Induction of an invasive phenotype by human parvovirus B19 in normal human synovial fibroblasts.

OBJECTIVE: To investigate the possible role of human parvovirus B19 as an etiologic agent in rheumatoid arthritis (RA), with particular emphasis on its ability to induce invasiveness in human synovial fibroblasts. METHODS: We established an experimental in vitro system in which normal primary human synovial fibroblasts were treated with or without parvovirus B19-containing human sera for 7 days. The fibroblasts were then tested for their ability to degrade reconstituted cartilage matrix using a well-characterized cartilage invasion assay system. RESULTS: Incubation with parvovirus B19-containing serum induced an invasive phenotype in normal human synovial fibroblasts. B19 serum-treated synovial fibroblasts exhibited an increase in invasion of up to 248% compared with the activity of fibroblasts in media alone, in contrast to B19-negative sera-treated synovial fibroblasts, which exhibited no significant change compared with that in media alone. In addition, preincubation of viremic serum with a neutralizing antibody to B19 abrogated the observed effect. CONCLUSION: These results provide direct evidence regarding the ability of parvovirus B19 to induce invasive properties in normal human synovial fibroblasts. Parvovirus B19 has been proposed as an etiologic agent of RA, and our data provide the first biologic link between exposure to B19 and phenotypic changes in normal human synovial fibroblasts.

Hepatitis E virus infection prevalence among selected populations in Iowa.

BACKGROUND: HEV causes an enteric infectious disease endemic in developing areas with hot climate. A case of endogenous HEV infection has been reported in the US. Recently, HEV-like virus was isolated from swine in Iowa. Swine production is a major industry in Iowa with the potential for human exposure to swine in and around industrial and family farm operations. OBJECTIVE: The study objective was to determine whether individuals in Iowa are exposed to HEV. STUDY DESIGN: Anti-HEV antibody prevalence in four selected Iowa populations was determined. Sera were collected from 204 patients with non-A, non-B, non-C hepatitis (non-A-C); 87 staff members of the Department of Natural Resources (DRN); 332 volunteer blood donors in 1989; and 111 volunteer blood donors in 1998. All sera were tested for anti-human HEV IgM and IgG by ELISA with confirmation of positivity by a peptide neutralization test. RESULTS: Both the patients with non-A, non-B, non-C hepatitis (4.9%) and the healthy field workers from the Iowa DNR (5.7%) showed significantly higher prevalence of anti-HEV IgG antibodies compared to normal blood donor sera collected in 1998 (P < 0.05). CONCLUSIONS: Human HEV or a HEV-like agent circulates in the Iowa geographical area. At-risk human populations with occupational exposure to wild animals and environmental sources of domestic animal wastes or with unexplained hepatitis have increased seroprevalence of HEV antibodies.

Human parvovirus B19 infection in acute fulminant liver failure.

We previously reported detection of human parvovirus B19 DNA in livers from patients requiring transplantation for acute fulminant liver failure. In this study, we used immune adherence PCR (IA-PCR) to bind B19 virions in recipient native liver onto solid phase with specific monoclonal antibodies followed by PCR amplification of virion DNA. IA-PCR had sensitivity and specificity similar to conventional PCR. We examined liver tissue from 16 patients with non-A, non-B, non-C, non-E (NA-E) acute fulminant liver failure (AFLF) (6 of unknown etiology associated with aplastic anemia (AA), 4 of unknown etiology without AA; and 6 patients with AFLF of known etiology). IA-PCR detected B19 virions in 5 of 6 (83%) of livers from patients with idiopathic NA-E AFLF associated with AA and in 2 of 3 (75%) without AA, compared to 1 of 6 (17%) of livers from patients with AFLF of known etiology and to 6 of 34 (18%) of 34 control patients with chronic or neoplastic liver disease. Viral mRNA encoding the structural protein was detected in the liver tissue from three B19 IA-PCR positive patients with AFLF. Detection of B19 virions and mRNA for capsid proteins provided strong evidence for B19 infection during the course of NA-E AFLF and argues for involvement of B19 virus in liver injury.

