No definite association between human parvovirus B19 infection and Behcet disease.
Behcet disease (BD) is a complex multi-organ inflammatory disease recognized with debilitating severe systemic vasculitis but with unknown etiology. The triad of recurrent oral aphthosis, genital ulcer, and uveitis are the main classic presentations of the BD. However, the International Study Group for Behcet Disease (ISGB) suggested the diagnostic criteria of oral ulcers in association with any two of the genitalia, eye, and skin involvement or a positive pathergy test to standardize the diagnosis. (1,2) Behcet appears to be endemic along the ancient Silk Road, in the Middle East, countries bordering the Mediterranean Sea, Europe, Korea, and Japan. (3) With such geographical distribution, the reported prevalence of the disease could vary widely depending on the target region, ethnicity of the population and the methodology used for the study. In general, BD can affect all age groups of males and females equally, although the disease onset is most common between the second through the fourth decades of life. (4)
Iran is also among the geographical regions with incidence of Behcet Disease. The incidence of the disease was estimated around 68 per 100,000 individuals. (5) In a detailed study, Davatchi et al. showed that most clinical features including mucocutaneous, ocular and joint manifestations of the Iranian people with BD are similar to findings from other regions. (6) Due to extreme variations in pathogenesis of BD, more than one mechanism has been suggested to be involved in the formation of the disease. In fact, evidence shows that genetics and environmental factors should both be responsible to modulate prevalence and expression of BD. (7-9) Among environmental factors, there have been observations in the past suggesting the role of infectious agents as etiologic cause. It was shown that positive pathergy decreases when the skin lesion is surgically cleaned. Similarly, others showed the effectiveness of penicillin on mucocutaneous lesion of patients diagnosed with BD. (10,11) Most importantly, Sezer et al. reported the isolation of a kind of virus from ocular fluid of a BD patient. He considered the virus as the BD causative agent when the inoculation of the virus in animal models caused symptoms resembling BD disease. However, these results could not be confirmed by others later on. (12) Since that time, with the availability of new techniques, more investigators searched to find clues to link BD with viral or other infectious agents. In this regard, researchers claimed finding viral DNA or RNA strands complementary to herpes simplex virus 1 (HSV-1) in peripheral blood cells or saliva from BD patients more frequently than in healthy people. (13,14) More recent data from animal model may support such findings. (15) However, many others could not reproduce those findings and instead detected HSV genome in clinical samples from oral lesions or blood leucocytes of patients with BD. (16) Hepatitis viruses have also been considered as etiologic cause for BD (17) as they have been shown to be associated with several rheumatologic diseases. (18) Many others have examined the association of BD with other viruses like human immunodeficiency virus, varicella zoster, or cytomegalovirus however; no one could show convincing evidence to consider those viruses as definite causative infectious factor for the disease.
Parvovirus B19 is a non-enveloped icosahedra single stranded DNA virus, infecting human with a wide spectrum of clinical presentations. The virus selectively targets the early erythroid precursor cells, megakaryocytes, endothelial cells, placental cells, and many other cells through binding to blood group P antigen on the cell surfaces. Infection with the virus can cause mild self-limiting erythema infectiosum in immunocompetent children, but produce lethal cytopenias in immunocompromised patients. Moreover, B19 infection could persist for a long time and triggers autoimmune inflammatory disorders. (19) B19 can be found worldwide and its seroprevalence increases with age. The virus is normally transmitted through the respiratory route; however, vertical transmission and transmission via transfused blood products have been reported. (20) B19 infection has been associated with some autoimmune disorders such as forms of collagen vascular diseases or conditions that mimic systemic lupus erythematosus (SLE). (21,22) Moreover, it was shown that patients with recent B19 infection may develop leukocytoclastic vasculitis. (23,24) Therefore, in this study in the southwest of Iran, we investigated whether there is an association between the presence of parvovirus B19 DNA in peripheral blood of BD patients as shown by other investigators. In addition, we examined whether the B19 serologic prevalence in the patients is higher than what exist in healthy individuals.
Material and Methods
Patients and Sampling
To assess the prevalence of parvovirus B19 viral infection, a cross-sectional case control study was accomplished during 2010-2012 in Fars province, southwest Iran.
