Clinical And Biomarker Profile Responses To Rehabilitation Treatment in Patients With Long COVID Characterized By Chronic Fatigue Part 1

Abstract: Long COVID (LC) syndrome is a complex multiorgan symptom that persists beyond >12 weeks after SARS-CoV-2 infection. The most frequently associated symptom is fatigue. Physical activity and exercise are recommended, although specific studies are lacking. The objectives of the present work are to analyze the impact of a supervised exercise program on the clinical evolution of LC with fatigue patients and to identify whether certain circulating biomarkers could predict the response to rehabilitation. The rehabilitation treatment response was analyzed in 14 women diagnosed with LC and fatigue, based on the changes in the 6-minute walk test and Borg/Fatigue Impact scales. Patients who showed improvement in the meters walked were considered “responders” to the therapy. A total of 65% of patients responded to the exercise program, with an improvement in the meters walked and in oxygen saturation, with stability in the percentage of meters walked. Participants with obesity and those double-vaccinated against SARS-CoV-2 presented a lower degree of fatigue. LC patients presented a favorable response to a supervised exercise program. Differences in creatinine and protein levels were observed between rehabilitation therapy “responders” and “nonresponders”. A good state of protein nutrition was related to a better rehabilitation response. The results are promising regarding possible predictive biomarkers of rehabilitation response, such as creatinine.

Cistanche can act as an anti-fatigue and stamina enhancer, and experimental studies have shown that the decoction of Cistanche tubulosa could effectively protect the liver hepatocytes and endothelial cells damaged in weight-bearing swimming mice, upregulate the expression of NOS3, and promote hepatic glycogen synthesis, thus exerting anti-fatigue efficacy. Phenylethanoid glycoside-rich Cistanche tubulosa extract could significantly reduce the serum creatine kinase, lactate dehydrogenase, and lactate levels, and increase the hemoglobin (HB) and glucose levels in ICR mice, and this could play an anti-fatigue role by decreasing the muscle damage and delaying the lactic acid enrichment for energy storage in mice. Compound Cistanche Tubulosa Tablets significantly prolonged the weight-bearing swimming time, increased the hepatic glycogen reserve, and decreased the serum urea level after exercise in mice, showing its anti-fatigue effect. The decoction of Cistanchis can improve endurance and accelerate the elimination of fatigue in exercising mice, and can also reduce the elevation of serum creatine kinase after load exercise and keep the ultrastructure of skeletal muscle of mice normal after exercise, which indicates that it has the effects of enhancing physical strength and anti-fatigue. Cistanchis also significantly prolonged the survival time of nitrite-poisoned mice and enhanced the tolerance against hypoxia and fatigue.

Click on Fatigue Causes

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Keywords: long COVID; chronic fatigue; physical rehabilitation; biomarkers; SARS-CoV-2.

1. Introduction

Coronavirus disease 19 (COVID-19) is an infectious disease caused by the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). Most people with COVID-19 experience mild-to-moderate illness, while approximately 10–15% develop severe illness and 5% become critically ill [1]. The average recovery time from COVID-19 is 2–3 weeks depending on symptomatology [2–4]. However, between 20–90% of patients may exhibit symptoms for several weeks or months [5–9]. This situation is named post-acute sequelae of COVID-19, also now known as long COVID-19 (LC), which is defined as the persistence of symptoms for >12 weeks or new symptoms attributable to COVID-19 [10]. Common complaints are fatigue, dyspnea, brain fog, orthostatic intolerance, and some systemic illnesses [11]. At least 65 million individuals worldwide are estimated to have LC, with cases increasing daily [12]. Specifically, the prevalence of LC reported in our geographical area, Spain, has been up to 48% [9].

