Chronic Arthralgia Research Articles

Acute Chikungunya Virus Infection Triggers a Diverse Range of T Helper Lymphocyte Profiles.

Chikungunya virus (CHIKV) is an arbovirus causing acute febrile illness with severe joint pain, often leading to chronic arthralgia. This study investigated the adaptive immune responses during the early stages of symptomatic acute CHIKV infection, focusing on the transcription factors and cytokines linked to Th1, Th2, Th17, and Treg cells. Thirty-six individuals were enrolled: nine healthy controls and 27 CHIKV-positive patients confirmed by qRT-PCR. Blood samples were analyzed for the mRNA expression of transcription factors (Tbet, GATA3, FoxP3, STAT3, RORγt) and cytokines (IFN-γ, IL-4, IL-17, IL-22, TGF-β, IL-10). The results showed the significant upregulation of Tbet, GATA3, FoxP3, STAT3, and RORγt in CHIKV-positive patients, with RORγt displaying the highest increase. Correspondingly, cytokines IFN-γ, IL-4, IL-17, and IL-22 were upregulated, while TGF-β was downregulated. Principal component analysis (PCA) confirmed the distinct immune profiles between CHIKV-positive and healthy individuals. A correlation analysis indicated that higher Tbet expression correlated with a lower viral load, whereas FoxP3 and TGF-β were associated with higher viral loads. Our study sheds light on the intricate immune responses during acute CHIKV infection, characterized by a mixed Th1, Th2, Th17, and Treg response profile. These results emphasize the complex interplay between different adaptive immune responses and how they may contribute to the pathogenesis of Chikungunya fever.

Mayaro Virus: An Emerging Alphavirus in the Americas.

Mayaro virus (MAYV) is an arbovirus first isolated in Trinidad and Tobago in 1954. MAYV is the causative agent of Mayaro fever, which is characterised by high fever, maculopapular rash, myalgia and arthralgia. The potential for chronic arthralgia is of particular clinical concern. Currently, MAYV outbreaks are restricted to South and Central America, with some cases reported in Africa as well as several imported cases in Europe. However, in recent years, MAYV has become a growing global concern due to its potential to emerge into urban transmission cycles. Challenges faced with diagnostics, as well as a lack of specific antivirals or licensed vaccines further exacerbate the potential global health threat posed by MAYV. In this review, we discuss this emerging arboviral threat with a particular focus on the current treatment and vaccine development efforts. Overall, MAYV remains a neglected arbovirus due to its limited area of transmission. However, with the potential of its urbanisation and expanding circulation, the threat MAYV poses to global health cannot be overlooked. Further research into the improvement of current diagnostics, as well as the development of efficacious antivirals and vaccines will be crucial to help prevent and manage potential MAYV outbreaks.

Compounds from Natural Products Candidates to Drug for Chikungunya Virus Infection: A Systematic Review

Introduction: Chikungunya fever is a disease caused by infection with the Chikungunya virus, transmitted by Aedes aegypti and Aedes albopictus mosquitoes. Despite its self-limited character, more than 60% of patients have chronic recurrent arthralgia with debilitating pain that lasts for years. Aim: The objective of this review was to gather and analyze evidence from the literature on potential therapeutic strategies with molecules from natural products for the treatment of Chikungunya fever. Methods: A search was performed for clinical trials, observational studies, in vitro or in vivo, without restriction of the year of publication or language in electronic databases (Medline/PubMed, EMBASE, Google Scholar, The Cochrane Library, LILACS (BVS), clinical trial registries (Clinical Trials.gov), digital libraries from CAPES theses and dissertations (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Brazil) and conference abstracts. A quality assessment of the selected studies was performed using the SYRCLE, RoB2 and SciRAP tools. Results: 42 studies were included, which showed molecules with potential antiviral pharmacological activity or with activity in reducing the joint complications caused by CHIKV infection. Conclusions: Among the molecules found in the survey of references, regarding the class of secondary metabolites, flavonoids stood out and for this reason, the molecules may be promising candidates for future clinical trials. Overall, evidence from in vitro studies was of acceptable quality; in vivo and intervention studies showed a high risk of bias, which is a limitation of these studies.

