Long COVID: rheumatologic/musculoskeletal symptoms in hospitalized COVID-19 survivors at 3 and 6 months.

OBJECTIVE: 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. METHODS: In this extension cohort study, two telephone surveys at 3 and 6 months following the hospitalization were carried out. In these telephone surveys, participants were asked regarding their symptoms through a previously designed standard questionnaire. RESULTS: At 3 months, 89.0% of survivors had at least one symptom, 74.6% had at least one rheumatic and musculoskeletal symptom, and 82.1% had at least one other COVID-19 symptom. At 6 months, 59.6% of survivors had at least one symptom, 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; and regarding the other-COVID-19-symptoms, 25.3% had dyspnea, 20.0% had hair loss, and 17.2% sweat at 6 months. 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. CONCLUSION: Approximately 3 in 5 patients had at least one symptom with ≈2 in 5 patients had at least one rheumatic and musculoskeletal symptom. Fatigue, joint pain, and myalgia were the most frequent rheumatic and musculoskeletal symptoms. Joint pain and myalgia were mostly widespread. This information guide rheumatologists to understand the nature and features of persistent rheumatic and musculoskeletal symptoms in hospitalized COVID-19 survivors and may contribute to better management of these individuals. Key Points • Approximately 3 in 5 patients had at least one symptom with ≈2 in 5 patients had at least one rheumatic and musculoskeletal symptom at 6 months • Fatigue, joint pain, and myalgia were the most frequent rheumatic and musculoskeletal symptoms followed by back pain, low back pain, and neck pain • Dyspnea, hair loss, and sweat were the most frequent other-COVID-19-symptoms.

Risk and prognosis of SARS-CoV-2 infection and vaccination against SARS-CoV-2 in rheumatic and musculoskeletal diseases: a systematic literature review to inform EULAR recommendations.

OBJECTIVES: Perform a systematic literature review (SLR) on risk and prognosis of SARS-CoV-2 infection and vaccination against SARS-CoV-2 in patients with rheumatic and musculoskeletal diseases (RMDs). METHODS: Literature was searched up to 31 May 2021, including (randomised) controlled trials and observational studies with patients with RMD. Pending quality assessment, data extraction was performed and risk of bias (RoB) was assessed. Quality assessment required provision of (1) an appropriate COVID-19 case definition, and (2a) a base incidence (for incidence data) or (2b) a comparator, >10 cases with the outcome and risk estimates minimally adjusted for age, sex and comorbidities (for risk factor data). RESULTS: Of 5165 records, 208 were included, of which 90 passed quality assessment and data were extracted for incidence (n=42), risk factor (n=42) or vaccination (n=14). Most studies had unclear/high RoB. Generally, patients with RMDs do not face more risk of contracting SARS-CoV-2 (n=26 studies) or worse prognosis of COVID-19 (n=14) than individuals without RMDs. No consistent differences in risk of developing (severe) COVID-19 were found between different RMDs (n=19). Disease activity is associated with worse COVID-19 prognosis (n=2), possibly explaining the increased risk seen for glucocorticoid use (n=13). Rituximab is associated with worse COVID-19 prognosis (n=7) and possibly Janus kinase inhibitors (n=3). Vaccination is generally immunogenic, though antibody responses are lower than in controls. Vaccine immunogenicity is negatively associated with older age, rituximab and mycophenolate. CONCLUSION: This SLR informed the July 2021 update of the European Alliance of Associations for Rheumatology recommendations for the management of RMDs in the context of SARS-CoV-2.

The mechanistic basis of protection by non-neutralizing anti-alphavirus antibodies.

Although neutralizing monoclonal antibodies (mAbs) against epitopes within the alphavirus E2 protein can protect against infection, the functional significance of non-neutralizing mAbs is poorly understood. Here, we evaluate the activity of 13 non-neutralizing mAbs against Mayaro virus (MAYV), an emerging arthritogenic alphavirus. These mAbs bind to the MAYV virion and surface of infected cells but fail to neutralize infection in cell culture. Mapping studies identify six mAb binding groups that localize to discrete epitopes within or adjacent to the A domain of the E2 glycoprotein. Remarkably, passive transfer of non-neutralizing mAbs protects against MAYV infection and disease in mice, and their efficacy requires Fc effector functions. Monocytes mediate the protection of non-neutralizing mAbs in vivo, as Fcγ-receptor-expressing myeloid cells facilitate the binding, uptake, and clearance of MAYV without antibody-dependent enhancement of infection. Humoral protection against alphaviruses likely reflects contributions from non-neutralizing antibodies through Fc-dependent mechanisms that accelerate viral clearance.

