Cossu, GiuliaKalcev, GocePrimavera, DiegoLorrai, StefanoPerra, AlessandraGaletti, AlessiaDemontis, RobertoTramontano, EnzoBert, FabrizioMontisci, RobertaMaleci, AlbertoCastilla, Pedro José FragosoJaramillo, Shellsyn GiraldoKurotschka, Peter K.Rocha, Nuno BarbosaCarta, Mauro GiovanniRocha, Nuno2025-12-152025-12-152025-07-29Cossu, G., Kalcev, G., Primavera, D., Lorrai, S., Perra, A., Galetti, A., Demontis, R., Tramontano, E., Bert, F., Montisci, R., Maleci, A., Castilla, P. J. F., Jaramillo, S. G., Kurotschka, P. K., Rocha, N. B., & Carta, M. G. (2025). The use of heart rate variability-biofeedback (HRV-BF) as an adjunctive intervention in chronic fatigue syndrome (CSF/ME) in long COVID: Results of a phase II controlled feasibility trial. Journal of Clinical Medicine, 14(15), 5363. https://doi.org/10.3390/jcm14155363http://hdl.handle.net/10400.22/31206Emerging evidence indicates that some individuals recovering from COVID-19 develop persistent symptoms, including fatigue, pain, cognitive difficulties, and psychological distress, commonly known as Long COVID. These symptoms often overlap with those seen in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME), underscoring the need for integrative, non-pharmacological interventions. This Phase II controlled trial aimed to evaluate the feasibility and preliminary efficacy of Heart Rate Variability Biofeedback (HRVBF) in individuals with Long COVID who meet the diagnostic criteria for CFS/ME. Specific objectives included assessing feasibility indicators (drop-out rates, side effects, participant satisfaction) and changes in fatigue, depression, anxiety, pain, and health-related quality of life. Participants were assigned alternately and consecutively to the HRV-BF intervention or Treatment-as-usual (TAU), in a predefined 1:1 sequence (quasirandom assignment). The intervention consisted of 10 HRV-BF sessions, held twice weekly over 5 weeks, with each session including a 10 min respiratory preparation and 40 min of active training. The overall drop-out rate was low (5.56%), and participants reported a generally high level of satisfaction. Regarding side effects, the mean total Simulator Sickness Questionnaire score was 24.31 (SD = 35.42), decreasing to 12.82 (SD = 15.24) after excluding an outlier. A significantly greater improvement in severe fatigue was observed in the experimental group (H = 4.083, p = 0.043). When considering all outcomes collectively, a tendency toward improvement was detected in the experimental group (binomial test, p < 0.0001). HRV-BF appears feasible and well tolerated. Findings support the need for Phase III trials to confirm its potential in mitigating fatigue in Long COVID.engHeart rate variability biofeedback (HRV-BF)Long COVIDChronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME)Feasibility studyjournal article10.3390/jcm141553632077-0383