Many individuals with COVID-19 continue to experience symptoms well beyond the acute phase of the disease, which can last for months or even years [1,2]. This persistent condition, known as post–COVID-19 condition (PCC), affects an estimated 6% to 15% of patients with COVID-19, and conservative estimates suggest that approximately 65 to 75 million people worldwide are experiencing PCC [3,4]. Consequences go beyond individual health, impacting social systems and the economy. For instance, the financial strain on the German health care and pension system was projected to reach €1.7 billion (US $1.96 billion) in 2021, with additional production losses and gross value-added losses amounting to €3.4 billion (US $3.91 billion) and €5.7 billion (US $6.56 billion), respectively [5].

PCC manifests as a multisystemic disorder with diverse clinical symptoms and can be categorized into 3 clusters: physical and cognitive impairments and mental disorders [3,6]. The most common symptoms among all the clusters are fatigue, hyperventilation, limitations in daily activities, cognitive impairments, and mental disorders [7]. Overall, 8% to 16% of patients with PCC meet the diagnostic criteria for myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) because they experience both chronic fatigue and postexertional malaise (PEM) [8-10]. Chronic fatigue, defined by fatigue persisting for at least 6 months, and PEM, characterized by physical, mental, or emotional stress intolerance with exacerbation of symptoms even during everyday activities, are the leading symptoms of ME/CFS [11]. In addition to physical, mental, or emotional stress, PEM in patients with PCC is often triggered by hypersensitivity to food, chemicals, noise, light, extreme temperatures, inadequate sleep, or illness [12].

Regardless of the severity of acute COVID-19, the symptoms listed can persist for months and lead to an impaired quality of life and ability to work [7,13]. Female sex, older age, overweight status, smoking habits, preexisting comorbidities, and previous hospitalization or intensive care unit admission are significantly associated with a higher risk of developing PCC [14]. The etiology of PCC is believed to involve a combination of organ damage caused by the pathogen; a misdirected immune response; and additional mechanisms such as viral persistence, autoimmunity, endothelial dysfunction, and dysautonomia [15]. However, the specific physiological and biochemical pathomechanisms remain elusive [15,16].

Consequently, the focus of PCC treatment is on symptom management via multidisciplinary therapeutic approaches [17,18]. A survey in German rehabilitation centers for PCC showed the effectiveness of such measures in alleviating symptoms and improving health-related quality of life and work capacity [19]. Notably, 96 (72%) of 134 rehabilitation facilities reported longer durations of follow-up care for individuals with PCC than for those with other diseases. The most important therapeutic areas include exercise and respiratory therapy, psychotherapy, and therapeutic relaxation. A recent review discussed the positive physiological effects of endurance and strength exercise programs, such as immunomodulatory optimization and anti-inflammatory effects, which could reduce the long-term and health-related effects of PCC [20]. Several systematic reviews have examined the effects of exercise and respiratory therapy, particularly on physical capacity, hyperventilation, and quality of life, in patients with PCC [21-24].

Hyperventilation has been identified as a potential contributor to dyspnea in patients with COVID-19 and ME/CFS [25] as it may result in reduced carbon dioxide levels, leading to respiratory alkalosis and related symptoms such as breathlessness, dizziness, and fatigue. This mechanism is particularly relevant for patients with PCC experiencing persistent dyspnea as dysfunctional breathing patterns, including hyperventilation, may exacerbate respiratory symptoms and negatively impact overall quality of life [26]. Consequently, addressing hyperventilation through targeted respiratory therapy could be an important approach to improving hyperventilation and enhancing rehabilitation outcomes. In general, exercise and respiratory therapy have been shown to be safe and effective; however, physical activity or structured exercise may also trigger PEM in some patients [12].

