Human parvovirus B19 infection

SUMMARY

A total of 220 patients with arthropathy were selected in Belem, Para between January 1994 and December 2000, and screened for the presence of human parvovirus B19 IgM and IgG antibodies by enzyme-linked immunosorbent assay (ELISA). A subgroup (n = 132) of patients with high levels of antibodies (either IgM+/IgG+ or IgM-/IgG+) were examined for the presence of DNA by polymerase chain reaction/nested PCR. Recent/active infection (detection of IgM and/or IgG-specific antibodies and presence of viral DNA) was identified in 47.7% of the 132 individuals with arthropathy. In our study, women were significantly more affected (59.7%) than men (35.4%) (P = 0.0006). The age group of 11-20 years (84.6%), among female patients, and 21-30 years (42.1%), among male, were those with the highest incidence rates. The analysis of the temporal distribution of B 19-associated arthropaties showed a cyclic pattern, with peak incidence rates occuring at 3-5 year intervals. Significant deference (P = 0.01) was observed when comparing both the highest (39.0%) and the lowest (11.0%) seropositivity rates for the years of 1995 and 2000, respectively. The interfalangial joints of hands and feet were mostly affected, with 50.0% and 48.0% of cases among both women and men, respectively. In a smaller proportion, other joints such as those of knee, ankle, pulse and shoulder were affected. As for the duration, symptoms lasted I to 5 days in 54.0% of the individuals, whereas in 46.0% of them the disease lasted 6-10 days, if considered the subgroup (n = 63) of patients with recent/active infection by parvovirus B 19. In our study, joint clinical manifestations occurred symmetrically. Our results indicate that B19 may be an important agent of arthropathies in our region, and this underscores the need for specific laboratory diagnosis when treating patients suffering from acute arthropathy, mainly pregnant women.

KEYWORDS: Parvovirus B19; Acute arthropathy.

INTRODUCTION

Human parvovirus B 19, discovered by COSSART et al.15, belongs to the family Parvoviridae, genus Erytrovirus39. The B19 transmission occurs mainly through respiratory secretions following human-to-human close contacts4,50. The B 19 infection is quite common, affecting children and adults, often being asymptomatic13,53. The erythema infectiosum (EI)7 is the most common clinical presentation of the B 19 infection in children. In adults, the primary B 19 infection has been associated with arthropathy, transient aplastic crises (TAC) in patients suffering from chronic haemolytic anemia, and chronic anemia in immunocompromised patients. Hydrops fetalis may develop as a consequence of infection during the second trimester of the pregnancy11,16,42,45,52.

Several viral agents have been implicated in the occurrence of the acute and chronic arthropathies. In the Amazon region, arthropathy is a common finding in rubella, arboviral diseases (ex.: Oropouche and Mayaro fevers), Epstein-Barr virus infection and cytomegalovirus infection1,23,38,51. Among of the parasitic and bacterial agents, Toxoplasm. gondii and Streptoccocus species may also cause arthropathy19,31.

The pathogenesis of B19 arthropathy needs to be fully elucidated. Previous studies support the assumption that the joint lesions are associated with immune complexes40,47. In addition, the tissue joint lysis caused by parvovirus B 19 has been postulated33. The chronic joint lesions has been associated with persistence of the viral agent in the tissue and synovial fluid20,34,35.

Several studies conducted in temperate countries2,7,10,24,36,40,44,47 have reported the joint involvement in association with recent/active B19 infections, with rates ranging from 30.0 to 59.0% among male and female adult patients, respectively. Furthermore, joint involvement has been reported in 8.0% children of both sexes. In tropical climate countries, like Brazil, there have been a few reports associating these viral agent with cases of arthropathy. Overall, these studies37,38 have shown that arthropathy is present among individuals with exanthematous illness, namely E.I, and the positivity rates usually range from 10.0 to 40.0% in men and women, respectively. It is therefore of our interest to improve our knowledge on the epidemiology/clinical features of parvovirus B19 infection in our region focussing on its potential for developing arthropathies.

