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PubMed2005

Human parvovirus B19 in patients with aplastic anemia.

Aplastic anemia is characterized by pancytopenia with hypoplastic bone marrow. Various factors including viral infections have been implicated as the precipitating factors. Human parvovirus B19 has been associated with red-cell aplasia, leukopenia, and thrombocytopenia. The present study was carried out to determine the role of parvovirus B19 in aplastic anemia patients. Twenty-seven aplastic anemia patients and 20 healthy controls were tested for the presence of parvovirus B19 infection by detecting parvovirus B19-specific IgM by ELISA and viral DNA by PCR. Parvovirus B19 IgM and viral DNA were detected in significantly higher numbers of patients in comparison to the controls (40.7% vs. 5%, P < 0.01; 37% vs. 0%, P < 0.001, respectively). The presence of parvovirus DNA in aplastic anemia patients indicates active or recent infection. However, more studies are needed to explore the mechanism of bone-marrow aplasia due to human parvovirus B19 infection.

Adolescent↗

PubMed1998

Acute parvovirus B19 infection associated with fulminant hepatitis of favourable prognosis in young children.

BACKGROUND: The cause of fulminant hepatitis (FH) in children is unexplained in up to 50% of cases. We report parvovirus B19 as an agent associated with FH in children and compare clinical characteristics of these patients with those of age-matched patients with FH of other origin. METHODS: 45 patients presented with FH. No cause was apparent in 21 patients. Parvovirus B19 genome was retrospectively sought by PCR in serum collected at admission in 41 patients. FINDINGS: Parvovirus B19 genome was detected in serum from four of 21 patients with unexplained FH (four of 11 younger than 5 years). No B19 DNA was detected in serum from patients with other types of FH or from 82 patients with biliary atresia. Parvovirus B19 IgM was detected in one of the four patients. Patients with parvovirus B19 infection had significantly lower bilirubin concentrations than age-matched patients with FH due to hepatitis A (nine) or other causes (nine) (poisoning with amanita excluded). All patients with parvovirus B19 survived without orthotopic liver transplantation, with restoration of normal liver function within 17 days. INTERPRETATION: In patients younger than 5 years with FH of unexplained origin, evidence of acute parvovirus B19 was associated with a distinct clinical pattern. In particular, low bilirubin concentrations and rapid recovery of liver function without transplantation were distinctive features.

Child, Preschool↗

PubMed1999

Parvovirus B19 infection causing red cell aplasia in renal transplantation on tacrolimus.

Parvovirus B19 infection is known to cause chronic anemia in immunocompromised hosts, including organ transplant recipients. Most reported cases of parvovirus B19-associated aplastic anemia in renal transplant recipients responded to intravenous immunoglobulin (IVIG) infusion. Tacrolimus is of special interest; it was proposed to be associated with pure red cell aplasia (PRCA) on its own because resolution of anemia on withdrawal of tacrolimus was previously observed. Interaction between parvovirus B19 infection and tacrolimus has not been reported. We report a case of parvovirus B19-associated PRCA in a renal transplant recipient treated with tacrolimus who failed to clear the virus despite repeated courses of IVIG. She showed complete recovery promptly after tacrolimus was switched to cyclosporine A. A well-documented concomitant decrease in serum parvovirus DNA polymerase chain reaction titer was also observed. This shows another mechanism by which tacrolimus can aggravate PRCA because of impaired clearance of parvovirus B19 infection in transplant recipients. For those patients receiving tacrolimus who have parvovirus B19 infection with refractory anemia and who fail to recover with IVIG, replacement of tacrolimus with cyclosporine A can be considered.

Adult↗

PubMed2004

Quantification of parvovirus B19 DNA using COBAS AmpliPrep automated sample preparation and LightCycler real-time PCR.

