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Research Paper

Prevalence and risk factors of musculoskeletal pain symptoms as long-term post-COVID sequelae in hospitalized COVID-19 survivors: a multicenter study

Fernández-de-las-Peñas, Césara,b,*; de-la-Llave-Rincón, Ana I.a; Ortega-Santiago, Ricardoa; Ambite-Quesada, Silviaa; Gómez-Mayordomo, Víctorc; Cuadrado, María L.c,d; Arias-Navalón, José A.e; Hernández-Barrera, Valentínf; Martín-Guerrero, José D.g; Pellicer-Valero, Oscar J.g; Arendt-Nielsen, Larsb,h

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doi: 10.1097/j.pain.0000000000002564
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1. Introduction

Clinical manifestations of the severe acute respiratory syndrome coronavirus (SARS-CoV)-2 are heterogeneous and affect respiratory, gastrointestinal, cardiovascular, neurological, or musculoskeletal systems.46 Generalized pain (myalgia) is a common symptom experienced by patients with the coronavirus 2, 2019 disease (COVID-19) during the acute phase with an estimated prevalence ranging from 15% to 20%.1,14,45 The potential implications of musculoskeletal pain symptoms associated with COVID-19 are not properly understood and suggest a heterogeneous physiological process.31

Owing to the worldwide COVID-19 outbreak, the incidence of musculoskeletal pain would be expected to raise by 3 different ways: (1) by the increasing number of people developing de novo musculoskeletal pain as a post-COVID sequelae; (2) by exacerbating pain in infected individuals with preexisting conditions; and in addition, (3) by increasing pain symptoms in noninfected people with musculoskeletal pain conditions due to COVID-19 surrounding factors (eg, lockdown, isolation, or stress).15 In fact, current literature supports that patients with chronic pain (but not infected) reported an increase in their symptoms and their pain interference during the main lockdown.18,28,33 In addition, female sex, people with lower education, worse disability, and higher catastrophizing have shown to be at a higher risk of social isolation during COVID-19 outbreak.25

Data about the first 2 assumptions are less clear to date. Different meta-analyses reported that almost 60% of COVID-19 survivors will develop post-COVID symptoms (ie, long COVID) in the following months after the infection.3,10,30 Although these texts described the presence of several post-COVID symptoms, specific data on pain are scarce.3,10,30 One meta-analysis focusing just on musculoskeletal post-COVID pain symptoms identified 33 studies.19 These authors found that most studies investigated follow-up periods between 1 and 4 months after infection.19 A remarkable finding of this meta-analysis was that, despite including 33 articles investigating post-COVID pain, large epidemiological studies specifically focusing on post-COVID pain symptoms are missing.5,19

Alizadeh and Aghsaeifard described in their study about 8 patients with history of chronic pain where COVID-19 triggered their previous pain symptoms.4 Two small cohort studies reported that the prevalence of musculoskeletal pain can reach up to 60.7% in COVID-19 survivors 1 month after infection.7,27 However, both studies included small sample sizes, did not differentiate whether pain symptoms were present before the infection or not, and included short-term follow-up periods.7,27 Soares et al.44 observed that almost 65.2% of COVID-19 survivors developed de novo post-COVID pain symptoms. Again, this study included a small sample of patients, just recruited from a single center, and included a follow-up period less than 3 months after.44

This multicenter study included a large cohort of previously hospitalized COVID-19 survivors with a long-term follow-up period. The aims of the current study were as follows: (1) to investigate the prevalence of musculoskeletal post-COVID pain symptoms in a large cohort of hospitalized COVID-19 survivors; (2) to determine whether musculoskeletal post-COVID pain is a new-onset (de novo) or an exacerbated symptom of preexisting musculoskeletal pain conditions; and (3) to investigate potential risk factors associated with the development of musculoskeletal post-COVID pain.

