The Use of Heart Rate Variability-Biofeedback (HRV-BF) as an Adjunctive Intervention in Chronic Fatigue Syndrome (CSF/ME) in Long COVID, 2025, Cossu

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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​

by
Giulia Cossu
1,
Goce Kalcev
1,*<i></i>,
Diego Primavera
1,
Stefano Lorrai
1,
Alessandra Perra
1,
Alessia Galetti
1,
Roberto Demontis
1,
Enzo Tramontano
2,
Fabrizio Bert
3,
Roberta Montisci
1,
Alberto Maleci
1,
Pedro José Fragoso Castilla
4,5,
Shellsyn Giraldo Jaramillo
6,
Peter K. Kurotschka
7,
Nuno Barbosa Rocha
8and
Mauro Giovanni Carta
1,4,9


1
Department of Medical Sciences and Public Health, University of Cagliari, 09124 Cagliari, Italy
2
Department of Life and Environmental Sciences, University of Cagliari, 09124 Cagliari, Italy
3
Department of Public Health and Pediatrics Sciences, University of Torino, 10124 Torino, Italy
4
PhD Program in Tropical Medicine, Universidad Popular del Cesar, Valledupar 200001, Colombia
5
Microbiology Program, Universidad Popular del Cesar, Valledupar 200001, Colombia
6
Faculty of Health, Universidad Popular del Cesar, Valledupar 200001, Colombia
7
Department of General Practice, University Hospital Würzburg, 97080 Würzburg, Germany
8
Center for Translational Health and Medical Biotechnology Research (TBIO), Health Research Network (RISE-Health), E2S, Polytechnic of Porto, R. Dr. António Bernardino de Almeida, 400, 4200-072 Porto, Portugal
9
Department of Nursing, Universidad Popular del Cesar, Valledupar 200001, Colombia
*
Author to whom correspondence should be addressed.
J. Clin. Med. 2025, 14(15), 5363; https://doi.org/10.3390/jcm14155363
Submission received: 29 June 2025 / Revised: 23 July 2025 / Accepted: 24 July 2025 / Published: 29 July 2025
(This article belongs to the Special Issue New Technologies and Translational Approach for an Early Diagnosis of Bipolar Spectrum and Hyperactive and Novelty Seeking Profiles)



Abstract​

Background:

Emerging 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 (HRV-BF) 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.

Methods:

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.

Results:

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).

Conclusions:

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.

Keywords:
heart rate variability biofeedback (HRV-BF); Long COVID; chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME); feasibility study

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The discussion section of this paper has to be some of the most amateurish nonsense I’ve ever read. It has nothing to do with the study, and goes on long rambling tangents about the NICE guidelines and Garner (linebreaks added):
The review of CBT shows (on four studies about 371 participants) a clinical response in the short term of 40% for CBT compared to 26% for usual care, so an advantage of just over 20% [63]. However, the interpretation of the efficacy studies of CBT is not univocal [4], and the associations of patients with CFS/ME express strong doubts about its use [76].

CBT may have even less effect if there is comorbidity with depression [77]. If this were confirmed, it would represent a serious problem because comorbidity with depression is very common, especially in the most severe forms [77]. In contrast, as HVB-BF could influence the biorhythm system [78,79,80], this aspect could be of particular interest in respect to stress, anxiety, and mood syndromes [81]; thus, in the frequent case of co-morbidity between these disorders and chronic fatigue syndromes.

Compared to CBT, the HVB-BF intervention does not claim to be therapeutic, at least in the sense that it does not aim to cure but simply to provide a tool to help the person in managing the disorder. Furthermore, it entails a more autonomous and immediate role for the user, both in applying the technique during training sessions and in independently implementing it in real-life stressful situations. For this reason, it might be that it is better accepted, and this can explain the very low dropout rate achieved.

Another systematic review, recently updated, conducted specifically on exercise therapy showed a possible (moderate) effect but without evident advantages compared to CBT or antidepressants [82].



The use of exercise has itself been the subject of fierce controversy. Since the publication of the previous NICE guidelines (2007) [4] and the PACE Trial (2011), the ME Association has been vehement in its argument that the use of graded, regulated and inflexible exercise therapy as a management approach for people with ME/CFS is wrong, ineffective, and can cause harm. The ME Association has called for NICE to withdraw its recommendation for the use of exercise, pointing out that research evidence has found methodological weaknesses in clinical trials proving the effectiveness of exercise and that surveys of the opinions of people who have used this therapy have shown that this treatment method can be perceived as ineffective and harmful [76].