Rheumatic manifestations of parvovirus B19 infection.

Human parvovirus B19 is an emerging DNA virus. B19 infection is common and widespread. Major manifestations of B19 infection are transient aplastic crisis, erythema infectiosum, hydrops fetalis, acute and chronic rheumatoid-like arthropathy, and, in the immunocompromised host, chronic or recurrent bone marrow suppression. A number of less common manifestations of B19 infection include various rash illnesses, neuropathies, and acute fulminant liver failure. Of rheumatologic interest, B19 infection must be differentiated from early presentation of more classic erosive rheumatoid arthritis and, in some cases, systemic lupus erythematosus. It is unlikely that B19 plays a role in classic erosive rheumatoid arthritis, but understanding pathogenesis of B19 arthropathy may provide insights into the mechanisms by which rheumatoid arthritis develops. Evidence for persistence of B19 infection suggests that human parvovirus B19 infection may serve as a model for the study of virus-host interactions and the role of viruses in the pathogenesis of rheumatic diseases.

Transient blood plasmacytosis in parvovirus B19 infection: a report of two cases.

Two patients with sickle cell disease were diagnosed with aplastic crisis caused by acute parvovirus B19 infection. One patient also developed thrombocytopenia associated with hemophagocytic histiocytosis in the bone marrow biopsy. Both patients developed transient blood plasmacytosis and hypocomplementemia soon after admission to the hospital. Transient blood plasmacytosis may be an immunological response to acute parvovirus B19 infection.

Parvovirus b19 infection associated with acute hepatitis, arthralgias, and rash.

Human parvovirus B19 is responsible for a wide variety of clinical syndromes, including erythema infectiosum, or fifth disease, polyarthritis, aplastic crisis in patients with hemolytic anemia, and chronic anemia in immunocompromised persons. Liver enzyme abnormalities are an infrequently reported association of parvovirus B19 infection in adults. We present a case of an acute transient hepatitis in the setting of parvovirus B19 infection, associated with arthralgias and an erythematous, edematous rash on the hands and leg.

Parvovirus B19 as a possible causative agent of fulminant liver failure and associated aplastic anemia.

We recently observed that more than one third of pediatric patients who presented with non-A, non-B fulminant liver failure (FLF) also developed aplastic anemia (AA) either before or shortly after liver transplantation. Factors involved in the suppression of bone marrow could be the same as those causing hepatic failure. We considered parvovirus B19 a candidate etiologic agent because of the known tropism of B19 for erythroid precursors. Archived liver and serum from six patients undergoing liver transplantation for non-A, non-B, non-C FLF with associated AA were analyzed for the presence of B19 DNA and anti-B19 serology. An age- and gender-matched control group (N = 44) was analyzed in parallel. B19 DNA studies and anti-B19 serology were performed in a blinded fashion. B19 serologies were performed by antibody capture enzyme-linked immunosorbent assay (ELISA). B19 DNA was detected after polymerase chain reaction (PCR) amplification of target B19 DNA sequences in liver and serum. Liver tissue showed evidence of B19 DNA in four of six (66%) patients with FLF and associated AA. Two of 4 patients with cryptogenic FLF but without AA had B19 DNA detected in the liver tissue. Of the 34 remaining controls, only 5 (15%) showed evidence of B19 DNA in liver tissue (66% vs. 15%, P = .016). B19 DNA was not detected in any of the test or control sera. This study provides evidence to support the role of parvovirus B19 in the development of FLF and associated AA.

Multiple glycosphingolipids determine the tissue tropism of parvovirus B19.

Infection with human parvovirus B19, the etiologic agent of fifth disease, is associated with numerous hematologic and nonhematologic complications. Recently, the receptor for parvovirus B19 was reported to be globoside (Gb4), a neutral glycosphingolipid (GSL) of red cell membranes. To ascertain if tissue Gb4 expression correlates with B19-associated disease, neutral GSLs from 16 human tissues were isolated and analyzed using high-performance thin-layer chromatography and immunostaining with anti-Gb4 monoclonal antibodies or B19 empty capsids. Gb4 was identified as a major neutral GSL in 11 tissues, especially in those of mesodermal origin. In addition to recognizing Gb4, B19 capsid bound to several tissue-specific GSLs, including two complex globo series GSLs (SSEA-3, SSEA-4) and paragloboside (neolactotetraglycosylceramide), as was demonstrated in red cell, granulocyte, kidney, liver, and bowel tissue. There was good correlation between tissue-neutral GSL expression, B19 capsid binding, and the tissue tropism observed clinically in B19 parvovirus-associated disease.

