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Objective: To examine the accuracy of a pulmonary hypertension screening strategy based on a combination of echocardiographic data and tomographic measurements (pulmonary artery diameter and pulmonary artery diameter to ascending aorta diameter ratio) in patients with chronic lung disease referred for lung transplantation. Methods: A retrospective observational study with patients with pulmonary emphysema or fibrosis referred for transplantation between 2012 and 2016. Pulmonary hypertension was defined as mean pulmonary artery pressure ≥25mmHg, or between 21 and 24mmHg, with pulmonary vascular resistance >3 Wood units on right heart catheterization. Tomographic measurements were made by two independent radiologists. Results: This sample comprised 13 patients with emphysema and 19 patients with pulmonary fibrosis. Of these, 18 had pulmonary hypertension. The level of agreement in tomographic measurements made by radiologists was high (intraclass correlation coefficients 0.936 and 0.940, for pulmonary artery diameter and pulmonary artery diameter to ascending aorta diameter ratio, respectively). Areas under the ROC curves constructed for pulmonary artery diameter, pulmonary artery diameter to ascending aorta diameter ratio, and pulmonary artery systolic pressure as predictors of pulmonary hypertension were 0.540, 0.629 and 0.783, respectively. The sensitivity, specificity and negative predictive value of pulmonary artery systolic pressure ≥40mmHg were 67%, 79% and 65%, respectively. The combined criterion (pulmonary artery diameter to ascending aorta diameter ratio >1 and/or pulmonary artery systolic pressure ≥40mmHg) achieved sensitivity of 72%, specificity of 79%, and a negative predictive value of 69%. Conclusion: Measurements of pulmonary artery and ascending aorta diameter were highly reproducible. The association of pulmonary artery and aortic diameter >1 and/or pulmonary artery systolic pressure ≥40mmHg improved the sensitivity and the negative predictive value for pulmonary hypertension screening. This strategy demands prospective validation to assess safety and cost-effectiveness.

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RATIONALE: C1-INH replacement therapy is well established for the prevention of HAE attacks. Two FDA approved treatments studied in independent randomized placebo-controlled clinical trials are available: CinryzeÒ (1000 IU IV twice weekly) and HaegardaÒ (C1-INH(SC) 60 IU/ kg). A population-based exposure-response analysis (PK/PD modelling) was performed to compare the relative efficacy of C1-INH IV vs SC based on the COMPACT studies. METHODS: The C1-INH functional activity (C1-INH[f]) data, obtained after administration of C1-INH (prophylaxis SC and on-demand IV) from 1 study in healthy volunteers (n516) and 2 studies in HAE subjects (n5108), were pooled to develop a population PK model (PopPK). Using the PK/PD model, the relative risk of an HAE attack in a model patient weighing 80 kg, treated with IV vs SC C1-INH was determined. RESULTS: The C1-INH(f) over time was described by a linear onecompartment model with first-order absorption and elimination. The PopPK model simulations revealed higher C trough with 60 IU/kg (47.0%) compared with 1000 IU IV (28.3%) and a lower peak-to-trough ratio with a more consistent elevation of the C1-INH(f) for 60 IU/kg SC doses compared with 1000 IU IV dose. The time to event model revealed an inverse relationship between C1-INH(f) and breakthrough attacks. Based on the PK/PD model for an 80 kg model patient, the 60 IU/kg SC dose predicted an additional 73.0% risk reduction of HAE attacks compared with 1000 IU IV twice weekly dosing. CONCLUSIONS: Based on PK/PD modeling data C1-INH(SC) is predicted to provide a superior preventive effect compared with C1-INH(IV) in the majority of patients.