Understanding PEM is important, especially for safe exercise therapy, and requires an analysis of the responses triggered by exercise. Objective pathological changes at the tissue level, particularly in blood and muscle tissue, can be observed following intense physical exertion in patients with PCC [27]. The cardiopulmonary exercise test (CPET), an objective assessment of cardiorespiratory fitness (CRF), oxygen uptake (VO₂), and ventilatory efficiency during exercise, is used to diagnose dysfunction at the pulmonary, cardiac, and muscle level [28]. Patients with PCC who are severely affected have decreased levels of CRF, lower VO₂ and ventilatory efficiency, and an impaired metabolic response during exercise and recovery [29-31]. Thus, the CPET serves as a valuable tool for the physiological characterization of patients with PCC, facilitating the prescription of personalized, symptom-titrated exercise programs.

Promising strategies for handling PEM in daily activities include pacing and the symptom-titrated approach to exercise therapy [32-34]. Both strategies focus on patient-centered care. Pacing therapy primarily aims to prevent the exacerbation of symptoms, especially fatigue and the onset of PEM, while promoting optimal activity levels for patients in their daily lives, whereas exercise therapy aims to improve their physical capacity. While pacing is widely used in the therapeutic treatment of patients with PCC and involves treatment as usual with a healthy lifestyle (eg, diet and sleep behavior) and drug treatment for accompanying symptoms, exercise therapy is controversially discussed, especially in patients with PCC who are severely affected, and is only used with reservations in standard care [35].

Given the widespread prevalence of PCC and its substantial impact on the health care system, telerehabilitation has emerged as a potentially cost-effective solution [36] for accessing a high number of patients irrespective of location and time [37,38]. Current systematic reviews on exercise and respiratory therapy–based telerehabilitation in patients with PCC [39,40] have reported improvements in quality of life and hyperventilation, as well as an increase in physical capacity.

Therefore, we developed a multimodal, personalized, and symptom-titrated telerehabilitation program that includes weekly teleconsultations, a pacing approach, and exercise and respiratory therapy for patients with PCC who are severely affected and unable to work. The primary aim of this study is to investigate the superiority of our telerehabilitation program compared to treatment as usual in terms of CRF (highest VO₂ rate achieved during the CPET [VO_2peak; mL/min/kg]) and hyperventilation (minute ventilation [VE]/carbon dioxide production [VCO₂] slope [full slope]). In addition, the secondary aim is to explore the clinical and exercise physiology processes associated with PCC. A better understanding of postviral fatigue conditions can improve not only medical treatment but also the management of return to work for patients with PCC and ME/CFS.

This study was reviewed and approved by the ethics committee of the Rhineland-Palatinate Medical Association at the University Medical Center Mainz (registration: 2023-17082) in June 2023. The research was conducted in full compliance with institutional and ethical standards of the Declaration of Helsinki for research with human participants. All participants provided written informed consent before participation in the study. Participants were informed about the study purpose, procedures, potential risks and benefits, the voluntary nature of their participation, and their right to withdraw from the study at any time without consequences. Regarding any secondary analyses using existing data, the original consent and ethics approval explicitly covered the possibility of secondary analysis without requiring additional consent from participants. All collected data were fully anonymized before analysis. No personally identifiable information was stored or used in any publications or supplementary materials. Appropriate technical and organizational measures were implemented to protect participants’ confidentiality and data security. Participants did not receive any monetary compensation for taking part in this study. Participation was entirely voluntary without financial incentive. No identifiable images of study participants are included in the manuscript or supplementary materials.

VW and AT are responsible for data management and analysis and are blinded. All analogue, digital, and biological study materials and data are pseudonymized. All the data entries and sensitive information about the participants are password protected and accessible only to the assigned researchers (VW and AT).

For data storage, transformation, and analysis, Microsoft Excel (version 2401; Microsoft Corp) and R (version 4.4.0) will be used. VW and AT do not know which IG receives which intervention (TG 1, TG 2, or TG 3). Standard statistical procedures will be performed according to the intention-to-treat principle.

Descriptive statistics will be used for all outcome variables at each test time point to obtain an overview of the changes in all relevant data. Descriptive statistics will include absolute and relative frequencies for categorically scaled data and means, 95% CIs, and SD or medians, 95% CIs, and IQRs for continuously scaled data. The normality of the distribution will be tested using the Shapiro-Wilk test and visual inspection of the data. The homogeneity of variance will be tested using the Levene test. In the case of a nonnormal distribution, the data will be log-transformed before statistical analysis to assess normality and variance homogeneity; alternatively, more robust statistical models such as mixed-effects models will be used.