The COBAS AmpliPrep instrument (Roche Diagnostics GmbH, D-68305 Mannheim, Germany) automates the entire sample preparation process of nucleic acid isolation from serum or plasma for polymerase chain reaction analysis. We report the analytical performance of the LightCycler Parvovirus B19 Quantification Kit (Roche Diagnostics) using nucleic acids isolated with the COBAS AmpliPrep instrument. Nucleic acids were extracted using the Total Nucleic Acid Isolation Kit (Roche Diagnostics) and amplified with the LightCycler Parvovirus B19 Quantification Kit. The kit combination processes 72 samples per 8-hour shift. The lower detection limit is 234 IU/ml at a 95% hit-rate, linear range approximately 10(4)-10(10) IU/ml, and overall precision 16 to 40%. Relative sensitivity and specificity in routine samples from pregnant women are 100% and 93%, respectively. Identification of a persistent parvovirus B19-infected individual by the polymerase chain reaction among 51 anti-parvovirus B19 IgM-negative samples underlines the importance of additional nucleic acid testing in pregnancy and its superiority to serology in identifying the risk of parvovirus B19 transmission via blood or blood products. Combination of the Total Nucleic Acid Isolation Kit on the COBAS AmpliPrep instrument with the LightCycler Parvovirus B19 Quantification Kit provides a reliable and time-saving tool for sensitive and accurate detection of parvovirus B19 DNA.

Antibodies, Viral↗

PubMed2001

Potentiation of a recombinant oncolytic parvovirus by expression of Apoptin.

The oncotropic and oncolytic behaviors of certain autonomous rodent parvoviruses make them promising vectors for anticancer gene therapies. However, these parvoviruses are often not potent enough to kill all tumor cells equally well. With the aim of enhancing the intrinsic antitumor effect and the range of natural parvoviruses, a recombinant H1 parvovirus vector was constructed that produces the Apoptin protein, a tumor cell-specific, p53-independent, Bcl-2-insensitive apoptotic effector. We compared the apoptotic activity exerted by a recombinant hH1/Apoptin virus with that of a Green Fluorescent Protein (GFP)-transducing recombinant virus, hH1/GFP, in three human tumor cell lines differing in their susceptibility to wild-type parvovirus H1-induced killing. We found that in cells that were rather resistant to the basal cytotoxic effect of wild-type H1 or the GFP recombinant virus, a parvovirus that expressed Apoptin caused a pronounced, additional cytotoxic effect. In contrast to its enhanced cytotoxicity toward tumor cells, hH1/Apoptin virus was not more toxic to normal human fibroblasts than was the wild-type H1 virus. Taken together, these data indicate that enhancing the oncotropic behavior of wild-type H1 parvoviruses with the tumor-specific apoptotic potency of Apoptin should lead to an effective replicative parvoviral vector.

Apoptosis↗

PubMed2000

Clinical illness due to parvovirus B19 infection after infusion of solvent/detergent-treated pooled plasma.

BACKGROUND: Lipid-enveloped viruses such as HIV, HBV, and HCV can be inactivated by treatment with solvents and detergents. HAV and human parvovirus B19 lack lipid envelopes and are not inactivated. Solvent/detergent-treated pooled plasma (S/D plasma) contains neutralizing antibodies, but it is not known whether the parvovirus B19 antibody content is sufficient to prevent transmission of the disease. A patient is described who developed a clinical illness due to parvovirus B19 infection after the infusion of S/D plasma. CASE REPORT: A 36-year-old woman with myasthenia gravis underwent five plasma exchange procedures from January 15 to January 25, 1999, using albumin, except for 5 units of SD plasma given because of a low fibrinogen level. Four of the 5 units were implicated in a recall after high levels of parvovirus B19 DNA were found in several lots. Two weeks after the infusion, the patient developed fatigue, a rash, and severe polyarthralgias. Parvovirus B19 IgG and IgM antibody titers were consistent with an acute infection. CONCLUSION: Clinically apparent parvovirus B19 infection can follow the use of S/D plasma that contains high levels of parvovirus B19 DNA.

Adult↗

PubMed2001

Diagnosing human parvovirus B19 infection: guidelines for test selection.

Human parvovirus B19 is the cause of a common childhood disease that usually has a mild and self-limited course. Complete viral replication and subsequent cell lysis are limited to early erythroid precursor cells expressing the globoside receptor. Individuals with shortened red blood cell half-lives and immunocompromised or immunosuppressed patients, as well as pregnant women and developing fetuses, are at risk for severe anemia and/or persistent infection from human parvovirus B19. Selection of the diagnostic test(s) to use to detect parvovirus B19 is patient dependent. Serological testing is most appropriate in immunocompetent individuals, including children and pregnant women, who have symptoms consistent with parvovirus B19 infection or a history of recent exposure. Conversely, a molecular amplification assay should be chosen to detect parvovirus B19 DNA in individuals lacking an adequate antibody-mediated immune response. In summary, it is critical that clinicians are educated about the most appropriate diagnostic test to detect parvovirus B19 infection in their patients because selecting an inappropriate or inaccurate test for parvovirus B19 can lead to misinformation and/or misdiagnosis.