Comparative pathogenesis of three Mayaro virus genotypes in the cynomolgus macaque.

Mayaro virus (MAYV), a mosquito-borne alphavirus, is considered an emerging threat to public health with epidemic potential. Phylogenetic studies show the existence of three MAYV genotypes. In this study, we provide a preliminary analysis of the pathogenesis of all three MAYV genotypes in cynomolgus macaques (Macaca facicularis, Mauritian origin). Significant MAYV-specific RNAemia and viremia were detected during acute infection in animals challenged intravenously with the three MAYV genotypes, and strong neutralizing antibody responses were observed. MAYV RNA was detected at high levels in lymphoid tissues, joint muscle and synovia over 1 month after infection, suggesting that this model could serve as a promising tool in studying MAYV-induced chronic arthralgia, which can persist for years. Significant leucopenia was observed across all MAYV genotypes, peaking with RNAemia. Notable differences in the severity of acute RNAemia and composition of cytokine responses were observed among the three MAYV genotypes. Our model showed no outward signs of clinical disease, but several major endpoints for future MAYV pathology and intervention studies are described. Disruptions to normal blood cell counts and cytokine responses were markedly distinct from those observed in macaque models of CHIKV infection, underlining the importance of developing non-human primate models specific to MAYV infection.

Elevated Complement Activation Fragments and C1q-Binding Circulating Immune Complexes in Varied Phases of Chikungunya Virus Infection.

Chikungunya virus (CHIKV) is a causative agent of a disease continuum, ranging from an acute transient chikungunya fever to chronic incapacitating viral arthralgia. The interaction between anti-CHIKV antibodies and the complement system has recently received attention. However, the contribution of complement activation in CHIKV-induced pathologies has not been fully elucidated. The present study was undertaken to delineate the possible contribution of complement activation in CHIKV-induced disease progression. In this study, using plasma specimens of chikungunya patients in the acute, chronic, and recovered phases of infection, we explicated the involvement of complement activation in CHIKV disease progression by ELISAs and Bio-Plex assays. Correlation analysis was carried out to demonstrate interrelation among C1q-binding IgG-containing circulating immune complexes (CIC-C1q), complement activation fragments (C3a, C5a, sC5b-9), and complement-modulated pro-inflammatory cytokines (IL-1β, IL-18,IL-6, andTNF-α). We detected elevated complement activation fragments, CIC-C1q, and complement-modulated cytokines in the varied patient groups compared with the healthy controls, indicating persistent activation of the complement system. Furthermore, we observed statistically significant correlations among CIC-C1q with complement activation fragments and C3a with complement modulatory cytokines IL-1β, IL-6, and IL-18 during the CHIKV disease progression. Taken together, the current data provide insight into the plausible association between CICs, complement activation, subsequent complement modulatory cytokine expression, and CHIKV etiopathology.

Clinical profile and management of a Spanish single-center retrospective cohort of patients with post-chikungunya associated complications

BackgroundThis study aims to describe post-chikungunya complications chronically developed cases in returning travelers from some epidemic/endemic regions, and the variables that are associated with the progression of acute or subacute cases to the chronic phase. MethodsThis single-center retrospective cohort study included chikungunya fever cases treated at La Paz-Carlos III University Hospital in Madrid, Spain, April 2014 to September 2016, when the chikungunya outbreak in Latin America started through the time of its greatest impact. ResultsThe analysis included 119 cases. Of these, 67.2 % were male, with a median age of 41.0 years [IQR 16.0 to 76.0] years. Only 25.6 % of the patients attended a pre-travel advice consultation. Most patients reported arthralgias, which significantly impacted their daily quality of life (86 %). The mean duration of joint symptoms was 129.4 days, with a median of 90 days [IQR 0 to 715]. Factors found to be associated with chronic arthralgia include female sex, country of infection, age at diagnosis, previous diseases, symptoms during the acute phase, pain in previously injured tendons/joints, acute phase severity, and various laboratory markers such as hemoglobin, hematocrit, total serum bilirubin, and creatinine. Progression to chronic arthralgia significantly increased the need for changes in daily activity. Furthermore, 42.6 % of patients with chronic arthralgia reported recurrence of symptoms once they felt they had disappeared. Targeted treatment regimens led to significant improvements in these patients. ConclusionsThe results of this study underscore the need for: (1) comprehensive pre-travel advice; (2) effective management of patients in specialized units, alongside early diagnosis and treatment, to prevent trivialization of these viral infections; and (3) the development of interdisciplinary recommendations to assist physicians in treating patients and enhancing outcomes.