A repeated-measure ANOVA or a linear mixed-effects model will be used to determine the differences between all groups and time points [70,71]. The primary analysis will focus on the comparison between the IG and CG at T0 and T1 to evaluate the superiority of telerehabilitation over usual care while minimizing potential waiting bias. Participants who transition from the CG to the IG (waiting group) will be analyzed separately to assess whether delayed intervention yields similar effects. In addition, the IG will be analyzed during the follow-up phase as these participants will continue training without therapeutic support, allowing for an exploration of long-term intervention sustainability.

The statistical significance will be set at α<.05. The magnitude of the changes between time points, as well as the magnitude of the differences in changes between the groups, will be assessed using effect sizes. The threshold values for effect sizes will be 0.2 (small), 0.6 (moderate), 1.2 (large), and 2.0 (very large) [72,73]. In addition, 95% CIs for the between-group differences in changes will be estimated, and magnitude-based inferences will be made with reference to the smallest worthwhile change, which is calculated as 0.2 multiplied by the between-subject variation at T0 [73]. Correlations between variables will be assessed using parametric (Pearson) and nonparametric (Spearman rank) tests depending on the distribution of the variables. In the case of multiple comparisons, P values will be adjusted using appropriate procedures.

The sample size estimation is based on an a priori power analysis (repeated measures; interaction between group [intervention vs control] and time [before vs after the intervention]) performed using G*Power (version 3.1.9.7). Assuming a power of 0.8 and a medium to large effect (Cohen f=0.35) on the VO_2peak (in accordance with the work by Bacon et al [74]), 67 participants are needed. Considering the calculated required sample size and a dropout rate of 15% to 20% [53,75], the target number of study participants is set at a total of 80, or 40 participants per group.

Adherence to the intervention is defined as the percentage of training sessions completed of the prescribed training sessions [75]. Participants who drop out of the intervention or complete <60% (ie, <17 of the predefined 24 training sessions for TG 1) of the prescribed training are defined as dropouts. For those in the IG, adherence during the follow-up phase will also be tracked to assess sustained engagement without therapeutic supervision. Adherence to the training requirements will be assessed based on the information provided by the participants via the CCTD. Participants will continue to be monitored after their withdrawal from the study if they agree.

The analysis strategy and publication plan include a comprehensive cross-sectional analysis of baseline assessments (T0) aimed at thoroughly characterizing participants’ clinical status (eg, symptoms, functional limitations, and comorbidities) and exercise physiology profiles (eg, CRF, ventilatory efficiency, and VO₂ efficiency). This analysis will encompass clinical history related to COVID-19 (eg, severity of COVID-19, duration of hospitalization, and previous rehabilitation) along with data from patient-reported outcome measures, clinical assessments, and exercise physiological measurements. These baseline data will be reported separately in a dedicated observational cross-sectional paper, providing a detailed clinical and exercise physiological characterization of patients with PCC who are severely affected.

The RCT analysis will primarily compare outcomes between the IG and CG. In addition, subgroup analyses will be conducted to assess differences in therapeutic efficacy across key patient categories, including hospitalized versus nonhospitalized patients and patients with PCC with versus without ME/CFS. The inclusion of these subgroup analyses aims to enhance comparability with other PCC rehabilitation trials and provide deeper insights into factors influencing rehabilitation outcomes.

Furthermore, the collected data will be used for various analyses in basic research aimed at gaining insights into critical aspects such as the molecular characterization of PCC pathogenesis, the pathophysiology of PCC, and the pathomechanisms of PEM. These investigations will contribute to a more comprehensive understanding of PCC and support the development of more targeted and effective rehabilitation interventions.

This study adheres to the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guidelines [76] (Multimedia Appendix 6) and follows the Consensus on Exercise Reporting Template [77].