Animals↗

PubMedDate not supplied

The role of parvovirus B19 infection in childhood acute lymphoblastic leukemia.

The authors hypothesized that parvovirus B19 with its hematotropic effects has the potential to precipitate varying forms of cytopenia in patients prior to or at the diagnosis of acute lymphoblastic leukemia (ALL). Consequently, and in view of the increasing number of cases reported, this retrospective study evaluated, for the first time, the possible role of parvovirus B19 infection in pediatric patients suffering from ALL, by investigating the frequency and clinical relevance of this infection at the time of the malignant diagnosis or, when applicable, during a phase of pre-ALL. Furthermore, a review of reported parvovirus B19 infections in pediatric ALL patients is presented. The serum of 65 consecutive pediatric patients with a diagnosis of ALL was examined for possible parvovirus B19 infection employing the polymerase chain reaction and ELISA techniques. Specific IgG was demonstrated in 30% of the patients. One patient diagnosed with pre-ALL had evidence of parvovirus B19 DNA in the serum during pancytopenia 5 months prior to the onset of ALL. The results suggest that there is an insignificant chance of finding a parvovirus B19 infection in pediatric patients with ALL at the time of diagnosis. However, parvovirus B19 infection may infrequently serve as a prodrome to ALL.

Adolescent↗

PubMed2002

Revised clinical presentation of parvovirus B19-associated intrauterine fetal death.

Adverse pregnancy outcome due to human parvovirus B19 (hereafter referred to as "parvovirus B19") has been characterized, in numerous reports, as an event that occurs during the first and second trimesters and is strongly associated with symptoms of fetal hydrops. Recent findings have indicated that parvovirus B19-associated intrauterine fetal death (IUFD) is also a problem in late gestation, although its clinical presentation is aberrant, lacking signs of fetal hydrops. We outlined the clinical presentation and assessed the frequency of parvovirus B19 infection in a retrospective analysis of 92 unselected cases of IUFD that occurred during or after gestational week 22. By polymerase chain reaction, parvovirus B19 DNA was detected in 13 (14%) of the 92 cases. Only 2 of the parvovirus B19 DNA-positive cases were hydropic, both representing early IUFDs. This finding indicates that parvovirus B19-associated IUFD in late gestation is a common finding and that hydropic presentation is rare. This knowledge may contribute to a reduction in the number of unexplained cases of IUFD.

Adult↗

PubMed2003

Prevalence of parvovirus B19 in liver tissue: no association with fulminant hepatitis or hepatitis-associated aplastic anemia.

Parvovirus B19 has been proposed as the etiological agent of fulminant hepatitis (FH) or hepatitis-associated aplastic anemia (HAA). We studied the prevalence of parvovirus B19 in liver-tissue samples from patients with FH and HAA and from control subjects. In the first study, parvovirus B19 DNA was detected by nested polymerase chain reaction (PCR) in 4 of 15 livers from patients with FH and in 3 of 22 livers from patients with nonviral hepatic disease. In a second confirmatory study, livers were tested for parvovirus B19 and its variant erythroviruses, V9 and A6. Tissues were also tested by reverse-transcriptase PCR for the presence of parvovirus B19 transcripts as a marker of viral replication. There was no significant difference in the prevalence of parvovirus B19 DNA in livers from patients with FH or HAA, compared with liver-tissue samples from patients with hepatitis B virus (HBV) or hepatitis C virus (HCV) infection; parvovirus B19 transcripts were not detected. There was a significant increase (P<.1) in the prevalence of variant erythrovirus sequences in livers of patients with HBV or HCV hepatitis, the reason for which is currently unknown.

Anemia, Aplastic↗

PubMed2006

Identification of novel murine parvovirus strains by epidemiological analysis of naturally infected mice.