LC is a complex multisystemic/multifactorial disorder with a not yet fully understood pathogenesis. However, based on the history of viral inflammatory diseases and other research evidence on SARS-CoV-2, it is suggested that the seeding and persistence of SARS-CoV-2 in different organs and its reactivation, and the immune response to unrelated viruses, autoimmunity, microbiota disruption, and uncontrolled inflammation, along with thromboembolism, lung dysfunction, and nervous system dysfunction due to occult neuronal injury during SARS-CoV-2 infection are major drivers of LC. This complex pathophysiology likely drives different clinical phenotypes [11,13–15].

Regarding weakness/fatigue and neurologic symptomatology, it appears that the combination of an exaggerated production of inflammatory cytokines, the demyelinating response in the central nervous system, and the role of the altered adaptive immune response could explain the symptoms of chronic muscle weakness, sensory abnormalities, or cognitive and autonomic dysfunction seen in LC. Another hypothesis underlying fatigue LC pathogenesis is a biochemical alteration of critical mitochondrial metabolic pathways that could produce apoptosis of muscle cells [13].

Fatigue is one of the most frequent extra-respiratory symptoms of SARS-CoV-2 infection, described in 41.4% of the patients included in the largest published cohort [16]. Regarding persistent fatigue, data published in two studies suggest a frequency of 35–53% at 4–8 weeks post-infection and 16% at 12 weeks post-infection [17,18]. In other studies,  this frequency is higher, up to 51% [7,8,19,20]. The nature of fatigue in COVID-19 patients shares features with chronic fatigue after other infections, such as SARS, MERS, and community-acquired pneumonia.

2. Materials and Methods 

2.1. Subjects

This study was approved by the institutional review board, and all participants gave written informed consent before taking part in the study (156/2021). A longitudinal prospective intervention pilot study was carried out, with a before–after analysis of the clinical response to the standardized and individualized rehabilitation program.

The study period was from September 2021 to May 2022. The study population consisted of 14 women, identified and recruited in the long COVID monographic consultation (LCMC) at the Hospital Universitari de Tarragona Joan XXIII (HJ23), diagnosed with LC  and predominant symptoms of fatigue.

2.2. Data Collection 

As shown in Figure 1, the patients were first visited in the consultation of LCMC, and later they were referred to the consultation of Rehabilitation. In both consultations, the participants underwent complete anamnesis and physical, anthropometric, and biochemical evaluations to obtain clinical and analytical data. Additionally, the patients were given the Fatigue Impact Scale (FIS) and the Borg scale to assess fatigue and dyspnea, respectively. A  first 6 min walk test (6MWT) was performed on all of them. If the result of 6MWT was >85%  of the predicted value, the patient was referred home with WHO’s global recommendations on physical activity for health [25]. Bearing in mind that a 6MWT result >85% indicates good walking ability that does not require rehabilitation intervention. If 6MWT <85%, they were referred to carry out the specific rehabilitation program in the rehabilitation service. Before starting the rehabilitation sessions, desaturation due to exertion and heart failure after COVID-19 were ruled out. Subjects were included in a supervised exercise program of 12 to 20 physiotherapy sessions for three months. In each session, an initial warm-up phase was carried out with stretching and light exercise (5 to 10 min), followed by aerobic exercise on a bicycle, of progressive duration (10 to 30 min) and intensity according to effort tolerance, with heart rate monitoring. In one of the weekly sessions, muscle-strengthening exercises for the upper extremities were performed. In addition, the patient was encouraged to perform an aerobic routine (walking) on the days that he/she did not come to the hospital. At the end of the guided hospital exercise program, a guideline was given to continue their practice at home. At the end of the treatment, a second 6MWT was performed, and the patients were classified into Group 1 “responders” and Group 2 “non-responders”. The patients who showed improvement in the meters walked were considered responders to the rehabilitation therapy. Moreover, all the patients were contacted by telephone to obtain data on the perception of fatigue at the end of the rehabilitation treatment (FIS) and their global satisfaction with participation in the study.