To our knowledge, the Mainz PCC telerehabilitation study is the first RCT to investigate the effects of a multimodal, personalized, symptom-titrated telerehabilitation program on CRF and hyperventilation in patients with PCC who are severely affected and have work disability. By integrating personalized teleconsultations, exercise therapy, and respiratory interventions, we expect improvements in VO_2peak (mL/min/kg) and the VE/VCO₂ slope, along with better management of PCC symptoms such as chronic fatigue and PEM. While previous studies have shown that telerehabilitation can enhance quality of life and symptom management in patients with PCC, its application in individuals who are severely affected remains largely unexplored. Moreover, previous interventions have relied primarily on self-reported outcomes and have been often conducted in mildly to moderately affected patients with PCC. Our study bridges this gap by integrating objective outcome measures, including CPETs and biomarker analysis, to provide a comprehensive evaluation of telerehabilitation effectiveness in this specific cohort. In contrast to standard telerehabilitation approaches, our intervention dynamically adapts the training load to the subjectively perceived symptom intensity, ensuring a symptom-titrated approach tailored to the current clinical condition of each patient. In addition to the expected improvements in VO_2peak and the VE/VCO₂ slope, this study will provide new insights into clinical and physiological adaptations associated with PCC and provide a structured framework for personalized telerehabilitation programs.

Exercise and respiratory therapy–based rehabilitation programs have been shown to improve physical capacity, hyperventilation, and health-related quality of life in patients with PCC. However, their effects on fatigue remain inconclusive [23,24]. A critical gap in previous research is the lack of evidence regarding the interaction between exercise training and fatigue, particularly in minimizing the risk of exercise-induced symptom exacerbation. While exercise and respiratory training are essential for improving CRF and ventilatory efficiency, pacing strategies have gained attention as a promising approach for managing PEM in daily activities [32].

Despite the growing body of research supporting exercise-based rehabilitation for PCC, previous interventions have largely relied on self-reported outcomes and have primarily been conducted in patients with mild to moderate disease severity [23,24]. Furthermore, most existing studies lack objective outcome measures, such as CPETs, lactate diagnostics, and muscle strength assessments, which are critical for accurately quantifying physiological responses and intervention efficacy [79-91]. To date, only 4 studies have incorporated objective outcome measures of CRF and clinical condition in patients with PCC [92-95]. While telerehabilitation has been shown to be a safe alternative to conventional rehabilitation [39,40], its overall efficacy remains uncertain. A recent meta-analysis of 16 RCTs found no significant improvements in clinical symptoms, pulmonary function, psychological well-being, or quality of life [96].

Building on these previous findings, our study introduces a novel, symptom-titrated telerehabilitation program that is designed to dynamically adjust the training load based on individual clinical responses. By integrating objective diagnostic tools, weekly teleconsultations, and structured pacing strategies, our approach seeks to address the shortcomings of previous telerehabilitation interventions and establish a personalized telerehabilitation program for patients with PCC who are severely affected.

A key strength of this study is its comprehensive assessment strategy, which includes objective outcome measures rather than relying solely on self-reported outcomes. By incorporating CPETs and other objective physiological measures, we aim to quantify the physiological adaptations triggered by telerehabilitation and provide robust evidence on exercise tolerance in patients with PCC who are severely affected.

In addition, risk stratification and individualized exercise prescription are major methodological strengths. Our baseline assessment systematically classifies patients based on CRF, performance, and ventilatory efficiency, ensuring that telerehabilitation is personalized and adapted to each patient’s specific condition [29,33,97]. This contrasts with previous studies that applied generic exercise protocols [79-91], which may not be appropriate for individuals with fluctuating symptoms and severe functional limitations.

Compared to traditional face-to-face rehabilitation, telerehabilitation presents several advantages. First, it allows for remote delivery of high-quality rehabilitation by health care professionals, including physicians, physiotherapists, and sports scientists [36-38]. This is particularly valuable for patients with PCC who are severely affected, who may face mobility restrictions and difficulties accessing in-person rehabilitation programs. Second, telerehabilitation provides a scalable and cost-effective solution, addressing health care system limitations and the growing demand for PCC rehabilitation services.

Our previous research has demonstrated that exercise-based telerehabilitation is safe, with both short-term [53,75,98,99] and long-term benefits [100] in various patient populations. Notably, no serious adverse events were reported, and the dropout rate remained relatively low (15%-20%). This evidence supports the feasibility and clinical applicability of a symptom-titrated telerehabilitation approach, particularly for patients with limited access to conventional rehabilitation.

