Persistent musculoskeletal presentations post-chikungunya fever: a case series in a state in northeast Brazil

Chikungunya fever (CF) is an arbovirosis caused by the Chikungunya virus (CHIKV). The main characteristic of CF is joint pain and more than half of infected patients experience chronic conditions. This case series study evaluated the persistent musculoskeletal presentations of CF in a sample of 72 patients with persistent symptoms ( ≥ 1 month) after CF confirmed by laboratory tests (detection of CHIKV by polymerase chain reaction [PCR] and/or immunoglobulin [Ig]M and/or IgG). The patients were followed up for 12 months after treatment at the outpatient clinic of the University Hospital of the Federal University of Sergipe ( Hospital Universitário da Universidade Federal de Sergipe - HU/UFS). They were evaluated at admission and after 1 month, 2 months, and then every 3 months for up to 12 months. Painful and/or swollen joints, periarticular symptoms, other important findings on physical examination, and visual analogue pain scale (VAS) were evaluated during all consultations. Main results: Among the patients evaluated, 84.7% were female, the mean age was 53.8 years, and the mean duration of musculoskeletal complaints was 6 months. Comorbidities were present in 61.1% of patients and previous musculoskeletal disease was present in 69.4%. The most frequent presentation on admission was polyarticular, which occurred in 76.4% of cases. The most affected joints were the hands, knees, ankles, and feet. VAS on admission was intense in 66.7% of patients. Tenosynovitis was present in 44.5% of patients and was more frequently reported in the ankles. Corticosteroids and chloroquine were administered to 65.3% and 31.98% of patients, respectively. The findings indicated that persistent musculoskeletal presentations occur frequently after CF. These results provide a better understanding of patient profiles, musculoskeletal involvement, and CF progression, and may guide effective strategies for therapeutic management. Flowchart 2 - Of patient progression and referrals to other specialties after 12 months of follow-up.

female, the mean age was 53.8 years, and the mean duration of musculoskeletal complaints was 6 months. Comorbidities were present in 61.1% of patients and previous musculoskeletal disease was present in 69.4%. The most frequent presentation on admission was polyarticular, which occurred in 76.4% of cases. The most affected joints were the hands, knees, ankles, and feet. VAS on admission was intense in 66.7% of patients. Tenosynovitis was present in 44.5% of patients and was more frequently reported in the ankles. Corticosteroids and chloroquine were administered to 65.3% and 31.98% of patients, respectively. The findings indicated that persistent musculoskeletal presentations occur frequently after CF. These results provide a better understanding of patient profiles, musculoskeletal involvement, and CF progression, and may guide effective strategies for therapeutic management. Keywords: Arbovirosis; Arthralgia; Chikungunya fever.

Introduction
Chikungunya fever (CF) is an arbovirosis caused by the Chikungunya virus (CHIKV), which is transmitted by the bite of female Aedes aegypti and Aedes albopictus mosquitoes. The name derives from a Makonde word and describes the stooped posture of people with severe arthralgia (Weaver & Lecuit, 2015).
In Brazil, the first CF case was confirmed in September 2014 in Oiapoque, Amapá, with almost simultaneous cases reported in Feira de Santana, Bahia. Since then, CF cases have been reported in different states of Brazil (Silva, 2018).
In 2016, Sergipe had the highest incidence rate of CF in northeastern Brazil (108.2 cases/100,000 inhabitants) (4). In 2020, Sergipe ranked second among states in the northeast, with an incidence rate above 100 cases/100,000 inhabitants (165.9 cases/100,000 inhabitants), second to the state of Bahia, with 273.1 cases/100,000 inhabitants (Brasil, 2020). The higher incidence in northeastern states is attributed to the favorable weather, the presence of the vector, and the deficient basic sanitation conditions in the region, which increase mosquito proliferation and disease spread (Cunha & Trinta, 2017).
Acute CHIKV infection is symptomatic in most (approximately 80%) of cases. After the acute phase, patients can progress to subacute (≥30 days to 3 months) or chronic (≥90 days) phases (Simon et al., 2015).
The prevalence of chronic rheumatologic conditions after CF infection ranges from 14.4% to 87.2% (Marques et al., 2017). The patterns of chronic joint involvement include persistent (20-40%) or recurrent (60-80%) complaints. Up to 72% of patients presenting significant initial improvement may have recurrences, with intervals ranging from 1 week to several years .
In the chronic phase, the most frequently affected joints are the knees, ankles, and small distal joints of the upper and lower limbs (Vairo et al., 2019). However, greater proximal (elbows, shoulders, and hips) and axial (neck) involvement has been reported (Nisar & Packianathan, 2017). Evidence indicates the development of chronic rheumatic diseases after CHIKV infection, with the main rheumatic presentations of CHIKV infection including arthritis and arthralgia (Benjamanukul et al., 2021).
In Brazil, no studies have yet reported the monitoring of patients with persistent musculoskeletal presentations after CF and there are few protocols guiding its conduct and treatment. The present study was conducted in a region with a high incidence of CF and assessed the persistent musculoskeletal presentations in CHIKV-infected patients followed up for 12 months.

