Robust COX-2-mediated prostaglandin response may drive arthralgia and bone destruction in patients with chronic inflammation post-chikungunya.

Patients following infection by chikungunya virus (CHIKV) can suffer for months to years from arthralgia and arthritis. Interestingly, methotrexate (MTX) a major immune-regulatory drug has proved to be of clinical benefit. We have previously shown that CHIKV can persist in the joint of one patient 18 months post-infection and plausibly driving chronic joint inflammation but through ill-characterized mechanisms. We have pursued our investigations and report novel histological and in vitro data arguing for a plausible role of a COX-2-mediated inflammatory response post-CHIKV. In the joint, we found a robust COX-2 staining on endothelial cells, synovial fibroblasts and more prominently on multinucleated giant cells identified as CD11c+ osteoclasts known to be involved in bone destruction. The joint tissue was also strongly stained for CD3, CD8, CD45, CD14, CD68, CD31, CD34, MMP2, and VEGF (but not for NO synthase and two B cell markers). Dendritic cells were rarely detected. Primary human synovial fibroblasts were infected with CHIKV or stimulated either by the synthetic molecule polyriboinosinic:polyribocytidylic acid (PIC) to mimic chronic viral infection or cytokines. First, we found that PIC and CHIKV enhanced mRNA expression of COX-2. We further found that PIC but not CHIKV increased the mRNA levels of cPLA2α and of mPGES-1, two other central enzymes in PGE2 production. IFNß upregulated cPLA2α and COX-2 transcription levels but failed to modulated mPGES-1 mRNA expression. Moreover, PIC, CHIKV and IFNß decreased mRNA expression of the PGE2 degrading enzyme 15-PGDH. Interestingly, MTX failed to control the expression of all these enzymes. In sharp contrast, dexamethasone was able to control the capacity of pro-inflammatory cytokines, IL-1ß as well as TNFα, to stimulate mRNA levels of cPLA2α, COX-2 and mPGES-1. These original data argue for a concerted action of CHIKV (including viral RNA) and cytokines plausibly released from recruited leukocytes to drive a major COX-2-mediated PGE2 proinflammatory responses to induce viral arthritis.

IL-18: a suggested target for immunomodulation in chikungunya virus infection.

Chronic joint pain is the most common pathology found in chikungunya virus (CHIKV)-infected patients. Eight cytokines were compared in CHIKV patients with and without joint pain. IL-4 and IL-13 levels were significantly lower in patients with joint pain (p = 0.006 and p < 0.0001, respectively). IL-18 levels were higher in the group of patients with joint pain (p < 0.0001) and were significantly higher on days 3 and 4 after onset (p = 0.0012 and p = 0.003, respectively). Moreover, TNF-α levels were significantly higher in patients with joint pain on day 3 (p = 0.028). This study demonstrated that cytokines, particularly IL-18, may be candidates for immunomodulation.

Atypical case of hantavirus infection in Sri Lanka mimicking leptospirosis: a case report.

BACKGROUND: Hantavirus infection is an emerging zoonotic infection which has two characteristic patterns of presentation: hantavirus pulmonary syndrome and hemorrhagic fever with renal syndrome. The clinical presentation of hantavirus infection closely mimics leptospirosis. CASE PRESENTATION: This case report describes a previously apparently well 36-year-old Sri Lankan Sinhalese man who presented with an acute febrile illness with myalgia, with liver involvement in the form of transaminitis, cardiac involvement in the form of myocarditis, acute kidney injury, and pulmonary involvement. He was initially managed as severe leptospirosis with multiorgan dysfunction with antibiotics, steroids, and N-acetyl cysteine. A diagnosis of acute hantavirus infection was made subsequently. He made an uneventful recovery. CONCLUSION: Hantavirus infections need to considered in the differential diagnosis of patients presenting with acute febrile illness with multiorgan involvement. Larger studies are needed to evaluate the seroprevalence of hantavirus in Sri Lanka because it could be an emerging serious public health problem.