2. Methods

2.1. Participants

This multicenter cohort study included individuals who had recovered from acute SARS-CoV-2 infection during the first wave of the pandemic (from March 20, 2020, to June 30, 2020) from 5 urban hospitals in Madrid (Spain). Participants were hospitalized because of SARS-CoV-2 infection, which was diagnosed with real-time reverse transcription-polymerase chain reaction assay of nasopharyngeal/oral swab samples and the presence of consistent clinical and radiological findings. All hospitalized COVID-19 survivors discharged from the participating hospitals (n = 7150) during the first wave of the pandemic were included in an anonymous database, and a random selection of 400 patients from each hospital was performed with an online randomization software. The study was approved by all local ethic committees (URJC0907202015920, HCSC20/495E, HUFA20/126, HUIL/092-20, HSO25112020, and HUF/EC1517). Participants were informed of the study, and all provided informed consent before their inclusion and before collecting any data.

2.2. Procedure

Clinical data (age, sex, height, weight, COVID-19–associated symptoms at hospital admission, preexisting medical comorbidities, intensive care unit [ICU] admission, and days at hospital) were collected from hospital records. Participants who agreed to participate in this study were scheduled for a semistructured telephone interview by trained healthcare researchers. A questionnaire focusing on musculoskeletal pain symptoms was developed by a multidisciplinary research team. Participants were asked for the presence of pain symptoms appearing after hospital discharge and whether the reported symptoms persisted at the time of the study. Particular attention was paid to the development of musculoskeletal post-COVID pain symptoms differentiating from headache, particularly migraine-like pain. We defined musculoskeletal post-COVID pain as follows: (1) pain symptoms compatible with diagnosis of chronic primary musculoskeletal pain, as defined by the International Association for the Study of Pain39; (2) symptoms experienced for at least 3 consecutive months after hospital discharge, and (3) absence of any underlying medical condition that could best explain pain, eg, arthritis. Finally, participants were asked to describe the location of their pain symptoms (eg, neck, shoulder, spine, lower extremity, upper extremity, and generalized) and to differentiate these symptoms from any pain condition that they experienced before being infected by SARS-CoV-2. We did not include headache symptoms because of the particular classification of headaches and need for a proper diagnosis according to the classification.

Anxiety/depressive symptoms and sleep quality were assessed with the Hospital Anxiety and Depression Scale (HADS) and the Pittsburgh Sleep Quality Index (PSQI), respectively, because both can be properly evaluated by telephone interview.22 From HADS, we included the scale assessing anxiety symptoms (HADS-A; 7 items and 0-21 points) and the scale assessing depressive symptoms (HADS-D; 7 items and 0-21 points). Higher scores suggest more anxiety/depressive levels, with a cutoff score >8 points being suggestive of anxiety/depressive disorder.23 In this study, we considered the cutoff scores recommended for Spanish population (HADS-A ≥ 12 points; HADS-D ≥ 10 points) indicative of anxiety and depressive symptoms, respectively.21 The PSQI (0-21 points) evaluates sleep quality by including 19 self-rated questions assessing different aspects of sleep during the previous month.8 Higher scores indicate worse sleep quality, and a score ≥8.0 points is indicative of poor sleep.8 The PSQI has shown good internal consistency and test–retest reliability.11

2.3. Statistical analysis

The STATA 16.1 program (StataCorp. 2019, Stata Statistical software: Release 16, College Station, TX: StataCorp LP) was used for consolidation of the multicenter records. Data are presented as means (SD) and/or percentages as appropriate. The McNemar χ2 test and the paired Student t test were conducted to compare proportions and means between patients with and without musculoskeletal post-COVID pain. Missing values were imputed using median imputation because of their small numbers. Univariate and multivariate logistic regressions were conducted to identify the association of the development of musculoskeletal post-COVID pain with COVID-19–associated variables collected at hospital admission (age, sex, height, weight, COVID-19 onset symptoms at hospital admission, preexisting medical comorbidities, ICU admission, and days at hospital) by using Python library statsmodels 0.11.1. Adjusted odds ratio (OR) and 95% confidence intervals (CIs) were calculated. A priori, the level of significance was set at 0.05.

3. Results

From 2000 participants randomly selected from the involved hospitals and invited to participate, 6 refused to participate, 11 could not be contacted after 3 attempts, and 14 had deceased after hospital discharge. Finally, a total of 1969 individuals (46.4% women, age: 61 years, SD: 16 years) were included.