Three Case Reports of Adult-onset Still Disease Associated with Breast Implantation.

Autoimmune syndrome induced by adjuvants (ASIA) is an uncommon clinical condition reported by Shoenfeld et al. Although this syndrome is not scientifically validated, numerous reports on it have been published, and the manifestations are postulated to be diverse, including generalized symptoms such as chronic fatigue, myalgia, arthralgia, or dry mouth, induced by exogenous substances, specifically adjuvants, which can encompass vaccines, organisms, and silicone. Concurrently, adult-onset Still disease (AOSD) is also an infrequent ailment, characterized by spiking fever, arthritis, skin rash, lymphadenopathy, and serositis. Although the precise pathogenesis remains incompletely understood, some case reports suggest that ASIA may be at the root of AOSD development with the same instigator. In this context, we present three cases of patients diagnosed with AOSD, which possibly could be considered an association with ASIA, years after undergoing breast reconstruction with silicone breast implants. In one case, the patient solely received medical treatment due to her refusal to have the implant removed, resulting in multiple flares and severe complications related to glucocorticoid therapy. Conversely, in the other two cases, a combination of immunosuppressive therapy and silicone breast implant explantation led to the complete resolution of clinical symptoms. To the best of our knowledge, there are only 10 documented case reports of AOSD associated with silicone breast implants insertion. We believe this report serves as a complementary addition to prior research and offers further insights into the ongoing debate about whether explantation should be carried out early in the clinical course or not.

Anodal tDCS over the motor cortex improves pain but not physical function in chronic chikungunya arthritis: Randomized controlled trial

BackgroundChikungunya virus (CHIKV) is a globally prevalent pathogen, with outbreaks occurring in tropical regions. Chronic pain is the main symptom reported and is associated with decreased mobility and disability. Transcranial direct current stimulation (tDCS) is emerging as a new therapeutic tool for chronic arthralgia. ObjectiveTo evaluate the effectiveness of 10 consecutive sessions of anodal tDCS on pain (primary outcome) in participants with chronic CHIKV arthralgia. Secondary outcomes included functional status, quality of life, and mood. MethodsIn this randomized, double-blind, placebo-controlled trial, 30 participants with chronic CHIKV arthralgia were randomly assigned to receive either active (n = 15) or sham (n = 15) tDCS. The active group received 10 consecutive sessions of tDCS over M1 using the C3/Fp2 montage (2 mA for 20 min). Visual analog scale of pain (VAS), health assessment questionnaire (HAQ), short-form 36 health survey (SF-36), pain catastrophizing scale, Hamilton anxiety scale (HAS), timed up and go (TUG) test, lumbar dynamometry, 30-s arm curl and 2-min step test were assessed at baseline, day 10 and at 2 follow-up visits. ResultsThere was a significant interaction between group and time on pain (p = 0.03; effect size 95 % CI 0.9 (-1.67 to -0.16), with a significant time interaction (p = 0.0001). There was no interaction between time and group for the 2-minute step test (p = 0.18), but the groups differed significantly at day 10 (p = 0.01), first follow-up (p = 0.01) and second follow-up (p = 0.03). HAQ and SF-36 improved but not significantly. There was no significant improvement in mental health, and physical tests. ConclusiontDCS appears to be a promising intervention for reducing pain in participants with chronic CHIKV arthralgia, although further research is needed to confirm these findings and explore potential long-term benefits. Trial RegistrationBrazilian Registry of Clinical Trials (ReBEC): RBR-245rh7.

