Introduction

Since the beginning of the SARS-CoV-2 pandemic, by the end of October 2024, over 770 million people worldwide have been infected with an immunogenic virus [31], which causes (long-term) health consequences of varying severity and duration (Figure 1). Following a SARS-CoV-2 infection, similar to other infectious diseases, persistent symptoms can occur in various organ systems (lungs, heart, brain, gastroenteric and other secondary organs) and/or various new symptoms can arise that persist over a longer period of time [12,18,19,29].

Figure 1: Process phases COVID-19/Post-COVID-19.

In the specialist literature and the AWMF-S1 guidelines, the term post-COVID syndrome (PCS) has become established for symptoms that occur or persist twelve weeks after a SARS-CoV-2 infection [3-5]. The frequency of occurrence of PCS is between 10 and 35% [13]. Using the Delphi consensus method, the WHO defined PCS as follows [22,29].

• Symptoms must still be present 12 weeks (3 months) after a SARS-CoV-2 infection and must last at least two months
• there is no other etiological explanation
• the course may be persistent, recurrent or fluctuating

There is currently no causal therapeutic approach based on evidence-based criteria for the treatment of post-COVID syndrome. The S2k guidelines of the German Society for Neurology (DGN) advocate that post-COVID-19 sufferers with sensory, sensorimotor, cognitive and/or emotional changes receive an adequate neurological evaluation and, if necessary, neuro rehabilitative care. The need for treatment arises either immediately after the acute treatment or during its course (e.g. after 3-6 months).

Due to the diversity and medical range of Post-COVID-19- key symptoms, the patient’s health status must be recorded and assessed by experts from different disciplines [6,14]. Such a multidisciplinary connection can be achieved, for example, with a cross-sector blended therapy structure (Figure 2). Blended therapy concepts implement a mixture of analog face-to-face therapy forms and digital intervention options. This combination can increase the effectiveness of face-to-face therapy [2]. For ex-ample, patient groups with little mobility or at great geographical distances are reached, and service providers can be integrated at a central and peripheral level as well as the coordination of patient treatment plans through shared data use. 

The digital intervention in the blended therapy concept enables a real-time analysis of load, performance and strain as well as the transition from treatment control to a close-meshed information technology control [23,24, 32]. The technological basis for this is the specially developed “Reha-Planet” system [21]. The implemented applications realize the following functions (Figure 4):

• Implementation of individual stress-controlled training to build performance while specifically avoiding overload and crashes

• Integration of a therapist known to the patient from the therapy center and other therapy members

• Creating an emotional connection to the system in order to create closeness de-spite the spatial distance for proportionate practice at home

Figure 2: Cross-sector structure of blended therapy.

Methodology

The combination of analog and digital forms of therapy (blended therapy) achieves a high level of flexibility in therapy design as well as better patient adherence [8,9,11]. The guidelines §3 (4) point 4 of the Federal Joint Committee recommend the use of digital therapy offers that take different symptoms of the basic assessment and individual stress levels into account [6,14].

A doctor-led intervention and observation study was implemented in the post-COVID-19-Center (PCZ) Lausitz (Senftenberg) from Q1-2021 to Q2-2024. The main syndromes “fatigue” and “sensorimotor instability” were treated with monocentric stresscontrolled training therapy (analog and digital intervention). At the same time, secondary psychosomatic treatment needs that often arise in the post-COVID-19-course with fatigue were treated.

407 vaccinated nucleocapsid-positive patients were available for screening in the PCZ (Table 1).

The nucleocapsid protein was determined through a blood sample and laboratory examination in the period from Q1-2021 to Q12023. At the same time, a functional status survey was carried out using a method developed by KLOK ET AL. [16] validated scale with five levels of severity, ranging from grade 0 = no functional limitation to grade 4 = severe functional limitation [18]. The 78 patients with reduced sensorimotor performance and fatigue (Table 1) were admitted after a standardized diagnosis in accordance with guidelines and considering the following exclusion criteria.

• Irreconcilable communication problems
• vestibular dysfunction (video head impulse test)
• Pacemaker
• non-compensatory visual limitations
• orthopaedic deficits of the lower extremities
• Inability to stand independently without the use of

assistive devices

All patients were of legal age and gave written informed consent before inclusion in the study. The implemented study design and the computer-controlled training sys-tem used were approved by the ethics committee of the TU Dresden (reference numbers EK 378092016, EK 356092017).

Study design

The treatment plan of the intervention and observation study at the PCZ consisted of two phases (Figure 3):

Treatment phase 1 (Intervention Study)

Stress-controlled training therapy to improve the quantified sensorimotor parameters and the Post-COVID-19-key symptoms (Q1-2021 - Q2-2023) with 78 patients.

Treatment phase 2 (Intervention and Observation Study)

Intensified cognitive behavioral therapy to improve fatigue and secondary psychosomatic symptoms (Q2-2023 - Q4-2023) with 19 patients from treatment phase 1. Questionnaire-based assessment of participation (IMET), health-related quality of life (VR-12), generalized anxiety disorders (GAD-7) and depressive disorders (PHQ-9) in Q2-2024 with 26 patients.

Figure 3: Methodology and procedure of the intervention- and observation-study.

