Publications by authors named "Stephen C Mathai"

120 Publications

Development of the Pulmonary Hypertension Functional Classification Self-Report: a patient version adapted from the World Health Organization Functional Classification measure.

Health Qual Life Outcomes 2021 Aug 24;19(1):202. Epub 2021 Aug 24.

Mayo Clinic, Rochester, MN, USA.

Background: Pulmonary arterial hypertension (PAH) is characterized by progressive limitations on physical activity, right heart failure, and premature death. The World Health Organization functional classification (WHO-FC) is a clinician-rated assessment used widely to assess PAH severity and functioning, but no equivalent patient-reported version of PAH symptoms and activity limitations exists. We developed a version of the WHO-FC for self-completion by patients: the Pulmonary Hypertension Functional Classification Self-Report (PH-FC-SR).

Methods: Semistructured interviews were conducted with three health care providers (HCPs) via telephone to inform development of the draft PH-FC-SR. Two rounds of semi-structured interviews were conducted with 14 US patients with a self-reported PAH diagnosis via telephone/online to elicit concepts and iteratively refine the PH-FC-SR.

Results: HCPs reported that the WHO-FC was a useful tool for evaluating patients' PAH severity over time and for making treatment decisions but acknowledged that use of the measure is subjective. Patients in round 1 interviews (n = 6) reported PAH symptoms, including shortness of breath (n = 6), fatigue (n = 5), syncope (n = 5), chest pains (n = 3), and dizziness (n = 3). Round 1 patients identified challenges with the original WHO-FC, including comprehensibility of clinical terms and overlapping descriptions of class II and III, and preferred the Draft 1 PH-FC-SR over the original WHO-FC. After minor changes were made to Draft 2, round 2 interviews (n = 8) confirmed patients understood the PH-FC-SR class descriptions, interpreting them consistently.

Conclusions: The HCP and patient interviews identified and confirmed certain limitations inherent within the clinician-rated WHO-FC, including subjective assessment and overlapping definitions for class II and III. The PH-FC-SR includes patient-appropriate language, symptoms, and physical activity impacts relevant to patients with PAH. Future research is recommended to validate the PH-FC-SR and explore its correlation with the physician-assessed WHO-FC and other outcomes.
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http://dx.doi.org/10.1186/s12955-021-01782-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8386063PMC
August 2021

A scoping review of palliative care outcome measures in interstitial lung disease.

Eur Respir Rev 2021 Sep 3;30(161). Epub 2021 Aug 3.

Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, USA.

Interstitial lung disease (ILD) confers a high mortality and symptom burden, substantially impacting quality of life. Studies evaluating palliative care in ILD are rapidly expanding. Uniform outcome measures are crucial to assessing the impact of palliative care in ILD. This scoping review evaluates existing outcome measures in general health-related quality of life (HRQoL), physical health, mental health, social health and advance care planning (ACP) domains in patients with ILD. Articles in English with quantitative assessment of at least one measure of general HRQoL, physical health, mental health, social health or ACP in patients with ILD were included. Searches across three databases yielded 3488 non-duplicate articles. 23 met eligibility criteria and included three randomised controlled trials (RCTs) or secondary analysis of an RCT (13%), three cross-sectional studies or secondary analysis of cross-sectional study (13%), one prospective study (4%) and 16 retrospective studies (70%). Among eligible articles, 25 distinct instruments were identified. Six studies assessed general HRQoL (26%), 16 assessed physical health (70%), 11 assessed mental health (48%), six assessed social health (26%) and 16 assessed ACP (70%). The ability to compare results across studies remains challenging given the heterogeneity in outcome measures. Future work is needed to develop core palliative care outcome measures in ILD.
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http://dx.doi.org/10.1183/16000617.0080-2021DOI Listing
September 2021

A novel approach to perioperative risk assessment for patients with pulmonary hypertension.

ERJ Open Res 2021 Jul 19;7(3). Epub 2021 Jul 19.

Dept of Medicine, Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, USA.

Rationale: Pulmonary hypertension (PH) is associated with significant perioperative morbidity and mortality. We hypothesised that pulmonary arterial hypertension (PAH) composite risk assessment scores could estimate perioperative risk for PH patients when adjusted for inherent procedural risk.

Methods: We identified patients in the Johns Hopkins PH Center Registry that had noncardiac surgery (including endoscopies) between September 2015 and January 2020. We collected information on preoperative patient-level and procedural variables and used logistic regression to evaluate associations with a composite outcome of death within 30 days or serious postoperative complication. We generated composite patient-level risk assessment scores for each subject and used logistic regression to estimate the association with adverse surgical outcomes. We adjusted multivariable models for inherent procedural risk of major cardiovascular events and used these models to generate a numerical PH perioperative risk (PHPR) score.

Results: Among 150 subjects, 19 (12.7%) reached the primary outcome, including 7 deaths (4.7%). Individual patient-level and procedural variables were associated with the primary outcome (all p<0.05). A composite patient-level risk assessment score built on three noninvasive parameters was strongly associated with reduced risk for poor outcomes (OR=0.4, p=0.03). This association was strengthened after adjusting the model for procedural risk. A PHPR score derived from the multivariable model stratified patients into low (0%), intermediate (≤10%), or high (>10%) risk of reaching the primary outcome.

Conclusion: Composite PAH risk assessment scores can predict perioperative risk for PH patients after accounting for inherent procedural risk. Validation of the PHPR score in a multicentre, prospective cohort is warranted.
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http://dx.doi.org/10.1183/23120541.00257-2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8287131PMC
July 2021

Health disparities and treatment approaches in portopulmonary hypertension and idiopathic pulmonary arterial hypertension: an analysis of the Pulmonary Hypertension Association Registry.