3.1. Prevalence of post-COVID musculoskeletal pain

Participants were assessed from 6 to 10 (mean: 8.4, SD 1.5) months after hospital discharge. At the time of the evaluation, 887 (45.1%) patients reported musculoskeletal post-COVID pain symptoms. The main locations of musculoskeletal post-COVID pain, being widespread, are illustrated in Figure 1, with lower extremity pain being the most prevalent.

F1
Figure 1.:
Location of musculoskeletal post-COVID pain symptoms 8 months after hospital discharge (n = 887).

Table 1 lists the comparison of clinical and hospitalization data between individuals developing and not developing musculoskeletal post-COVID pain symptoms. Individuals reporting musculoskeletal post-COVID pain showed a greater number of COVID-19 symptoms at hospital admission, with a greater prevalence of myalgia and headache (both, P < 0.001); longer stay of hospitalization, and higher incidence of ICU admission than those not reporting long-term musculoskeletal post-COVID pain. Individuals with musculoskeletal post-COVID pain also exhibited higher anxiety and depression scores and poor sleep quality (P < 0.001, Table 1).

Table 1 - Demographic, hospitalisation, and clinical data of COVID-19 patients according to the presence or absence of musculoskeletal (MSK) post-COVID pain.
MSK post-COVID pain (n = 887) No MSK post-COVID pain (n = 1082) Missing (%)
Age, mean (SD), y 60.5 (15.0) 61.5 (17.0) 0.15
Sex, male/female, n (%)* 426 (48)/461 (52) 628 (45)/454 (42) 0
Weight, mean (SD), kg* 76.2 (16.3) 73.8 (14.1) 1.93
Height, mean (SD), cm 165 (9.5) 166 (9) 1.88
No. of medical comorbidities 0.9 (0.9) 0.8 (0.85) 0
Medical comorbidities 0
 Hypertension 256 (28.9%) 258 (23.8%)
 Diabetes 102 (11.5%) 134 (12.4%)
 Cardiovascular diseases 117 (13.2%) 117 (10.8%)
 Asthma 73 (8.2%) 53 (4.9%)
 Obesity 54 (6.1%) 34 (3.1%)
 Chronic obstructive pulmonary disease 39 (4.4%) 38 (3.5%)
 Rheumatological diseases 19 (2.1%) 12 (1.1%)
 Migraine 32 (3.6%) 25 (2.4%)
 Other (cancer and kidney disease) 171 (19.3%) 161 (14.9%)
Previous musculoskeletal pain, n (%)* 442 (49.8%) 364 (33.6%) 0
No. of COVID-19 symptoms at hospital admission, mean (SD)* 2.4 (0.8) 2.0 (0.8) 0
Symptoms at hospital admission, n (%) 0
 Fever 643 (72.5%) 826 (76.3%)
 Dyspnoea 303 (34.1%) 317 (25.5%)
 Cough 249 (28.1%) 300 (27.7%)
 Myalgias* 328 (37%) 276 (25.5%)
 Headache* 199 (22.4%) 133 (12.3%)
 Diarrhoea 113 (12.7%) 97 (9%)
 Anosmia 69 (7.8%) 98 (9.1%)
 Ageusia 66 (7.5%) 79 (7.3%)
 Throat pain 59 (6.6%) 43 (4%)
 Vomiting 28 (3.1%) 27 (2.5%)
 Dizziness 37 (4.2%) 29 (2.7%)
Stay at the hospital, mean (SD), d* 12.5 (11.5) 10.2 (11.0) 0.20
Intensive care unit (ICU) admission 0
 Yes/no, n (%)* 79 (8.9)/806 (91.1%) 51 (4.7%)/1029 (95.3%)
 Stay at ICU, mean (SD), d 13.0 (12.5) 12.5 (16.5)
HADS-D (0-21), mean (SD)* 5.7 (5.0) 3.8 (4.5) 0.05
 Depressive symptoms (HADS-D ≥ 10 points), n (%) 223 (25.1) 150 (13.8%)
HADS-A (0-21), mean (SD)* 5.8 (5.2) 4.1 (5.1) 0.05
 Anxiety symptoms (HADS-A ≥ 12 points), n (%) 156 (17.6) 152 (14.05%)
PSQI (0-21), mean (SD)* 7.6 (5.0) 5.6 (3.5) 0.05
 Poor sleep quality (SQI ≥ 8 points), n (%) 408 (46.0) 266 (24.6%)
*Statistically significant differences between groups (P < 0.01).
HADS, hospital anxiety and depression scale (A: anxiety; D: depression); n, number; PSQI, Pittsburgh Sleep Quality Index.