Live-attenuated chikungunya virus vaccine

Although Chikungunya fever does not a have a high fatality rate (<10%), it has a huge morbidity toll due to lingering chronic arthralgia. The recent FDA approval of Ixchiq, a vaccine designed to prevent infection caused by the chikungunya virus (CHIKV), provides hope that its use can prevent future CHIKV outbreaks. To view this Bench to Bedside, open or download the PDF.

Understanding transmission risk and predicting environmental suitability for Mayaro Virus in Central and South America.

Mayaro virus (MAYV) is a mosquito-borne Alphavirus that is widespread in South America. MAYV infection often presents with non-specific febrile symptoms but may progress to debilitating chronic arthritis or arthralgia. Despite the pandemic threat of MAYV, its true distribution remains unknown. The objective of this study was to clarify the geographic distribution of MAYV using an established risk mapping framework. This consisted of generating evidence consensus scores for MAYV presence, modeling the potential distribution of MAYV in select countries across Central and South America, and estimating the population residing in areas suitable for MAYV transmission. We compiled a georeferenced compendium of MAYV occurrence in humans, animals, and arthropods. Based on an established evidence consensus framework, we integrated multiple information sources to assess the total evidence supporting ongoing transmission of MAYV within each country in our study region. We then developed high resolution maps of the disease's estimated distribution using a boosted regression tree approach. Models were developed using nine climatic and environmental covariates that are related to the MAYV transmission cycle. Using the output of our boosted regression tree models, we estimated the total population living in regions suitable for MAYV transmission. The evidence consensus scores revealed high or very high evidence of MAYV transmission in several countries including Brazil (especially the states of Mato Grosso and Goiás), Venezuela, Peru, Trinidad and Tobago, and French Guiana. According to the boosted regression tree models, a substantial region of South America is suitable for MAYV transmission, including north and central Brazil, French Guiana, and Suriname. Some regions (e.g., Guyana) with only moderate evidence of known transmission were identified as highly suitable for MAYV. We estimate that approximately 58.9 million people (95% CI: 21.4-100.4) in Central and South America live in areas that may be suitable for MAYV transmission, including 46.2 million people (95% CI: 17.6-68.9) in Brazil. Our results may assist in prioritizing high-risk areas for vector control, human disease surveillance and ecological studies.

Adult-onset Still’s disease and Muckle-Wells syndrome - two sides of the same coin?

Introduction. Adult-onset Still?s disease (AOSD), a systemic inflammatory disorder, often represents a heterogeneous entity and diagnosis requires the exclusion of mimicking disorders, including autoinflammatory diseases. We present a patient who meets the diagnostic criteria for AOSD and Muckle?Wells syndrome (MWS). Case outline. A 35-year-old male presented with lymphadenopathy and a chronic nonspecific rash, fever spikes, widespread arthralgia, and joint effusions. Laboratory results showed increased inflammation, leukocytosis, neutrophilia, thrombocytosis, and elevated liver enzymes, accompanied by negative immunoserological tests. Patient was diagnosed with AOSD and prednisone (15 mg/d), methotrexate (10 mg/w) and chloroquine (250 mg/d) are introduced in therapy. Due to refractory course, patient was introduced with anti IL-6 biological agent tocilizumab in 2014 (8 mg/kg monthly). However, after three doses, the drug is stopped due to disease exacerbation. In 2015, there was suspicion that there was another underlying disease from the autoinflammatory spectrum, but DNA analysis of the most common mutations in the NLRP3 gene was negative. In 2017, an ear, nose, and throat specialist confirmed bilateral sensorineural hearing loss, and in 2019, amyloidosis was confirmed after biopsy of the duodenum. Patient fulfilled a new-proposed diagnostic criteria for MWS and confirmation of mutation in NLRP3 gene is not obligatory according to Eurofever registry. Conclusion. The symptoms of AOSD and MWS partly overlap, as well as their diagnostic criteria. In chronic refractory cases of AOSD, evaluation of diagnosis should be performed and autoinflammatory syndromes must be kept in mind.

