Abbreviations: PCS: Post-COVID-19 Syndrome; PEM: PostExertional Malaise; ME/CFS: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; EBV: Epstein-Barr Virus; MCAS: Mast Cell Activation Syndrome; MCAD: Mast Cell Activation Disorder; POTS: Postural Orthostatic Tachycardia Syndrome; CNIL: French Data Protection Authority; CCC: Canadian Consensus Criteria; ICC: International Consensus Criteria; CDC SI: Center for Disease Control and Prevention Symptom Inventory; FSS: Fatigue Severity Scale; OH: Orthostatic Hypotension; OI: Orthostatic Intolerance

Introduction

Post-COVID-19 Syndrome (PCS), commonly known as long COVID, refers to the continuation or development of new symptoms 3 months after the initial SARS-CoV-2 infection, with these symptoms lasting for at least 2 months with no other explanation [1].

Approximately 10-20% of non-hospitalized [2] and 10-12% of vaccinated patients [3] experience post-COVID symptoms, which are heterogeneous, involving multiple organ systems, and severely impacting patients’ quality of life [4]. PCS was linked to unemployment and inversely associated with working full time [5].

Fatigue is a prevalent complaint, manifesting in over 90% of PCS patients [6]. Other frequent symptoms include cognitive dysfunction, sleep disturbances, orthostatic intolerance, myalgia, headaches, dyspnea, palpitations, dizziness, balance disorders, and Post-Exertional Malaise (PEM) [7].

PEM is the hallmark symptom of Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS), and its presence is mandatory to establish this diagnosis [8-10]. PEM is characterized by an exacerbation of some or all baseline ME/CFS symptoms after exposure to physical, cognitive, emotional, or orthostatic exertion that were normally tolerated before [8-10], and in some patients, the emergence of new unusual symptoms [11]. The onset of PEM typically occurs several hours after the initial stressor, with an onset that may reach the next day or even later [8-10]. PEM usually necessitates 24 hours or longer to recover [8,9], and is significantly associated with disability [12], and poorer outcomes for patients [13].

PEM was observed in PCS patients, and was persisting in 73.3

% of PCS patients beyond 6 months [7]. In fact, PCS and ME/ SFC exhibit numerous shared characteristics. ME/CFS is often triggered by viral infections, especially Epstein-Barr virus [14], and similar to PCS, ME/CFS is frequently associated with reactivated herpesviruses such as EBV and human cytomegalovirus [15,16]. Both conditions occur predominantly in previously healthy and active females [17]. The majority of PCS symptoms are similar to those observed in ME/CFS [18], and they are often exacerbated or relapsed after minimal physical or mental exertion as is the case with ME/CFS [7]. The overlap in the clinical features of PCS and ME/CFS prompted some authors to propose the term “postCOVID-19 ME/CFS” [7,18,19].

Despite insufficient current knowledge regarding the precise pathophysiology of both conditions, some mechanisms were reported, including mitochondrial dysfunction, systemic and neuro-inflammation, and inappropriate immune response in both PCS and ME/CFS patients [20]. Other examples of the similarities between PCS and ME/CFS include the absence of biomarkers [21], the lack of an approved treatment, and the effectiveness of pacing strategies [22].

Furthermore, some comorbidities are frequently associated with both conditions such as Mast Cell Activation Syndrome (MCAS) [23-25], Mast Cell Activation Disorder (MCAD) [26], and Postural Orthostatic Tachycardia Syndrome (POTS) [2730]. The POTS, which is a variant of cardiovascular autonomic disorder is characterized by excessive heart rate increase on standing, in association with various symptoms that are reported in both PCS and ME/CFS patients. These symptoms include postural light-headedness, presyncope, palpitations, chest pain, dyspnea, headache, cognitive impairment, nausea, gastrointestinal symptoms, sleep disturbances, and fatigue [31]. It is noteworthy that POTS can be triggered by various viral infections, including SARS-CoV-2, which is now recognized as a distinct phenotype of PCS [32]. A notable body of evidence was emerged indicating the potential involvement of mast cell activation in the pathogenesis of POTS [33].

Given that some, but not all, of PCS patients develop PEM, the primary aim of the study was to define possible factors that could be associated with the emergence of PEM in patients suffering from PCS. In addition, owing to the fact that PEM is known to be significantly associated with disability and poorer outcomes in ME/CFS patients [12,13], we hypothesized that PEM could have similar effects in PCS patients. Thus, the secondary objective of the study was to assess the prognosis of PCS patients with and without PEM.

