Introduction

Since the emergence in the late of 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread across the world leading an unexpected, large, and serious global pandemic [1,2,3,4,5]. By the 5th of July 2021, 182,319,261 confirmed cases of coronavirus disease 2019 (COVID-19), involving 3,954,324 deaths, have been identified worldwide according to the World Health Organization (WHO) [6]. Even though as COVID-19 vaccination becomes more available throughout the world and the COVID-19 infection/death rates are dropping, clinicians have still caring the COVID-19 survivors who were previously infected and recovered from acute infection and now experience a broad range of persistent symptoms, which are called as post-acute COVID-19 syndrome, long COVID, long-haul COVID, post-COVID condition, or post-acute sequelae of SARS-CoV-2 infection (PASC) [7, 8].

Several observational studies have recently evaluated the persistent symptoms in hospitalized COVID-19 survivors beyond 3 months [9,10,11,12,13]. Although some of these studies have partly described the persistent fatigue, myalgia, and joint pain in hospitalized COVID-19 survivors, they only reported their prevalence. In other words, the severity, type (local or widespread), and locations of persistent rheumatic and musculoskeletal symptoms have not been documented in detail.

Thus, we aimed to document the detailed characteristics including severity, type, and locations of rheumatic and musculoskeletal symptoms along with other COVID-19 persistent symptoms in hospitalized COVID-19 survivors at 3 and 6 months. We also sought to evaluate whether an association exists between the presence of symptoms (i.e., fatigue, myalgia, joint pain) and age, sex, body mass index (BMI), and duration of hospital stay.

Materials and methods

Study design, setting, and ethical approval

We conducted an extension cohort study of our previously published investigation reporting 1-month results [14]. We carried out this study in a tertiary hospital, namely Gülhane Training and Research Hospital. We obtained an ethical approval for this extension study by the Ethic Committee of the Gülhane Scientific Researches, University of Health Sciences (2021/187). We obtained informed verbal consent to participate in the study at the beginning of the telephone interviews. We informed by Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) [15] in reporting our study and by standard recommendations [16] in reporting our results.

Study cohort

COVID-19 survivors who aged 18 to 70 years old and who had been discharged after hospital stay due to the acute COVID-19 infection anytime during the November 18, 2020, through January 30, 2021, were included. We included COVID-19 survivors who had been only treated in hospital ward unit; in other words, we excluded survivors who admitted/or were transferred to intensive care unit during their hospital stay.

Data gathering

One author (FK) carried out all telephone surveys at 3 and 6 months following the hospitalization. In these telephone surveys, participants were asked regarding their symptoms through a previously designed standard questionnaire. The following rheumatic and musculoskeletal symptoms were systematically gathered: fatigue, myalgia, joint pain, low back pain, back pain, and neck pain. The type (local, widespread) and locations of myalgia, and joint pain were asked as well. Additionally, the other COVID-19 symptoms were gathered: fever, cough, lack of appetite, dyspnea, diarrhea, sore throat, headache, dizziness, absence of taste, and absence of smell. We evaluated the severity of all these symptoms through a 5-point Likert-type scale.

Statistical analyses

We conducted the analysis with the use of the SPSS v. 21.0 (IBM, Armonk, NY). We analyzed the data and variables through descriptive statistical analyses and expressed the results either as mean ± standard deviation (SD) or number (%). We also tested whether there is an association between the presence of symptoms (i.e., fatigue, myalgia, joint pain) and age, sex, BMI, and duration of hospital stay at 6 months using generalized estimating equations by a selection of binary logistic regression models. The 95% confidence interval (CI) values that did not include 1 indicated statistical significance.

Results

Baseline characteristics

We included a total of 300 COVID-19 survivors in our previous publication presenting 1-month results [14]. At 3 months, there were 9 missing, and at 6 months, there were 6 additional missing survivors. The reasons of these 15 missings were dead (n = 2), could not be reached through telephone (n = 4), did not answer to telephone (n = 7), staying in intensive care unit at the time of assessment (n = 1), and abdominal hysterectomy with bilateral salpingo-oophorectomy (n = 1). We presented the baseline demographic and clinical features of the study cohort at 3 (n = 291) and 6 (n = 285) months in Table 1.