Proinflammatory Cytokines and Chemokines as Biomarkers of Persistent Arthralgia and Severe Disease After Chikungunya Virus Infection: A 5-Year Follow-Up Study in Southern Thailand.

Chikungunya fever is a re-emerging viral disease caused by chikungunya virus (CHIKV). The disease is generally self-limiting, but chronic arthralgia/arthritis may persist for months or years. We evaluated the expression of 12 cytokines/chemokines and matrix metalloproteinases (MMP)-1 and MMP-3 using enzyme-linked immunosorbent assays (ELISAs) and compared among patients who still had arthralgia (persistent arthralgia), patients who had fully recovered, and healthy controls. There was a significant increase in interleukin (IL)-1ß, IL-6, IL-8, monocyte chemotactic protein-1 (MCP-1), MMP-1, and MMP-3 levels in patients with persistent arthralgia in comparison to healthy controls (p < 0.05) and a significant increase in tumor necrosis factor-alpha (TNF-α), MMP-1, and MMP-3 levels in patients with persistent arthralgia in comparison to patients who had fully recovered (p < 0.05). Interferon (IFN)-γ, IL-6, and transforming growth factor beta (TGF-ß) levels tended to be increased in patients with chronic CHIKV-induced arthritis compared with fully recovered. TNF-α, IL-12, and MCP-1 levels were elevated (p < 0.05), whereas regulated on activation, normal T cell expressed and secreted (RANTES) levels were decreased in patients with severe pain compared with patients with nonsevere pain (p < 0.05). IFN-γ, IL-1ß, IL-6, and IL-8 levels tended to be elevated in patients with severe pain compared with patients with nonsevere pain. We proposed a role played by TNF-α, IL-6, IL-8, and MCP-1 in persistent arthralgia or chronic disease through the activation of MMP-1 and MMP-3. The increase in TNF-α, IL-12, and MCP-1 levels (and the tendency toward an increase in IFN-γ, IL-1ß, IL-6, and IL-8 levels) in patients with severe pain compared with patients with nonsevere pain suggests the role of these inflammatory markers in chronic disease and severity of the disease.

Beyond Members of the Flaviviridae Family, Sofosbuvir Also Inhibits Chikungunya Virus Replication.

Chikungunya virus (CHIKV) causes a febrile disease associated with chronic arthralgia, which may progress to neurological impairment. Chikungunya fever (CF) is an ongoing public health problem in tropical and subtropical regions of the world, where control of the CHIKV vector, Aedes mosquitos, has failed. As there is no vaccine or specific treatment for CHIKV, patients receive only palliative care to alleviate pain and arthralgia. Thus, drug repurposing is necessary to identify antivirals against CHIKV. CHIKV RNA polymerase is similar to the orthologue enzyme of other positive-sense RNA viruses, such as members of the Flaviviridae family. Among the Flaviviridae, not only is hepatitis C virus RNA polymerase susceptible to sofosbuvir, a clinically approved nucleotide analogue, but so is dengue, Zika, and yellow fever virus replication. Here, we found that sofosbuvir was three times more selective in inhibiting CHIKV production in human hepatoma cells than ribavirin, a pan-antiviral drug. Although CHIKV replication in human induced pluripotent stem cell-derived astrocytes was less susceptible to sofosbuvir than were hepatoma cells, sofosbuvir nevertheless impaired virus production and cell death in a multiplicity of infection-dependent manner. Sofosbuvir also exhibited antiviral activity in vivo by preventing CHIKV-induced paw edema in adult mice at a dose of 20 mg/kg of body weight/day and prevented mortality in a neonate mouse model at 40- and 80-mg/kg/day doses. Our data demonstrate that a prototypic alphavirus, CHIKV, is also susceptible to sofosbuvir. As sofosbuvir is a clinically approved drug, our findings could pave the way to it becoming a therapeutic option against CF.