Viral arthritis including HIV.

Viruses are attractive candidates for infectious etiologic agents or cofactors in the development of rheumatic diseases. The epidemic of HIV infection and the recognition of "emerging viruses" continues to fuel interest in the possible role of viruses in the pathogenesis of diseases without defined etiologies. During 1994, roles for parvovirus B19 in vasculitis and erosive rheumatoid arthritis were entertained. We were reminded that rubella infection may present with polyarthritis. Our understanding of the rheumatic disease manifestations of hepatitis C virus infection was broadened to include polyarthritis. A possible role for herpesviruses in Sjögren's syndrome continued to be explored without definite resolution. Paramyxoviruses were offered as an agent in the development of Paget's disease. The retroviruses continued to attract attention because of rheumatic disease syndromes in AIDS patients and the ability of retroviruses to latently infect the host and alter host immune responses. This review highlights efforts made in the past year to elucidate the role of viral infection in rheumatic disease.

Absence of parvovirus B19 infection in chronic fatigue syndrome.

OBJECTIVE: To evaluate the presence of infection with parvovirus B19 in patients with chronic fatigue syndrome (CFS) who also had rheumatologic symptoms and mild hematologic abnormalities. METHODS: Seven patients meeting the Centers for Disease Control and Prevention working case definition for CFS who also had mild leukopenia, thrombocytopenia, or anemia were studied. Bone marrow was aspirated from each patient, and examined for morphologic abnormalities, including features seen in marrow infections with parvovirus B19, as well as for parvoviral DNA, using polymerase chain reaction (PCR) amplification. Serum obtained at the time of marrow aspiration was also evaluated for parvoviral DNA, using the PCR method, and was examined for the presence of IgM and IgG antibodies to the virus. RESULTS: No evidence of marrow involvement with parvovirus B19 was found in any patient. One patient had antibody evidence of a transient parvoviral infection, during which time an underlying thrombocytopenia worsened. CONCLUSION: Despite examining a selected group of patients thought most likely to have parvoviral infection, based on clinical and hematologic measures, no evidence of clinically important parvoviral infection was noted. Thus, it seems unlikely that parvovirus B19 plays a role in CFS, even though it has been associated with fibromyalgia, a clinically similar syndrome.

Infection due to parvovirus B19 in patients infected with human immunodeficiency virus.

Parvovirus B19 has been described as a cause of chronic anemia in immunosuppressed patients, including those infected with human immunodeficiency virus (HIV). In this study serological assays and the polymerase chain reaction (PCR) were used to establish the prevalence of both prior and active infection due to parvovirus B19 among a general population of 105 HIV-infected individuals (cohort I) and among 22 HIV-infected patients with anemia (cohort II). Eight individuals in cohort I (7.6%) had IgG antibodies to parvovirus B19, while none had B19-specific IgM antibodies. In cohort II, four patients (18.2%) had B19-specific IgG antibodies and none had IgM antibodies. Only one person in cohort I (0.95%) and one person in cohort II (4.5%) had evidence on PCR of persistent infection with parvovirus B19; both of these patients lacked IgG and IgM antibodies to parvovirus. Both individuals with B19 viremia were anemic and had CD4 lymphocyte counts suggesting advanced immunosuppression (< 50/mm3). The observed low prevalences of B19 seropositivity and active B19 infection differ from the rates documented in previous studies and indicate that infection with parvovirus B19 is uncommon in some groups of HIV-infected patients.

Viral infection including HIV and AIDS.