Sampling of the participants (based on a confidence level of 95% and the margin of error of 15%) comprised of 42 healthy individuals and 55 patients with BD diagnosis classified according to the criteria proposed by the International Study Group for Behcet's disease. (1) The patients and age and sex matched controls were from similar ethnicities of south west Iran. The selected patients were divided into two groups of patients with active and inactive disease according to their clinical presentations. Active phase of the disease was defined if one of the symptoms of uveitis, subcutaneous venous thrombosis, skin lesions (such as erythema nodosum), genital ulcers, arthritis, intestinal ulceration, progressive central nervous system lesions, progressive vasculitis, and epididymitis were found to be persistent for more than two weeks in screening. Patients in the active group were subdivided into mild, moderate, and severe conditions based on the disease severity. The total clinical severity score (CSS) of the disease was determined as described in the literature. (25) In this way, patients with more than 6 points were grouped as severe, patients with scores between 4 and 6 grouped in the moderate group and those scored less than 4 were grouped as mild. Additionally, patients should have at least two weeks history of persisting oral aphthous, skin or genital lesion and uveitis to be included in the active phase of the disease. Most patients were receiving standard chemotherapeutic medications at the time of sampling. The study was approved by the Ethics Committee of Shiraz University of Medical Sciences and performed in the department of Immunology and Internal Medicine of Shiraz University of Medical Sciences, Shiraz, Iran in accordance with the 1964 Declaration of Helsinki. All participants gave their informed consent before being enrolled in the study.
Blood samples from patients and age/sex matched healthy controls were drawn by venipuncture. Plasma samples were subjected to nucleic acid extraction with spin column; designed for viral nucleic acid extraction and done based on manufacturer's instruction (Invitek, Germany). The eluted viral nucleic acid samples were kept at -80[degrees]C until the next step of real time PCR. Aliquots of plasma samples were also kept frozen for the serological studies.
Anti-parvovirus B19 IgG and IgM were measured in the plasma samples by a commercial enzyme linked immunosorbent assay (Euroimmun, Germany). The procedure and interpretation of the results were done according to the manufacturer's instruction.
Detection and Quantitation of Human Parvovirus B19 by Quantitative Real Time PCR
To detect traces of human parvovirus (B19) virus in the plasma samples, commercial virus specific real time PCR Kit (Shanghai ZJ BioTech, China) was used. The primers in the kit allow specific amplification of a 76 bp region of the parvovirus B19 genome. An internal control was added in the amplification reactions to identify possible PCR inhibition by measuring the VIC/JOE fluorescence of the internal control amplification. Moreover, the presence of an external positive control with definite copy numbers of target sequence (1 x [10.sup.7] copies/ml) was used for the quantitative measurement of the viral loads. Multiple serial dilutions (up to 10 copies/ml) of the positive control were prepared for each run and quantitative standard curve was plotted against the Ct values to extrapolate the actual viral loads in each sample. PCR reactions of 40 [micro]l were set with the following protocol on ABI 7500 thermocycler device (ABI, USA) for amplification at 94[degrees]C for 2-5 min followed by 40 cycles of 93[degrees]C for 15 sec [right arrow] 60[degrees]C for 60 sec.
The amplification of B19 specific primers was detected through FAM with the fluorescent quencher BHQ1 at the end of the extended time at 60[degrees]C. Melting curve was used to confirm fluorescent emission from the target sequence.
To evaluate the normal distribution of the collected samples, one sample Kolmogorov-Smirnovtest was used. Significance of differences of numeric variables was evaluated by the student t-test and the nonparametric Kruskal-Wallis test was used to evaluate non-numeric variables. Ordinal variables were compared by chi-square test (linear by linear association) and nominal variables were compared by chi-square or Fisher's exact test. Correlations were tested by Spearman rank test. Data were analyzed by SPSS (version 16.0) and P values less than 0.05 were considered as significant.