Chikungunya Virus Infection-associated Arthralgia in Adult Jamaicans Post-outbreak / Artralgia asociada con la infección del virus de Chikunguña en jamaicanos adultos con posterioridad al brote

ABSTRACT Objective: To report demographic and self-reported clinical characteristics associated with persistent and severe arthralgia 8-12 months post-chikungunya virus (CHIKV) infection. Methods: A cross-sectional study of 306 adults who self-reported CHIKV infection was conducted. Subjects were consecutively enrolled at public primary healthcare centres in urban and rural areas in Jamaica. Adults with arthralgic conditions were compared with those who reported no arthralgia. Binary logistic regression models were used to determine demographic and self-reported clinical factors associated with severe arthralgia and persistent arthralgia. Results: Most subjects (70.3%) reported arthralgia after CHIKV outbreak (age: 47.6 ± 18.5 years). Medical consultation (36.2%) and laboratory confirmation (1.4%) were low. The prevalence of persistent and severe arthralgia in the previous month was 30.3% and 27.5%, respectively. Severe arthralgia was associated with the female gender (odds ratio (OR): 2.44; 95% confidence level (CI): 1.08, 5.52) and pre-existing arthritis (OR: 3.78; 95% CI: 1.23, 11.62). Females showed a greater likelihood of persistent arthralgia (OR: 2.18; 95% CI: 1.09, 4.39). Conclusion: Self-perceived arthralgia was an important feature 8-12 months post-CHIKV infection and has implications for the recognition and management of arthritis/rheumatic conditions.

RESUMEN Objetivo: Reportar las características clínicas demográficas y auto-reportadas asociadas con una artralgia persistente y severa de 8-12 meses tras la infección del virus de chikunguña (CHIKV). Métodos: Se llevó a cabo un estudio transversal de 306 adultos que auto-reportaron su infección de CHIKV. Los sujetos fueron alistados consecutivamente en centros públicos de atención primaria en zonas urbanas y rurales de Jamaica. Los adultos con condiciones artrálgicas fueron comparados con adultos que no reportaron artralgia alguna. Los modelos de regresión logística binaria fueron utilizados para determinar los factores clínicos demográficos y auto-reportados que se asocian con artralgia severa y artralgia persistente. Resultados: La mayoría de los sujetos (70.3%) reportaron artralgia después del brote de CHIKV (edad: 47.6 ± 18.5 años). La consulta médica (36.2%) y la confirmación del laboratorio (1.4%) fueron bajas. La prevalencia de la artralgia persistente y la severa en el mes anterior fue de 30.3%y 27.5%, respectivamente. La artralgia severa estuvo asociada al género femenino (odds-ratio (OR): 2.44; intervalo de confianza (IC): 1.08, 5.52), y artritis preexistente (OR: 3.78; 95% (IC: 1.23, 11.62). Las hembras mostraron una mayor probabilidad de artralgia persistente (OR: 2.18; 95% IC: 1.09, 4.39). Conclusión: La artralgia auto-percibida fue una característica importante de la infección post-CHIKV de 8-12 meses, y tiene implicaciones para el reconocimiento y tratamiento de la artritis y las condiciones reumáticas.

Antibody-mediated enhancement aggravates chikungunya virus infection and disease severity.

The arthropod-transmitted chikungunya virus (CHIKV) causes a flu-like disease that is characterized by incapacitating arthralgia. The re-emergence of CHIKV and the continual risk of new epidemics have reignited research in CHIKV pathogenesis. Virus-specific antibodies have been shown to control virus clearance, but antibodies present at sub-neutralizing concentrations can also augment virus infection that exacerbates disease severity. To explore this occurrence, CHIKV infection was investigated in the presence of CHIKV-specific antibodies in both primary human cells and a murine macrophage cell line, RAW264.7. Enhanced attachment of CHIKV to the primary human monocytes and B cells was observed while increased viral replication was detected in RAW264.7 cells. Blocking of specific Fc receptors (FcγRs) led to the abrogation of these observations. Furthermore, experimental infection in adult mice showed that animals had higher viral RNA loads and endured more severe joint inflammation in the presence of sub-neutralizing concentrations of CHIKV-specific antibodies. In addition, CHIKV infection in 11 days old mice under enhancing condition resulted in higher muscles viral RNA load detected and death. These observations provide the first evidence of antibody-mediated enhancement in CHIKV infection and pathogenesis and could also be relevant for other important arboviruses such as Zika virus.