Pulm Circ 2021 Jul-Sep;11(3):20458940211020913. Epub 2021 May 17.

Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.

Compared to idiopathic pulmonary arterial hypertension (IPAH), patients with portopulmonary hypertension (POPH) have worse survival. Health disparities may contribute to these differences but have not been studied. We sought to compare socioeconomic factors in patients with POPH and IPAH and to determine whether socioeconomic status and/or POPH diagnosis were associated with treatment and health-care utilization. We performed a cross-sectional study of adults enrolled in the Pulmonary Hypertension Association Registry. Patients with IPAH (n = 344) and POPH (n = 57) were compared. Compared with IPAH, patients with POPH were less likely to be college graduates (19.6% vs. 34.9%, p = 0.02) and more likely to be unemployed (54.7% vs. 30.5%, p < 0.001) and have an annual household income below poverty level (45.7% vs. 19.0%, p < 0.001). Patients with POPH had similar functional class, quality of life, 6-min walk distance, and mean pulmonary arterial pressure with a higher cardiac index. Compared with IPAH, patients with POPH were less likely to receive combination therapy (46.4% vs. 62.2%, p = 0.03) and endothelin receptor antagonists (28.6% vs. 55.1%, p < 0.001) at enrollment with similar treatment at follow-up. Patients with POPH had more emergency department visits (1.7 ± 2.1 vs. 0.9 ± 1.2, p = 0.009) and hospitalizations in the six months preceding enrollment (1.5 ± 2.1 vs. 0.8 ± 1.1, p = 0.02). Both POPH diagnosis and lower education level were independently associated with a higher number of emergency department visits. Compared to IPAH, patients with POPH have lower socioeconomic status, are less likely to receive initial combination therapy and endothelin receptor antagonists but have similar treatment at follow-up, and have increased health-care utilization.
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http://dx.doi.org/10.1177/20458940211020913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8186121PMC
May 2021

Comprehensive echocardiographic evaluation of the right heart in patients with pulmonary vascular diseases: the PVDOMICS experience.

Eur Heart J Cardiovasc Imaging 2021 Jun 7. Epub 2021 Jun 7.

Bluhm Cardiovascular Institute, Northwestern University, 676 N Saint Clair, Chicago Illinois 60611 USA.

Aims: There is a wide spectrum of diseases associated with pulmonary hypertension, pulmonary vascular remodelling, and right ventricular dysfunction. The NIH-sponsored PVDOMICS network seeks to perform comprehensive clinical phenotyping and endophenotyping across these disorders to further evaluate and define pulmonary vascular disease.

Methods And Results: Echocardiography represents the primary non-invasive method to phenotype cardiac anatomy, function, and haemodynamics in these complex patients. However, comprehensive right heart evaluation requires the use of multiple echocardiographic parameters and optimized techniques to ensure optimal image acquisition. The PVDOMICS echo protocol outlines the best practice approach to echo phenotypic assessment of the right heart/pulmonary artery unit.

Conclusion: Novel workflow processes, methods for quality control, data for feasibility of measurements, and reproducibility of right heart parameters derived from this study provide a benchmark frame of reference. Lessons learned from this protocol will serve as a best practice guide for echocardiographic image acquisition and analysis across the spectrum of right heart/pulmonary vascular disease.
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http://dx.doi.org/10.1093/ehjci/jeab065DOI Listing
June 2021

Pulmonary hypertension due to interstitial lung disease or chronic obstructive pulmonary disease: a patient experience study of symptoms and their impact on quality of life.

Pulm Circ 2021 Apr-Jun;11(2):20458940211005641. Epub 2021 Apr 1.

Patient-Centered Outcomes Assessment, RTI Health Solutions, Ann Arbor, MI, USA.

Pulmonary hypertension resulting from chronic lung disease such as chronic obstructive pulmonary disease and interstitial lung disease is categorized by the World Health Organization as Group 3 pulmonary hypertension. To identify the symptoms and impacts of World Health Organization Group 3 pulmonary hypertension and to capture data related to the patient experience of this disease, qualitative research interviews were undertaken with 3 clinical experts and 14 individuals with pulmonary hypertension secondary to chronic obstructive pulmonary disease or interstitial lung disease. Shortness of breath, fatigue, cough, and swelling were the most frequently reported symptoms of pulmonary hypertension due to chronic obstructive pulmonary disease or interstitial lung disease, and shortness of breath was further identified as the single most bothersome symptom for most patients (71.4%). Interview participants also described experiencing a number of impacts related to pulmonary hypertension and pulmonary hypertension symptoms, including limitations in the ability to perform activities of daily living and impacts on physical functioning, family life, and social life as well as emotional impacts, which included frustration, depression, anxiety, isolation, and sadness. Results of these qualitative interviews offer an understanding of the patient experience of pulmonary hypertension due to chronic obstructive pulmonary disease or interstitial lung disease, including insight into the symptoms and impacts that are most important to patients in this population. As such, these results may help guide priorities in clinical treatment and assist researchers in their selection of patient-reported outcome measures for clinical trials in patients with pulmonary hypertension due to chronic obstructive pulmonary disease or interstitial lung disease.
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http://dx.doi.org/10.1177/20458940211005641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020242PMC
April 2021

Assessment of right ventricular reserve utilizing exercise provocation in systemic sclerosis.

Int J Cardiovasc Imaging 2021 Jul 16;37(7):2137-2147. Epub 2021 Apr 16.

Division of Rheumatology, Johns Hopkins University, Baltimore, MD, USA.