Patients and Clinical Findings
Fifty-five patients (22 males and 33 females, M/F=0.66) with Behcet's disease, diagnosed according to the ISG criteria, and an additional 42 healthy controls (16 males and 26 females, M/F=0.61) were enrolled in this study. The male/female sex ratio in the studied groups were not significantly different (P > 0.8). The mean age of the patients and the controls was 37.40 and 37.69 years, respectively. The mean age of the patients at the time of the disease onset was 28.92 [+ or -] 7.15 years, with a mean duration of 7 [+ or -] 5.906 years. The disease duration of more than 10 years was detected in 29.1% of the patients.
Detailed clinical and paraclinical workouts were performed for all patients. All patients had normal values of white blood cell (WBC) count, rheumatoid factor (RF), anti-nuclear antibody (ANA), anti-double-stranded DNA, and anti-neutrophil cytoplasmic antibody (ANCA); although the results of the erythrocyte sedimentation rate (ESR) test and C-reactive protein (CRP) test in some patients (12.7% and 11.8%, respectively) showed some abnormalities. At the time of the study, only 8 patients (14.5%) showed inactive disease. Only one male patient with inactive disease was among them while there was no significant difference between males and females in the active disease groups.
The most common clinical manifestations of the patients were mucocutaneous lesions, including oral and genital aphthous and skin rashes (89.1%). Intestinal and pulmonary vasculitis were the least common clinical manifestations observed in the patients (N=1, 1.8%). Table 1 summarizes the distribution of the clinical findings among patients with different disease severities.
The majority of the patients (N=50, 90.1%) were receiving systemic immunosuppressive drugs. Almost half of them (N=24) had cytotoxic regimen while the rest (N=26) had combinations of colchicine and/or steroid and DMARD. The rest of the patients (N=5) were treated with herbal medications.
Obviously, there were significant correlations between the disease severity score and ocular lesions (P < 0.0001), CNS involvement (P < 0.0003), and mucocutaneous manifestations (P < 0.005). However, there was no statistically significant correlation between the disease severity score and other variables such as age, gender, age at the onset of the disease, duration of the disease, CRP, vascular and articular manifestations or pulmonary and intestinal vasculitis (P > 0.05). Younger patients in our study showed more obvious mucocutaneous manifestations compared with elderly patients. In fact, the mean age of the patients with mucocutaneous involvement was 36.44 [+ or -] 8.48 years and in patients without mucocutaneous involvement was 45.16 [+ or -] 6.33 years (P=0.019). In the study of association between mucocutaneous presentation and other serious manifestations of BD including ocular, CNS, peripheral vascular thrombosis and arthritis, we did not find a significant statistical correlation (P > 0.4) although all patients with CNS involvement and vascular thrombosis had apparent mucocutaneous lesions (P > 0.048). Fatigue was also not in association with either of ocular, CNS, vascular and articular manifestations (P > 0.2). However, there was no significant correlation between having ocular lesions, CNS, vascular and articular manifestations and age of patients (P > 0.08). Similarly, there was no correlation of the clinical manifestations to either sex. Peripheral vascular thrombosis was reported in only three patients and all were male.
Thirty-eight of the patients had known HLA type. Of those, 33 patients (86.8%) were HLAB51 type. Data showed that, ocular lesions were detectable only in the HLA-B51 positive patients and neither of the patients with negative HLAB51 showed ocular disease (P < 0.0001).
Anti-B19 IgG antibody was found in 72.7% (N=40, 16 male and 24 female) of the patients and 85.7% (N=36, 13 male and 23 female) of the healthy individuals. The rate of IgG seroprevalence was not significantly different between the patients and the healthy participants (P > 0.1). Ten patients (18%) and five healthy persons (11.9%) had detectable B19-specific IgM antibody in their plasma. Comparison of B19 IgM prevalence did not show significant difference between the patients and the healthy group (P=0.3). Figure 1 demonstrates the distribution of IgG and IgM immunoglobulin concentrations of the patients and controls. Interestingly, in both studied groups, individuals with B19 IgM simultaneously had detectable amounts of IgG antibody in their plasma. Among the studied patients, no statistically significant correlation was found between B19 seroconversion and disease severity, disease onset history or other studied clinical findings (P > 0.1). Figure 2 shows the distribution of the seropositive and seronegative patients with different disease severity. There was no statistically significant difference in the frequency of patients with B19 antibodies among patients with different therapy regimens (P > 0.3).