Chikungunya Pathogenesis: From the Clinics to the Bench.

Chikungunya alphavirus has caused large epidemics worldwide and leads to acute incapacitating polyarthralgia. The inflammatory reaction over several days will drive robust innate and humoral responses essential to control the infection. Critically, fatal cases and mother-to-child transmission have also been described. Chikungunya can give rise to chronic musculoskeletal diseases, which can last for months to years, particularly in elderly individuals, and occasionally leads to seronegative rheumatoid arthritis-like pathologies. Histopathological studies of patient biopsy specimens and animal models have revealed that chikungunya virus can hide in tissue sanctuaries, and ongoing research should help to decipher the inflammatory mechanisms of tissue injuries.

Pharmacologic management of pain in patients with Chikungunya: a guideline

Abstract From the arrival of Chikungunya virus in the Americas in 2013 until March 2016, approximately two million cases of the disease have been reported. In Brazil, the virus was identified in 2014 and thousands of people have been affected. The disease has high attack rates, infecting 50% of a population within a few months. Approximately 50% of infected people develop chronic symptoms lasting for months or years. Joint involvement is the main clinical manifestation of Chikungunya. It is characterized by swelling and intense pain that is poorly responsive to analgesics, both in the acute and chronic phase of the disease. This significantly compromises quality of life and may have immeasurable psychosocial and economic repercussions, constituting therefore, a serious public health problem requiring a targeted approach. Physicians are often not familiar with how to approach the management of pain, frequently prescribing limited analgesics, such as dipyrone, in sub-therapeutic doses. In addition, there are few published studies or guidelines on the approach to the treatment of pain in patients with Chikungunya. Some groups of specialists from different fields have thus developed a protocol for the pharmacologic treatment of Chikungunya-associated acute and chronic joint pain; this will be presented in this review.

Increased prevalence of JC polyomavirus viruria was associated with arthritis/arthralgia in patients with systemic lupus erythematosus.

OBJECTIVE: The objective of this paper is to investigate the prevalence of reactivation of the human polyomavirus John Cunningham virus (JCV) in patients with systemic lupus erythematosus (SLE) and its associated clinical manifestations. METHODS: Sixty-one patients with SLE and 22 controls were enrolled. Urine JCV viral load was quantified by real-time polymerase chain reaction (PCR). Length variants of the VP1 gene were analyzed using capillary electrophoresis. RESULTS: The prevalence of JCV viruria (63.9% vs. 18.2%, p < 0.001) and urine JCV viral load (2.92 ± 2.76 vs. 0.81 ± 1.85 copies/ml by log10 scale, p < 0.001) were significantly higher in patients with SLE compared with controls. JCV viruria (+) SLE patients had a higher occurrence of arthritis/arthralgia compared with JCV viruria (-) SLE patients (64.1% vs. 22.7%, p = 0.003). In SLE patients, the urine JCV viral load was significantly associated with the occurrence of arthritis/arthralgia. SLE patients with urine JCV viral load >10,000 copies/ml exhibited a 12.75-fold (95% confidence interval 2.88-56.40) risk in clinical arthritis/arthralgia, 18.90-fold (95% confidence interval 2.10-170.39) risk in persistent arthritis, and significantly greater number of length variants in the VP1 gene of JCV compared with JCV viruria (-) SLE patients. CONCLUSION: Reactivation of JCV in the urinary tract of SLE patients was very common. Both JCV viruria and urine JCV viral load were associated with the occurrence of arthritis/arthralgia in patients with SLE. High urine JCV viral load also was associated with the genetic variant in the VP1 gene.