MATERIAL AND METHODS

The study was conducted in Belem, Para between January, 1994 and December, 2000. A total of 220 blood samples were collected from individuals with arthropathies (arthritis and/or arthralgy) at the Virology Section of "Instituto Evandro Chagas". This subgroup of patients (n = 220) was selected from 3,000 individuals with arthropathies who tested negative for the following agents: measles, rubella, cytomegalovirus, Epstein-Barr virus, arbovirus (Mayaro, Oropouche and dengue), Toxoplasma gondii and Streptococcus. Of these, 114 patients were female and 106 were male, with ages ranging from 2 to 68 years (mean age, 35 years). The blood samples were collected by antecubital venepuncture. Sera were kept at - 20 deg C until processing.

The detection of IgM and IgG antibodies to parvovirus B19 was made using a commercial enzyme-linked immunosorbent assay (ELISA) developed by DENKA SEIKEN(TM) (Tokyo, Japan). This is an assay that includes a solid-phase multiple-wells system coated with anti-human IgM monoclonal antibody, as previously described6,43. Lyophilized, purified human parvovirus B19 recombinant antigen was used. Sensitivity and specificity of this assay have been found to be 100% and 97%, respectively, as based on its comparison with the (gold standard) radioimmunoassay14. Sera were tested at a (single) dilution of 1:200, according to the manufacturer. The results of ELISA were calculated dividing optical density (O.D) values of serum samples by the mean absorbance of cut-off. The serum samples with IgM antibodies with absorbance >= 1.00 were regarded as positive.

A subgroup (n = 132) of individuals with B19 IgM+/IgG+ antibodies (absorbance, >= 1.00) and IgM-/IgG+ (0.D of serum samples >5 times the mean O.D of cut-oft) were selected for the B 19 DNA detection, using the polymerase chain reaction (PCR). The PCR technique was performed in two steps, essentially as reported before18,32. First, amplification was done using a mixture of external oligonucleotide primers (PI and P6), followed by a second amplification (the nested PCR) that involved a mixture of the internal primers P2 and P5. The B 19 recent/active infection was defined as the presence of IgM+ and/or IgG specific antibodies plus viral DNA detection in this subgroup (n = 132) of selected individuals. Conventional ELISA and immunofluorescence indirect assays were used for the detection of both IgM and IgG antibodies to rubella, measles, Epstein-Barr virus, cytomegalovirus and Toxoplasma gondii, as previously reported8,12,17,25,29. Serum specimens were also tested by haemagglutination-inhibition (HI), as described before46, for the determination of antibodies to Mayaro, Oropouche and dengue viruses, which are well-know viral agents of exanthematous illnesses in the Amazon region. The latex assay was used for the detection of the antiestreptolysin O, for the diagnosis of infection by Streptococcus as a possible cause of rheumatic fever, as previously described30, in a subgroup (n = 12) of patients that presented with tonsillar pharyngitis.

The data were analysed using the EPI-INFO software, version 6.0 (Atlanta, GA, USA). Rates were compared by using the Mantel-Haenszel chi square test of association or Fisher's exact test, as appropriate. Significance was defined as P

RESULTS

Nineteen (8.6%) of the 220 patients were IgM and IgG positive (IgM+/ IgG+) to B19 (Table 1). One hundred and sixty nine patients (76.8%) were identified as being immune, since they were IgM-/IgG+, and 32 (14.6%) of them had neither IgM nor IgG antibodies (IgM-/IgG-). The results of PCR and nested PCR are shown in the Table 2. The viral DNA was detected in 17 (12.9%) and 46 (34.8%) of the 132 patients who were either IgM+/IgG+ (n = 19) and IgM-/IgG+ (n = 113), respectively. The detection of B 19 DNA among female and male patients were 59.7% and 35.4%, respectively (Table 2). Significant difference was observed when comparing the joint involvement in the subjects of both sexes: P = 0.0006 (a vs b) and P = 0.005 (c vs d) for the age groups 11-20 years and the subtotal, respectively (Table 2). In the children

The analysis of the temporal distribution of B19-associated arthropathies shows a cyclic pattern, with peak incidence rates at 3-5 years intervals. Significant difference (P = 0.01) was observed when comparing both the highest (39.0%) and the lowest (11.0%) seropositivity rates, corresponding to 1995 and 2000, respectively (Fig. 1).