Resistance exercises improve physical function in chronic Chikungunya fever patients: a randomized controlled trial.

BACKGROUND: Chikungunya fever is an arboviral disease, caused by an alphavirus, the Chikungunya virus, characterized by fever and joint pain that is generally disabling in the acute phase and may last from months to years, with the potential to evolve into chronic musculoskeletal symptoms, as polyarthralgia and arthritis, which can lead to significant impairment of physical function. The non-pharmacological treatment is very important for these patients, and resistance exercises may be one rehabilitation option. AIM: This study aimed to evaluate the efficacy of a resistance exercise protocol on the physical function, pain, and quality of life of patients with chronic Chikungunya fever. DESIGN: A randomized, controlled, blind trial for the evaluators. SETTING: Clinic-school of Physical therapy. POPULATION: Thirty-one patients with Chikungunya fever and musculoskeletal symptoms lasting more than three months, recruited from the Rheumatology outpatient clinic at Clinical Hospital, Federal University of Pernambuco (HC-UFPE). METHODS: Patients (aged 56±10 years) were randomly assigned into one of two groups: Resistance Exercise Group (REG, N.=15) or Control Group (CG, N.=16). REG performed progressive resistance exercises with elastic bands (24 sessions over 12 weeks). CG only had their symptoms monitored through phone calls, maintaining the usual care treatment. Assessments were taken at baseline and after 6 and 12 weeks of the following: physical function (30-second Chair Stand Test (30-s CST), 4-step Stair Climb Power Test (4SCPT), 40-m Fast-paced Walk Test (40m FPWT), and Disabilities of the Arm, Shoulder, Hand (DASH) questionnaire); pain (VAS and painful joints count); quality of life (Medical Outcomes Study 36-Item Short-Form Health Survey [SF-36]); and Patient Global Impression of Change (PGIC) scale. RESULTS: There was a reduction of pain (P=0.01; d=-0.83) and an improvement of 30-s CST (P=0.04; d=0.85) in REG participants after 12 weeks. There was no significant change in the domains of SF-36. Nearly 70% of trained patients reported improvement on PGIC. CONCLUSIONS: Resistance exercises improved physical function in sitting and standing and reduced pain in patients with chronic Chikungunya fever. CLINICAL REHABILITATION IMPACT: Resistance exercises can be considered as a treatment approach for patients with musculoskeletal disorders in the chronic stage of Chikungunya fever.

Syndemics & syndemogenesis in COVID-19 and rheumatic and musculoskeletal diseases: old challenges, new era.

People with rheumatic and musculoskeletal diseases (RMDs) are facing several challenges during the COVID-19 pandemic, such as poor access to regular health services and drug shortages, particularly in developing countries. COVID-19 represents a syndemic, synergistic condition that interacts with and exacerbates pre-existing diseases such as RMDs, other co-morbidities and social conditions. The emerging evidence on both biological and non-biological factors implicated in worse outcomes in people with RMDs affected by the COVID-19 pandemic, whether infected by the virus or not, calls for the need to use more novel and holistic frameworks for studying disease. In this context, the use of a syndemic framework becomes particularly relevant. We appeal for a focus on the identification of barriers and facilitators to optimal care of RMDs in the context of the COVID-19 pandemic, in order to tackle both the pandemic itself and the health inequities inherent to it.

A cross-reactive antibody protects against Ross River virus musculoskeletal disease despite rapid neutralization escape in mice.

Arthritogenic alphaviruses cause debilitating musculoskeletal disease and historically have circulated in distinct regions. With the global spread of chikungunya virus (CHIKV), there now is more geographic overlap, which could result in heterologous immunity affecting natural infection or vaccination. Here, we evaluated the capacity of a cross-reactive anti-CHIKV monoclonal antibody (CHK-265) to protect against disease caused by the distantly related alphavirus, Ross River virus (RRV). Although CHK-265 only moderately neutralizes RRV infection in cell culture, it limited clinical disease in mice independently of Fc effector function activity. Despite this protective phenotype, RRV escaped from CHK-265 neutralization in vivo, with resistant variants retaining pathogenic potential. Near the inoculation site, CHK-265 reduced viral burden in a type I interferon signaling-dependent manner and limited immune cell infiltration into musculoskeletal tissue. In a parallel set of experiments, purified human CHIKV immune IgG also weakly neutralized RRV, yet when transferred to mice, resulted in improved clinical outcome during RRV infection despite the emergence of resistant viruses. Overall, this study suggests that weakly cross-neutralizing antibodies can protect against heterologous alphavirus disease, even if neutralization escape occurs, through an early viral control program that tempers inflammation.