Methodology
Study design. This case series study included a sample of 72 patients with musculoskeletal complaints for at least 1 month after CF diagnosis from an outpatient clinic and who were followed up at a University Hospital in northeastern Brazil for 1 year.
This study evaluated patients aged over 18 years who presented joint and/or periarticular pain associated or not with joint edema at the onset or significant subsequent worsening (if previous rheumatologic disease) of confirmed CF (IgG and/or IgM serology and/or CHIKV polymerase chain reaction [PCR]) progressing for at least 1 month, who agreed to participate in the study. Patients with a new joint condition or worsening of an existing condition justified by another infectious or neoplastic disease were excluded. Data collection started after approval by the CEP-HU/UFS and included patients who agreed to participate by signing the Informed Consent Form (ICF).

Data collection and patient follow-up
Patients referred from other outpatient clinics of the same hospital underwent an initial assessment. Only those meeting the clinical-epidemiological criteria for suspected CF were followed up. The inclusion criteria were a sudden onset of fever >38.5°C, severe arthralgia or acute onset of arthritis not explained by other conditions, a resident or having visited endemic or epidemic areas up to 2 weeks before symptom onset, and having epidemiological association with a confirmed case (Brasil, 2015).
After admission, the patients were followed up in subsequent consultations after 1 month, 2 months, and then every 2 months until for a total of 12 months. Anamnesis and physical examination were always performed by the same examiner. After 1 year of follow-up, the asymptomatic patients were discharged. The patients with persisting musculoskeletal symptoms continued to be monitored at the rheumatology outpatient clinic or were referred to other specialties, if necessary, at the HU/UFS.  Patients with suspected CF with musculoskeletal symptoms lasting ≥30 days seen at the HU-UFS Chikungunya outpatient clinic (n=113)

Results
Among a total of 113 patients in the outpatient clinic, this study included 72 patients with persistent musculoskeletal symptoms after CF confirmed by laboratory tests. Their sociodemographic and clinical characteristics are described in Tables 1 and 2, respectively.  The onset of the joint condition was mostly polyarticular and present in 55 patients (76.4%). Tenosynovitis was reported in 32 patients (44.5%) and occurred more frequently in the ankles. Hand paresthesia occurred in 58 patients (80.5%).

Increased levels of inflammatory markers (erythrocyte sedimentation rate [ESR] and/or C-reactive protein [CRP)]) were
present in eight patients on admission (11.1%). Of these, five had normalized levels in the third month and two in the sixth month, while one maintained high levels of inflammatory markers (ESR and CRP) until month 12. Three patients (4.2%) were positive for rheumatoid factor (RF).
Radiographic changes were present in 34 patients (47.2%), with knee osteoarthritis the most frequent finding, followed by calcaneal enthesopathy, and hand osteoarthritis. No patient with progression of the joint condition lasting for more than 3 months had erosive lesions on the hands, wrists, feet, and/or ankles.
The most prevalent treatments prescribed during the follow-up were analgesics (90.3%) and prednisone (65.3%) ( Table   3). The monitoring of the musculoskeletal condition of the patients included three time points for comparisons (months 0, 6, and 12), in which pain was evaluated by VAS and the presence of painful and swollen joints on physical examination.
On admission (month 0), 71 of 72 patients were in pain, 48 of whom showed severe pain (VAS ≥7). In the last month of follow-up (month 12), 48 patients had no pain and 24 had some degree of pain (Figure 1). There was a statistically significant improvement in pain (p <0.001) during follow-up.  Twenty-three patients (31.9%) were referred for continued follow-up in general rheumatology, four in orthopedics (5.5%), four in neurology (5.5%), one in vascular surgery (1.4%), two in rheumatology and vascular surgery (2.8%), and one in rheumatology and neurology (1.4%). Of the 26 patients referred to the rheumatology clinic, 11 (42.3%) had diffuse musculoskeletal pain, seven (26.9%) had localized musculoskeletal pain, and eight (30.8%) had chronic inflammatory joint disease. Among those with chronic inflammatory joint disease, four (50%) met the criteria for rheumatoid arthritis (RA), one (12.5%) for psoriatic arthritis (PA), two (25%) for post-Chikungunya chronic inflammatory joint disease (CIJD), and one (12.5%) for gout.
Flowchart 2 -Of patient progression and referrals to other specialties after 12 months of follow-up.