Beyond survival: unraveling the dynamics of Ebola virus resurgence in Sub-Saharan Africa and the remarkable journey of survivors

Ebola virus disease (EVD) remains a significant public health threat, with sporadic outbreaks occurring in Sub-Saharan Africa. Survivors of EVD may experience various post-infection symptoms, collectively known as post-Ebola virus syndrome (PES), which include chronic arthralgia, uveitis, headache, and psychosocial stressors. In this review, we discuss the persistence of Ebola virus in survivors and its possible role in the reemergence of current outbreaks. We highlight that waning immunity of survivors enhances viral persistence and may lead to viral reactivation and recurrence of disease in previously affected tissues. The delicate equilibrium between diminished immune cell surveillance and limited viral replication may lead to enduring chronic inflammation. Our systematic review, based on an extensive survivor cohort, underscores the importance of continued research and preparedness efforts to combat future outbreaks through adequate surveillance and timely public health interventions. This review serves as a comprehensive guide to understanding the complexities of EVD survivorship, the challenges of PES, and the strategies to mitigate its impact.

Quality of life analysis in bladder pain syndrome/interstitial cystitis: implications for a multimodal integrated treatment.

The aim of this study was to evaluate whether there is a higher prevalence of anxiety-depressive disorders in women with BPS/IC (bladder pain syndrome/interstitial cystitis) than in women with chronic non-neoplastic pain with or without fibromyalgia, to examine possible correlations between urological and psychiatric symptoms. The patients included in the study were divided into two groups: 1) group 0: patients with an existing diagnosis of BPS/IC. BPS/IC was confirmed by reviewing medical record; group 1+2: patients with chronic non-neoplastic pain, suffering from fibromyalgia or other types of chronic pain (chronic arthralgia or lower back pain). Three questionnaires were administered: PHQ-9 to investigate psychological symptoms, O'Leary Saint (ICSI-ICPI) to investigate urological symptoms in women with BPS/IC and BPI to investigate specifically pain. The survey included 69 patients, 42 patients had a diagnosis of BPS/IC while 27 of them had chronic non-neoplastic pain. The average PHQ-9 Score was 10.3 in BPS/IC group, considered as major depression (score between 10 and 14); the average score of PHQ-9 was 6.9 in group 1+2, as in sub-threshold depression (between 5-9). The chronic pain of BPS/IC can affect mood more than in other painful conditions, as more than half of this population has a score that identifies depression with the PHQ-9 questionnaire, confirming the hypothesis that the syndrome is associated with a higher prevalence of an anxious-depressive condition.

Multicenter study of the natural history and therapeutic responses of patients with chikungunya, focusing on acute and chronic musculoskeletal manifestations – a study protocol from the clinical and applied research in Chikungunya (REPLICK network)