Arboviruses related with chronic musculoskeletal symptoms.

Arboviruses (ARthropods BOrne VIRUSES) are disease-causing viruses transmitted through the bite of hematophagous arthropods, such as mosquitoes and ticks. Among these, the alphavirus, genus of the Togaviridae family, is considered the most arthritogenic species, responsible for diseases such as chikungunya fever (CHIK), O'nyong-nyong virus fever, Ross River virus disease, Barmah Forest virus disease, Sindbis virus disease, and Mayaro fever. These arboviral diseases, especially CHIK, have impacted public health in recent decades, leading to devastating epidemics, particularly in developing countries, due to their high potential for chronicity, functional impairment, and great impact on the quality of life. In a similar way, chronic musculoskeletal symptoms have been described in all alphavirus infections. However, CHIK is the best studied. The purpose of this article is to review physiopathology, clinical manifestations, diagnosis, and treatment of alphaviruses, focusing on CHIK and chronic evolution of musculoskeletal symptoms.

Treatment of chikungunya musculoskeletal disorders: a systematic review.

INTRODUCTION: Chikungunya virus is amongst the fastest expanding vector transmissible diseases in recent years and has been causing massive epidemics in Africa, Asia, Latin America and the Caribbean. Despite human infection by this virus being first described in the 1950s, there is a lack of adequate therapeutic evaluations to guide evidence-based recommendations. The current guidelines rely heavily in specialists' opinion and experience instead of using higher rated evidence. Areas covered: A systematic review of the literature was performed- not restricted to clinical trials - reporting the therapeutic response against this infection with the intent to gather the best evidence of the treatment options against musculoskeletal disorders following chikungunya fever. The 15 studies included in the analysis were categorized considering the initiation of treatment during the acute, subacute and chronic phase. Expert commentary: This review demonstrates the complexity of chikungunya fever and difficulty of therapeutic management. This review found no current evidence-based treatment recommendations for the musculoskeletal disorders following chikungunya fever. To provide an optimal treatment that prevents perpetuation or progression of chikungunya infection to a potentially destructive and permanent condition without causing more harm is an aim that must be pursued by researchers and health professionals working with this disease.

Extrahepatic manifestations of HCV: the role of direct acting antivirals.

INTRODUCTION: Hepatitis C virus (HCV) represents a major health concern, as nearly 3 million people become newly infected by this pathogen annually. The majority of infected individuals fail to clear the virus, and chronicity is established. Chronic HCV patients are at high risk for liver disease, ranging from mild fibrosis to cirrhosis and severe hepatocellular carcinoma. Over the last few years, the development of multiple direct acting antivirals (DAA) have revolutionized the HCV infection treatment, demonstrating cure rates higher than 90%, and showing less side effects than previous interferon-based regimens. Areas covered: Besides liver, HCV infection affects a variety of organs, therefore inducing diverse extrahepatic manifestations. This review covers clinical, experimental, and epidemiological publications regarding systemic manifestations of HCV, as well as recent studies focused on the effect of DAA in such conditions. Expert commentary: Though further research is needed; available data suggest that HCV eradication is often associated with the improvement of extrahepatic symptoms. Therefore, the emergence of DAA would offer the opportunity to treat both HCV infection and its systemic manifestations, requiring shorter treatment duration and driving minor adverse effects.

Characteristics of the musculoskeletal symptoms observed among survivors of Ebola virus disease in the Postebogui cohort in Guinea.

Objective: Previous studies show that arthralgia is the most common symptom experienced by Ebola virus disease (EVD) survivors. Nevertheless, specific analyses of rheumatological sequelea are still lacking. Methods: The Postebogui study is a prospective, multicentre cohort aiming to evaluate the long-term outcomes of EVD survivors infected during the 2014-15 outbreak in Guinea. Of the 216 participants enrolled in the study in October 2015, 44 patients with arthralgia/myalgia underwent a physical examination by a rheumatologist (the Eborheum cohort). Data were collected using a standardized questionnaire. Results: In the Eborheum cohort, 61% of patients were female, the median age was 31.1 years, and the median time from Ebola Treatment Centre discharge was 8.8 months. Pain manifestation started after Ebola infection in all but one patient. Patients had mainly both mechanical and inflammatory pain (45%) and low back pain (77%). All patients reported pain in at least one peripheral joint. Pain in large joints was more frequently reported than in small joints (73 vs 41%). Oligo- and polyarticular presentations were similar, with symmetrical pain distribution. Furthermore, 36 patients had at least one painful 18-tender point count, most of whom reported extensive pain (n = 19) and symmetrical distribution (91%). Diagnoses were mainly non-specific musculoskeletal disorders (59%) and mechanical back pain (52%). No polyarthritis was observed. We found a higher percentage of depressed patients compared with the remaining Postebogui group (42 vs 11%; P < 0.001). Conclusion: Results from the study come from the first complete rheumatological examination of a cohort of EVD survivors, nearly 9 months after Ebola Treatment Centre discharge. Importantly, we found that patients with arthralgia/myalgia included in the Eborheum cohort were more likely to experience depression than survivors not reporting these symptoms, highlighting the impact of pain symptoms among survivors.