Right ventricular (RV) capacity to adapt to increased afterload is the main determinant of outcome in pulmonary hypertension, a common morbidity seen in systemic sclerosis (SSc). We hypothesized that supine bicycle echocardiography (SBE), coupled with RV longitudinal systolic strain (RVLSS), improves detection of limitations in RV reserve in SSc. 56 SSc patients were prospectively studied during SBE with RV functional parameters compared at rest and peak stress. We further dichotomized patients based on resting RV systolic pressure (RVSP) to determine the effects of load on contractile response. Our pooled cohort analysis revealed reduced global RVLSS at rest (-16.2 ± 3.9%) with normal basal contractility (-25.6 ± 7.7%) and relative hypokinesis of the midventricular (-14.1 ± 6.0%) and apical (-8.9 ± 5.1%) segments. With exercise, global RVLSS increased significantly (p = 0.0005), however despite normal basal contractility at rest, there was no further augmentation with exercise. Mid and apical RVLSS increased with exercise suggestive of RV contractile reserve. In patients with resting RVSP < 35 mmHg, global and segmental RVLSS increased with exercise. In patients with resting RVSP ≥ 35 mmHg, global and segmental RVLSS did not increase with exercise and there was evidence of exertional RV dilation. Exercise provocation in conjunction with RVLSS identified differential regional contractile response to exercise in SSc patients. We further demonstrate the effect of increased loading conditions on RV contractile response exercise. These findings suggest subclinical impairments in RV reserve in SSc that may be missed by resting noninvasive 2DE-based assessments alone.
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http://dx.doi.org/10.1007/s10554-021-02237-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292174PMC
July 2021

Exercise right ventricular ejection fraction predicts right ventricular contractile reserve.

J Heart Lung Transplant 2021 Jun 17;40(6):504-512. Epub 2021 Feb 17.

Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address:

Background: Right ventricular (RV) contractile reserve shows promise as an indicator of occult RV dysfunction in pulmonary vascular disease. We investigated which measure of RV contractile reserve during exercise best predicts occult RV dysfunction and clinical outcomes.

Methods: We prospectively studied RV contractile reserve in 35 human subjects referred for right heart catheterization for known or suspected pulmonary hypertension. All underwent cardiac magnetic resonance imaging, echocardiography, and supine invasive cardiopulmonary exercise testing with concomitant RV pressure-volume catheterization. Event-free survival was prospectively adjudicated from time of right heart catheterization for a 4-year follow-up period.

Results: RV contractile reserve during exercise, as measured by a positive change in end-systolic elastance (Ees) during exertion, was associated with elevation in pulmonary pressures but preservation of RV volumes. Lack of RV reserve, on the other hand, was tightly coupled with acute RV dilation during exertion (R = 0.76, p< 0.001). RV Ees and dilation changes each predicted resting RV-PA dysfunction. RV ejection fraction during exercise, which captured exertional changes in both RV Ees and RV dilation, proved to be a robust surrogate for RV contractile reserve. Reduced exercise RV ejection fraction best predicted occult RV dysfunction among a variety of resting and exercise RV measures, and was also associated with clinical worsening.

Conclusions: RV ejection fraction during exercise, as an index of RV contractile reserve, allows for excellent identification of occult RV dysfunction, more so than resting measures of RV function, and may predict clinical outcomes as well.
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http://dx.doi.org/10.1016/j.healun.2021.02.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169559PMC
June 2021

Burden and Unmet Needs with Portable Oxygen in Patients on Long-Term Oxygen Therapy.

Ann Am Thorac Soc 2021 Sep;18(9):1498-1505

Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins School of Medicine, and.

Over 1.5 million Americans receive long-term oxygen therapy (LTOT) for the treatment of chronic hypoxemia to optimize functional status and quality of life. However, current portable oxygen equipment, including portable gas tanks (GTs), portable liquid tanks (LTs), and portable oxygen concentrators (POCs), each have limitations that can hinder patient mobility and daily activities. To examine patient experiences with portable oxygen to guide equipment innovation and thereby improve patient care on oxygen therapy. The burden and unmet needs with portable oxygen equipment were assessed in 836 LTOT patients with chronic lung disease (chronic obstructive pulmonary disease [COPD], interstitial lung disease, and pulmonary hypertension) through an online survey. The survey included a combination of multiple-choice, Likert-scale, short-answer, and open-ended questions. Distribution was achieved through patient support organizations, including the U.S. COPD Coalition, the Pulmonary Fibrosis Foundation, and the Pulmonary Hypertension Association. Improvements in portability were ranked as the highest priority by patients across all equipment types, followed by increases in the duration of oxygen supply for GTs, accessibility for LTs, and flow capabilities for POCs. All device types were found to be burdensome, with the greatest burden among GT users, 51% of whom characterized GT use as "strenuous" or "extremely strenuous" (high burden). POCs ranked as the most common (61%) and least burdensome devices; however, 29% of POC users still reported a high associated burden. Forty-seven percent of POC respondents described using a POC despite it not meeting their oxygen needs to benefit from advantages over alternative equipment. Among non-POC users, limited oxygen flow rate capabilities and cost were the top reasons preventing POC use. Although improvements have been made to portable oxygen equipment, this study highlights the burden that remains and reveals a clear need for advances in technology to improve the functional status and quality of life of portable LTOT users.
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http://dx.doi.org/10.1513/AnnalsATS.202005-487OCDOI Listing
September 2021

Performance Under Pressure: The Relevance of Pulmonary Vascular Response to Exercise Challenge in Scleroderma.

Chest 2021 02;159(2):481-483

Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.