The interfalangial joints of hands and feet were mostly affected, with 50.0% and 48.0% (data not shown in Fig. 2) of cases among both women and men, respectively. In a smaller proportion of patients, other joints such as those of knee, ankle, pulse and shoulder were affected. As for the duration, symptoms lasted I to 5 days in 54.0% of the individuals, whereas in 46.0% of them the disease lasted 6-10 days, if considered the subgroup (n = 63) of patients with recent/active infection for the parvovirus B 19. In our study, joint involvement occurred symmetrically (data not shown in Fig. 2).

Negative results were yielded when testing sera for antibodies to a variety of other pathogens that might be related to arthropathies in our region, including dengue virus.

DISCUSSION

The analysis of the serologic "status" in the group (n = 220) of subjects with arthropathies made it possible the selection of a subgroup (n = 132) of patients who had presented high IgM+/IgG+ and IgM- / IgG+ antibody levels for B 19. Overall, 132 of these serum samples were examined by PCR/nested PCR techniques, according to previous studies10,32. These techniques present greater sensitivity than the ELISA, mainly in situations that require the diagnosis of recent/active B19 infection leading to joint manifestations9,26. This fact was confirmed by the results of this investigation, when comparing the number of recent/ active infections detected by ELISA and those detected by nested PCR: significant difference, as indicated by P = 0.0001. The absence of IgM antibodies for B 19 in sera doesn't rule out the possibility of recent/active infection, since these sera may have B19 DNA if it contains high levels of IgM-/IgG+ antibodies. This condition, observed in our study, has already been demonstrated by CASSINOTTI et al.9. The sera not examined (n = 88) by PCR/nested PCR were those showing either no B 19 specific IgG or low levels of B 19 specific IgG antibodies detected by ELISA. In this study, the arthropathies prevailed among female patients (c vs d, P = 0.005, Table 2), mainly among young women (a vs b, P = 0.0006). A smaller proportion of male adults were affected, and cases of polyarthritis and polyarthralgy also involved children

The temporal distribution of B19 infection throughout our study period support the cyclic pattern proposed for the occurrence B19 infections, as recorded by FREITAS et al.21 in Belem, Para, with peaks of viral activity at 3-5 year intervals. Of note, the high number of arthropathies recorded in 1998 were not associated with the B19 and other bacterial and/or parasitic agents investigated. This fact raises the possibility that pathogens not investigated in our study be associated with the disease, as demonstrated in others regions37,41,48,49. Because of situations like this,36,38,40 it has been stressed the importance of making differential diagnosis with arthropathies due to other pathogens, so that proper therapeutic measure can be taken. In our study, interfalangial joints of hands and feet were mostly affected. Less often, other joints such as those of knee, ankle, pulse and shoulder were affected. The arthropathies associated with the recent/active B19 infection presented short duration (maximum of 10 days), symmetrical distribution and disappeared without sequelae. These clinical features have been recorded in previous studies36,38. In our study, the absence of chronic arthropathies associated with parvovirus B19, as previously described34,36, could be explained by the fact that a low number of patients (n = 13) with chronic joint symptoms (lasting months or years) were enrolled in the present study. Therefore, arthropathies due to collagen or connective tissue diseases seemed not having prevailed among our study patients and there was no evidence that such cases were recent/active B19 infection.