Patients and Methods

Ethics

The study was approved by the Ethics Committee of Angers University Hospital (2024/154) and was conducted in compliance with the Helsinki Agreement. Data collection was approved by the French Data Protection Authority (CNIL).

Study population and data collection

We retrospectively reviewed all medical records of patients who attended the post-COVID clinic at the Internal Medicine Department of Angers University Hospital between June 2020 and June 2024. Medical records with missing data were excluded. Patients with a history of COVID-related hospitalization as well as those with a prior diagnosis of ME were not included.

The diagnosis of PCS in all patients was established according to the World Health Organization clinical case definition [1]. All patients were referred to our post-COVID clinic from primary care physicians or specialists. They all underwent a standardized assessment that was carried out by the same physician, and included a detailed medical history taking and in-depth clinical examination. Data about epidemiological characteristics, occupational status, current therapies and associated conditions, especially MCAS or MCAD, and POTS, were recorded for all patients. Information concerning COVID-19 infection was also noted: date of onset, number of episodes, vaccination status, and related clinical manifestations including, persistent, recurrent, and/ or new-onset symptoms and signs, 12 weeks after infection.

A special attention was paid for the presence or not of PEM. The identification of PEM was made according to the Canadian Consensus Criteria (CCC) [8] and the International Consensus Criteria (ICC) [9] for ME/CFS. When present, information concerning PEM was noted. Basal fatigue severity and its impact on personal and professional patients’ activities were evaluated for all patients.

PEM definition

PEM is the worsening of some or all baseline symptoms after exposure to physical, cognitive, emotional, or orthostatic exertion that were normally tolerated before [8-10]. Some patients may also experience the emergence of new unusual symptoms [11]. Its onset can be immediate or delayed by several hours or longer after the stressor. PEM duration varies largely between patients and within the same patient. It can last several days, weeks or even months.

PEM duration required for diagnosis is 24 hours or longer [8,9].

Analysis of PEM Features

We collected data concerning PEM features by means of a standardized questionnaire (Additional file 1) that we have designed and previously used in ME/CFS patients for the analysis of PEM occurring in PCS patients [11]. All PCS patients experiencing PEM were asked about the type of PEM stressors, the timing of onset of baseline symptom exacerbation, elapsed time between the exposure to a stressor and symptom exacerbation, PEM manifestations and worsened symptoms, potential emergence of new or unusual symptoms, the time of occurrence of new or nontypical symptoms, and the duration of PEM recovery.

PEM assessment

The PEM item from the standardized auto-questionnaire of Center for Disease Control and Prevention Symptom Inventory (CDC SI) [34] was used to measure PEM symptoms over the past month. Perceived frequency of PEM was rated on a 4-point scale (1 = a little of the time, 2 = some of the time, 3 = most of time, 4 = all of the time), and its intensity was measured on a 3-point scale (1 = mild, 2 = moderate, 3 = severe). The intensity score was converted into equidistant score (0 = symptom not reported, 1 = mild, 2.5 = moderate, 4 = severe). The PEM severity score was obtained by the multiplication of the frequency and intensity scores, ranging from 0-16.

Fatigue assessment

The Fatigue Severity Scale (FSS) [35] was used to evaluate fatigue levels in all patients at the initial and the follow-up visits. This reliable and valid nine-item auto questionnaire measures the impact of fatigue and detects change over time [36]. Each item is rated on seven-point scales from 1 (completely disagree) to 7 (completely agree). A mean fatigue score ranging from 1 to 7 was obtained by averaging the nine items. A mean FSS score ≥ 4 is in favour of clinically significant fatigue, and a reduction of 0.5 points is clinically significant [37].

POTS assessment

POTS was confirmed by active standing test and/or head-up tilt [38].

Standing test

Blood pressure and heart rate are measured after the patient has been supine for at least 5 minutes, and again after 1, 3, 5, and 10 minutes of standing. POTS patients should exhibit orthostatic tachycardia in the absence of orthostatic hypotension.

Passive head-up tilt table testing

Blood pressure and heart rate are measured while the patient is supine on a standard tilt table, and after an incline to greater than 60° head-up angle.