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http://dx.doi.org/10.1016/j.chest.2020.10.012DOI Listing
February 2021

Long-Term Outcomes in Patients With Connective Tissue Disease-Associated Pulmonary Arterial Hypertension in the Modern Treatment Era: Meta-Analyses of Randomized, Controlled Trials and Observational Registries.

Arthritis Rheumatol 2021 05 29;73(5):837-847. Epub 2021 Mar 29.

University of Michigan, Ann Arbor.

Objective: Data on the magnitude of benefit of modern therapies for pulmonary arterial hypertension (PAH) in connective tissue disease (CTD)-associated PAH are limited. In this study, we performed meta-analyses of randomized, controlled trials (RCTs) and registries to quantify the benefit of these modern therapies in patients with CTD-PAH.

Methods: The PubMed and Embase databases were searched for articles reporting data from RCTs or registries published between January 1, 2000 and November 25, 2019. Eligibility criteria included multicenter studies with ≥30 CTD-PAH patients. For an RCT to be included, the trial had to evaluate an approved PAH therapy, and long-term risks of clinical morbidity and mortality or 6-minute walk distance had to be reported. For a registry to be included, survival rates had to be reported. Random-effects models were used to pool the data.

Results: Eleven RCTs (total of 4,329 patients; 1,267 with CTD-PAH) and 19 registries (total of 9,739 patients; 4,008 with CTD-PAH) were included. Investigational therapy resulted in a 36% reduction in the risk of clinical morbidity/mortality events both in the overall PAH population (hazard ratio [HR] 0.64, 95% confidence interval [95% CI] 0.54, 0.75; P < 0.001) and in CTD-PAH patients (HR 0.64, 95% CI 0.51, 0.81; P < 0.001) as compared to control subjects. The survival rate was lower in CTD-PAH patients compared to all PAH patients (survival rate 62%, 95% CI 57, 67% versus 72%, 95% CI 69, 75% at 3 years). The survival rate in CTD-PAH patients treated primarily after 2010 was higher than that in CTD-PAH patients treated before 2010 (survival rate 73%, 95% CI 62, 81% versus 65%, 95% CI 59, 71% at 3 years).

Conclusion: Modern therapy provides a similar reduction in morbidity/mortality risk in patients with CTD-PAH when compared to the PAH population overall. Risk of death is higher in CTD-PAH patients than in those with PAH overall, but survival has improved in the last 10 years, which may be related to increased screening and/or new treatment approaches. Early detection of PAH in patients with CTD and up-front intensive treatment are warranted.
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http://dx.doi.org/10.1002/art.41669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251834PMC
May 2021

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

Eur Respir J 2021 02 25;57(2). Epub 2021 Feb 25.

Division of Pulmonary and Critical Care Medicine, Stanford University School of Medicine, Stanford, CA, USA

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.
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http://dx.doi.org/10.1183/13993003.00414-2020DOI Listing
February 2021

Clinical Differences and Outcomes between Methamphetamine-associated and Idiopathic Pulmonary Arterial Hypertension in the Pulmonary Hypertension Association Registry.

Ann Am Thorac Soc 2021 04;18(4):613-622

Department of Medicine and.

Single-center studies demonstrated that methamphetamine use is associated with pulmonary arterial hypertension (Meth-APAH). We used the Pulmonary Hypertension Association Registry to evaluate the national distribution of Meth-APAH and to compare its impact on patient-reported and clinical outcomes relative to idiopathic PAH. To determine if patients with Meth-APAH differ from those with idiopathic PAH in demographics, regional distribution in the United States, hemodynamics, health-related quality of life, PAH-specific treatment, and health care use. The Pulmonary Hypertension Association Registry is a U.S.-based prospective cohort of patients new to care at a Pulmonary Hypertension Care Center. The registry collects baseline demographics, clinical parameters, and repeated measures of health-related quality of life, World Health Organization functional class, 6-minute walk distance, therapy, and health care use. Repeated measures of functional class, health-related quality of life, type of therapy, emergency department visits, and hospitalizations were compared using generalized estimating equations. Of 541 participants included, 118 had Meth-APAH; 83% of Meth-APAH arose in the western United States. The Meth-APAH group was younger and had a poorer socioeconomic status and lower cardiac index than the idiopathic PAH group, despite no difference in mean pulmonary artery pressure or pulmonary vascular resistance. The Meth-APAH group had a more advanced functional class in longitudinal models (0.22 points greater; 95% confidence interval [CI], 0.07 to 0.37) and worse PAH-specific (emPHasis-10) health-related quality of life (-5.4; 95% CI, -8.1 to -2.8). There was no difference in dual combination therapy; however, participants with Meth-APAH were less likely to be initiated on triple therapy (odds ratio [OR], 0.43; 95% CI, 0.24 to 0.77) or parenteral therapy (OR, 0.10; 95% CI, 0.04 to 0.24). Participants with Meth-APAH were more likely to seek care in the emergency department (incidence rate ratio, 2.30; 95% CI, 1.71 to 3.11) and more likely to be hospitalized (incidence rate ratio, 1.42; 95% CI, 1.10 to 1.83). Meth-APAH represents a unique clinical phenotype of PAH, most common in the western United States. It accounts for a notable proportion of PAH in expert centers. Assessment for methamphetamine use is necessary in patients with PAH.
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http://dx.doi.org/10.1513/AnnalsATS.202007-774OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174020PMC
April 2021

Insulin-like growth factor binding protein-2: a new circulating indicator of pulmonary arterial hypertension severity and survival.

BMC Med 2020 10 6;18(1):268. Epub 2020 Oct 6.

Division of Pediatric Cardiology, Department of Pediatrics, Johns Hopkins University, 720 Rutland Ave. Ross RM 1143, Baltimore, MD, 21205, USA.

