRs) after chest tube removal unless clinical symptoms such as worsening respiratory status and hemodynamic compromise are present. Material and Methods A four-year retrospective study was conducted using the Cleveland Clinic Foundation database. A chart review was performed, and 1,032 patients were screened, with 200 patients meeting inclusion criteria. The inclusion criteria included patients who underwent chest tube insertion for non-surgical reasons. The primary outcome was the percentage of clinically significant pneumothoraces detected by routine CXR after chest tube removal. Results Out of the 200 patients included in the study, 53 had a CXR after chest tube removal showing a residual pneumothorax. Out of the 53 patients, 50 ended up not needing chest tube re-insertion, as the patients were asymptomatic and hemodynamically stable. Only three patients required chest tube re-insertion due to respiratory symptoms and significant hemodynamic changes after the chest tubes were removed. In all three cases, the symptoms manifested prior to the CXRs being obtained; therefore, the decision to reinsert each chest tubes was made based on clinical signs rather than imaging. As expected, the practice of repeating CXRs after removal of the chest tubes resulted in delayed discharges despite patients reporting no symptoms and being hemodynamically stable. Conclusions Our study findings correlate with prior smaller studies on surgical patients. Symptoms and hemodynamic data seem to be a better predictor of whether a patient will require chest tube re-insertion or not. Routine CXR after chest tube removal also leads to prolonged hospital stay.

Case of Missing Plastic: Foreign Body Bronchiectasis.

Bronchiectasis is a well-known entity where the airways abnormally dilate losing their natural function. Most common causes of non-cytic fibrosis bronchiectasis in the middle age group include secondary immunodeficiency, aspiration, and allergic bronchopulmonary aspergillosis (ABPA). Obstructive foreign body is an uncommon cause of bronchiectasis and is often a missed diagnosis in a localized disease. Foreign bodies can be missed making the diagnosis and treatment more challenging and hence foreign body bronchiectasis should be considered in patients presenting with focal disease. Here we describe a patient with a retained foreign body that was discovered post lobectomy during gross pathological examination of the specimen with no significant aspiration history, non-diagnostic imaging of the chest and negative bronchoscopy.

Granulomatous-lymphocytic interstitial lung disease as the first manifestation of common variable immunodeficiency.

Common variable immunodeficiency (CVID) is one of the most common primary immunodeficiencies, which is characterized by reduced serum immunoglobulin levels and B-lymphocyte dysfunction. There are many clinical manifestations of this disease, the most common of which are recurrent respiratory tract infections. Among the most recently recognized autoimmune manifestation of CVID is a disease described as granulomatous-lymphocytic interstitial lung disease (GLILD), where CVID coexists with a small airway lymphoproliferative disorder, mimicking follicular bronchiolitis, or lymphocytic interstitial pneumonitis (LIP) on histology specimens. We herein describe the clinical and radiological features of GLILD in a 55-year-old woman where the diagnosis of CVID was actively pursued and eventually confirmed after her lung biopsy showed characteristic features of GLILD. The patient had dramatic response to treatment with IVIG and corticosteroids for 3 months followed by Mycophenolate mofetil for maintenance therapy.

Assessing the Safety and Clinical Impact of Thoracoscopic Lung Biopsy in Patients with Interstitial Lung Disease.

INTRODUCTION: The clinical relevance of surgical lung biopsy in Interstitial Lung Disease (ILD) is supported in the literature. Yet most reports reflect institutional or personal bias. AIM: To evaluate the validity of radiologic diagnosis and clinical impact of lung biopsy to help clarify which patient benefit most from biopsy. MATERIALS AND METHODS: We performed a retrospective analysis of a prospectively managed database. All patients who had a surgical lung biopsy for ILD within a period of four year (2009 to 2013) were included. Data included patient demographics, peri-operative variables and outcomes. Preoperative Computed Tomography (CT) imaging was reviewed by a thoracic radiologist blinded to the original report and pathologic information. RESULTS: A total of 47 patients were included. Lung tissue was obtained via a thoracoscopic approach in all but two that had mini-thoracotomy. Mean operating time was 51.1 minutes (18-123), median hospital stay was two days (1-18). Most (87.2%) of the patients were discharged within 72 hours. Thirty day mortality for elective surgery was 4.5% (2/44). Post-operative complications occurred in about one third of the patients. Complications in elective procedures included pneumothorax (10.4%), re-intubation (5.4%) and prolonged intubation (2.7%). Full concordance of radiographic diagnosis with the final diagnosis was significantly higher when reviewed by a cardiothoracic radiologist (60.5% vs. 21.3%). The preoperative clinical diagnosis was fully concordant with the final diagnosis in only 28.2% of cases. In 13.0% of patients the preoperative diagnosis was incorrect. Malignancy was the final diagnosis in two (4.3%) patients. In 51.1% of the patients, results of the biopsy did alter therapy. CONCLUSION: Diagnosis of specific ILD by a cardiothoracic radiologist is more specific and accurate and will probably lead to more appropriate therapy. Elective thoracoscopic surgical lung biopsy is a safe procedure, leads to a more accurate diagnosis of ILD and impacts therapy.

Pulmonary Artery Dimensions as a Prognosticator of Transplant-Free Survival in Scleroderma Interstitial Lung Disease.