BackgroundChikungunya is associated with high morbidity and the natural history of symptomatic infection has been divided into three phases (acute, post-acute, and chronic) according to the duration of musculoskeletal symptoms. Although this classification has been designed to help guide therapeutic decisions, it does not encompass the complexity of the clinical expression of the disease and does not assist in the evaluation of the prognosis of severity nor chronic disease. Thus, the current challenge is to identify and diagnose musculoskeletal disorders and to provide the optimal treatment in order to prevent perpetuation or progression to a potentially destructive disease course.MethodsThe study is the first product of the Clinical and Applied Research Network in Chikungunya (REPLICK). This is a prospective, outpatient department-based, multicenter cohort study in Brazil. Four work packages were defined: i. Clinical research; ii) Translational Science – comprising immunology and virology streams; iii) Epidemiology and Economics; iv) Therapeutic Response and clinical trials design. Scheduled appointments on days 21 (D21) ± 7 after enrollment, D90 ± 15, D120 ± 30, D180 ± 30; D360 ± 30; D720 ± 60, and D1080 ± 60 days. On these visits a panel of blood tests are collected in addition to the clinical report forms to obtain data on socio-demographic, medical history, physical examination and questionnaires devoted to the evaluation of musculoskeletal manifestations and overall health are performed. Participants are asked to consent for their specimens to be maintained in a biobank. Aliquots of blood, serum, saliva, PAXgene, and when clinically indicated to be examined, synovial fluid, are stored at -80° C. The study protocol was submitted and approved to the National IRB and local IRB at each study site.DiscussionStandardized and harmonized patient cohorts are needed to provide better estimates of chronic arthralgia development, the clinical spectra of acute and chronic disease and investigation of associated risk factors. This study is the largest evaluation of the long-term sequelae of individuals infected with CHIKV in the Brazilian population focusing on musculoskeletal manifestations, mental health, quality of life, and chronic pain. This information will both define disease burden and costs associated with CHIKV infection, and better inform therapeutic guidelines.

Prevalence of hepatitis C virus among patients with arthralgia: is it logic for screening?

BackgroundHepatitis C virus (HCV) is well-known to be associated with multiple extrahepatic manifestations such as arthralgia, myalgia, arthritis, and vasculitis. Many studies reported frequent rheumatologic manifestations among patients infected by HCV. The purpose of this study was to determine the prevalence of HCV among chronic unexplained arthralgia patients in order to aid in the early detection and treatment of silent HCV infection.MethodsThis study was a cross-sectional observational study conducted from July 2020 to May 2022. It included 145 individuals suffering from chronic unexplained arthralgia, with vast majority having oligoarticular joint pain (110, 75.9%). They were 103 (71%) females and 42 (29%) males. Serum samples from all patients were examined for the presence of anti-HCV antibodies using a rapid immunochromatographic assay. Seropositive samples were further examined using polymerase chain reaction (PCR) for detection of HCV RNA to confirm HCV infection.ResultsOut of 145 patients who complained of arthralgia, seven patients tested positive for anti-HCV with a seroprevalence of 4.8% while five patients tested positive for HCV-RNA with a molecular prevalence of 3.4%. All positive patients were males (11.9%) with high statistical significance (χ2 = 12.7 and p = 0.002). No association was found between HCV infection and age, blood transfusion, surgery, using personal shaving tools, or being a health-care worker.ConclusionsThe prevalence of HCV was high among males who complained of arthralgia. Patients with arthralgia, especially male patients, are recommended to perform HCV screening test.

Safety and immunogenicity of a single-shot live-attenuated chikungunya vaccine: a double-blind, multicentre, randomised, placebo-controlled, phase 3 trial