Fiebre de Chikungunya: reporte de tres casos del Hospital Naval Almirante Nef / Chikungunya fever: report of three cases from Almirante Nef Naval Hospital

Chikungunya fever is an emerging infection in our country due to travelers to endemic areas. It presents acutely with high fever, fatigue, headache, myalgia, skin rash and arthritis, usually as a symmetric polyarthritis compromising the interphalangeal and metacarpophalangeal joints, wrist, elbow, ankle and knee. While most of the symptoms last about a week, arthralgias may become chronic and generate significant functional impairment. Chikungunya has been postulated as a triggering factor for rheumatoid arthritis because of the presence of positive rheumatoid factor. We present the three confirmed cases in Almirante Nef Naval Hospital with the review of the published literature...

La fiebre de Chikungunya es una infección novedosa en nuestro país pues su contagio se produce por viajeros en zonas endémicas. Se presenta generalmente en forma aguda con fiebre alta, astenia, cefalea, mialgia, rash cutaneo y artritis, mayoritariamente como poliartritis simétrica comprometiendo las articulaciones interfalángicas, metacarpofalángicas, muñecas, codos, tobillo y rodillas. Si bien la mayoría de los síntomas duran aproximadamente una semana, las artralgias pueden hacerse crónicas y generar un importante deterioro funcional. Se ha postulado que podría ser un factor gatillante de artritis reumatoide ante la presencia de factor reumatoideo positivo. A continuación se presentan los tres casos confirmados del Hospital Naval Almirante Nef junto a la revisión de la literatura publicada hasta el momento...

Osteoclastogenesis induced by CHIKV-infected fibroblast-like synoviocytes: a possible interplay between synoviocytes and monocytes/macrophages in CHIKV-induced arthralgia/arthritis.

Fibroblast-like synoviocytes are known to migrate from joint to joint and are proposed to be one of the key players in the inflammatory cascade amplification in rheumatoid arthritis patients. In the recent CHIKV epidemic, patients developed arthritis-like syndrome and the synoviocyte is one of the suspected players in CHIKV-induced polyarthritis. Thus, to learn more on this syndrome, the responses of fibroblast-like synoviocytes to chikungunya virus (CHIKV) infection, and the interaction between CHIKV-infected synoviocytes and phagocytes, were investigated. Primary human fibroblast-like synoviocyte (HFLS) cultures were infected with clinical isolates of CHIKV at an MOI of 0.001pfu/cell. Data indicated that HFLS are permissive to CHIKV replication, generating peak titers of 10(5)-10(6)pfu/ml. Interestingly, CHIKV-infected HFLS cultures secreted mainly the mediators that are responsible for phagocytes recruitment and differentiation (RANKL, IL-6, IL-8 and MCP-1) but not arthritogenic mediators (TNF-α, IL-1ß, MMP-1, MMP-2 or MMP-13). The interaction between CHIKV-infected synoviocytes and phagocytes was studied using UV-irradiated, CHIKV-infected HFLS supernatant. Data revealed that supernatants from CHIKV-infected HFLS cultures not only induced migration of primary human monocytes, but also drove monocytes/macrophages into osteoclast-like cells. These differentiated osteoclast-like cells produced high levels of TNF-α and IL-6, principal mediators of arthritis. This data suggests a potential interplay between infected HFLS and recruiting phagocytes which may responsible for the arthralgia/arthritis in CHIKV-infected patients.

Rheumatic manifestations of hepatitis B and C and their association with viral load and fibrosis of the liver.

The objective of this study is to investigate rheumatologic manifestations of hepatitis B and C and their relation with viral load and degree of hepatic fibrosis. Thirty-six HBV and 36 HBV patients were included. Liver biopsy was performed for all participants. We detected arthralgia 53-50%, myalgia 58-61% and fatigue 64-81% in HBV and HCV groups in order. All manifestations did not differ between groups significantly. Pain intensity was higher in HCV group (P = 0.023). Arthralgia is associated with viral load of the patients in both groups (P = 0.000 and P = 0.001). Viral load and fatigue are correlated in both groups (P = 0.000 and P = 0.001). There is a considerable relation between inflammation and arthralgia (P = 0.000) and myalgia (P = 0.033). We conclude that rheumatologic manifestations are common both in HBV and HCV and related with viral load and fibrosis.

Ocular involvement associated with an epidemic outbreak of chikungunya virus infection.