Thus, our multimodal telerehabilitation program—which combines objective diagnostics, personalized symptom-titrated exercise therapy, and teleconsultations—represents a promising alternative to standard rehabilitation or a valuable adjunct to outpatient physiotherapy and self-directed therapy. By addressing critical gaps in prior work and implementing a robust methodological design, this study has the potential to advance telerehabilitation as a viable rehabilitation strategy for patients with PCC, particularly those with severe disease manifestations.

Despite the strengths of this study, certain limitations must be acknowledged. A key challenge in our approach is the introduction of asynchronous exercise training, where participants engage in rehabilitation without real-time supervision from therapists. Previous telerehabilitation interventions have predominantly relied on synchronous models, allowing for direct therapist interaction during exercise sessions [81,95,101]. While the asynchronous format enhances accessibility and flexibility, particularly for patients with PCC who are severely affected, it may also pose challenges in adherence and compliance as PCC symptoms can fluctuate daily. To mitigate this issue, we integrated weekly teleconsultations via Mattermost, providing participants with opportunities to seek guidance, discuss symptoms, and adjust their rehabilitation plans accordingly. However, the absence of real-time therapist feedback may still present risks, particularly in individuals considered vulnerable. Future studies should explore the potential integration of live internet-based supervision or automated biofeedback mechanisms to optimize adherence and safety. Another limitation of this study is the extensive number of questionnaires, which participants must complete at multiple test time points. Although we have implemented measures to minimize response fatigue—such as allowing participants to distribute questionnaire completion over several days—the risk of response depletion remains. In addition, an important limitation of this study is the reliance on self-reported adherence and symptom tracking through the CCTD. While the digital training diary and RPSS offer valuable insights into training loads and symptom fluctuations, they lack objective physiological monitoring, such as heart rate variability, oxygen saturation, or movement data. Without these objective markers, it is challenging to precisely quantify exercise intensity and patient responses. Previous research has highlighted the potential benefits of wearable technology, which could enhance exercise monitoring by providing real-time physiological feedback [102,103]. Although this study does not incorporate such technology, future research should explore the use of wearable sensors and mobile health apps to enable real-time tracking and personalized exercise adjustments, thereby improving intervention precision. However, using digital technologies such as the internet, PCs, smartphones, or smartwatches for monitoring clinical condition and training load control may present challenges [104], especially for populations considered vulnerable, such as patients with PCC. Finally, a further limitation is the potential confounding effects of concurrent medical treatments. Participants may receive additional interventions during the study period, including pharmacological therapy, relaxation treatments (eg, massage), or other symptom management strategies, which could influence outcomes. While we have minimized this risk by excluding individuals undergoing structured physiotherapy or other exercise-based interventions, this study cannot fully control for the impact of all external treatments. Future research should consider subgroup analyses to examine how concurrent treatments interact with telerehabilitation outcomes, enabling a more comprehensive understanding of multimodal rehabilitation strategies.

The findings of the Mainz PCC telerehabilitation study will be disseminated through three channels:

The Mainz PCC telerehabilitation study aims to provide insights into the clinical and exercise physiological effects of an 8-week multimodal, personalized, and symptom-titrated telerehabilitation program for patients with PCC who are severely affected. The effectiveness of the intervention on CRF and ventilatory efficiency will be primarily assessed through VO_2peak and the VE/VCO₂ slope. Furthermore, this study aims to determine whether weekly teleconsultations can enhance treatment adherence compared to self-directed rehabilitation approaches.

While this study is not designed to establish causal relationships, its findings may support the further development of CPET-based diagnostic approaches, risk stratification models, and personalized exercise and respiratory therapy prescriptions. Moreover, the results may provide preliminary evidence for evaluating work ability and rehabilitation planning in patients with PCC and ME/CFS who are severely affected. Future research should build on these findings to validate the long-term effectiveness and safety of telerehabilitation and refine rehabilitation strategies for postviral fatigue conditions.