3.2. New-onset (de novo) or exacerbated musculoskeletal post-COVID pain

The prevalence of preexisting musculoskeletal pain symptoms before the infection was significantly higher (P < 0.001) in those reporting musculoskeletal post-COVID pain (49.8%) than in those without post-COVID pain (33.6%). No significant differences were seen in the location of previous pain symptoms in the body between individuals developing or not developing musculoskeletal post-COVID pain (Fig. 2). From 887 patients reporting musculoskeletal post-COVID pain, almost 50% (n = 442) reported musculoskeletal pain symptoms before infection. Accordingly, the remaining 445 (50.1%) developed new-onset musculoskeletal post-COVID–related pain because they did not experience symptoms before the infection. In addition, from those 442 individuals experiencing previous symptoms, 220 (24.8%) reported that post-COVID pain symptoms were different from previous symptomatology (new-onset musculoskeletal post-COVID pain), whereas the remaining 222 (25.1%) patients experienced an increase in the previous symptoms (exacerbated musculoskeletal post-COVID related-pain) on their intensity (n = 89, 40.1%), the extension (n = 42, 18.9%), frequency (n = 55, 24.8%) and both intensity and extension (n= 36, 16.2%): the prevalence of new-onset post-COVID musculoskeletal pain in the total sample was up to 74.9%.

F2
Figure 2.:
Location of previous musculoskeletal pain symptoms before infection in those experiencing musculoskeletal post-COVID pain (n = 442, left side) or not experiencing musculoskeletal post-COVID pain (n = 364, right side).

3.3. Risk factors associated with musculoskeletal post-COVID pain

Table 2 summarizes the results of univariate and multivariate analyses. The univariate analysis revealed that age (P = 0.001); weight (P = 0.001); ICU admission (P = 0.015); the presence of several medical comorbidities, e.g., diabetes (P = 0.04), cardiovascular disease (P = 0.024), asthma (P = 0.02), obesity (P = 0.044), or chronic obstructive pulmonary disease (P = 0.045); and the presence of some COVID-19 onset symptoms at hospital admission such as dyspnoea (P = 0.04), cough (P = 0.03), anosmia (P = 0.025), or throat pain (P = 0.03) were associated with musculoskeletal post-COVID pain; however, these variables were not significant in the multivariate analysis.

