Minimal Clinically Important Difference in the 6-minute-walk Distance for Patients with Pulmonary Arterial Hypertension.

Rationale: The 6-minute-walk distance (6MWD) is an important clinical and research metric in pulmonary arterial hypertension (PAH); however, there is no consensus about what minimal change in 6MWD is clinically significant. Objectives: We aimed to determine the minimal clinically important difference in the 6MWD. Methods: We performed a meta-analysis using individual participant data from eight randomized clinical trials of therapy for PAH submitted to the U.S. Food and Drug Administration to derive minimal clinically important differences in the 6MWD. The estimates were externally validated using the Pulmonary Hypertension Association Registry. We anchored the change in 6MWD to the change in the Medical Outcomes Survey Short Form physical component score. Measurements and Main Results: The derivation (clinical trial) and validation (Pulmonary Hypertension Association Registry) samples were comprised of 2,404 and 537 adult patients with PAH, respectively. The mean ± standard deviation age of the derivation sample was 50.5 ± 15.2 years, and 1,849 (77%) were female, similar to the validation sample. The minimal clinically important difference in the derivation sample was 33 meters (95% confidence interval, 27-38), which was almost identical to that in the validation sample (36 m [95% confidence interval, 29-43]). The minimal clinically important difference did not differ by age, sex, race, pulmonary hypertension etiology, body mass index, use of background therapy, or World Health Organization functional class. Conclusions: We estimated a 6MWD minimal clinically important difference of approximately 33 meters for adults with PAH. Our findings can be applied to the design of clinical trials of therapies for PAH.

EmPHasis-10 as a measure of health-related quality of life in pulmonary arterial hypertension: data from PHAR.

INTRODUCTION: While the performance of the emPHasis-10 (e10) score has been evaluated against limited patient characteristics within the United Kingdom, there is an unmet need for exploring the performance of the e10 score among pulmonary arterial hypertension (PAH) patients in the United States. METHODS: Using the Pulmonary Hypertension Association Registry, we evaluated relationships between the e10 score and demographic, functional, haemodynamic and additional clinical characteristics at baseline and over time. Furthermore, we derived a minimally important difference (MID) estimate for the e10 score. RESULTS: We analysed data from 565 PAH (75% female) adults aged mean±sd 55.6±16.0 years. At baseline, the e10 score had notable correlation with factors expected to impact quality of life in the general population, including age, education level, income, smoking status and body mass index. Clinically important parameters including 6-min walk distance and B-type natriuretic peptide (BNP)/N-terminal proBNP were also significantly associated with e10 score at baseline and over time. We generated a MID estimate for the e10 score of -6.0 points (range -5.0--7.6 points). CONCLUSIONS: The e10 score was associated with demographic and clinical patient characteristics, suggesting that health-related quality of life in PAH is influenced by both social factors and indicators of disease severity. Future studies are needed to demonstrate the impact of the e10 score on clinical decision-making and its potential utility for assessing clinically important interventions.

Prediction of patient outcomes through social determinants of health: The Pulmonary Hypertension Association Registry (PHAR) evaluation.

Outcomes of patients with pulmonary arterial hypertension (PAH) may be associated with social determinants of health (SDOH) and other baseline patient characteristics. At present, there is no prognostic model to predict important patient outcomes in PAH based on SDOH. Utilizing information from the Pulmonary Hypertension Association Registry (PHAR), we derive a model (PHAR Evaluation or PHARE) to predict an important composite patient outcomes based on SDOH and other patient characteristics. Baseline data regarding SDOH from adult patients with PAH enrolled in the PHAR between 2015 and March 23, 2020, were included for analysis. We performed repeated measures logistic regression modeling with dichotomous outcome data (0 for no events, 1 for one or more events) to derive the PHARE. Here, 1275 consecutive adult patients enrolled in the PHAR from 47 participating centers were included. Variables included in our model are race, gender, ethnicity, household income, level of education, age, body mass index, drug use, alcohol use, marital status, and type of health insurance. Interaction effect between variables was analyzed and several interactions were also included in the PHARE. The PHARE shows a c-statistic of 0.608 (p < 0.0001) with 95% confidence intervals (0.583, 0.632). Using SDOH and baseline characteristics from the PHAR, the PHARE correlates with our composite patient outcome. Further work evaluating the role of SDOH in prognostic modeling of PAH is indicated.

Impact of Face Masks on 6-Minute Walk Test in Healthy Volunteers.

Our objective was to establish the impact of wearing a face mask on the outcome of six-minute walk test in healthy volunteers. In a study of 20 healthy volunteers who each completed two 6MWTs, one with a mask and one without, there was no difference in distance walked. However, there was a significant difference in perception of dyspnea between the two groups.

Development of Pulmonary Hypertension in Heart Failure With Preserved Ejection Fraction.