Discussion
This study was motivated by the first CF outbreak in Brazil in 2016, when there were more reported cases in the country and in Sergipe, with an increasing number of new cases in the last 5 years.
The mean duration of musculoskeletal symptoms until the patients presented to the Chikungunya outpatient clinic was 6 ± 4.7 months, with two patients reporting joint complaints that had lasted for 2  al., 2018). One of the largest retrospective studies on patients infected with CHIKV, conducted in the Réunion Islands, reported the persistence of symptoms in patients more than 6 years post-CF (Arroyo & Vilá, 2015).
In the present study, the most frequent comorbidities were SAH, DM, and DLP. Patients with previous rheumatologic disease were defined as those with a previous rheumatologic history and/or previous joint damage on admission radiography.
Most patients showed previous rheumatologic disease, with a predominance of worsening of the joint condition after CF (Runowska et al., 2018).
We observed no association between the presence of comorbidities and/or rheumatologic history and a more intense condition at the beginning of the follow-up. Regarding the characterization of the joint condition, the most frequent presentation was polyarticular, most often affecting the hands (wrists, proximal interphalangeal, and metacarpophalangeal joints), knees, ankles, and feet, consistent with previous studies (Marques et al., 2016 andEssackjee et al., 2013), indicating that polyarthralgia, especially distal, showed the most frequent presentation in acute, subacute, and chronic phases.
Finger paresthesia was observed in 80.5% of patients. Electroneuromyographical assessment was not possible in these patients, even when requested, due to difficulties in scheduling this test. However, a case series with a population also from Sergipe by Neves and Nunes (Neves & Nunes, 2018) of 29 patients with hand paresthesia after CF reported that 93% of the studied median nerves showed carpal tunnel syndrome in the electrophysiological studies.
In the present study, CHIKV was confirmed by laboratory tests, as it was the first outbreak of the disease, to confirm that the persistent musculoskeletal complaints were attributed to CF. Then, the 72 patients had CHIKV confirmation by serology and/or viral PCR.
Of the 72 patients, 26 were positive for CHIKV by PCR even 1 month after experiencing CF. We cannot conclude that these patients had persisting virus in the blood or had previously been infected by other viruses, confusing the condition with CF. There may also have been an error in the dates reported by patients regarding their symptom onset.
Inflammatory tests (ESR and CRP) were increased on admission in eight patients (11.1%), being normalized during follow-up. Only one patient maintained high ESR and CRP until the end of follow-up, meeting the criteria for RA. The literature describes increased inflammatory tests as a frequent finding in CF patients (Vu et al., 2017 andHibl et al., 2021). The low frequency found in this study could be associated with the previous use of corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs) in patients before starting follow-up.
The radiographs of the hands, wrists, ankles, and feet of the 51 patients in the chronic phase of the disease showed no joint lesions typical of RA (cysts, bone erosions, and juxta-articular osteopenia). In contrast, radiographs of the affected joints of patients with suspected osteoarthritis showed degenerative changes typical of osteoarthritis (subchondral sclerosis, osteophytosis, and reduced joint space) in 34 of the 72 patients, with a predominance of knee osteoarthritis and spondylarthrosis.
In the clinic setting, the therapeutic approach was based on the recommendations of the Brazilian the Ministry of Health and Brito et al. (2016). Most patients (90.3%) reported oral or injectable steroid use on their own or prescribed by another physician for short periods before presenting to the outpatient clinic. In general, patients reported short-term steroid use (5-7 days), mainly in the subacute phase of the disease, with joint pain and inflammation worsening after discontinuation who highlighted the risk of a rebound effect in arthralgia, arthritis, and tenosynovitis (Page, 2012).
At the outpatient clinic, 65.3% of the patients were prescribed prednisone (20 mg/day), with progressive weaning for 30 days until discontinuation. When necessary, prednisone was repeated in short cycles with efforts to gradually wean off treatment. At the last evaluation (month 12), six patients were under low-dose prednisone therapy.
Chloroquines were the most commonly prescribed synthetic DMARDs in the outpatients setting. Methotrexate (MTX) was prescribed in eight patients with chronic musculoskeletal complaints who met the criteria for inflammatory joint disease.
One patient meeting the criteria for RA was prescribed leflunomide (LFN) associated with MTX. No studies have reported on the use of LFN in the treatment of joint symptoms after CF (Simon, 2015 andMarques, 2017).
As mentioned above, while physical therapy was indicated for most patients (94.4%), only 30.5% were able to undergo therapy due to scheduling difficulties in the public health system in Brazil. Similarly, while physical activity was recommended for all patients, it was not possible to assess the response, as no pattern of physical activity was followed.
The literature is consistent regarding the prescription of physical therapy, as it has shown positive results in patients in the subacute and chronic stages of CF. However, the therapeutic protocols of most studies do not include the details of the therapy (Page, 2012;Oliveira & Silva, 2017).

Conclusion
The monitoring of musculoskeletal conditions showed a statistically significant improvement in pain, as assessed by VAS, as well as a decreased number of painful and swollen joints. However, even with regular follow-up and treatment, 37 patients (51.4%) maintained some complaints, and 33.3% showed persisting musculoskeletal pain, most commonly diffuse musculoskeletal pain.
The results of this study provide a better understanding of the patient profile, musculoskeletal involvement, and progression of CF; furthermore, they may guide effective strategies for therapeutic management.