Table 2 - Adjusted odds ratio (95% confidence interval) of the univariate and multivariate regression analyses.
Multivariate Univariate
Age 0.995 (0.988, 1.002) 0.997 (0.995, 0.998)*
Female sex 1.349 (1.059, 1.720)* 1.015 (0.892, 1.156)
Weight 1.010 (1.002, 1.019)* 0.998 (0.997, 0.999)*
Height 0.992 (0.978, 1.005) 0.999 (0.998, 1.000)
No. of medical comorbidities 0.562 (0.273, 1.156) 1.008 (0.939, 1.082)
Medical comorbidities
 Hypertension 0.992 (0.835, 1.180) 2.016 (0.954, 4.259)
 Diabetes 1.414 (0.654, 3.057) 0.761 (0.588, 0.985)*
 Cardiovascular diseases 1.000 (0.774, 1.292) 2.478 (1.126, 5.453)*
 Asthma 1.377 (0.967, 1.962) 2.720 (1.196, 6.189)*
 Obesity 1.588 (0.998, 2.439) 2.489 (1.026, 6.039)*
 Chronic obstructive pulmonary disease 1.026 (0.657, 1.604) 2.395 (1.010, 5.677)*
 Rheumatological diseases 1.583 (0.769, 3.262) 2.722 (0.921, 8.040)
 Other (cancer and kidney disease) 1.062 (0.856, 1.317) 2.078 (0.962, 4.490)
Previous musculoskeletal pain 1.553 (1.271, 1.898)* 1.214 (1.057, 1.395)*
No. of symptoms at hospital admission 1.172 (0.936, 1.476) 0.977 (0.941, 1.014)
Symptoms at hospital admission
 Dyspnoea 0.956 (0.817, 1.119) 1.351 (1.018, 1793)*
 Cough 1.054 (0.789, 1.408) 0.830 (0.702, 0.982)*
 Myalgias* 1.546 (1.155, 2.070)* 1.188 (1.013, 1.395)*
 Headache* 1.866 (1.349, 2.580)* 1.496 (1.201, 1.864)*
 Diarrhoea 1.359 (0.943, 1.959) 1.165 (0.888, 1.528)
 Anosmia 0.850 (0.564, 1.281) 0.704 (0.517, 0.958)*
 Ageusia 1.163 (0.757, 1.785) 0.835 (0.603, 1.158)
 Throat pain 1.372 (0.926, 2.033) 1.707 (1.058, 2.756)*
 Vomiting 1.118 (0.610, 2.050) 1.037 (0.611, 1.759)
 Dizziness 1.349 (0.778, 2.336) 1.276 (0.785, 2.074)
Days at the hospital 1.013 (1.004, 1.022)* 1000 (0.994, 1.005)
Intensive care unit admission 1.477 (0.981, 2.224) 1.549 (1.089, 2.203)*
* Statistically significance

The multivariate analysis revealed that, after adjusting by all variables, female sex (OR 1.349, 95% CI 1.059-1.720, P = 0.01), history of musculoskeletal pain (OR 1.553, 95% CI 1.271-1.898, P < 0.001), the presence of myalgia (OR 1.546, 95% CI 1.155-2.070, P = 0.003) and headache (OR 1.866, 95% CI 1.349-2.580, P < 0.001) as COVID-19–associated symptoms at the acute phase, and days at hospital (OR 1.013, 95% CI 1.004-1.022, P = 0.006) were associated with the presence of long-term musculoskeletal post-COVID pain symptoms.

4. Discussion

This multicenter study found that the prevalence of musculoskeletal post-COVID pain 8 months after hospital discharge was 45.1%. Based on the presence of previous symptoms, the prevalence of de novo musculoskeletal post-COVID pain was 74.9%. Female sex, history of musculoskeletal pain, the presence of myalgia and headache as COVID-19–associated symptoms, and days at hospital were risk factors.

4.1. Post-COVID musculoskeletal pain

We reported that the prevalence of musculoskeletal post-COVID pain 8 months after hospitalization was 45.1%. Our results reveal higher prevalence rate than those reported in a recent meta-analysis, which observed a prevalence of 10.9% and 7.7% for myalgias and arthralgias, respectively, 6 months after hospital discharge.19 Differences in age, sex, preexisting comorbidities—particularly history of musculoskeletal pain (data not considered in most studies)—or severity of the disease could explain discrepancies. On the contrary, our results fall slightly below from those reported by 3 small cohort studies providing prevalence rates of musculoskeletal post-COVID pain up to 60% after 17,27 and 344 months. Only one study considered the presence of previous musculoskeletal pain.44 Our study is the largest multicenter study providing prevalence data of long-term musculoskeletal post-COVID pain in hospitalized survivors.

We found that widespread pain and lower extremity pain were the most common forms of musculoskeletal post-COVID pain. Soares et al.44 and Numan37 also found that lower extremity was the most affected location. Similarly, subjects who had survived to SARS also exhibit widespread pain as a sequela after 1 year.35 Current evidence suggests that musculoskeletal post-COVID pain tend to be heterogeneous, but a tendency to widespread symptoms seems to be present. Such widespread pain symptomatology, as commonly observed in, eg, fibromyalgia, has been suggested to be related to deficient immune regulatory mechanisms41 and could indicate a prolonged immune system impact in people who experience post-COVID.