NICE then completely revised the ME/CFS guideline and, after a full assessment of the evidence [83], withdrew its support for the use of exercise in CFS/ME. The new NICE guidelines warn against the use of exercise in Long COVID [4].

The case of Paul Garner, a professor in Liverpool, is emblematic of these controversies [84]. Garner was affected by severe CFS and Long COVID. After participating in an intensive physical exercise program, he relapsed dramatically with severe fatigue syndrome [84].

After the use of techniques to reduce symptoms and related stress, Garner slowly recovered. His journey led him to the belief that “post-exertional” malaise after an exercise plays a role in people with CFS/ME, as an automatic learnt brain response [84].

The ME patient associations, which were always against a “psychologizing” interpretation of the syndrome, turned against Garner. The purpose of a typical physical exercise training was thus considered a “psychologizing” interpretation [84].

It may be somewhat ambiguous because today physical exercise is known to produce bio-physiological consequences [85,86]. But this is understandable because in a recent survey of over 2000 people suffering from ME/CFS, most reported worsening of symptoms after physical exercise [87].

Garner himself reiterated that, while there is still a tendency to “psychologize” a problem for which there are no clear solutions, one must also recognize that excessive medicalization of the issue, reinforced by media coverage, fosters the belief in irreversible biological damage and, consequently, amplifies the impact [88].

This impasse could be addressed by adopting approaches that enable healthcare professionals to offer supportive interventions which, while not claiming to be curative, may enhance patients’ ability to manage their condition. If confirmed to yield these preliminary improvements, biofeedback could play a meaningful role in this regard.

Firstly, because the role of the person suffering from the disorder can have a much more autonomous and independent role than in CBT, where, by definition, the role of the therapist is pivotal, and secondly, because the intervention could present fewer side effects than physical exercise, could be more accessible and, ultimately, would marry very well with other therapies aimed at the “physiopathogenetic” treatment of the disorder.
 
Utsikt said:
The discussion section of this paper has to be some of the most amateurish nonsense I’ve ever read. It has nothing to do with the study, and goes on long rambling tangents about the NICE guidelines and Garner (linebreaks added):
The review of CBT shows (on four studies about 371 participants) a clinical response in the short term of 40% for CBT compared to 26% for usual care, so an advantage of just over 20% [63]. However, the interpretation of the efficacy studies of CBT is not univocal [4], and the associations of patients with CFS/ME express strong doubts about its use [76].

CBT may have even less effect if there is comorbidity with depression [77]. If this were confirmed, it would represent a serious problem because comorbidity with depression is very common, especially in the most severe forms [77]. In contrast, as HVB-BF could influence the biorhythm system [78,79,80], this aspect could be of particular interest in respect to stress, anxiety, and mood syndromes [81]; thus, in the frequent case of co-morbidity between these disorders and chronic fatigue syndromes.

Compared to CBT, the HVB-BF intervention does not claim to be therapeutic, at least in the sense that it does not aim to cure but simply to provide a tool to help the person in managing the disorder. Furthermore, it entails a more autonomous and immediate role for the user, both in applying the technique during training sessions and in independently implementing it in real-life stressful situations. For this reason, it might be that it is better accepted, and this can explain the very low dropout rate achieved.

Another systematic review, recently updated, conducted specifically on exercise therapy showed a possible (moderate) effect but without evident advantages compared to CBT or antidepressants [82].



The use of exercise has itself been the subject of fierce controversy. Since the publication of the previous NICE guidelines (2007) [4] and the PACE Trial (2011), the ME Association has been vehement in its argument that the use of graded, regulated and inflexible exercise therapy as a management approach for people with ME/CFS is wrong, ineffective, and can cause harm. The ME Association has called for NICE to withdraw its recommendation for the use of exercise, pointing out that research evidence has found methodological weaknesses in clinical trials proving the effectiveness of exercise and that surveys of the opinions of people who have used this therapy have shown that this treatment method can be perceived as ineffective and harmful [76].