B19 Viral DNA Findings
Using virus specific primers and probes adapted in the commercial kit, we tested plasma samples of all participants for the presence of parvovirus B19 genome traces. Only one patient (1.8%) and one of the healthy individuals (2.4%) had detectable loads of the parvovirus B19 DNA. The viral loads, was not significantly different in both groups (54.34 p/ml vs. 57.21 p/ml, respectively). The patient with detectable B19 DNA had positive B19-IgM and IgG results, however the healthy person was found negative for both antibodies. No significant correlation was found between B19 DNA load and Behcet disease severity or other clinical findings (P > 0.1).
Although strong association of B19 infection and rheumatoid arthritis (RA) has been shown by some evidence, (26-28) the relationship between this viral infection and Behcet disease remained obscure. BD is a complex and multi-organ inflammatory disease with severe systemic vasculitis. In fact, the complexity of the disease and variations in the diagnosis could be one of the major hindrances in this regard. Therefore, in this study, we selected a series of 55 patients with best matched criteria to the ISG guidelines and explicated their clinical manifestations as possible. Further to the clinical manifestations, we analyzed the plasma samples of the patients for the presence of B19 viral DNA plus IgG and IgM antibodies against the virus and compared the results to the findings from the healthy individuals of the same geographical region. Commercial high sensitivity quantitative real time PCR and ELISA kits were used for the analysis. With a similar prevalence of B19 specific IgG (72.7% and 85.4%, respectively) both groups of the patients and the controls showed comparable history of B19 infection. Results from previous studies in the same geographical region detected anti B19 IgG in 61% of tested women, (29) which is slightly lower than our findings. In our study, patients showed slightly higher rate B19 IgM than controls (18% vs. only 11.9%). All those individuals were positive for IgG too, which can show mounting a potent immune response against the virus in those people. Other researchers also have shown such observation in their study. Kozireva et al. showed that most tested patients (83.3%) with rheumatoid arthritis and healthy individuals had detectable levels of both IgG and IgM anti-B19 antibodies in their sera. (30)
When investigating the presence of viral DNA, only one person of each group of the patients or the controls (1.8% vs. 2.4%, respectively) was found to have detectable amounts of B19 viral DNA in his/her plasma. The patient with positive real time PCR result had high titers of both IgG and IgM; however, the person from the control group was negative for both antibody classes. Lack of antibody in this person could be explained by possible chronic viral infection at the time of sampling. Alternatively, he might have been in the pre-seroconversion period of the infection or may have failed to mount a strong detectable humoral response. The lack of anti-B19 antibody has also been reported in patients with systemic lupus erythematosis with confirmed B19 DNA in their sera (31) or in RA patients that had B19 DNA in their peripheral blood cells (30) or in thalassemic patients that showed B19 virus in their blood. (32) Therefore, the parvovirus B19 seroprevalence patterns of our patients and controls were similar and followed the typical pattern of reaction.
It has been shown that B19 viremia occurs 1 week after exposure and lasts up to 5 days. Anti-B19 antibodies can be detected later about day 10 to day 12, which can persist for a long time. (33) Reports show that viral DNA can be detected in plasma after the infection even longer than it was previously thought. In fact, Lindblom et al. could detect B19 DNA 128 weeks after the development of anti-B19 IgG antibodies. (34) This is in spite that we failed to detect viral DNA in plasma samples of all individuals with IgM or IgG anti-B19 antibodies. We used a commercial probe based real time PCR system to detect B19 DNA, which showed reasonably low background and linear results in detection range in all experiments. However, still there might be the possibility of false negative results due to variation in sequences and different genotypes in different regions. Similar to our findings, some other investigators also were not able to detect B19 DNA from significant numbers of the patients they tested, although they were found seropositive for the virus. In a report by Irschick et al., B19 viral DNA was not found in BD patients. (35) All these data could be translated to a big controversy in findings about the direct role of parvovirus B19 infection in BD. Moreover, beside B19, other infectious particles, including HSV-1, HBV, Chlamydophila pneumoniae or hepatitis viruses have also been suspected by researchers, where others failed to prove their direct role as infectious etiologic agent of BD. (17,35-37) Here, in spite of earlier findings but similar to others, our findings could not support the assumption of parvovirus B19 as the etiologic agent for Behcet disease. Nevertheless, factors such as limited number of patients (due to stringent clinical criteria in the selection process), potential technical limitation for detection of the virus (due to different genotype) and possible overlapping diseases with Behcet might have affected the result of the study.