Random-source DNA samples obtained from naturally infected laboratory mice (n=381) were evaluated by PCR and RFLP analysis to determine the prevalence of murine parvovirus strains circulating in contemporary laboratory mouse colonies. Mouse parvovirus (MPV) was detected in 77% of samples, Minute virus of mice (MVM) was detected in 16% of samples and both MVM and MPV were detected in 7% of samples. MVMm, a strain recently isolated from clinically ill NOD-mu chain knockout mice, was detected in 91% of MVM-positive samples, with the Cutter strain of MVM (MVMc) detected in the remaining samples. The prototypic and immunosuppressive strains of MVM were not detected in any of the samples. MPV-1 was detected in 78% of the MPV-positive samples and two newly identified murine parvoviruses, tentatively named MPV-2 and MPV-3, were detected in 21 and 1% of the samples, respectively. The DNA sequence encompassing coding regions of the viral genome and the predicted protein sequences for MVMm, MPV-2 and MPV-3 were determined and compared with those of other rodent parvovirus strains and LuIII parvovirus. The genomic organization for the newly identified viral strains was similar to that of other rodent parvoviruses, and nucleotide sequence identities indicated that MVMm was most similar to MVMc (96.1%), MPV-3 was most similar to hamster parvovirus (HaPV) (98.1%) and MPV-2 was most similar to MPV-1 (95.3%). The genetic similarity of MPV-3 and HaPV suggests that HaPV epizootics in hamsters may result from cross-species transmission, with mice as the natural rodent host for this virus.

Amino Acid Sequence↗

PubMed2000

An epidemic of parvovirus B19 in a population of 3,596 pregnant women: a study of sociodemographic and medical risk factors.

OBJECTIVES: To estimate the incidence of human parvovirus B19 among pregnant women before and during an epidemic, to elucidate possible sociodemographic and medical risk factors during pregnancy and to estimate the association between parvovirus B19 infection and negative pregnancy outcome. DESIGN: Prospective study among pregnant women followed from their first antenatal visit before 24 full weeks of gestation until delivery. SETTING: Department of Obstetrics and Gynaecology, Odense University Hospital, Denmark, November 1992 to February 1994. METHODS: 3,596 pregnant women were invited to participate. The women were examined at first antenatal visit in the period from November 1992 to February 1994 and at delivery. The last delivery was in August 1994 and samples were thus collected before and during a large parvovirus B19 epidemic in Denmark January to September 1994. A blood sample for parvovirus B19 serology was taken at enrollment and from the umbilical cord at delivery. Three questionnaires were completed during 2nd and 3rd trimesters and a registration form at delivery. In total, 3,174 (87.6%) were enrolled and 79.5% completed the study. RESULTS: The prevalence of B19 IgG seropositivity at the first antenatal visit before 24 full weeks of gestation was 66% . The cumulative prevalence proportion of acute parvovirus B19 infection during pregnancy among IgG negative women was found to be 10.3% (IgM seropositivity and/or IgG seroconversion). The IgG seroconversion incidence increased significantly from 1.0% to 13.5% among 932 seronegative pregnant women before and during the epidemic, respectively (P < 0.001). Independent risk factors related to increased risk of B19 infection during pregnancy, adjusted for other sociodemographic and medical factors, were: children at home (adjusted OR 2.1, 95% CI 1.3-3.2); serious medical disease (adjusted OR 3.0, 95% CI 1.0-8.5); and a stressful job (adjusted OR 1.8, 95% CI 1.0-3.3). Parvovirus B 19 IgM seropositivity was associated with events of late spontaneous abortions and stillbirths (crude OR 9.9; 95% CI 3.3-29.4). CONCLUSION: Before and during an epidemic of acute B19 infection incidences were measured among pregnant women to be 1.0% and 13.5%, respectively. Three factors, significantly increasing the risk of acute B19, were identified as: having children at home; suffering from serious medical diseases; and having a stressful job. IgM positivity for parvovirus B19 was associated with negative outcome of pregnancy.

Abortion, Spontaneous↗

PubMed2000

No serological indications that systemic lupus erythematosus is linked with exposure to human parvovirus B19.

