The Fuvid Study: Functional Characterization of Children with Pulmonary Embolism in a Prospective Multicenter Cohort Study

Background and Significance: Exercise intolerance and dyspnea on exertion (DOE) are frequent after pulmonary embolism (PE) despite anticoagulation and may impact quality of life. There is little research that fully explains why this occurs, nor are there specific treatments or guidelines for PE complications in children or young adults. The FUVID Program (NCT04583878) will examine the impact of 3 mechanisms underlying exercise intolerance and DOE: cardiac (right ventricular maladaptation and its coupling with the pulmonary circulation) dysfunction, pulmonary limitations secondary to persistent vascular obstruction, and skeletal muscle metabolic abnormalities on exercise intolerance and DOE after PE.

Study Design and Methods: This prospective, multi-center, observational study is enrolling previously healthy patients ages 8-21 years with acute, first-episode PE with or without DVT. A positive control group with no PE but with physical activity restrictions mimicking a deconditioning effect as patients with PE (cohort 1) and control group with no prescribed physical activity restrictions and otherwise considered healthy (cohort 2) will be enrolled. Patients will be enrolled within 8 weeks of diagnosis of PE from 13 enrollment and 25 recruitment sites across the US. Due to the complexity of the cutting-edge metabolic and functional tools only available at UTSW (namely, MR spectroscopy at 7 Telsa to study in-vivo muscle metabolic function and perfusion and exercise cardiac MRI), research assessments will occur centrally at 3- and 12-months post-diagnosis. Exercise capacity will be defined as peak oxygen uptake (VO₂), expressed as a percent predicted based on ideal body weight during cardiopulmonary exercise testing. The primary comparison will be between participants with and without exercise intolerance. Key secondary subgroup analyses will include: sex (male/female), PE category (low risk/non-low-risk), and thrombolysis (yes/no).

Results/Discussion: We have enrolled 67 PE participants (planned=80) from participating enrollment sites and 30 case-controls (planned=30). We propose that 1) the right ventricle will be unable to overcome afterload placed on it during exercise, preventing optimal coupling with pulmonary circulation, 2) arterial desaturation during maximal cycling exercise combined with dysfunctional breathing of deconditioning will provoke greater DOE and intolerance, and 3) depletion and recovery of muscle phosphocreatine in-vivo will predict exercise intolerance. Our results will provide critically informative data to phenotype pediatric post-PE syndrome accurately and allow investigation of cardiac, vascular, and musculoskeletal mechanisms associated with post-PE syndrome assessed during exercise.

Schaefer:CSL Behring: Honoraria, Other: Speaker fees; Hema Biologics: Honoraria, Other: Speaker fees; Sanofi: Honoraria, Other: Speaker fees; Octapharma: Honoraria, Other: Speaker fees. Crary:ASC Therapeutics: Consultancy; Novartis: Consultancy; Sanofi: Membership on an entity's Board of Directors or advisory committees; Medexus: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. O'Brien:AstraZeneca: Consultancy; Pharmacosmos: Consultancy. Tarango:Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Betensky:Abbot: Honoraria; Aziyo: Honoraria; Boston Scientific: Honoraria; Zoll: Honoraria; NHLBI K23: Research Funding. Amos:Genentech: Honoraria; Sanofi: Honoraria, Speakers Bureau. Goldenberg:NHLBI K24: Research Funding; Pfizer: Consultancy; J&J: Consultancy; Chiesi: Consultancy; Bayer: Consultancy; Anthos: Consultancy; Boehringer Ingelheim: Research Funding. Jesudas:Merck: Consultancy, Honoraria. Wilson:Octapharma: Consultancy. Weyand:Takeda: Consultancy, Honoraria, Research Funding; Hemab: Consultancy; Octapharma: Honoraria; Novo Nordisk: Honoraria, Research Funding; Bayer: Honoraria; Biomarin: Honoraria; Pfizer: Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Genentech: Honoraria. Zia:COR2ED GmbH: Membership on an entity's Board of Directors or advisory committees; Hema Biologics: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Star Therapeutics: Membership on an entity's Board of Directors or advisory committees.