Table 1 Baseline characteristics of study population, which have data for 3- and 6-month follow-up

Symptoms at 3 months

At 3 months, 89.0% of survivors had at least one symptom (in other words, 11.0% had no symptoms), 74.6% had at least one rheumatic and musculoskeletal symptom, and 82.1% had at least one other-COVID-19-symptom. Regarding the rheumatic and musculoskeletal symptoms, 59.5% had fatigue, 40.6% had myalgia, and 39.2% had joint pain. Regarding the other COVID-19 symptoms, 46.1% had hair loss, 45.0% had dyspnea, and 26.8% had sweat (Tables 2 and 3, Fig. 1).

Table 2 Prevalence of symptoms at 3 and 6 months
Table 3 Severity of symptoms at 3 and 6 months
Fig. 1
figure 1

Severity of rheumatic/musculoskeletal symptoms and other COVID-19 symptoms at 3 and 6 months. Data are percentage

Symptoms at 6 months

At 6 months, 59.6% of survivors had at least one symptom (in other words, 40.4% had no symptoms), 43.2% had at least one rheumatic and musculoskeletal symptom, and 51.2% had at least one other COVID-19 symptom. Regarding the rheumatic and musculoskeletal symptoms, 31.6% had fatigue, 18.6% had joint pain, and 15.1% had myalgia. Regarding the other COVID-19 symptoms, 25.3% had dyspnea, 20.0% had hair loss, and 17.2% sweat (Tables 2 and 3, Fig. 1).

Location of arthralgia and myalgia at 6 months

Joint pain and myalgia were widespread (64.2% and 69.8%, respectively); if regional, joint pain was mostly in the knee, foot–ankle, and shoulder, and myalgia was mostly in the lower leg, arm, and shoulder girdle (Table 4).

Table 4 Location of myalgia and arthralgia symptoms at 3 and 6 months

Regression analyses results

In an adjusted model, female patients were more likely to have fatigue (OR: 1.99, 95% CI: 1.18–3.34), myalgia (3.00, 1.51–5.98), and joint pain (3.39, 1.78–6.50) at 6 months, whereas no association was observed between age/BMI/duration of hospital stay and fatigue/myalgia/joint pain (Table 5).

Table 5 Association between the presence of symptoms (i.e., fatigue, myalgia, joint pain) and age, sex, BMI, and duration of hospital stay at 6 months

Discussion

We showed that approximately 3 in 5 patients had at least one symptom with approximately 2 in 5 patients had at least one rheumatic and musculoskeletal symptom and just over than half of the patients had at least one other COVID-19 symptom at 6 months. Fatigue (approximately 1 in 3), joint pain (approximately 1 in 5), and myalgia (approximately 1 in 7 patients) were the most frequent rheumatic and musculoskeletal symptoms. Joint pain and myalgia were mostly widespread. Dyspnea (approximately 1 in 4), hair loss (approximately 1 in 5), and sweat (approximately 1 in 6) were the most frequent other COVID-19 symptoms. Furthermore, female patients were more likely to have fatigue, myalgia, and joint pain at 6 months.

