Symptom profiles in long COVID compared to functional somatic disorder and the general population

Long COVID affects millions globally and includes symptoms in the central nervous, cardiopulmonary and musculoskeletal systems [1, 2]. Functional somatic disorder (FSD) is characterised by persisting physical symptoms that cannot be better explained by other physical or mental conditions. The persistence of physical symptoms has been observed after other viral infections besides COVID-19 [3], and prior infections have been reported in patients with FSD [4]. However, research on the possible overlap between FSD and long COVID symptoms is lacking. This comparison is crucial for exploring shared mechanisms and treatments. We compared symptom prevalence and profiles among three Danish cohorts: patients with long COVID, patients with severe FSD and a general population sample, expecting to find symptom profiles similar to those of FSD in some patients with long COVID.

Methods

Study samples

Patients in the clinical cohorts were ≥ 18 years and referred from their GP to Aarhus University Hospital (AUH), Denmark. All three cohorts completed self-reported questionnaires, including the bodily distress syndrome (BDS) checklist, a diagnostic aid for diagnosing FSD.

The long COVID cohort included patients with complex and prolonged symptoms lasting at least 12 weeks after SARS-CoV-2 infection [5, 6]. If they met long COVID criteria, including attribution to infection with SARS-CoV-2 [5], patients were diagnosed with long COVID (DB948A) and enrolled [6, 7]. During 2021, a total of 436 patients with long COVID were included in the cohort.

The FSD cohort included patients referred to the Research Clinic for Functional Disorders at the AUH, with symptoms present for at least six months and suspected FSD of the multi-organ type. The waiting time was two years. During 2020-2023, a total of 264 patients were included. Data were obtained from the national clinical database, FuncData [8].

The general population cohort came from the Danish Study of Functional Disorders (DanFunD), gathered between 2011 and 2015 [9]. The DanFunD baseline cohort includes a total of 9,656 persons (33.7% of those invited) aged 18-76 years from the western part of Copenhagen.

The bodily distress syndrome checklist

The validated 25-item BDS checklist measured physical symptoms of FSD [10]. It categorises symptoms into four clusters: cardiopulmonary, gastrointestinal, musculoskeletal (MS) and general symptoms (GS), and separates patients into three categories: No FSD, single-organ FSD (i.e., symptoms from one or two clusters) and multi-organ FSD (i.e., symptoms from ≥ 3 clusters) [10]. We compared the prevalence of all 25 symptoms as well as profiles in the four symptom clusters, considering profiles alike if the same symptoms in the cluster were most frequent in the compared cohorts.

Cohort characteristics

Health risk factors, including diagnoses before long COVID, were systematically collected in the patients’ files. Psychological strains and socioeconomic parameters were included in the patient-reported questionnaire.

Variables were compared using risk ratios with 95% confidence intervals (CI) and χ² test for statistical significance, using StataNow/MP 18.5.

Trial registration: not relevant.

Results

Sociodemographic and clinical characteristics

The long COVID cohort showed sociodemographic differences compared to the FSD and the general population cohorts (Table 1). Patients with long COVID had diabetes and cardiovascular diseases less often than the general population cohort, whereas symptoms of depression and anxiety were more frequent in the long COVID than in the general population cohort but less so than in the FSD cohort.

Functional somatic disorder in patients with long COVID

The prevalence of patients meeting criteria for any FSD according to the BDS checklist was 65% in patients with long COVID, 88% in patients with FSD, and 16% among patients in the general population cohort. Among patients with long COVID, 11% met criteria for multi-organ FSD, compared to 41% in patients with FSD and 1% in the general population cohort. Single-organ criteria were met in 55% of patients with long COVID and 47% of patients with FSD (Table 1).

Symptom profiles

Symptom prevalence was lower among patients with long COVID than among patients with FSD and higher than in the general population cohort (Figure 1 A). GS and, to a lesser degree, MS symptoms predominated in the long COVID cohort. The symptom profiles were visually similar between the long COVID and the FSD cohort, in the GS and MS clusters (Figure 1 A). The subgroup of 11% of patients with long COVID who met the criteria for FSD of the multi-organ type exhibited symptom prevalence and profiles in all four clusters similar to those of patients with FSD (Figure 1 B).

Discussion

In this comparative study, we found that patients with long COVID reported more physical symptoms than the general population and fewer symptoms than patients referred to an FSD clinic. At diagnosis (median seven months after SARS-CoV-2 infection), 11% of patients with long COVID met the criteria for multi-organ FSD, and these patients had similar symptom prevalence and profiles to those in the FSD cohort.

Long COVID symptoms have been widely documented [1, 11]. More than 200 symptoms have been attributed to long COVID [12]. The higher symptom prevalence than in the general population cohort was therefore not surprising. The lower symptom prevalence in long COVID than in patients with FSD aligns with referral criteria based on suspected FSD.

General symptoms such as headaches, concentration and memory problems, fatigue and muscle pain predominated in patients with long COVID. The frequent occurrence of fatigue (Figure 1 A) – a common feature of post-viral conditions – raises the question of whether it represents a physiological post-viral reaction or bodily and mental stress following infection that may trigger the development of FSD, and whether there is an overlap in disease mechanisms [3, 13].

Persistent symptoms have been observed following infections such as Epstein-Barr virus (EBV) infection [14], dengue, chikungunya [15], viral meningitis [16] and human herpesvirus 6 infection [17]. Fatigue following EBV and cognitive issues after viral meningitis have been documented, but comparisons of symptom profiles are limited [14, 16]. Similarities suggest common pathogenesis, with inflammatory mechanisms and potential neuromuscular damage [18] along with mitochondrial defects noted in patients with long COVID and in patients with chronic fatigue [19, 20]. Some patients with FSD may have developed FSD triggered by infection, and it is important to explore whether predominant GS symptoms or other characteristics are descriptive of such patients.

The BDS checklist was used for research purposes without diagnostic verification. Bias may arise from differences in study design, age, sex, symptom duration, comorbidities, calendar effects, geographic variations and questionnaire presentation. Patient selection was influenced by disease severity, health literacy and healthcare structure. The graphical similarities of profiles were not statistically tested and should be interpreted with caution. Despite these limitations, this study is the first to compare symptom prevalence and profiles among patients with long COVID, patients with FSD, and the general population. This study cannot determine shared disease mechanisms, and similarities may be due to selection bias.

CONCLUSIONS

Patients meeting the criteria for multi-organ FSD exhibited similar symptom profiles. GS, including fatigue and muscle pain, were common in both the long COVID and FSD cohorts, suggesting a potential overlap in pathogenesis. Prospective studies on various infections are needed to further investigate shared symptom profiles, underlying mechanisms and treatment options.