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Introduction: Contemporary risk assessment tools categorise patients with pulmonary arterial hypertension (PAH) as low, intermediate or high risk. A minority of patients achieve low risk status with most remaining intermediate risk. Our aim was to validate a four-stratum risk assessment approach categorising patients as low, intermediate-low, intermediate-high or high risk, as proposed by the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) investigators., Methods: We evaluated incident patients from the French PAH Registry and applied a four-stratum risk method at baseline and at first reassessment. We applied refined cut-points for three variables: World Health Organization functional class, 6-min walk distance and N-terminal pro-brain natriuretic peptide. We used Kaplan-Meier survival analyses and Cox proportional hazards regression to assess survival according to three-stratum and four-stratum risk approaches., Results: At baseline (n=2879), the four-stratum approach identified four distinct risk groups and performed slightly better than a three-stratum method for predicting mortality. Four-stratum model discrimination was significantly higher than the three-stratum method when applied during follow-up and refined risk categories among subgroups with idiopathic PAH, connective tissue disease-associated PAH, congenital heart disease and portopulmonary hypertension. Using the four-stratum approach, 53% of patients changed risk category from baseline compared to 39% of patients when applying the three-stratum approach. Those who achieved or maintained a low risk status had the best survival, whereas there were more nuanced differences in survival for patients who were intermediate-low and intermediate-high risk., Conclusions: The four-stratum risk assessment method refined risk prediction, especially within the intermediate risk category of patients, performed better at predicting survival and was more sensitive to change than the three-stratum approach., Competing Interests: Conflict of interest: A. Boucly reports personal fees from Actelion, Bayer and Merck, outside the submitted work. Conflict of interest: J. Weatherald reports grants, personal fees and non-financial support from Janssen Inc., grants, personal fees and non-financial support from Actelion, personal fees and non-financial support from Bayer, personal fees from Novartis, outside the submitted work. Conflict of interest: L. Savale reports personal fees from Actelion, personal fees from MSD, grants and personal fees from GSK, outside the submitted work. Conflict of interest: P. de Groote reports consulting fees from Actelion, Janssen, MSD, Novartis, Servier, Boehringer Ingelheim, Abbott, Boston, AstraZeneca, Bayer; lecture honoraria from Abbott, Vifor, MSD, Servier, Novartis, AstraZeneca, Actelion, Janssen, Medtronic; outside the submitted work. Conflict of interest: V. Cottin reports advisory board fees and non-financial support from Actelion, advisory board fees from Bayer/MSD, outside the submitted work. Conflict of interest: G. Prévot reports personal fees from Actelion and GSK, outside the submitted work. Conflict of interest: A. Chaouat reports consulting fees from GSK, Actelion and Bayer, outside the submitted work. Conflict of interest: F. Picard has nothing to disclose. Conflict of interest: D. Horeau-Langlard reports grants from Acceleron, outside the submitted work. Conflict of interest: A. Bourdin reports grants from AstraZeneca and Boehringer Ingelheim; consulting fees from AstraZeneca, GSK, Novartis, Boehringer Ingelheim, Chiesi, Sanofi Regeneron, Amgen; lecture honoraria from AstraZeneca, GSK, Novartis, Boehringer Ingelheim, Chiesi, Sanofi Regeneron, Roche; travel support from Boehringer Ingelheim, Chiesi, Sanofi Regeneron, AstraZeneca, GSK, Roche; participation on advisory boards at AB science, AstraZeneca, GSK, Sanofi Regeneron, Novartis, Acceleron; and acted as investigator in clinical trials for Vertex, Abbvie, Galapagos, Fibrogen, Nuvaira, PulmonX, Gossamer, Acceleron; outside the submitted work. Conflict of interest: E-M. Jutant has nothing to disclose. Conflict of interest: A. Beurnier has nothing to disclose. Conflict of interest: M. Jevnikar has nothing to disclose. Conflict of interest: X. Jais reports grants from Bayer, Janssen and Merck; lecture honoraria from Janssen and Merck; outside the submitted work. Conflict of interest: G. Simonneau reports grants and personal fees from Janssen (formerly Actelion), Bayer and MSD; personal fees from Acceleron, outside the submitted work. Conflict of interest: D. Montani reports grants from Acceleron, Janssen and Merck; steering committee fees from Acceleron; lecture honoraria from Bayer, Janssen and Merck; outside the submitted work. Conflict of interest: O. Sitbon reports grants from Acceleron, Janssen, GSK and MSD; steering committee fees from Gossamer Bio, Janssen and MSD; lecture honoraria from AOP Orphan, Janssen, Ferrer and MSD; advisory board participation at Acceleron, Janssen and MSD; outside the submitted work. Conflict of interest: M. Humbert reports grants, steering committee consulting fees, and advisory board participation from Acceleron, Janssen and Merck; lecture honoraria from AOP, Janssen and Merck; steering committee participation at United Therapeutics; outside the submitted work., (Copyright ©The authors 2022.)

Rationale: Pulmonary hypertension (PH) has been described in patients treated with leflunomide. Objectives: To assess the association between leflunomide and PH. Methods: We identified incident cases of PH in patients treated with leflunomide from the French PH Registry and through the pharmacoVIGIlAnce in Pulmonary ArTerial Hypertension (VIGIAPATH) program between September 1999 to December 2019. PH etiology, clinical, functional, radiologic, and hemodynamic characteristics were reviewed at baseline and follow-up. A pharmacovigilance disproportionality analysis using the World Health Organization's global database was conducted. We then investigated the effect of leflunomide on human pulmonary endothelial cells. Data are expressed as median (min-max). Results: Twenty-eight patients treated with leflunomide before PH diagnosis was identified. A total of 21 (75%) had another risk factor for PH and 2 had two risk factors. The median time between leflunomide initiation and PH diagnosis was 32 months (1-120). Right heart catheterization confirmed precapillary PH with a cardiac index of 2.37 L⋅min -1 ⋅m -2 (1.19-3.1) and elevated pulmonary vascular resistance at 9.63 Wood Units (3.6-22.1) without nitric oxide reversibility. Five patients (17.9%) had no other risk factor for PH besides exposure to leflunomide. No significant hemodynamic improvement was observed after leflunomide withdrawal. The pharmacovigilance disproportionality analysis using the World Health Organization's database revealed a significant overrepresentation of leflunomide among reported pulmonary arterial hypertension-adverse drug reactions. In vitro studies showed the dose-dependent toxicity of leflunomide on human pulmonary endothelial cells. Conclusions: PH associated with leflunomide is rare and usually associated with other risk factors. The pharmacovigilance analysis suggests an association reinforced by experimental data.

We report a case of disseminated Scedosporium/Pseudallescheria infection due to Pseudallescheria boydii sensu stricto after lung transplantation in a patient with cystic fibrosis. Dissemination occurred under voriconazole. Despite surgery and combination therapy with voriconazole, caspofungin, and terbinafine, the patient died 8 months after transplantation. Previously reported cases are reviewed.