PURPOSE: To study the range of ocular symptoms in a cohort of patients with chikungunya infection. DESIGN: Retrospective, observational case series. METHODS: Patients attending a tertiary eye care hospital in South India were included in the study. We included adult patients with serologically confirmed chikungunya virus infection who received clinical care at the Aravind Eye Hospital, Madurai, South India. They were assessed for demographic characteristics, ocular symptoms, laboratory parameters, and chikungunya virus infection severity. Patients underwent a complete ophthalmologic examination that included visual acuity, slit-lamp examination, and indirect funduscopic examination. Visual outcome at the end of three months was the main outcome measure. RESULTS: The charts of 37 patients were analyzed based on the clinical picture and the serologic results. Forty patients were included as controls and tested negative. There were 21 males and 16 females with a mean age of 44.17 years. The main ocular symptoms included granulomatous and nongranulomatous anterior uveitis, optic neuritis retrobulbar neuritis, and dendritic lesions. Of the 26 patients who were followed up for three months, the visual acuity improved in 11 patients (42.3%), remained the same in 12 patients (46.15%), and worsened in three patients (11.5%). CONCLUSIONS: The main ocular manifestation associated with the recent epidemic outbreak of chikungunya virus infection in South India included granulomatous and nongranulomatous anterior uveitis, optic neuritis, retrobulbar neuritis, and dendritic lesions. The visual prognosis generally was good, with most patients recovering good vision. Further studies are needed to understand the pathogenesis of this disease.

Clinical manifestations associated with HTLV type I infection: a cross-sectional study.

Human T-lymphotropic virus type I (HTLV-I) causes HTLV-I-associated myelopathy/tropical spastic paraparesis and adult T cell leukemia in a small percentage of infected individuals. HTLV-I infection is increasingly associated with clinical manifestations. To determine the prevalence of clinical manifestations in HTLV-I infected individuals, we conducted a cross-sectional study of 115 HTLV-I-infected blood donors without myelopathy and 115 age- and sex-matched seronegative controls. Subjects answered a standardized questionnaire and underwent physical examination. Compared with controls, HTLV-I-infected subjects were more likely to report arm or leg weakness (OR = 3.8, 95% CI: 1.4-10.2; OR = 4.0, 95% CI: 1.6-9.8, respectively), hand or foot numbness (OR = 2.1, 95% CI: 1.1-3.9; OR = 4.8, 95% CI: 2.0-11.7, respectively), arthralgia (OR = 3.3, 95% CI: 1.7-6.4), nocturia (OR = 2.7, 95% CI: 1.04-6.8), erectile dysfunction (OR = 4.0, 95% CI: 1.6-9.8), and to have gingivitis (OR = 3.8, 95% CI: 1.8-7.9), periodontitis (OR = 10.0, 95% CI: 2.3-42.8), and dry oral mucosa (OR = 7.5, 95% CI: 1.7-32.8). HTLV-I infection is associated with a variety of clinical manifestations, which may occur in patients who have not developed myelopathy.

Predominance of type 1 (Th1) cytokine production in the liver of patients with HCV-associated mixed cryoglobulinemia vasculitis.

BACKGROUND/AIMS: Patients with hepatitis C virus (HCV) mixed cryoglobulinemia (MC) vasculitis have a higher mortality rate and more frequent incidence of cirrhosis than their cryoglobulin-negative counterparts. To compare the cytokine profile of liver-infiltrating T cells in HCV-infected patients with or without MC vasculitis. METHODS: Hepatic biopsy specimens were obtained from HCV infected patients with and without MC vasculitis. Using intracellular staining and flow cytometry, we assessed the ability of freshly isolated liver T cells from these biopsies to produce IFN-gamma, TNF-alpha, IL-2, IL-4, and IL-10 in response to stimulation with PMA and ionomycin. RESULTS: HCV-MC vasculitis patients compared to HCV-MC negative controls have an enhanced hepatic T cells production of Th1-type cytokines [i.e. TNF-alpha(30.3 +/- 13% vs. 15.5 +/- 5%, P = 0.01), IL-2 (20.2 +/- 9% vs. 10 +/- 4%, P = 0.01) and IFN-gamma (22.2 +/- 11% vs. 9.4 +/- 4%, P = 0.008)], whereas IL-10, a representative Th2-type cytokine, was significantly lower (7.2 +/- 4% vs. 17 +/- 7%, P = 0.01). CONCLUSIONS: T cell from the liver of HCV-MC vasculitis patients display a significantly augmented liver Th1 profile compared to MC-negative controls. This enhanced production of type-1 cytokines may account for a more severe course of liver disease.