It is also possible that location of musculoskeletal post-COVID pain is related to the location of symptoms (eg, myalgias) experienced at the acute phase. Şahin et al.42 observed that pain symptoms in the extremities were highly prevalent during the acute phase. Pain at the acute phase of the infection may be widespread (viral-induced myalgias), and in some cases, it could be the main complaint. The presence of pain at hospital admission and how early the pain begins can provide guidance on the prognosis of post-COVID pain. We did not collect the area of symptoms at hospital admission in our cohort, but this hypothesis should be explored in future studies.

4.2. De novo or exacerbated musculoskeletal post-COVID pain

We hypothesized that the existence of musculoskeletal pain before COVID-19 may predispose not only to the development of de novo (new-onset) pain but also to an exacerbation of preexisting pain, possibly due to the cytokine storm. Our results support both hypotheses because49.75% (n = 220/442) of patients developed “de novo” musculoskeletal post-COVID pain and 50.2% (n = 222/442) experienced an increase in previous symptoms (exacerbated musculoskeletal post-COVID–related pain). In agreement with our results, Soares et al.44 reported that 60% of COVID-19 survivors developed de novo post-COVID pain.

4.3. Risk factors

Identification of patients at risk of developing musculoskeletal post-COVID pain is important.29 Our study revealed that female sex, history of musculoskeletal pain, the presence of myalgia and headache as COVID-19 onset symptoms, and days at hospital were risk factors associated with musculoskeletal post-COVID pain.

Female sex has been previously suggested as a risk factor of post-COVID symptoms.26 Our study supports that female individuals are at a higher risk of musculoskeletal post-COVID pain than male individuals. This could be expected because musculoskeletal pain is more prevalent in female individuals.32,34 Another explanation can be biological sex differences on expression of angiotensin-converting enzyme(ACE)2 and also transmembrane protease serine (TMPRSS)2 receptors.9

An important risk factor was history of pre-existing musculoskeletal pain before the infection. Accordingly, the presence of preexisting musculoskeletal pain should be considered in the initial screening of COVID-19 patients to avoid confusion in the characterization of such pain. This would be highly relevant in individuals experiencing viral-induced myalgia as an onset symptom because these patients were also more prone to develop musculoskeletal post-COVID pain symptom. This is an interesting finding because the presence of pain at onset is associated with good prognosis for hospitalization,40 yet it is associated with musculoskeletal post-COVID pain in our study. The hypothesis that experiencing myalgia as an onset symptom is a risk factor of post-COVID pain has been recently supported by a case–control study.20 This study increases evidence on the hypothesis that not only myalgia but also the presence of headache at the acute phase is also a risk factor of musculoskeletal post-COVID pain. It is important to consider that these 2 COVID-19 pain symptoms are not considered as bothersome symptoms when compared with others, eg, fever or dyspnea. Accordingly, monitoring of musculoskeletal symptoms, COVID-19–associated onset myalgia or headache, and musculoskeletal post-COVID pain would be carefully needed.

Finally, we also observed that a longer hospital stay was a risk factor, but showing a smaller influence, for musculoskeletal post-COVID pain, in agreement with a previous study.7 It is possible that hospitalization factors such as physical inactivity or treatment received for managing the infection could promote future musculoskeletal post-COVID pain.

4.4. Underlying mechanisms of musculoskeletal post-COVID pain

Several hypotheses explaining musculoskeletal post-COVID pain are suggested. The first step would be the prolonged proinflammatory responses (cytokine and interleukin storms) associated with SARS-CoV-2 infection could lead to an exuberant immune response by inducing a hyperactivation of T cells, macrophages, and natural killer cells.16,36 This response could promote different mechanisms associated with musculoskeletal pain, eg, an atypical response of the mast cells2 and an overexpression of ACE2 receptors.31,43 The presence of ACE2 and TMPRSS-2 receptors is higher in the muscle,17 which would explain the development of widespread post-COVID pain. Accordingly, SARS-CoV-2 infection could trigger “nociplastic pain” by altering balance between the neuromodulation systems of nociception.12 We hypothesize that SARS-CoV-2 cytokine/interleukin–associated storms may lead to hyperexcitability of peripheral and central nervous systems throughout different pathways and, in predisposed individuals, lead to development of new-onset musculoskeletal post-COVID pain or to a worsening of preexisting pain symptoms.