All controversies about the role of infections in BD plus a diverse spectrum of symptoms of the disease may demonstrate a more complex etiology of the disease instead of simple accusation of an infectious organism as etiologic agent. It is possible that in patients with genetic predispositions, like HLA-B51, infections with certain viruses or bacteria trigger some unwanted or pathologic cascade of immune responses. These reactions could eventually lead to symptoms of BD. More information is necessary to find the exact relation between infections and BD in such scenario. Animal models (36) should be exploited in experimental studies in conjunction with detailed evidence from patients to answer questions in this regards.
This article has Continuous Medical Education (CME) credit for Iranian physicians and paramedics. They may earn CME credit by reading this article and answering the questions on page 552.
This study was funded by grant No. 88-1841 and No.89-5160 provided by the Research Deputy of Shiraz University of Medical Sciences. The authors are also grateful to all patients and healthy individuals who participated in the study.
Conflict of interest: None declared.
(1.) Criteria for diagnosis of Behcet's disease. International Study Group for Behcet's Disease. Lancet. 1990; 335:1078-80. PubMed PMID: 1970380.
(2.) Sakane T, Takeno M, Suzuki N, Inaba G. Behcet's disease. N Engl J Med. 1999; 341:1284-91. doi: 10.1056/ NEJM199910213411707. PubMed PMID: 10528040.
(3.) Khairallah M, Accorinti M, Muccioli C, Kahloun R, Kempen JH. Epidemiology of Behcet disease. Ocul Immunol Inflamm. 2012; 20:324-35. doi: 10.3109/09273948.2012.723112. PubMed PMID: 23030353.
(4.) Dalvi SR, Yildirim R, Yazici Y Behcet's Syndrome. Drugs. 2012; 72:2223-41. PubMed PMID: 23153327.
(5.) Davatchi F, Jamshidi AR, Banihashemi AT, Gholami J, Forouzanfar MH, Akhlaghi M, et al. WHO-ILAR COPCORD Study (Stage 1, Urban Study) in Iran. J Rheumatol. 2008; 35:1384. PubMed PMID: 18464299.
(6.) Davatchi F, Shahram F, Chams-Davatchi C, Shams H, Nadji A, Akhlaghi M, et al. Behcet's disease in Iran: analysis of 6500 cases. Int J Rheum Dis. 2010; 13:367-73. doi: 10.1111/j.1756-185X.2010.01549.x. PubMed PMID: 21199472.
(7.) Papoutsis NG, Abdel-Naser MB, Altenburg A, Orawa H, Kotter I, Krause L, et al. Prevalence of Adamantiades-Behcet's disease in Germany and the municipality of Berlin: results of a nationwide survey. Clin Exp Rheumatol. 2006; 24:S125. PubMed PMID: 17067445.
(8.) Calamia KT, Wilson FC, Icen M, Crowson CS, Gabriel SE, Kremers HM. Epidemiology and clinical characteristics of Behcet's disease in the US: a population-based study. Arthritis Rheum. 2009; 61:600-4. doi: 10.1002/ art.24423. PubMed PMID: 19405011; PubMed Central PMCID: PMC3024036.
(9.) Kural-Seyahi E, Fresko I, Seyahi N, Ozyazgan Y, Mat C, Hamuryudan V, et al. The long-term mortality and morbidity of Behcet syndrome: a 2-decade outcome survey of 387 patients followed at a dedicated center. Medicine (Baltimore). 2003; 82:60-76. doi: 10.1097/00005792-200301000-00006. PubMed PMID: 12544711.