Pulmonary hypertension (PH) is common in patients with heart failure with preserved ejection fraction (HFpEF). While PH-HFpEF may affect more than a million patients in the United States alone, it has been difficult to study its epidemiology and response to treatment due to difficulty in properly defining the illness. While chronic remodeling of the pulmonary vasculature is related to chronic passive congestion of the pulmonary circulation from the pulmonary veins, there are likely other contributors to the development of PH-HFpEF. We explore the potential direct contributions of obesity, diabetes mellitus, genetics, and sleep apnea on the pulmonary circulation in those with PH-HFpEF, and we discuss the potential role of exercise testing or fluid challenge during diagnostic testing.

Massive dilatation of the pulmonary artery in association with pulmonic stenosis and pulmonary hypertension.

Congenital pulmonary valve stenosis has been associated with the development of massive pulmonary arterial (PA) dilatation. Over time, this dilatation may distort surrounding structures and lead to compression of the left main coronary artery (LMCA) or the left mainstem bronchus. In this report, we describe a patient with a history of chronic thromboembolic pulmonary hypertension (CTEPH) and congenital pulmonic stenosis with massive PA dilatation. He develops exertional chest pain, presenting an unusual differential diagnosis. Novel diagnostic testing was performed to help narrow the differential diagnosis, and the patient responded well to pulmonary vasodilator treatment for progressive pulmonary hypertension.

Enhanced allergen-induced airway inflammation in paucity of lymph node T cell (plt) mutant mice.

BACKGROUND: Dendritic cells and lymphocytes play a central role in allergic asthma. Chemokines for these cells include the CCR7 agonists secondary lymphoid chemokine/CCL21 and EBV-induced lymphoid chemokine/CCL19, but their role in allergic asthma is poorly understood. OBJECTIVE: We sought to determine the effects of abrogation of lymphoid tissue expression of CCR7 agonists on allergic airway responses. METHODS: Paucity of lymphocyte T cell (plt) mutant mice, deficient in EBV-induced lymphoid chemokine/CCL19 and the lymphoid form of secondary lymphoid chemokine/CCL21, were evaluated in an established ovalbumin (OVA)-induced asthma model (plt-OVA group) and compared with similarly immunized +/+ BALB/c mice (+/+OVA group). RESULTS: APTI responses to methacholine increased similarly in OVA-challenged plt and +/+ mice. However, airway inflammation was strikingly enhanced in plt-OVA mutants over +/+OVA mice and included increased numbers of eosinophils, CD4 and B cells, neutrophils, and total leukocytes in bronchoalveolar lavage fluid and inflammatory cell cuffing around pulmonary arterioles. Enhanced airway inflammation was accompanied by an increase in lung T(H)2 activity, with increased levels of IL-4 and monocyte-derived chemoattractant/CCL22. CONCLUSIONS: Induction of allergic asthma in mutant mice with impaired CCR7 responses results in characteristics that resemble severe asthma in human subjects, including severe bronchial lymphocytosis, eosinophilia, and neutrophilia, but not in enhancement in airway hyperreactivity. CLINICAL IMPLICATIONS: Disruption of chemokines responsible for trafficking of antigen-processing cells and lymphocytes to the draining lymph nodes might lead to enhanced allergic airway responses.

Delay of CMV infection in high-risk CMV mismatch lung transplant recipients due to prophylaxis with oral ganciclovir.

Cytomegalovirus (CMV) is a common opportunistic infection in lung transplant recipients. Despite the use of early post-operative intravenous ganciclovir, most high-risk patients develop CMV infection. We conducted this retrospective study to determine the efficacy of extended CMV prophylaxis with oral ganciclovir in high-risk, donor-positive-recipient-negative, lung recipients. All patients initially received 3 months of intravenous ganciclovir and CMV hyperimmune globulin. Clinical outcomes in all CMV mismatch patients undergoing lung transplant surviving at least 3 months were included (n = 42). Since 1998, 14 patients received no oral ganciclovir prophylaxis (group 1) and 28 patients received indefinite oral ganciclovir after completion of intravenous therapy (group 2). In those patients receiving oral ganciclovir, the prevalence of post-transplant CMV infection was significantly reduced over the first 180 d post-transplant (50% in group 1 vs. 4% in group 2; p < 0.001). Although some CMV events were observed with additional follow-up in group 2, there remained a significantly greater freedom from CMV infection by Kaplan-Meier analysis in group 2 as compared with group 1, with over 30 months follow-up time in each group (log-rank, p = 0.02). A moderate rate of drug discontinuation was observed in group 2, and no severe drug-related events occurred. In high-risk lung transplant recipients, CMV prophylaxis with intravenous ganciclovir, followed by indefinite oral ganciclovir, significantly delays and reduces post-transplant CMV infections. A larger prospective randomized study is needed to confirm the benefits of oral ganciclovir on CMV prevention.