VLA1553 is a live-attenuated vaccine candidate for active immunisation and prevention of disease caused by chikungunya virus. We report safety and immunogenicity data up to day 180 after vaccination with VLA1553. This double-blind, multicentre, randomised, phase 3 trial was done in 43 professional vaccine trial sites in the USA. Eligible participants were healthy volunteers aged 18 years and older. Patients were excluded if they had history of chikungunya virus infection or immune-mediated or chronic arthritis or arthralgia, known or suspected defect of the immune system, any inactivated vaccine received within 2 weeks before vaccination with VLA1553, or any live vaccine received within 4 weeks before vaccination with VLA1553. Participants were randomised (3:1) to receive VLA1553 or placebo. The primary endpoint was the proportion of baseline negative participants with a seroprotective chikungunya virus antibody level defined as 50% plaque reduction in a micro plaque reduction neutralisation test (μPRNT) with a μPRNT50 titre of at least 150, 28 days after vaccination. The safety analysis included all individuals who received vaccination. Immunogenicity analyses were done in a subset of participants at 12 pre-selected study sites. These participants were required to have no major protocol deviations to be included in the per-protocol population for immunogenicity analyses. This trial is registered at ClinicalTrials.gov, NCT04546724. Between Sept 17, 2020 and April 10, 2021, 6100 people were screened for eligibility. 1972 people were excluded and 4128 participants were enrolled and randomised (3093 to VLA1553 and 1035 to placebo). 358 participants in the VLA1553 group and 133 participants in the placebo group discontinued before trial end. The per-protocol population for immunogenicity analysis comprised 362 participants (266 in the VLA1553 group and 96 in the placebo group). After a single vaccination, VLA1553 induced seroprotective chikungunya virus neutralising antibody levels in 263 (98·9%) of 266 participants in the VLA1553 group (95% CI 96·7-99·8; p<0·0001) 28 days post-vaccination, independent of age. VLA1553 was generally safe with an adverse event profile similar to other licensed vaccines and equally well tolerated in younger and older adults. Serious adverse events were reported in 46 (1·5%) of 3082 participants exposed to VLA1553 and eight (0·8%) of 1033 participants in the placebo arm. Only two serious adverse events were considered related to VLA1553 treatment (one mild myalgia and one syndrome of inappropriate antidiuretic hormone secretion). Both participants recovered fully. The strong immune response and the generation of seroprotective titres in almost all vaccinated participants suggests that VLA1553 is an excellent candidate for the prevention of disease caused by chikungunya virus. Valneva, Coalition for Epidemic Preparedness Innovation, and EU Horizon 2020.

Levels of preoperative cerebrospinal fluid pro-inflammatory mediators and chronic pain after total knee arthroplasty surgery.

Patients undergoing total knee arthroplasty (TKA) surgery are at high risk of chronic postsurgical pain (CPSP). Accumulating evidence suggests an active role of neuroinflammation in chronic pain. However, its role in the progression to CPSP following TKA surgery remains unanswered. Here, we examined the associations between preoperative neuroinflammatory states and pre- and postsurgical chronic pain in TKA surgery. The data of 42 patients undergoing elective TKA surgery for chronic knee arthralgia at our hospital were analyzed in this prospective study. Patients completed the following questionnaires: brief pain inventory (BPI), hospital anxiety and depression scale, painDETECT, and pain catastrophizing scale (PCS). Cerebrospinal fluid (CSF) samples were collected preoperatively and concentrations of IL-6, IL-8, TNF, fractalkine, and CSF-1 were measured by electrochemiluminescence multiplex immunoassay. CPSP severity was ascertained, using the BPI, 6 months postsurgery. While no significant correlation was observed between the preoperative CSF mediator levels and preoperative pain profiles, the preoperative fractalkine level in the CSF showed a significant correlation with CPSP severity (Spearman's rho = -0.525; p = .002). Furthermore, multivariate linear regression analysis revealed that the preoperative PCS score (standardized β coefficient [β]: .11; 95% confidence interval [CI]: 0.06-0.16; p < .001) and CSF fractalkine level (β: -.62; 95% CI: -1.10 to -0.15; p = .012) were independent predictors of CPSP severity 6 months after TKA surgery. We identified the CSF fractalkine level as a potential predictor for CPSP severity following TKA surgery. In addition, our study provided novel insights into the potential role of neuroinflammatory mediators in the pathogenesis of CPSP.

Comparative Efficacy of Mayaro Virus-Like Particle Vaccines Produced in Insect or Mammalian Cells.