In the literature, some observational studies investigated the persistent symptoms in hospitalized COVID-19 survivors beyond 3 months [9,10,11,12,13]. Ghosn and colleagues analyzed 1137 hospitalized survivors (of which 288 admitted to the intensive care unit) and found that 60% had at least one symptom at 6 months, most frequently fatigue, dyspnea, joint pain, and muscle pain [11]. Peghin and colleagues evaluated 599 survivors (outpatients, n = 442; hospital ward unit, n = 134; the intensive care unit, n = 23) and reported that 52% of hospital ward unit survivors had post-COVID-19 syndrome at 6 months [12]. Our data at 6 months showed that 59.6% of survivors had at least one symptom, in consistent with previous two studies [11, 12]. Garrigues and colleagues assessed 120 survivors through telephone surveys after a mean of 111 days after admission either to the hospital ward unit (n = 96) or to the intensive care unit (n = 24) and documented that 54.2% had fatigue, 39.6% had dyspnea, 14.6% had cough, 14.6% had anosmia, and 9.4% had ageusia in the hospital ward unit group [9]. González-Hermosillo and colleagues assessed 130 survivors through telephone surveys and reported that 46.9% had fatigue, 43.8% joint pain, 42.3% had dyspnea, 36.2% muscle pain, 6.9% had anosmia, and 5.4% had ageusia at 6 months [10]. Fortini and colleagues assessed 59 survivors after a median of 123 days after discharge from the hospital ward unit and observed that 42.4% had fatigue, 37.3% had dyspnea, 16.9% had ageusia, 15.2% had anosmia, 11.9% had cough, 8.5% joint pain, and 8.5% myalgia [13]. In those earlier investigations, generally fatigue and dyspnea were the most frequent symptoms. In our study, fatigue (approximately 1 in 3) and dyspnea (approximately 1 in 4) were the two most common symptoms as well. Also, we showed that joint pain and myalgia were each observed in approximately one-sixth of patients, and back pain, low back pain, and neck pain were each observed in approximately one-tenth of patients. With regard to the other COVID-19 symptoms, hair loss and sweat were each observed in approximately one-fifth of patients with less frequently, headache, sore throat, dizziness, cough, absence of smell, lack of appetite, absence of taste, diarrhea, lack of appetite, and fever. Considering the broad range of symptoms, multidisciplinary teams involving rheumatologists should provide a care for COVID-19 survivors.

In a study evaluating severe fatigue on 239 COVID-19 patients confirmed by PCR/CT, it was shown that severe fatigue lasted 12–23 weeks after the initial symptoms of the disease. It has been stated that the prevalence of long-term persistence of severe fatigue is high [17]. In another study, excessive fatigue persisted in 26 (33.3%) of 78 patients at 3-month follow-up and in 9 (39.1%) of 23 patients at 6-month follow-up [18]. In our study, severe/very severe fatigue was present in 10.7% of patients at 3 months and 3.2% at 6 months.

We showed that female patients were more likely to have fatigue, myalgia, and joint pain at 6 months. This finding was consistent with two previous studies [11, 12], which showed an association of female sex and post-COVID symptoms. Our study provides information on association of female sex with rheumatic/musculoskeletal symptoms, therefore, extends the results of previous studies.

In the recent review, possible mechanisms that predominantly contribute to post-acute COVID-19 symptoms were listed as cellular invasion by SARS-COV-2, inflammatory and the immune response, and sequelae of post-critical illness [19]. Also, transforming growth factor beta (TGF-β) overexpression causing a prolonged state of immunosuppression and fibrosis was proposed as a unifying hypothesis mechanism for persistent post-COVID syndrome [20]. However, further research is warranted to elaborate the pathophysiologic mechanisms of wide spectrum of manifestations including rheumatologic/musculoskeletal involvement of post-COVID syndrome.

Limitations and strengths

We must acknowledge the limitations of our study. As we only included COVID-19 survivors who had been treated in hospital ward unit, our results are not generalizable to outpatient survivors or to those who admitted to intensive care unit. Also, it was an uncontrolled cohort study, the results would have been better interpreted if a comparative group who were hospitalized for other reasons than COVID-19 could exist. Furthermore, some factors such as medicines patients used might contribute to developing symptoms; however, the study did not investigate these factors. On the other hand, our study has several strengths. It was a prospective study with a relatively long-term follow-up period.

Conclusion

Approximately 3 in 5 patients had at least one symptom with ≈2 in 5 patients had at least one rheumatic and musculoskeletal symptom and just over than half of the patients had at least one other COVID-19 symptom at 6 months. Fatigue, joint pain, and myalgia were the most frequent rheumatic and musculoskeletal symptoms. Joint pain and myalgia were mostly widespread. Dyspnea, hair loss, and sweat were the most frequent other COVID-19 symptoms. Furthermore, female patients were more likely to have fatigue, myalgia, and joint pain at 6 months. This information guide rheumatologists to understand the nature and features of persistent rheumatic and musculoskeletal symptoms in hospitalized COVID-19 survivors and may translate into improved management of such individuals with persistent symptoms who had recovered from acute COVID-19 infection.