Viruses have long been considered candidates for infectious etiologic agents or cofactors in the development of rheumatic diseases. The current epidemic of HIV infection and the recognition of "emerging viruses" has focused interest on the possible role of viruses in pathogenesis of diseases without defined etiology. Over the past year, the role of parvovirus B19 in chronic arthropathy was further defined. Additional data added to our understanding of the mechanisms by which rubella virus may cause chronic arthritis. We were reminded of the potential the togaviruses have to cause epidemics of febrile arthritis. The developing story of hepatitis C virus in essential mixed cryoglobulinemia encourages us to explore strategies for specific antiviral therapies. The members of the herpesvirus family came under scrutiny for their role in Sjögren's syndrome. The retroviruses continue to attract attention because of rheumatic disease syndromes in AIDS patients and the suggestion that still undefined retroviruses may play an etiologic role in rheumatoid arthritis. This review highlights efforts made in the past year to elucidate the role of viral infection in rheumatologic disease.

Established fibromyalgia syndrome and parvovirus B19 infection.

OBJECTIVE: To determine the seroprevalence of prior and persistent parvovirus B19 (B19) infection in a group of patients with fibromyalgia (FS) compared with controls. METHODS: Fifteen female patients with FS who recalled a viral prodrome (+VP) preceding the onset of FS symptoms and eleven patients with FS who did not recall any such illness (-VP) were selected from a referral practice. We excluded patients with FS who described a history of trauma prior to the onset of FS symptoms. Twenty-six female medical workers served as controls. Serum IgM and IgG anti-B19 antibodies were measured by ELISA: Polymerase chain reaction (PCR) products from serum were analyzed by dot blot hybridization for B19 DNA. Fisher's 2-tailed exact test was used to compare the proportion of positive serologies in each group. RESULTS: No patient or control had positive IgM levels. For all patients with FS, the prevalence of prior B19 infection was comparable to that of healthy controls (11/26 vs 12/26, p = 1.00) and that of the general population. No significant difference was found in the prevalence of prior B19 infection in FS + VP and FS-VP patients (8/15 vs 3/11, p = 0.25). None of the patients or controls showed evidence for persistent B19 viremia, as determined by PCR analysis. CONCLUSION: Our data do not suggest that B19 plays a pathogenic role in this population of patients with FS. Testing for IgM against B19 within 2-3 months of symptom onset may prove more helpful in further defining the role of B19 in FS.

Parvovirus B19 infection in human immunodeficiency virus type 1-infected persons failing or intolerant to zidovudine therapy.

To determine the incidence of B19 infection in patients with AIDS who were being treated with dideoxyinosine, serial sera (n = 28) taken over a 2-year period from 14 individuals were analyzed with respect to anti-B19 serology and the presence of B19 DNA. All 14 individuals were anti-B19 IgM negative. Nine of 14 had B19 viremia by Southern analysis of polymerase chain reaction product. Five of 9 with B19 viremia had > or = 1 anti-B19 IgG-positive sample; none of 5 without viremia had anti-B19 IgG. Four of 9 viremic individuals had serially positive samples. All 4 had severe anemia (hemoglobin < 8.5 g/dL) while taking zidovudine. A fifth individual whose severe anemia resolved after zidovudine was discontinued did not have B19 viremia. Therefore, a significant proportion of this group of patients with AIDS who developed severe anemia while receiving zidovudine had persistent B19 infection. These results suggest that B19 infection should be considered in anemic patients with AIDS.

Viral infection including HIV and AIDS.

Viruses have long been considered candidates for infectious etiologic agents or cofactors in the development of rheumatic diseases. The current epidemic of HIV infection has focused both scientific and lay interest on identifying such agents and understanding their role in precipitating and perpetuating disease. During 1992, the role of hepatitis C virus infection in cryoglobulinemia was further defined. Interest in members of the Herpesviridae family was raised. The potential for postvaccination rubella arthritis was popularized. Additional clinical presentations of parvovirus B19 infection were described. Studies in patients and in vitro continued to provide tantalizing clues to the possible role of retroviruses, both exogenous and endogenous, in rheumatic disease. This review highlights efforts made during the past year to elucidate the role of viral infection in rheumatologic disease.