Background: Pulmonary arterial hypertension (PAH) is a fatal disease that results from cardio-pulmonary dysfunction with the pathology largely unknown. Insulin-like growth factor binding protein 2 (IGFBP2) is an important member of the insulin-like growth factor family, with evidence suggesting elevation in PAH patients. We investigated the diagnostic and prognostic value of serum IGFBP2 in PAH to determine if it could discriminate PAH from healthy controls and if it was associated with disease severity and survival.

Methods: Serum IGFBP2 levels, as well as IGF1/2 levels, were measured in two independent PAH cohorts, the Johns Hopkins Pulmonary Hypertension program (JHPH, N = 127), NHLBI PAHBiobank (PAHB, N = 203), and a healthy control cohort (N = 128). The protein levels in lung tissues were determined by western blot. The IGFBP2 mRNA expression levels in pulmonary artery smooth muscle cells (PASMC) and endothelial cells (PAEC) were assessed by RNA-seq, secreted protein levels by ELISA. Association of biomarkers with clinical variables was evaluated using adjusted linear or logistic regression and Kaplan-Meier analysis.

Results: In both PAH cohorts, serum IGFBP2 levels were significantly elevated (p < 0.0001) compared to controls and discriminated PAH from controls with an AUC of 0.76 (p < 0.0001). A higher IGFBP2 level was associated with a shorter 6-min walk distance (6MWD) in both cohorts after adjustment for age and sex (coefficient - 50.235 and - 57.336 respectively). Cox multivariable analysis demonstrated that higher serum IGFBP2 was a significant independent predictor of mortality in PAHB cohort only (HR, 3.92; 95% CI, 1.37-11.21). IGF1 levels were significantly increased only in the PAHB cohort; however, neither IGF1 nor IGF2 had equivalent levels of associations with clinical variables compared with IGFBP2. Western blotting shown that IGFBP2 protein was significantly increased in the PAH vs control lung tissues. Finally, IGFBP2 mRNA expression and secreted protein levels were significantly higher in PASMC than in PAEC.

Conclusions: IGFBP2 protein expression was increased in the PAH lung, and secreted by PASMC. Elevated circulating IGFBP2 was associated with PAH severity and mortality and is a potentially valuable prognostic marker in PAH.
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http://dx.doi.org/10.1186/s12916-020-01734-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537100PMC
October 2020

Pulmonary and systemic hemodynamics are associated with myocardial injury in the acute respiratory distress syndrome.

Pulm Circ 2020 Jul-Sep;10(3):2045894020939846. Epub 2020 Jul 23.

Department of Emergency Medicine, University of Michigan Medical School, Ann Arbor, USA.

Background: Whether right and left heart hemodynamics are associated with myocardial injury in the acute respiratory distress syndrome (ARDS) is not known.

Methods: We performed a retrospective cohort study of subjects who had right heart catheterization within the ALVEOLI trial and Fluid and Catheter Treatment Trial. Myocardial injury was assessed using a highly sensitive troponin assay (hsTn; Abbot ARCHITECT). Hemodynamic variables included right atrial pressure, pulmonary artery wedge pressure, cardiac index and stroke volume, pulmonary vascular resistance, pulmonary arterial compliance, and pulmonary effective arterial elastance. We performed linear, logistic, and Cox regression to determine the association of hemodynamic variables with myocardial injury and to determine if hemodynamics mediated the association between myocardial injury and death.

Results: Among 252 ARDS patients, median day 0 troponin was 65.4 (13.8-397.8) ng/L. Lower cardiac index (β -0.23 SE 0.10; P < 0.001) and stroke volume (β -0.26 SE 0.005; P < 0.001), higher pulmonary vascular resistance (β 0.22 SE 0.11; P < 0.001), lower pulmonary arterial compliance (β -0.24 SE 0.06; P < 0.001), and higher arterial elastance (β 0.27 SE 0.43; P < 0.001) were associated with greater myocardial injury in univariable and adjusted models. Changes in stroke volume, cardiac index, pulmonary arterial compliance, pulmonary vascular resistance, and arterial elastance were all associated with progressive myocardial injury over three days. hsTn levels were associated with mortality; however, the association was attenuated after adjustment for each of stroke volume, pulmonary vascular resistance, pulmonary arterial compliance, and arterial elastance.

Conclusion: Pulmonary vascular hemodynamics are associated with myocardial injury in ARDS, while filling pressures are not. Pulmonary vascular disease may represent a treatable contributor to myocardial injury in ARDS.
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http://dx.doi.org/10.1177/2045894020939846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378723PMC
July 2020

A comprehensive echocardiographic method for risk stratification in pulmonary arterial hypertension.

Eur Respir J 2020 09 24;56(3). Epub 2020 Sep 24.

University Hospital Giessen und Marburg GmbH, Pulmonary Hypertension Division, Medical Clinic II, Giessen, Germany.

Question Addressed: Echocardiography is not currently considered as providing sufficient prognostic information to serve as an integral part of treatment goals in pulmonary arterial hypertension (PAH). We tested the hypothesis that incorporation of multiple parameters reflecting right heart function would improve the prognostic value of this imaging modality.