It is also important to consider that emotional and social factors surrounding the COVID-19 outbreak, eg, catastrophic social alarm, post-traumatic stress disorder, fear, somatization, or uncertainty about prognosis, may also play a role in the development of musculoskeletal post-COVID pain.13 We see that people developing musculoskeletal post-COVID pain exhibited higher levels of anxiety or depression and worse sleep quality than those not developing post-COVID pain. Nevertheless, we did not assess the presence of anxiety/depressive levels at hospital admission or during hospital stay, factors that could contribute to the development of long-term musculoskeletal post-COVID pain.

It seems that musculoskeletal post-COVID pain has a multifactorial genesis, where factors related to the pathogen (SARS-CoV-2–associated factors) intersect with the host response to the infection (within-individual factors), as well as with external factors related to therapies used (hospitalization-related factors) and emotional factors (COVID-19 outbreak surrounding elements).12

4.5. Limitations

First, current data can be only applicable to hospitalized COVID-19 survivors. Specific data on musculoskeletal post-COVID pain in nonhospitalized patients remain lacking. Thus, our cohort included Anglo-American participants; hence, ethnic differences could not be investigated. Second, we did not collect laboratory measures, eg, estimation of infection severity or inflammatory biomarkers that could help to elucidate whether these parameters are risk factors of musculoskeletal post-COVID pain. Of interest, Hickie et al.24 observed that individuals experiencing viral and nonviral infections exhibited similar postinfectious pain symptoms than post-COVID patients, but these symptoms were not related to the inflammatory response at the acute phase. In addition, we did not evaluate COVID-19 severity, and the number of individuals requiring ICU admission was small. Similarly, hospitalization treatments, eg, medication intake received for management of the acute infection or use of analgesic drugs during the hospital stay, or use of analgesic drugs at the time of the interview were not collected. Third, data were collected over telephone, a procedure with a potential bias in population-based survey studies. It should be noted that most studies investigating post-COVID symptoms had used similar methods for data collection.19 Fourth, the cross-sectional design does not allow to further determine the evolution of musculoskeletal post-COVID pain during all the follow-up period. In fact, it is difficult to exclusively attribute to SARS-CoV-2 infection the presence of post-COVID pain 8 months after hospital because no medical examination was conducted. Therefore, we cannot completely rule out the development of de novo medical diseases explaining the development of musculoskeletal pain. Furthermore, not only musculoskeletal but also neuropathic pain has been described as post-COVID sequelae,6 although the role of ACE2 receptors on peripheral small-fiber sensory neurons is still unknown.38 It is possible that some of the subjects also experienced neuropathic post-COVID pain. Finally, we did not collect the severity, eg, intensity and related-disability, of musculoskeletal post-COVID pain.

5. Conclusions

This multicenter cohort study found 45.1% prevalence of musculoskeletal post-COVID pain 8 months after hospital discharge. Female sex, history of musculoskeletal pain, the presence of myalgia and headache as COVID-19 onset symptoms, and the number of days at hospital were risk factors associated with musculoskeletal post-COVID pain.

Conflict of interest statement

The authors have no conflicts of interest to declare.

Acknowledgements

The Center for Neuroplasticity and Pain (CNAP) is supported by the Danish National Research Foundation (DNRF121) and Norvo Nordic Foundation (NNF21OC0067235). The LONG-COVID-EXP-CM is supported by Fondo Europeo De Desarrollo Regional—Recursos REACT-UE del Programa Operativo de Madrid 2014-2020.

Supported by a grant from the Novo Nordisk Foundation 0067235 (Denmark) and by a grant associated with the Fondo Europeo De Desarrollo Regional—Recursos REACT-UE del Programa Operativo de Madrid 2014-2020, en la línea de actuación de proyectos de I+D+i en materia de respuesta a COVID 19 (LONG-COVID-EXP-CM). Both sponsors had no role in the design, collection, management, analysis, or interpretation of the data, draft, review, or approval of the manuscript or its content. The authors were responsible for the decision to submit the manuscript for publication, and the sponsor did not participate in this decision.

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Keywords:

COVID-19; Musculoskeletal pain; Post-COVID; Risk factors; Prevalence

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