In our study, arthralgy was more frequent than arthritis. The interfalangial joints (hands and feet) were more related arthralgy, mainly among women. These results were also reported in other studies36,38. Viruses other than B19, bacteria or parasitic agents capable to produce acute arthropathies in our region were ruled out as possible aetiological agents.36,38

In our investigation, the frequent joint manifestations associated with parvovirus B19, mainly among women, indicate the need for laboratorial diagnosis of this viral agent, therefore avoiding unproper treatment.

The arthritis/arthralgy in pregnant women may constitute an important indicator of B19 infection, known to be potentially hazardous for the concept3,27,28.

RESUMO

Associacao entre parvovirus B19 e artropatias em Belem, Para, norte do Brasil

Um total de 220 individuos portadores de artropatias foi seleciona-- do em Belem, Para, entre janeiro de 1994 e dezembro de 2000 e, posteriormente, examinado com o proposito de se detectarem anticorpos IgM e IgG para o parvovirus B19, utilizando-se a tecnica imunoenzimatica (ELISA). Um subgrupo (n = 132) de individuos com amostras de soro apresentando altos niveis de anticorpos (IgM+/IgG+ e IgM-/IgG+) foi usado para deteccao de DNA do B19 atraves da reacao em cadeia da polimerase (PCR) e do "nested" PCR. Infeccao recente/ativa (deteccao de IgM e/ou IgG mais a presenca de DNA viral) foi diagnosticada em 47,7% dos 132 individuos apresentando comprometimento das articulacoes. O sexo feminino foi mais afetado (59,7%) que o masculino (35,4%), com diferenca estatisticamente significativa (P = 0,0006). Os grupos ctarios mais atingidos foram os de 11-20 anos (84,6%), no sexo feminino, e 21-30 anos (42,1%), no masculino. A analise da distribuicao temporal mostrou um padrao ciclico, com periodos de maior e menor atividade viral que variam de 3 a 5 anos. Diferenca estatisticamente significativa (P = 0,01) foi observada quando comparadas as frequencias de positividade mais alta (39,0%) e mais baixa (11,0%) para os anos de 1995 e 2000, respectivamente. As articulacoes mais atingidas foram, em ordem de frequencia, as interfalangianas de maos e pes, com 50,0% e 48,0% para o sexo feminino e masculino, respectivamente. Em menor proporcao outras articulacoes tais como as do joelho, tornozelo, pulso e ombro foram afetadas. Quanto a duracao das manifestacoes articulares, 54,0% evoluiram por 1-5 dias, e 46,0% ao longo de 6-10 dias, considerando o subgrupo (n = 63) de individuos corn infeccao recente/ativa para o B19 em ambos os sexos. Em nosso estudo, o comprometimento das articulacoes apresentou carater simetrico. Os resultados encontrados demonstraram o frequente acometimento articular associado as infeccoes recentes/ativas por parvovirus B19, ressaltando a necessidade do diagnostico laboratorial dessa virose, principalmente entre gestantes.

ACKNOWLEDGMENTS

We thank Dr. Elisabete Santos and Marinete Povoa for carrying out the serological tests for rubella, measles, cytomegalovirus infections and Toxoplasma gondii. We are grateful to Dr. Pedro Vasconcelos for performing the serological tests for Mayaro, Oropouche and dengue viruses. Thanks are also due Mrs. Edna Filizzola for technical assistence.

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Received: 8 October 2001

Accepted: 28 December 2001

Ronaldo B. FREITAS(1), Talita A.F. MONTEIRO(1), Manoel G. SILVA FILHO(2) & Alexandre C. LINHARES(1)

(1) Virology Section, Evandro Chagas Institute, National Foundation of Health, Ministry of Health, Belem, Para,Brazil.

(2) Clinical Pathology Section, Evandro Chagas Institute, National Foundation of Health, Ministry of Health, Belem,Para, Brazil.

Correspondence to: Dr. Ronaldo B. Freitas, Evandro Chagas Institute, Av. Almirante Barroso 492, 66090-000 Belem, ParA, Brazil, e-mail: ronaldofreitas@iec.pa.gov.br

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