Methods And Main Results: We pooled individual patient data from a total of 517 patients (mean age 52±15 years, 64.8% females) included in seven observational studies conducted at five European and United States academic centres. Patients were subdivided into three groups representing progressive degrees of right ventricular dysfunction based on a combination of echocardiographic measurements, as follows. Group 1 (low risk): normal tricuspid annular plane systolic excursion (TAPSE) and nonsignificant tricuspid regurgitation (TR) (n=129); group 2 (intermediate risk): normal TAPSE and significant TR or impaired TAPSE and nondilated inferior vena cava (IVC) (n=256); group 3 (high risk): impaired TAPSE and dilated IVC (n=132). The 5-year cumulative survival rate was 82% in group 1, 63% in group 2 and 43% in group 3. Low-risk patients had better survival rates than intermediate-risk patients (log-rank Chi-squared 12.25; p<0.001) and intermediate-risk patients had better survival rates than high-risk patients (log-rank Chi-squared 26.25; p<0.001). Inclusion of other parameters such as right atrial area and pericardial effusion did not provide added prognostic value.

Answer To The Question: The proposed echocardiographic approach integrating the evaluation of TAPSE, TR grade and IVC is effective in stratifying the risk for all-cause mortality in PAH patients, outperforming the prognostic parameters suggested by current guidelines.
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http://dx.doi.org/10.1183/13993003.00513-2020DOI Listing
September 2020

Multi-Beat Right Ventricular-Arterial Coupling Predicts Clinical Worsening in Pulmonary Arterial Hypertension.

J Am Heart Assoc 2020 05 8;9(10):e016031. Epub 2020 May 8.

Department of Medicine Medical University of South Carolina Charleston SC.

Background Although right ventricular (RV) to pulmonary arterial (RV-PA) coupling is considered the gold standard in assessing RV dysfunction, its ability to predict clinically significant outcomes is poorly understood. We assessed the ability of RV-PA coupling, determined by the ratio of multi-beat (MB) end-systolic elastance (Ees) to effective arterial elastance (Ea), to predict clinical outcomes. Methods and Results Twenty-six subjects with pulmonary arterial hypertension (PAH) underwent same-day cardiac magnetic resonance imaging, right heart catheterization, and RV pressure-volume assessment with MB determination of Ees/Ea. RV ejection fraction (RVEF), stroke volume/end-systolic volume, and single beat-estimated Ees/Ea were also determined. Patients were treated with standard therapies and followed prospectively until they met criteria of clinical worsening (CW), as defined by ≥10% decline in 6-minute walk distance, worsening World Health Organization (WHO) functional class, PAH therapy escalation, RV failure hospitalization, or transplant/death. Subjects were 57±14 years, largely WHO class III (50%) at enrollment, with preserved average RV ejection fraction (RVEF) (47±11%). Mean follow-up was 3.2±1.3 years. Sixteen (62%) subjects met CW criteria. MB Ees/Ea was significantly lower in CW subjects (0.7±0.5 versus 1.3±0.8, =0.02). The optimal MB Ees/Ea cut-point predictive of CW was 0.65, defined by ROC (AUC 0.78, =0.01). MB Ees/Ea below this cut-point was significantly associated with time to CW (hazard ratio 5.1, =0.001). MB Ees/Ea remained predictive of outcomes following multivariate adjustment for timing of PAH diagnosis and PAH diagnosis subtype. Conclusions RV-PA coupling as measured by MB Ees/Ea has prognostic significance in human PAH, even in a cohort with preserved RVEF.
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http://dx.doi.org/10.1161/JAHA.119.016031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660856PMC
May 2020

Exercise Echocardiography as a Screening Tool in Systemic Sclerosis.

J Rheumatol 2020 05;47(5):643-645

Johns Hopkins University, Division of Pulmonary and Critical Care Medicine, Baltimore, Maryland, USA.

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http://dx.doi.org/10.3899/jrheum.191249DOI Listing
May 2020

Diffusing Capacity Is an Independent Predictor of Outcomes in Pulmonary Hypertension Associated With COPD.

Chest 2020 08 14;158(2):722-734. Epub 2020 Mar 14.

Johns Hopkins University Division of Pulmonary and Critical Care, Baltimore, MD. Electronic address:

Background: Patients with COPD who experience pulmonary hypertension (PH) have worse mortality than those with COPD alone. Predictors of poor outcomes in COPD-PH are not well-described. Diffusing capacity of the lung (Dlco) assesses the integrity of the alveolar-capillary interface and thus may be a useful prognostic tool among those with COPD-PH.

Research Question: Using a single center registry, we sought to evaluate Dlco as a predictor of mortality in a cohort of patients with COPD-PH.

Study Design And Methods: This retrospective cohort study analyzed 71 COPD-PH patients from the Johns Hopkins Pulmonary Hypertension Registry with right-sided heart catheterization (RHC)-proven PH and pulmonary function testing data within one year of diagnostic RHC. Transplant-free survival was calculated from index RHC. Adjusted transplant-free survival was modelled using Cox proportional hazard methods; age, pulmonary vascular resistance, FEV, oxygen use, and N-terminal pro-brain natriuretic peptide were included as covariates.

Results: Overall unadjusted transplant-free 1-, 3-, and 5-year survivals were 87%, 60%, and 51%, respectively. Survival was associated with reduced Dlco across the observed range of pulmonary artery pressures and pulmonary vascular resistance. Severe Dlco impairment was associated with poorer survival (log-rank χ 13.07) (P < .001); adjusting for covariates, for every percent predicted decrease in Dlco, mortality rates increased by 4% (hazard ratio, 1.04; 95% CI, 1.01-1.07).

Interpretation: Among patients with COPD-PH, severe gas transfer impairment is associated with higher mortality, even with adjustment for airflow obstruction and hemodynamics, which suggests that Dlco may be a useful prognostic marker in this population. Future studies are needed to further investigate the association between Dlco and morbidity and to determine the utility of Dlco as a biomarker for disease risk and severity in COPD-PH.
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http://dx.doi.org/10.1016/j.chest.2020.02.047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173778PMC
August 2020

Progress in Understanding, Diagnosing, and Managing Cardiac Complications of Systemic Sclerosis.