Mayaro virus (MAYV) is a mosquito-transmitted alphavirus that causes often debilitating rheumatic disease in tropical Central and South America. There are currently no licensed vaccines or antiviral drugs available for MAYV disease. Here, we generated Mayaro virus-like particles (VLPs) using the scalable baculovirus-insect cell expression system. High-level secretion of MAYV VLPs in the culture fluid of Sf9 insect cells was achieved, and particles with a diameter of 64 to 70 nm were obtained after purification. We characterize a C57BL/6J adult wild-type mouse model of MAYV infection and disease and used this model to compare the immunogenicity of VLPs from insect cells with that of VLPs produced in mammalian cells. Mice received two intramuscular immunizations with 1 μg of nonadjuvanted MAYV VLPs. Potent neutralizing antibody responses were generated against the vaccine strain, BeH407, with comparable activity seen against a contemporary 2018 isolate from Brazil (BR-18), whereas neutralizing activity against chikungunya virus was marginal. Sequencing of BR-18 illustrated that this virus segregates with genotype D isolates, whereas MAYV BeH407 belongs to genotype L. The mammalian cell-derived VLPs induced higher mean neutralizing antibody titers than those produced in insect cells. Both VLP vaccines completely protected adult wild-type mice against viremia, myositis, tendonitis, and joint inflammation after MAYV challenge. IMPORTANCE Mayaro virus (MAYV) is associated with acute rheumatic disease that can be debilitating and can evolve into months of chronic arthralgia. MAYV is believed to have the potential to emerge as a tropical public health threat, especially if it develops the ability to be efficiently transmitted by urban mosquito vectors, such as Aedes aegypti and/or Aedes albopictus. Here, we describe a scalable virus-like particle vaccine against MAYV that induced neutralizing antibodies against a historical and a contemporary isolate of MAYV and protected mice against infection and disease, providing a potential new intervention for MAYV epidemic preparedness.

Chikungunya virus entry and infectivity is primarily facilitated through cell line dependent attachment factors in mammalian and mosquito cells.

Chikungunya virus (CHIKV) is the causative agent of the human disease chikungunya fever, characterized by debilitating acute and chronic arthralgia. No licensed vaccines or antivirals are currently available for CHIKV. Therefore, the prevention of attachment of viral particles to host cells is a potential intervention strategy. As an arbovirus, CHIKV infects a wide variety of cells in both its mammalian and mosquito host. This broad cell tropism might stem from CHIKV's ability to bind to a variety of entry factors in the host cell including phosphatidylserine receptors (PSRs), glycosaminoglycans (GAGs), and the proteinaceous receptor Mxra8, among others. In this study, we aimed to determine the relevance of each attachment factor during CHIKV entry into a panel of mammalian and mosquito cells. Our data suggest that the importance of particular binding factors during CHIKV infection is highly cell line dependent. Entry into mammalian Vero cells was mediated through attachment to PSRs, mainly T-cell immunoglobulin mucin domain-1 (TIM-1). Conversely, CHIKV infection into HAP1 and NIH3T3 was predominantly mediated by heparan sulfate (HS) and Mxra8, respectively. Entry into mosquito cells was independent of PSRs, HS, and Mxra8. Although entry into mosquito cells remains unclear, our data denotes the importance of careful evaluation of reagents used to identify receptor use in invertebrate cells. While PSRs, GAGs, and Mxra8 all enhance entry in a cell line dependent manner, none of these factors are necessary for CHIKV entry, suggesting additional host factors are involved.

Understanding the Biology and Immune Pathogenesis of Chikungunya Virus Infection for Diagnostic and Vaccine Development.

Chikungunya virus, the causative agent of chikungunya fever, is generally characterized by the sudden onset of symptoms, including fever, rash, myalgia, and headache. In some patients, acute chikungunya virus infection progresses to severe and chronic arthralgia that persists for years. Chikungunya infection is more commonly identified in tropical and subtropical regions. However, recent expansions and epidemics in the temperate regions have raised concerns about the future public health impact of chikungunya diseases. Several underlying factors have likely contributed to the recent re-emergence of chikungunya infection, including urbanization, human travel, viral adaptation to mosquito vectors, lack of effective control measures, and the spread of mosquito vectors to new regions. However, the true burden of chikungunya disease is most likely to be underestimated, particularly in developing countries, due to the lack of standard diagnostic assays and clinical manifestations overlapping with those of other endemic viral infections in the regions. Additionally, there have been no chikungunya vaccines available to prevent the infection. Thus, it is important to update our understanding of the immunopathogenesis of chikungunya infection, its clinical manifestations, the diagnosis, and the development of chikungunya vaccines.