(10.) Fresko I, Yazici H, Bayramicli M, Yurdakul S, Mat C. Effect of surgical cleaning of the skin on the pathergy phenomenon in Behcet's syndrome. Ann Rheum Dis. 1993; 52:619-20. doi: 10.1136/ard.52.8.619. PubMed PMID: 8215629; PubMed Central PMCID: PMC1005124.
(11.) Calguneri M, Ertenli I, Kiraz S, Erman M, Celik I. Effect of prophylactic benzathine penicillin on mucocutaneous symptoms of Behcet's disease. Dermatology. 1996; 192:125-8. PubMed PMID: 8829493.
(12.) Sezer FN. The isolation of a virus as the cause of Behcet's diseases. Am J Ophthalmol. 1953; 36:301-15. doi: 10.1016/0002 9394(53)91372-5. PubMed PMID: 13030630.
(13.) Eglin RP, Lehner T, Subak-Sharpe JH. Detection of RNA complementary to herpes-simplex virus in mononuclear cells from patients with Behcet's syndrome and recurrent oral ulcers. Lancet. 1982; 2:135661. PubMed PMID: 6129461.
(14.) Lee S, Bang D, Cho YH, Lee ES, Sohn S. Polymerase chain reaction reveals herpes simplex virus DNA in saliva of patients with Behcet's disease. Arch Dermatol Res. 1996; 288:179-83. doi: 10.1007/ BF02505221. PubMed PMID: 8967789.
(15.) Sohn S, Lee ES, Bang D. Learning from HSV-infected mice as a model of Behcet's disease. Clin Exp Rheumatol. 2012; 30:S96-103. PubMed PMID: 22766172.
(16.) Nomura Y, Kitteringham N, Shiba K, Goseki M, Kimura A, Mineshita S. Use of the highly sensitive PCR method to detect the Herpes simplex virus type 1 genome and its expression in samples from Behcet disease patients. J Med Dent Sci. 1998; 45:51-8. PubMed PMID: 12160245.
(17.) Munke H, Stockmann F, Ramadori G. Possible association between Behcet's syndrome and chronic hepatitis C virus infection. N Engl J Med. 1995; 332:400-1.doi: 10.1056/NEJM199502093320616. PubMed PMID: 7646634.
(18.) Cacoub P, Maisonobe T, Thibault V, Gatel A, Servan J, Musset L, et al. Systemic vasculitis in patients with hepatitis C. J Rheumatol. 2001; 28:109-18. PubMed PMID: 11196510.
(19.) Meyer O. Parvovirus B19 and autoimmune diseases. Joint Bone Spine. 2003; 70:6-11. doi: 10.1016/S1297-319X(02)00004-0. PubMed PMID: 12639611.
(20.) Puccetti C, Contoli M, Bonvicini F, Cervi F, Simonazzi G, Gallinella G, et al. Parvovirus B19 in pregnancy: possible consequences of vertical transmission. Prenat Diagn. 2012; 32:897-902. doi: 10.1002/pd.3930. PubMed PMID: 22777688.
(21.) Chen DY, Chen YM, Lan JL, Tzang BS, Lin CC, Hsu TC. Significant association of past parvovirus B19 infection with cytopenia in both adult-onset Still's disease and systemic lupus erythematosus patients. Clin Chim Acta. 2012; 413:855-60. doi: 10.1016/j.cca.2012.01.027. PubMed PMID: 22309679.
(22.) Tovari E, Mezey I, Hedman K, Czirjak L. Self limiting lupus-like symptoms in patients with parvovirus B19 infection. Ann Rheum Dis. 2002; 61:662-3. doi: 10.1136/ard.61.7.662 PubMed PMID: 12079921; PubMed Central PMCID: PMC1754149.
(23.) Ohtsuka T, Yamazaki S. Prevalence of human parvovirus B19 component NS1 gene in patients with Henoch-Schonlein purpura and hypersensitivity vasculitis. Br J Dermatol. 2005; 152:1080-1. doi: 10.1111/j.1365-2133. 2005.06566.x. PubMed PMID: 15888184.
(24.) Chakravarty K, Merry P. Systemic vasculitis and atypical infections: report of two cases. Postgrad Med J. 1999; 75:544-6. doi: 10.1136/pgmj.75.887.544. PubMed PMID: 10616688; PubMed Central PMCID: PMC1741339.