Assessment and management of musculoskeletal disorders among patients living with HIV.

HIV is a global pandemic. However, anti-retroviral therapy has transformed the prognosis and, providing compliance is good, a normal life expectancy can be anticipated. This has led to increasing numbers of people with chronic prevalent, treated infection living to older ages. Musculoskeletal pain is commonly reported by HIV patients and, with resumption of near-normal immune function, HIV-infected patients develop inflammatory rheumatic diseases that require assessment and management in rheumatology clinics. Moreover, it is becoming apparent that avascular necrosis and osteoporosis are common comorbidities of HIV. This review will contextualize the prevalence of musculoskeletal symptoms in HIV, informed by data from a UK-based clinic, and will discuss the management of active inflammatory rheumatic diseases among HIV-infected patients taking anti-retroviral therapy, highlighting known drug interactions.

Suramin treatment reduces chikungunya pathogenesis in mice.

The chikungunya virus (CHIKV), an arthritogenic alphavirus, has caused explosive epidemics involving millions of cases. Globally expanding pandemics involving CHIKV and post-CHIKV rheumatic disorders are increasing public health concerns. However, no antiviral interventions or vaccines to control CHIKV infection have yet been approved. Although suramin has been possess anti-CHIKV activity in vitro, whether suramin has anti-CHIKV activity in vivo remains unknown. This study aimed to determine whether suramin treatment could ameliorate CHIKV-induced arthritis in a C57BL/6 mice model. C57BL/6 mice were infected with CHIKVs to evaluate anti-CHIKV activities of suramin in terms of histopathology, viral burden and disease score. Not only did suramin treatment substantially decrease viral loads, but it also significantly ameliorated acute foot lesions in mice. In addition, suramin treatment markedly restores cartilage integrity and reduces the number of IHC positive chondrocyte in mice infected with CHIKV strains 0810bTw and 0706aTw. This in vivo study highlights the potential ability of suramin to treat CHIKV infection in clinical settings.

Perosomus elumbis in a Holstein calf infected with bovine viral diarrhea virus.

The detection of bovine viral diarrhea virus (BVDV) in a female Holstein calf presented with perosomus elumbis, a congenital anomaly, is reported here. A cow with dystocia was evaluated and an abnormal dead calf was detected during vaginal examination. The calf was retrieved via caesarean section and exhibited abnormalities characteristic of PE, such as vertebral and pelvic malformations. These abnormalities were further confirmed using radiographic and necropsy examinations. At necropsy cerebellar hypoplasia was an additional finding, which is a typical lesion associated with bovine virus diarrhea (BVD). Several tissue samples from the calf were tested for the presence of antigens of BVDV and bovine herpesvirus-1 (BHV-1) by ELISA. In addition, sera samples from the dam and calf were tested for the presence of antibodies against BVDV, BHV-1, and bluetongue disease virus (BTV) using a virus neutralization assay. Results indicated that the calf was congenitally infected with BVDV, whereas there was no evidence for the presence of BHV-1 and BTV. In the dam's serum no antibodies against BVDV, BHV-1, and BTV were detected. Even though the etiology of perosomus elumbis is unknown, BVDV, which causes fetal anomalies at early gestation in cows, may have been a contributing factor in this case.

Musculoskeletal infection in acquired immunodeficiency syndrome.

Musculoskeletal infection is one of the common manifestations of patients infected with human immunodeficiency virus and acquired immunodeficiency syndrome. With immune deficiency, patients are susceptible to a variety of nonopportunistic and opportunistic infections that can result in significant morbidity and mortality. Infection can involve any anatomical compartments resulting in infectious arthritis, osteomyelitis, pyomyositis, and soft tissue and skin infection. Imaging plays an important role in the early diagnosis and treatment planning for these patients. This article reviews the clinical manifestations of musculoskeletal infection together with reported causative organisms. We discuss the role of imaging and present radiological examples.