Parvovirus B19 in the acute arthropathies and juvenile rheumatoid arthritis.

OBJECTIVE: To evaluate the prevalence of recent parvovirus B19 infection in a cohort of children presenting with acute arthropathy and to determine the prevalence of a subsequent diagnosis of juvenile rheumatoid arthritis in this cohort. METHOD: In this prospective study, parvovirus B19 IgM antibody was investigated in 75 patients who were referred to our clinic with acute joint complaints and also in 75 healthy controls. One patient in each group was excluded due to neuroblastoma and acute lymphoblastic leukaemia. The characteristics of parvovirus B19 IgM positive patients who were accepted as parvovirus B19 arthropathy were further evaluated. All the patients were followed up for at least 6 weeks and the patients with chronic progression of joint complaints were followed for at least 6 months to determine their progress. The cases of juvenile rheumatoid arthritis in this chronic group were identified. RESULTS: Parvovirus B19 IgM was detected in 16 of 74 patients (21.6%) with acute arthropathy compared with 3 of 74 (4.1%) in the healthy control group (chi(2) = 8.67; P = 0.003). The parvovirus B19 positive patients with arthropathy were more likely to become chronic (P = 3.7 x 10(-7)) and to be diagnosed as juvenile rheumatoid arthritis (P = 0.03) than the parvovirus B19 IgM negative group with arthropathy. Additional joint destruction developed in one case who was parvovirus B19 IgM positive in whom juvenile rheumatoid arthritis was diagnosed during follow up. CONCLUSION: These data support the hypothesis that parvovirus B19 infection may be associated with the onset of juvenile rheumatoid arthritis in a proportion of patients.

Chronic fatigue syndrome and arthralgia following parvovirus B19 infection.

OBJECTIVE: To determine the incidence of arthralgia and fatigue complicating B19 infection, along with associated B19 markers and autoantibodies. METHODS: We studied patients with acute B19 infection (n = 51), patients followed from the time of acute B19 infection (mean 22.5 mo) (n = 39), and healthy controls (n = 50). Clinical details were collected using a questionnaire and blood was tested for B19 markers and autoantibodies. RESULTS: Acute B19 arthralgia occurred in 31 patients and was associated with female sex (p = 0.007) and age > 20 years (p = 0.02). Acute B19 fatigue occurred in 8 patients and was not significantly associated with any marker. At followup, symptoms consisted of arthralgia (n = 5), arthralgia and fatigue (n = 6), fatigue (n = 7), lymphadenopathy (n = 1), and purpura due to thrombocytopenia (n = 2). Chronic B19 arthralgia was associated with persistent B19 viremia (p = 0.029). Comparison of the B19 followup group with the controls revealed a significantly increased prevalence of arthralgia (p = 0.0002), fatigue (p < 0.0001), and all other markers. Chronic B19 arthralgia was associated with both acute B19 arthralgia (p = 0.0168) and positive ANA at acute infection (p = 0.0043). Chronic B19 fatigue was associated with acute B19 fatigue (p = 0.011). Five patients fulfilled the Centers for Disease Control criteria for a diagnosis of chronic fatigue syndrome (CFS) and one of these was negative for serum anti-B19 IgG at followup by both Western blot and immunofluorescence. However, there was no characteristic pattern of B19 markers/autoantibodies in patients with B19 associated chronic fatigue. CONCLUSION: CFS may follow acute parvovirus B19 infection; however, attribution of a case of CFS to B19 infection may be extremely difficult in the absence of serological confirmation of acute infection at fatigue onset.