BACKGROUND: Systemic sclerosis is a chronic debilitating autoimmune disease characterized by endothelial dysfunction and multi-organ fibrosis. Interstitial lung disease, a common manifestation of SSc, is termed scleroderma-related interstitial lung disease (SSc-ILD) and along with pulmonary hypertension contributes to a majority of deaths in SSc. SSc-ILD patients frequently develop pulmonary hypertension, which prognosticates a poorer outcome. We investigated pulmonary artery dimensions as an outcome predictor in patients with SSc-ILD. METHODS: A retrospective chart review abstracting data from SSc-ILD patients evaluated at a large tertiary care center was performed. HRCT imaging was reviewed and pulmonary artery (PA) and ascending aorta (Ao) diameters were measured for calculation of the PA:Ao ratio. Additionally, demographics, vital signs, spirometric parameters, comorbidities, and mean pulmonary artery pressures were collected when available. Outcome analysis with lung transplant or death events within 4 years based on pulmonary artery size as well as PA:Ao ratio was performed. RESULTS: 70 SSc-ILD patients were identified. Mean pulmonary artery diameter and PA:Ao ratio was 31.17 and 1.07 mm, respectively. Patients with a pulmonary artery diameter ≥32 mm had higher risk of lung transplantation or death (p < 0.001) within 4 years. Patients with a PA:Ao ratio ≥1.1 also had higher risk of lung transplantation or death (p < 0.001) within 4 years. Unadjusted outcomes analyses also identified PA:Ao ratio ≥1.1 as an independent outcome predictor (hazard ratio 3.30, p < 0.001). CONCLUSIONS/CLINICAL IMPLICATIONS: In SSc-ILD patients, a PA:Ao ratio ≥1.1 is associated with higher risk of lung transplant or death. These data suggest that PA:Ao dimension may be used for prognostication in SSc-ILD.

Pulmonary Artery Invasion Caused by Mycobacterium tuberculosis.

Extrapulmonary tuberculosis refers to Mycobacterium tuberculosis involving organs other than the lungs (eg, pleura, lymph nodes, genitourinary tract, abdomen, skin, joints and bones, or meninges). In non-HIV-endemic areas, where reactivation is the predominant mechanism of tuberculosis, pleural involvement occurs in 4% of cases. We present an extremely rare case of a 62-year-old immunocompetent patient with pleural tuberculosis confirmed by surgical pleural biopsies, who presented with a large mediastinal mass and evidence of pulmonary artery invasion on CT scanning and endobronchial ultrasonography imaging, highlighting a unique and malignant-like character of the disease.

Shared medical appointments in pulmonary hypertension.

We aimed to adapt the shared medical appointment (SMA) model to the care of pulmonary hypertension (PH) patients and evaluate patient satisfaction. Our SMA team included a PH specialist, a PH nurse, and one research fellow. Eight to twelve PH patients with a family member were invited during office visits and by phone calls. Attendance was verified and encouraged by phone calls and informational letters. The meetings started with a 30-minute presentation on various PH topics, which was followed by each patient's individual visit and a focused examination in front of the group, allowing group questions and interaction. Of the total number of patients (n = 53), 84% stated that they would attend a future SMA. The care provided was rated excellent to very good by 98% of the patients. Ninety-two percent stated that they improved their understanding of the disease and treatment options, and 59% acknowledged a preference for the group visit over the private visit. Twenty-five percent of patients stated that they were very likely to likely to some extent to agree to change or seek a change in treatment modality on the basis of conversation with other patients in the SMA. The majority of our patients expressed no privacy concerns before the meeting (76%), and even more expressed no such concerns afterward (88%). In conclusion, the SMA model allows PH patients to increase understanding of their disease process while integrating peer support, promoting social interaction, and addressing patients' emotional needs. Other (rare) pulmonary diseases may benefit from this model.

Shortness of breath after AV ablation: case of left phrenic nerve palsy.

Phrenic nerve palsy has been recognized as a complication of catheter ablation with a prevalence of 0.11-0.48% after atrial fibrillation ablation, independent of the type of ablation catheter or energy source, likely due to the anatomical relationship of the nerves. This report describes a case of new onset of shortness of breath (SOB) due to left diaphragm paralysis following transcatheter radiofrequency ablation in a patient with underlying chronic obstructive pulmonary disease.

Current trends in critical care nutrition.

Nutrition in the intensive care setting is a vital part of patient care, and may even be referred to as "nutritional therapy". Current nutritional practices have progressed a lot over the past few years, and draw from a large body of accumulating evidence. Yet, as with other trends in critical care, there are a lot of variations in the way nutrition is approached between institutions, as well as between individual physicians. This review attempts to look at some of these differences and provide recommendations based upon the available literature.

Generation of oxidants by hypoxic human pulmonary and coronary smooth-muscle cells.

BACKGROUND: Pulmonary vasoconstriction in response to hypoxia is unusual inasmuch as local exposure of nonpulmonary vasculature to hypoxia results in vasodilation. It has been suggested that pulmonary artery smooth-muscle cells may relax in response to intracellular generation of reactive oxygen species (ROS) and that the production of ROS decreases under hypoxia. However, other workers report increased ROS production in human pulmonary artery smooth-muscle cells (HPASMC) during hypoxia. METHODS: Using dihydrodichlorofluorescein diacetate, dihydroethidium, and Amplex Red (Molecular Probes; Eugene, OR), we estimated ROS generation by confluent primary cultures of HPASMC and human coronary artery smooth-muscle cells (HCASMC) under normoxia (20%) and acute hypoxia (5%). RESULTS: All three assay systems showed that HPASMC production of ROS is decreased under hypoxia and to a greater extent than the decrease in ROS production by HCASMC. A substantially greater percentage of normoxic ROS production by HPASMC is mitochondrial (> 60%) compared to HCASMC (< 30%). CONCLUSIONS: These results support the conclusion that ROS generation decreases, rather than increases, in HPASMC during hypoxia. However, as ROS production also decreases in HCASMC during hypoxia, the reason for the opposite change in vascular tone is not yet apparent.