In the face-to-face visits at the LCMC, the health personnel collected: clinical data from the participants, symptoms of acute COVID-19 infection, radiological findings, hospital admission and analytical data and treatment received, current symptoms of LC, physical examination constants (blood pressure, O2 saturation, heart rate (HR), and respiratory rate), cardiopulmonary, abdominal, and neurological examination, and body mass index (BMI), electrocardiogram (ECG), neuropsychological screening using the Hospital Anxiety and Depression (HAD) scale and Montreal cognitive assessment (Moca scale) [26]. The evaluation in the RHBC, the initial physical condition was evaluated, measuring fatigue and other symptoms through the 6 MWT; then the initial and final constants (systolic blood pressure (SBP), cardiac frequency, peripheral oxygen saturation) were collected and the initial and final Borg dyspnea and fatigue scale scores (FIS) were evaluated, as well as the number of meters walked and the percentage of predicted value (calculated using the reference equation for 6MWT appropriate to the age, height, weight, and sex of the patient).

2.3. Biochemical Analyses

All of the subjects included underwent physical, anthropometric, and biochemical assessments. Blood samples were obtained from the patients at the time of the initial assessment in the LCMC for basic hematological and biochemical analysis, serological profile, and determination of the levels of proinflammatory molecules (interleukin 6 (IL-6) and C-reactive protein (CRP)) and autoimmune molecules (antinuclear antibodies (ANA), lupus anticoagulant (AcL) and beta-2-glycoprotein I (B2GPI)), using conventional automated analyzers after 12 h of fasting.

2.4. Rehabilitation Intervention and Evaluation

Due to the nature and duration of the intervention, it was not possible to blind the research team or the participants to the treatment allocation. After performing the 6MWT  at the initial visit to the RHBC, two groups of patients were identified according to the percentage of meters walked, according to Casanova et al. [27]. As described, those with 6MWT > 85% carried out a set of rehabilitation exercises at home (aerobic exercise), while subjects with 6MWT < 85% were included in a supervised exercise program in the hospital rehabilitation service, similar to the one described by Cattadori et al. [28]. It is important to note that the patients did not receive any new medication or related supplements coinciding with the rehabilitation program.

Once the rehabilitation therapy was carried out, the response to it was evaluated by comparing the initial and final data of the 6 MWT. The difference in the walked meters was used to classify the patients as favorable evolution (“responder” patients) or unfavorable (“nonresponder”). We also valued differences in the percentage of meters, the fatigue score (FIS), and the oxygen saturation percentage. Finally, we also analyzed the response to the rehabilitation treatment according to the presence of obesity (obese: body mass index (BMI) > 30 Kg/m2; non-obese: BMI < 30 Kg/m2 ).

2.5. Statistical Analysis

The data were analyzed using the SPSS/PC+ for Windows statistical package (version 23.0; SPSS, Chicago, IL, USA). The Kolmogorov-Smirnov test was used to assess the distribution of variables. Continuous variables are reported as the mean (SD); noncontinuous variables are reported as the median and 25th–75th percentile. Categorical variables are expressed as absolute frequencies or percentages. The comparative analyses were performed using a Student’s t-test for parametric variables or a nonparametric Mann-Whitney U test. Regarding the categorical variables, significant differences between the two groups were assessed using the chi-square test. The strength of the association between variables was calculated using Spearman’s rho correlation test. p values < 0.05 were considered statistically significant.

3. Results 

3.1. Baseline Characteristics of Subjects

The baseline characteristics of patients and features of acute COVID-19 are given in Table 1. 

It is worth mentioning that of the 14 patients initially included, 5 had a result of 6MWT >85% and were referred home with recommendations for basic exercise. One of the participants was lost to follow-up before carrying out the RHBC, so she could not be classified by treatment. The rest of them entered the rehabilitation program of the hospital,  and after rehabilitation treatment and with the results of the second 6MWT, were classified 1 (“responders”) and 2 (“non-responders”).