Orthostatic hypotension (OH) assessment

Blood pressure and heart rate are measured after five minutes in the supine position and three minutes after moving to a standing position. A decrease in blood pressure ≥20 mm Hg systolic or ≥10 mm Hg diastolic within three minutes of standing from the supine position is diagnostic of OH [39].

Work-related outcomes

We referred to the definition of patient’s recovery and patient’s improvement described elsewhere [40,41]. Recovered patients were able to return to work, on a full or part-time basis while improved patients were not able to return to work but they experienced a reduction in the number and/or severity of symptoms thanks to pacing strategies.

Patients’ grouping

We classified the study population into 2 groups for comparative analysis according to the presence or absence of PEM.

Statistical analysis

Quantitative data were presented in medians and quartiles, and were compared between two groups for univariate analysis using a Student’s t-test or a Mann-Whitney test according to distribution normality, assessed by using the D’Agostino-Pearson test. Qualitative data were presented as absolute values and percentages, and were compared using the Fisher’s test or Chi-square test as appropriated. Multivariate analysis was performed by means of

binary logistic regression. The variables included in the model were age, sex, and those showing significant statistical difference between PCS/PEM+ and PSC/PEM- groups in univariate analysis. The Odds Ratios (OR) were presented with a 95% confidence interval (CI). The alpha risk was set at 5%. The analyses were performed using Graphpad Prism v6.01 (Graphpad Software, La Jolla, CA, USA) and Jamovi software v2.3.9.

Results

Characteristics of the study population

We collected retrospective data from medical records of 313 patients with PCS. After exclusion of 32 patients (12 with missing medical record data, 17 patients with a history of COVID-related hospitalization, and 3 with prior diagnosis of ME/CFS), the study’s final sample size was 281 patients (Figure 1).

Figure 1: Flowchart of patients’ inclusion. ^*Myalgic encephalomyelitis/chronic fatigue syndrome.

The characteristics of the study population are presented in Table 1. Patients primarily were women (228/281, 85.1%), the median age at the onset of the disease was 43 [34 -50] years, and the median time since infection to diagnosis was 16 [9-25] months. The overall population included 162/281 (57.7%) unvaccinated patients. The most prevalent symptom was fatigue, reported by 274/281 (97.5%) patients, followed by cognitive deficit (219/281,77.9%), and sleep disturbance (189/281,67.3%). PEM was found in 73/281 (26.0%) patients.

Table 1: Characteristics of patients with post-COVID syndrome with and without post-exertion malaise.

Factors associated with PEM in PCS patients

We classified included patients into 2 groups according to the presence or absence of PEM for comparison. The presence of PEM among PCS patients was associated with the onset of more cases of COVID infection in years 2020/2021 (p=0.001), a higher number of unvaccinated patients (p=0.04), a higher frequency of palpitations (p<0.001) and OH (p<0.001), and the occurrence of more frequent cases of POTS (p=0.001). PCS patients with PEM had significantly higher basal FSS scores than those without PEM (p<0.001).

Variables that persisted to be positively associated with PEM occurrence in PCS patients on the multivariate binary logistic regression analysis were the years of COVID onset 2020/2021 (OR 2.75 [95% CI: 1.04-7.25], p=0.04), the presence of POTS (OR 4.38 [95% CI:

1.43 - 13.38], p=0.01), and higher FSS score (OR 1.93 [95% CI: 1.34-2.78], p<0.001) (Table 2).

Table 2: Multivariate analysis of factors associated with post-exertion malaise occurrence in patients with post-COVID syndrome.

Prognosis of PCS patients according to the presence of PEM

Follow-up data were available for (220/281, 78.3%) of patients. The median time of follow-up did not differ between patients with and without PEM (11 [7-22] vs. 9 [6-14] months, p=0.07).

Compared to PCS patients without PEM, PCS patients with PEM had significantly higher FSS scores at last follow-up assessment (5.2 [4.3-5.8] vs. 4.7 [3.8-5.3], p=0.002), and lower recovery/improvement rates (30/58 (51.7%) vs. 127/162 (78.4%), p<0.001) (Figure 2).

Figure 2: Prognosis of patients with post-COVID syndrome with and without post-exertion malaise. A. FSS scores of PCS patients with and without PEM at last assessment. B. Recovered/improved  PCS patients with and without PEM at last assessment. FSS: Fatigue severity scale. PCS; Post-COVID syndrome. PEM: Post-exertion malaise.