OBJECTIVES: Infectious agents like parvovirus have been implicated as exogenous factors that could trigger onset of systemic lupus erythematosus (SLE). A number of case reports describing a SLE-like presentation of acute human parvovirus B19 infection have been published, but no systematic investigation of the actual seroprevalence in epidemiologically defined SLE populations has previously been reported. METHODS: Sera from 99 SLE patients from a defined area in Southern Sweden, representing 88% of all new SLE cases 1981-1995 within the Lund-Orup Health Care district with 175 000 adult inhabitants (> 15 years of age), and sera from 99 age and sex matched healthy controls were investigated for the presence of IgG parvovirus antibodies. Two different commercially available EIA kits were used; one using E coli synthesised parvovirus VP1/VP2 antigen, and one using baculovirus derived parvovirus VP2 antigen. RESULTS: The EIA using baculovirus derived antigen was more sensitive and surprisingly the controls were more often positive than the SLE patients were (79% versus 65%, chi(2) p=0.027). No difference between the groups was seen with the EIA using E coli derived antigen (46% versus 49%). Titration experiments indicated that the discordance between the two tests was a matter of sensitivity rather than specificity. CONCLUSION: No evidence was found of human parvovirus B19 infection being more prevalent among SLE patients. On the contrary, in one of the parvovirus EIAs the controls were more often positive than the SLE patients were.

Adolescent↗

PubMed1997

Detection of parvovirus B19 in macerated fetal tissue using in situ hybridisation.

AIMS: To compare the application of a non-radioactive in situ hybridisation (ISH) technique with an immunocytochemical technique for the detection of human parvovirus B19 in formalin fixed, paraffin wax embedded sections of macerated fetal tissue. METHODS: Archived samples of liver, lung or kidney from 19 human fetuses were investigated for parvovirus B19 using a full length digoxigenin labelled DNA probe of 5.5 kb; bound probe was detected using an anti-digoxigenin (alkaline phosphatase) conjugate and visualised using NBT/BCIP. Immunocytochemical detection of parvovirus B19 was performed using a monoclonal mouse antiparvovirus B19 antiserum, with a streptavidin-biotin complex (horse radish peroxidase) method. Cases were selected to provide a range of diagnostic certainty and a range of degrees of macerative degeneration. RESULTS: Parvovirus B19 was found in 15 of 19 cases using the B19 ISH technique compared with 8 of 19 cases using the immunocytochemical technique. The four negative cases were all controls known to be parvovirus B19 free. All ISH positive cases showed excellent staining with low background regardless of extent of maceration and tissue type. In comparison, sections stained by the immunocytochemical method showed considerable non-specific immunoreactivity in many cases, particularly with severe maceration. Kidney and lung tissues gave the cleanest results. CONCLUSIONS: ISH is more effective than the immunocytochemical technique for the detection of human parvovirus B19 in macerated fetal tissue. The lack of detectable background staining with the ISH technique led to easier interpretation suggesting that this technique should be the method of choice for the investigation of parvovirus B19 in macerated postmortem tissues.

Female↗

PubMed2003

Cytokine gene polymorphisms associated with symptomatic parvovirus B19 infection.

BACKGROUND: The immune system has been implicated in the pathogenesis of certain clinical manifestations of parvovirus B19 infection, including rash and arthralgia. Cytokines feature in the pathogenesis of parvovirus B19 infection, so inherited variability in cytokine responses to B19 infection might have a bearing on the symptomatology of parvovirus B19 infection. AIMS: To investigate the possible role of cytokine gene polymorphisms in the clinical manifestations of parvovirus B19 infection. METHODS: Thirty six patients with a variety of symptoms at acute infection and follow up (mean, 22.0 months) and controls (99-330, depending on the locus) were examined for the following cytokine polymorphisms: tumour necrosis factor alpha (TNF alpha), -308; interferon gamma (IFN-gamma), +874; interleukin 6 (IL-6), -174; IL-10, -592, -819, and -1082; and transforming growth factor beta1 (TGF beta 1), +869 (codon 10) and +915 (codon 25). RESULTS: The TNF alpha -308*A allele occurred in 13.9% of the parvovirus group compared with 27.0% of the control group (odds ratio (OR), 0.44; p = 0.02). The TGF beta 1 CG/CG haplotype was more frequent in the parvovirus group than in the controls (16.7% v 5%; OR, 4.8; p = 0.02). Within the B19 infected group, the TGF beta 1 +869 T allele was associated with skin rash at acute infection (p = 0.005), whereas at follow up the IFN-gamma +874 T allele was associated with the development of anti-B19 non-structural protein 1 antibodies (p = 0.04). CONCLUSIONS: The results of the present study suggest that inherited variability in cytokine responses may affect the likelihood of developing symptoms during parvovirus infection.