NICE then completely revised the ME/CFS guideline and, after a full assessment of the evidence [83], withdrew its support for the use of exercise in CFS/ME. The new NICE guidelines warn against the use of exercise in Long COVID [4].

The case of Paul Garner, a professor in Liverpool, is emblematic of these controversies [84]. Garner was affected by severe CFS and Long COVID. After participating in an intensive physical exercise program, he relapsed dramatically with severe fatigue syndrome [84].

After the use of techniques to reduce symptoms and related stress, Garner slowly recovered. His journey led him to the belief that “post-exertional” malaise after an exercise plays a role in people with CFS/ME, as an automatic learnt brain response [84].

The ME patient associations, which were always against a “psychologizing” interpretation of the syndrome, turned against Garner. The purpose of a typical physical exercise training was thus considered a “psychologizing” interpretation [84].

It may be somewhat ambiguous because today physical exercise is known to produce bio-physiological consequences [85,86]. But this is understandable because in a recent survey of over 2000 people suffering from ME/CFS, most reported worsening of symptoms after physical exercise [87].

Garner himself reiterated that, while there is still a tendency to “psychologize” a problem for which there are no clear solutions, one must also recognize that excessive medicalization of the issue, reinforced by media coverage, fosters the belief in irreversible biological damage and, consequently, amplifies the impact [88].

This impasse could be addressed by adopting approaches that enable healthcare professionals to offer supportive interventions which, while not claiming to be curative, may enhance patients’ ability to manage their condition. If confirmed to yield these preliminary improvements, biofeedback could play a meaningful role in this regard.

Firstly, because the role of the person suffering from the disorder can have a much more autonomous and independent role than in CBT, where, by definition, the role of the therapist is pivotal, and secondly, because the intervention could present fewer side effects than physical exercise, could be more accessible and, ultimately, would marry very well with other therapies aimed at the “physiopathogenetic” treatment of the disorder.
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How utterly bizzare.
 
There statistical analysis seems to me rather odd, and their justifications are not compelling.

> In the statistical analyses we had to take into account (1) that these were analyses of a preliminary two-phase study on samples of small size, (2) that sometimes the assumption of the normal distribution of the populations from which the samples were supposed to be extracted was not respected, and (3) that some instruments such as visual pain were declared to be on ordinal measures and not on numerical intervals. The statistical analyses of comparison between groups were therefore conducted on ordinal scales by establishing at T1 three levels for each group and for each measure; that is, the first level was the number of individuals with an improvement in outcome from T0 to T1, the second level was the number of individuals with an unchanged outcome level from T0 to T1, and the third level was the number of individuals with the outcome under examination worsened from T0 to T1.
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This categorical approach was chosen due to the small sample size and the non-normal distribution of several variables, which limited the use of parametric methods. Furthermore, defining discrete levels of change allowed for a more interpretable and clinically meaningful analysis of individual symptom trajectories in a feasibility framework.
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Comparison for each outcome measure (one primary and four secondary) was conducted using the Kruskal–Wallis test. Measurement of the homogeneity of the trends in the five measurements was conducted using a binomial test. Verification of the acceptance of the hypothesis that the hypothetical reference populations of the samples had a normal distribution was conducted with the Shapiro–Wilks test.
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Transforming your variables into this trichotomy would be expected to *reduce* statistical power, which is especially problematic given the small sample size to start off with.

And the fact that the variables are not normally distributed doesn't make this categorisation necessary, as there are non-parametric methods developed for this exact situation (which they clearly know about as they refer to the Kruskal-Wallis test).

Speaking of which, how exactly are they applying the Kruskal-Wallis test to something that has been transformed into count data (Table 2)?
 
The authors said:
heart rate variability (HRV), which is now considered a crucial marker of psychological well-being
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This morning my HRV between 0733 and 0839 ranged from 25-58, the next hour between 27 and 86. So what's your point?
 
Yes, heart rate variability is affected by numerous things and is a very POOR/non-specific marker of anything in particular and especially psychological well-being.

HRV decreases during exercise, so that means exercise is bad, right? RIGHT?

Decrease of heart rate variability during exercise: An index of cardiorespiratory fitness - PMC

The present study proposes to measure and quantify the heart rate variability (HRV) changes during effort as a function of the heart rate and to test the capacity of the produced indices to predict cardiorespiratory fitness measures. Therefore, the ...
pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
 
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