Curr Rheumatol Rep 2019 12 7;21(12):68. Epub 2019 Dec 7.

Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, USA.

Purpose Of The Review: Systemic sclerosis (scleroderma) is a complex autoimmune disease that commonly involves the cardiovascular system. Even if often subclinical, cardiac involvement is considered a poor prognostic factor as it is a leading cause of death in scleroderma patients. We review the cardiac manifestations of scleroderma, the diagnostic methods useful in detection, and current advances in therapeutic management.

Recent Findings: Beside the routine exams for the assessment of cardiac status (including EKG, standard echocardiography, provocative tests) novel techniques such as myocardial strain imaging on echocardiography, cardiac magnetic resonance imaging, invasive hemodynamic assessment, and endomyocardial biopsy have been demonstrated to be useful in understanding the cardiac alterations that typically affect scleroderma patients. Recent application of novel cardiac detection strategies is providing increased insight into the breadth and pathogenesis of cardiac complications of scleroderma. Further studies coupling exercise provocation, invasive and imaging assessment, and mechanistic studies in scleroderma cardiac tissue are needed to develop the optimal approach to early detection of cardiac disease in scleroderma and targeted therapies.
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http://dx.doi.org/10.1007/s11926-019-0867-0DOI Listing
December 2019

Serum uric acid as a marker of disease risk, severity, and survival in systemic sclerosis-related pulmonary arterial hypertension.

Pulm Circ 2019 Jul-Sep;9(3):2045894019859477. Epub 2019 Jul 29.

Department of Medicine Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, USA.

The object of this paper is to assess associations between serum uric acid (UA) and pulmonary arterial hypertension (PAH) risk, disease severity, and mortality in a well-characterized cohort of systemic sclerosis (SSc) patients referred for evaluation of possible PAH. Consecutive SSc patients aged >18 years with serum UA drawn within two weeks of a diagnostic right heart catheterization (RHC) were included. Associations between baseline serum UA and PAH at RHC were examined using logistic regression and receiver operating characteristic curves. Relationships between UA levels and metrics of disease severity were assessed using Pearson and Spearman correlation. Associations between UA and survival were assessed using Kaplan-Meier analysis and Cox proportional hazard modeling. A total of 162 SSc patients were included; 82 received a diagnosis of PAH at RHC. Patients found to have PAH had significantly higher UA than those without PAH. Elevated baseline UA was associated with significantly increased odds of PAH diagnosis at RHC (odds ratio [OR] = 4.07, 95% confidence interval [CI] = 2.11-7.87,  < 0.001). Each mg/dL higher UA was associated with a 14% increase in mortality (hazard ratio [HR] = 1.14, 95% CI = 1.02-1.28,  < 0.05). In multivariable models adjusting for potential confounders of the relationship between UA and survival, UA > 6.3 mg/dL remained significantly associated with increased mortality (HR = 1.84, 95% CI = 1.02-3.32,  < 0.05). Among SSc patients with suspected PAH, elevated serum UA is associated with increased risk of SSc-PAH. Among individuals diagnosed with SSc-PAH by RHC, UA is associated with disease severity and survival. These results indicate UA is a useful predictor of PAH risk and prognosis in SSc.
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http://dx.doi.org/10.1177/2045894019859477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6664664PMC
July 2019

Oxygen use in chronic heart failure to relieve breathlessness: A systematic review.

Heart Fail Rev 2020 03;25(2):195-205

Johns Hopkins University School of Nursing, 525 N. Wolfe Street, Baltimore, MD, 21205, USA.

To appraise published studies on the use of supplemental oxygen in chronic heart failure. Chronic breathlessness is a characterizing symptom of symptomatic heart failure resulting in substantial disability and healthcare utilization and is the primary reason for emergency room visits and hospitalizations. In spite of the variable evidence, oxygen therapy is commonly administered both acutely and chronically. Moreover, the role of oxygen therapy to relieve chronic breathlessness in heart failure is not well described, particularly in normoxemic or mild or intermittent hypoxemic states. In fact, several studies have shown the detrimental effects of oxygen therapy with normal oxygen saturation levels. A systematic review using PRISMA guidelines. Four databases PubMed, Embase, CINAHL, and Web of Science were systematically searched from January 2001 to January 2019 investigating the use of oxygen in heart failure. Duplicate articles were removed from the review. Titles and abstracts were screened for inclusion and exclusion criteria. The remaining full-text articles were reviewed and hand-searched for additional references. The quality of the full-text articles was assessed using standardized critical appraisal instruments by the Joanna Briggs Institute. A total of 11 studies, including three intervention and eight non-interventions studies, were included in this review from 1072 non-duplicated records retrieved. Sample size ranged from 4 to 5862. In spite of common usage, this review suggests that there are scant data available to justify the use of oxygen in individuals with non-hypoxemic chronic heart failure and chronic breathlessness.
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http://dx.doi.org/10.1007/s10741-019-09814-0DOI Listing
March 2020

A crossroads between the heart and lungs: air pollution and pulmonary hypertension.

Eur Respir J 2019 May 30;53(5). Epub 2019 May 30.

Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, USA.

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http://dx.doi.org/10.1183/13993003.00654-2019DOI Listing
May 2019

Validation of the REVEAL Prognostic Equation and Risk Score Calculator in Incident Systemic Sclerosis-Associated Pulmonary Arterial Hypertension.

Arthritis Rheumatol 2019 10 26;71(10):1691-1700. Epub 2019 Aug 26.

The Johns Hopkins University School of Medicine, Baltimore, Maryland.