Adolescent↗

PubMed2004

Cancer gene therapy through autonomous parvovirus--mediated gene transfer.

Parvoviruses are small nuclear replicating DNA viruses. The rodent parvoviruses are usually weakly pathogenic in adult animals, bind to cell surface receptors which are fairly ubiquitously expressed on cells, and do not appear to integrate into host chromosomes during either lytic or persistent infection. The closely related rodent parvoviruses MVM, H-1 and LuIII efficiently infect human cell lines. Most interesting, malignant transformation of human and rodent cells was often found to correlate with a greater susceptibility to parvovirus-induced killing (oncolysis) and with an increase in the cellular capacity for amplifying and / or expressing the incoming parvoviral DNA. These and other interesting properties make these autonomous rodent parvoviruses and recombinant derivatives promising candidate antitumor vectors. Capsid replacement vectors have been produced from MVM or H-1 virus that carry transgenes encoding either therapeutic products (cytokines/chemokines, Apoptin, herpes simplex virus thymidine kinase) or marker proteins (green fluorescent protein, chloramphenicolacetyl transferase, luciferase). This review describes the current state of the art regarding the potential application of wild-type parvoviruses and derived vectors for the treatment of cancer. In particular, recent successes with the development of replication-competent virus-free vector stocks are discussed and results from pre-clinical studies using recombinant parvoviruses transducing various cytokines/chemokines are presented.

Genetic Therapy↗

PubMed1999

[Parvovirus B19 infection in pregnancy: a cause of non-immune hydrops fetalis].

Four pregnancies, in two women aged 39 and two women aged 34 years respectively, were complicated by foetal parvovirus B19 infection. First-trimester intrauterine death resulting from multiple congenital anomalies was diagnosed in one patient with proven foetal parvovirus B19 infection. In three patients foetal hydrops was found in the second trimester with variable clinical course. In one of them, foetal hydrops resulted in second-trimester foetal death; in another, foetal hydrops resolved following intrauterine blood transfusion and in a third foetal hydrops resolved spontaneously. Foetal parvovirus B19 infection was diagnosed by polymerase chain reaction (PCR) using foetal cells obtained by amnioscentesis. It is concluded that maternal parvovirus B19 infection is mostly asymptomatic. However, the clinical impact of maternal infection on the foetus is diverse, i.e. infection may result in foetal death or--transient--foetal morbidity, in particular foetal anaemia. In mothers with proven foetal parvovirus B19 infection close monitoring of the foetus by ultrasound is warranted. Occasionally intrauterine transfusion is required. From the literature to date, the estimated incidence of maternal parvovirus B19 infection in pregnancy is 3-7%. The vertical transmission rate approximates 30%. When pregnancy is complicated by foetal hydrops foetal parvovirus B19 infection should be kept in mind.

Adult↗

PubMed2003

[Research on Parvovirus B19 infections and chronic articular manifestations in a Tunisian hospital].

Parvovirus B19 infection is often associated with acute and chronic joint diseases thus suggesting an etiologic role for the virus in these pathologies. In this work, we looked for a possible correlation between Parvovirus B19 infection and certain types of chronic inflammatory rheumatisms. We therefore, screened a population of 100 patients with different chronic inflammatory rheumatismal affections for serological markers of Parvovirus B19 infection. All patients were Tunisians of both sexes, who presented at the service of Rheumatology of the Charles Nicolle Hospital, Tunis. One hundred blood donors were taken as controls. Specific Immunoenzyme Assays of the ELISA type (Biotrin International, France) were used to detect anti-Parvovirus IgG and IgM. On the other hand, viral DNA was sought by nested PCR in synovial fluid from 14 patients. The data obtained indicate that specific anti-Parvovirus B19 IgG was detectable in the sera of 80.7% of patients and 43% of controls. In contrast, none of the sera was found positive for specific IgM antibodies. Synovial fluid samples could be collected from 14 anti-Parvovirus B19 seropositive patients and were tested for the presence of viral DNA. None of the samples was found positive. The results of our serological study reinforce the hypothesis that Parvovirus B19 infection is associated with rheumatismal joint affections. However, the lack of detectable viral DNA in synovial fluid of the tested seropositive patients points to an indirect role of the virus in these joint disorders.

Adolescent↗