The cohort had a mean age of 44.21 years and comprised all women. Only 35.7%  presented comorbidities, and 21.4% had allergies. No patient presented normal weight,  half of the sample was overweight (50%), and 92.1% of the sample was between overweight and grade II obesity. A total of 78.6% of the participants exhibited a low level of baseline physical activity.

Regarding the COVID-19 disease picture, all of the patients were diagnosed with COVID-19 between 27 October 2020, and 1 August 2021, in the context of the Delta variant. In the total cohort, no patient was asymptomatic, 64.3% presented mild/moderate clinical symptoms, and 35.7% showed severe symptoms requiring hospital admission. A  total of 35.7% of the subjects presented pathological findings on chest X-rays. Regarding vaccination, 78.6% of patients were vaccinated, 28.6% with a single dose, and 50% with a booster dose. As a treatment, 100% of participants required symptomatic treatment, 42.9%  required antibiotic treatment, 35.7% required treatment with corticosteroids, 35.7% required treatment with low molecular weight heparin, and 7.1% (n = 1) required treatment with remdesivir. There were no candidates for tocilizumab.

The subjects who had required hospital admission for acute COVID-19 (n=5) presented the analytical results of admission shown in Table 2, highlighting a mean of the sample above the reference values for aspartate aminotransferase (AST, 71.40 (68.30)) and alanine aminotransferase (ALT, 89.80 (78.20)), C-reactive protein (CRP, 2.48 (2.00)), D-dimer (759.50 (458.90)) and interleukin (IL)-6 (24.26 (14.60)). These values were different from those of the laboratory tests carried out in the LCMC, although these differences were not statistically significant, probably due to the small number of patients who had required hospital admission. Nevertheless, protein levels significantly increased in the LCMC. During the study, two patients became reinfected.

Long COVID Syndrome 

The four symptoms with the highest frequency of appearance in the participants (n=14) were fatigue (since its presence was a study inclusion criterion), headache, dyspnea, and amnesia (Figure 2). The participants presented a mean of 4.07 (1.70) symptoms, and 35.7% of participants manifested more than 4 symptoms.

3.2. Clinical Assessment 

3.2.1. Long COVID Monographic Consultation 

The data collected in the initial assessment carried out using the LCMC are summarized in Table 3. 

The data collected during the consultation remained within normal ranges and the physical examination was normal except for 21.4% of the subjects (the cardiorespiratory auscultation of two patients and the abdominal examination of one patient were pathological). All of the electrocardiograms were normal.

About the analysis requested in the consultation, the values of fibrinogen (445.58 (57.90)) and glomerular sedimentation rate (GSR) (14.92 (8.40)) were increased. A total of 16.7% of the patients presented some markers of autoimmunity, two patients were positive for ANA (titers 1/320 and 1/640), and one was positive for AcL. Antibodies against SARS-CoV-2 were detected in all subjects. When comparing the values of the laboratory data on admission with the values of the analytics performed in the consultation, we found no significant differences. As shown in Table 2, it can be observed that the values of AST, ALT, CRP, and D-dimer at admission were much higher than those of the laboratory tests performed months later, although without significant differences. In the neuropsychological screening, it was observed that 57.1% of the participants had anxiety and 14.3% had depression.

3.2.2. Rehabilitation Consultation

As mentioned, five patients did not enter the hospital rehabilitation program and were sent home with recommendations for basic physical exercise. Nine patients started a hospital rehabilitation program. When we compared both group's pathological history, clinical characteristics, and current analytical parameters, we did not find any significant differences.

The data obtained in the 6MWT performed in the RHBC before and after carrying out the rehabilitation treatment are detailed in Table 4. It is important to note that the parameters measured in the first visit to the RHBC (before receiving rehabilitation treatment)  and in the second visit (after receiving it) were within normal limits. Regarding the meters walked in the initial test, the participants covered an average of 431.92 (58.90) meters in 6 min, and the average percentage of meters covered was 78.50 (9.90).

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