Objective: A prognostic equation and risk score calculator derived from the Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management (REVEAL) are being used to predict 1-year survival in patients with pulmonary arterial hypertension (PAH), but little is known about the performance of these REVEAL survival prediction tools in systemic sclerosis (SSc)-associated PAH (SSc-PAH).

Methods: Prospectively gathered data from the Johns Hopkins Pulmonary Hypertension Program and Pulmonary Hypertension Assessment and Recognition of Outcome in Scleroderma Registries were used to evaluate the predictive accuracy of the REVEAL models for predicting the probability of 1-year survival in patients with SSc-PAH. Model discrimination was assessed by comparison of the Harrell's C-index, model fit was assessed using multivariable regression techniques, and model calibration was assessed by comparing predicted to observed survival estimates.

Results: The validation cohort consisted of 292 SSc-PAH patients with a 1-year survival rate of 87.4%. The C-index for predictive accuracy of the REVEAL prognostic equation (0.734, 95% confidence interval [95% CI] 0.652-0.816) and for the risk score (0.743, 95% CI 0.663-0.823) demonstrated good discrimination, comparable to that in the model development cohort. The calibration slope was 0.707 (95% CI 0.400-1.014), indicating that the overall model fit was marginal (P = 0.06). The magnitude of risk assigned to low distance on the 6-minute walk test (6MWD) and elevated serum levels of brain natriuretic peptide (BNP) was lower in the validation cohort than was originally seen in the REVEAL derivation cohort. Model calibration was poor, particularly for the highest risk groups.

Conclusion: In predicting 1-year survival in patients newly diagnosed as having SSc-PAH, the REVEAL prognostic equation and risk score provide very good discrimination but poor calibration. REVEAL prediction scores should be interpreted with caution in newly diagnosed SSc-PAH patients, particularly those with higher predicted risk of poor 1-year survival resulting from a low 6MWD or a high BNP serum level.
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http://dx.doi.org/10.1002/art.40918DOI Listing
October 2019

Pulmonary Embolism.

Med Clin North Am 2019 May;103(3):549-564

John Hopkins Hospital, 830 East Monument Street, 1830 Building 5th Floor Pulmonary, Baltimore, MD 21287, USA.

Venous thromboembolism (VTE) includes pulmonary embolism (PE) and deep vein thrombosis. PE is the third most common cause of cardiovascular death worldwide after stroke and heart attack. Management of PE has evolved recently with the availability of local thrombolysis; mechanical extraction devices; hemodynamic support devices, like extracorporeal membrane oxygenation; and surgical embolectomy. There has been development of multidisciplinary PE response teams nationwide to optimize the care of patients with VTE. This review describes the epidemiology of PE, discusses diagnostic strategies and current and emerging treatments for VTE, and considers post-PE follow-up care.
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http://dx.doi.org/10.1016/j.mcna.2018.12.013DOI Listing
May 2019

Identifying Patients with Pulmonary Arterial Hypertension Using Administrative Claims Algorithms.

Ann Am Thorac Soc 2019 07;16(7):797-806

7 Alpert Medical School of Brown University; Brown University School of Public Health, Providence, Rhode Island.

Retrospective administrative claims database studies provide real-world evidence about treatment patterns, healthcare resource use, and costs for patients and are increasingly used to inform policy-making, drug formulary, and regulatory decisions. However, there is no standard methodology to identify patients with pulmonary arterial hypertension (PAH) from administrative claims data. Given the number of approved drugs now available for patients with PAH, the cost of PAH treatments, and the significant healthcare resource use associated with the care of patients with PAH, there is a considerable need to develop an evidence-based and systematic approach to accurately identify these patients in claims databases. A panel of pulmonary hypertension clinical experts and researchers experienced in retrospective claims database studies convened to review relevant literature and recommend best practices for developing algorithms to identify patients with PAH in administrative claims databases specific to a particular research hypothesis.
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http://dx.doi.org/10.1513/AnnalsATS.201810-672CMEDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6600840PMC
July 2019

Disconnect between Fibrotic Response and Right Ventricular Dysfunction.

Am J Respir Crit Care Med 2019 06;199(12):1550-1560

1 Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria.

Remodeling and fibrosis of the right ventricle (RV) may cause RV dysfunction and poor survival in patients with pulmonary hypertension. To investigate the consequences of RV fibrosis modulation and the accompanying cellular changes on RV function. Expression of fibrotic markers was assessed in the RV of patients with pulmonary hypertension, the murine pulmonary artery banding, and rat monocrotaline and Sugen5416/hypoxia models. Invasive hemodynamic and echocardiographic assessment was performed on galectin-3 knockout or inhibitor-treated mice. Established fibrosis was characterized by marked expression of galectin-3 and an enhanced number of proliferating RV fibroblasts. Galectin-3 genetic and pharmacologic inhibition or antifibrotic treatment with pirfenidone significantly diminished RV fibrosis progression in the pulmonary artery banding model, without improving RV functional parameters. RV fibrotic regions were populated with mesenchymal cells coexpressing vimentin and PDGFRα (platelet-derived growth factor receptor-α), but generally lacked αSMA (α-smooth muscle actin) positivity. Serum levels of galectin-3 were increased in patients with idiopathic pulmonary arterial hypertension but did not correlate with cardiac function. No changes of galectin-3 expression were observed in the lungs. We identified extrapulmonary galectin-3 as an important mediator that drives RV fibrosis in pulmonary hypertension through the expansion of PDGFRα/vimentin-expressing cardiac fibroblasts. However, interventions effectively targeting fibrosis lack significant beneficial effects on RV function.
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http://dx.doi.org/10.1164/rccm.201809-1737OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6580669PMC
June 2019
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