Evaluation of Post-COVID-19-key Symptoms, Motor and Cognitive Fatigue

The stress-controlled training therapy was evaluated based on the key Post-COVID-19-symptoms (fatigue, sensorimotor instability, cardiopulmonary/autonomic dysfunction, neuropsychiatric symptoms, secondary psycho-somatic symptoms and pain) as well as motor fatigue parameters (Berg Balance Scale, Dynamic Gate Index, Functional Reach Test, Monopedal Stand and 10-meterwalk test).

Motor fatigability rep-resents an objectively measurable indicator of motor performance and allows for a higher medical assessment of the effectiveness of therapy [3,10,17,27,28]. The statistical analysis of the quantitatively collected data was carried out with instruments of descriptive statistics and inferential statistics, using the statistical program SPSS. The effect size (Cohen’s d) was used to evaluate the pre-post results of motor fatigability. It represents the ratio of the mean treatment difference based on the pooled standard deviation. The following effect sizes are distinguished [15].

• low effect: 0.2 < d £ 0.5
• medium effect: 0.5 < d £ 0.8
• large effect: d > 0.8

As part of treatment phase 2 (Figure 2), intensified cognitive behavioral therapy was carried out for the group of therapy participants from treatment phase 1 with “secondary psychosomatic symptoms”. A connection between the organic and psycho-logicalemotional sides is the patient’s self-control (control of thoughts, feelings and behavior) [1]. With the intensification of cognitive behavioral therapy (structured, pre-sent-oriented short-term psychotherapy) in the period Q2-2023 to Q4-2023, the changes in secondary psychosomatic syndromes were examined (cognitive fatigue parameters). In Q2-2024, an assessment of participation (IMET), health-related quality of life (VR-12), generalized anxiety disorders (GAD-7) and depressive disorders (PHQ-9) was also carried out.

Control of Blended Therapy

Blended therapy in treatment phase 1 is based on the building blocks “presence”, “computer-aided training system” and “mobile application”. On the one hand, it took place in a training center belonging to the PCZ and, on the other hand, in the patient’s home in order to achieve sufficient training density (at least 2 training units per week). A computer-based training system was used in the training center (in-person) and in the home. The system structure and the methodology used in blended therapy are based on three steps (Figure 4).

• Initial determination of the severity of functional limitations in the training center
• Digital intervention of stress-controlled training therapy in the training center and at home
• Load control and monitoring of training therapy

Patients for whom a computer-controlled training system could not be used at home due to spatial and/or technical restrictions either a) carried out the exercises independently with measurement of the pulse rate (ECG recordings if necessary) via a) smartwatch and documentation of the results, or b) used the computer-aided training system based on a mobile application with the following functionalities.

• Training plan with video instructions for carrying out the standardized exercises
• regular training reminder
• Digital trainer that optimizes exercise complexity and length through user feed-back
• Overview of the practice times with review
• Recording and recording quality of life using the SF 36 questionnaire
• Point system to increase motivation and adherence
• Meditation tool with guided relaxation exercises

In the experience of post-COVID-19 sufferers, increasing thought dysfunction can develop over time (including during the course of therapy in treatment phase 1) from stress insufficiency experienced in everyday work and at home [12,25]. The aim of treatment phase 2 was to improve the self-management of reduced resources as well as the often largely limited participation in social and professional life.

Figure 4: System structure and methodology of blended therapy.

Results

An example of a cross-sector blended therapy was implemented, which puts the post-COVID syndromes fatigue and sensorimotor instability at the center of the considerations. The therapy evaluation is based on the qualitative and quantitative evaluation parameters presented as well as the analysis of the management process of the stress-controlled intervention. There were no strong gender differences. Deviations exist in individual sub-phases and have an impact on the timing of the therapy process and on the outcome.

Post-COVID-19-key Symptoms

The overall analysis with N=78 (Table 1) produced the following results:

• Improvement in “fatigue” by around 71%, “sensorimotor instability” by around 56%, “neuropsychiatric symptoms” by around 72%, “cardiopulmonary/autonomic dysfunction” by around 76% and “pain” by around around 14% through pre-post survey of post-COVID-19 key symptoms (Fig. 2)
• Worsening of “secondary psychosomatic symptoms” by around 72%

In the men (N = 37), all values improved compared to the women except for “pain” (no improvement). One reason may be the faster process flow in the period “Initial infection-1. Appointment PCZ” and “1. Appointment PCZ-1. Appointment therapy center” can be seen. Women showed a very strong deterioration in the “secondary psychosomatic symptoms”. The slower process flow in the above-mentioned cases can be the cause. Periods compared to men, overestimation of (residual) performance or evasive behavior, especially in hyperdynamic young women in the form of dysfunctional psychological reactions.

Motor Fatigability Parameters

The Wilcoxon test was carried out to evaluate the effectiveness of therapy because there was no normal distribution in the pre- and post-data sets. The strength of the effect of the training therapy on the respective fatigue parameter is determined using the Cohen’s d value (Table 1).

Overall (N = 78), a therapeutic effect was demonstrated for all motor fatigue parameters. The Functional Reach Test (FRT) achieved a medium effect size. There was a small effect size for all other motor fatigability parameters.

In men, no treatment effect could be demonstrated for the 10 m walk test. The Berg Balance Score (BBS) and the FRT showed medium effect sizes. Small effect sizes were found for the dynamic gait index (DGI) and monopedal stance (MPS).

In the women’s cohort (N = 41), there were no treatment effects for the dynamic gait index (DGI) and monopedal stance (MPS). The FRT achieved a medium effect size. Small effect sizes were found for the BBS and 10 m walking test.

Table 1: Presentation of the total results.