(25.) Akman A, Kacaroglu H, Donmez L, Bacanli A, Alpsoy E. Relationship between periodontal findings and Behcet's disease: a controlled study. J Clin Periodontol. 2007; 34:485-91. doi: 10.1111/j.1600-051X.2007.01085.x. PubMed PMID: 17451414.
(26.) Tello-Winniczuk N, Diaz-Jouanen E, DiazBorjon A. Parvovirus B19-associated arthritis: report on a community outbreak. J Clin Rheumatol. 2011; 17:449-50. doi: 10.1097/RHU.0b013e31823abf1 a. PubMed PMID: 22089996.
(27.) Tzang BS, Tsai CC, Tsay GJ, Wang M, Sun YS, Hsu TC. Anti-human parvovirus B19 nonstructural protein antibodies in patients with rheumatoid arthritis. Clin Chim Acta. 2009; 405:76-82. doi: 10.1016/j. cca.2009.04.002. PubMed PMID: 19362081.
(28.) Colmegna I, Alberts-Grill N. Parvovirus B19: its role in chronic arthritis. Rheum Dis Clin North Am. 2009; 35:95-110. doi: 10.1016/j. rdc.2009.03.004. PubMed PMID: 19480999.
(29.) Ziyaeyan M, Rasouli M, Alborzi A. The seroprevalence of parvovirus B19 infection among to-be-married girls, pregnant women, and their neonates in Shiraz, Iran. Jpn J Infect Dis. 2005; 58:95-7. PubMed PMID: 15858287.
(30.) Kozireva SV, Zestkova JV, Mikazane HJ, Kadisa AL, Kakurina NA, Lejnieks AA, et al. Incidence and clinical significance of parvovirus B19 infection in patients with rheumatoid arthritis. J Rheumatol. 2008; 35:1265-70. PubMed PMID: 18484700.
(31.) Hsu TC, Tsay GJ. Human parvovirus B19 infection in patients with systemic lupus erythematosus. Rheumatology (Oxford). 2001; 40:152-7. doi: 10.1093/ rheumatology/40.2.152. PubMed PMID: 11257151.
(32.) Siritantikorn S, Kaewrawang S, Siritanaratkul N, Theamboonlers A, Poovorawan Y, Kantakamalakul W, et al. The prevalence and persistence of human parvovirus B19 infection in thalassemic patients. Asian Pac J Allergy Immunol. 2007; 25:169-74. PubMed PMID: 18035805.
(33.) Corcoran A, Doyle S. Advances in the biology, diagnosis and host-pathogen interactions of parvovirus B19. J Med Microbiol. 2004; 53:459-75. doi: 10.1099/ jmm.0.05485-0. PubMed PMID: 15150324.
(34.) Lindblom A, Isa A, Norbeck O, Wolf S, Johansson B, Broliden K, et al. Slow clearance of human parvovirus B19 viremia following acute infection. Clin Infect Dis. 2005; 41:1201-3. doi: 10.1086/444503. PubMed PMID: 16163641.
(35.) Irschick EU, Philipp S, Shahram F, Schirmer M, Sedigh M, Ziaee N, et al. Investigation of bacterial and viral agents and immune status in Behcet's disease patients from Iran. Int J Rheum Dis. 2011; 14:298-310. doi: 10.1111/j.1756-185X.2011. 01601.x. PubMed PMID: 21816027.
(36.) Choi B, Lee ES, Sohn S. Vitamin D3 ameliorates herpes simplex virus-induced Behcet's disease-like inflammation in a mouse model through down-regulation of Toll-like receptors. Clin Exp Rheumatol. 2011; 29:S13-9. PubMed PMID: 21269574.
(37.) Farajzadeh S, Shakibi MR, Moghaddam SD, Rahnama Z. Behcet disease: clinical spectrum and association with hepatitis B and C viruses. East Mediterr Health J. 2005; 11:68-72. PubMed PMID: 16532673.
Mojtaba Habibagahi , PhD; Zahra Habibagahi , MD; Said-Mostafa Saidmardani , MD; Faezeh Sadeghian , MD
 Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran;
 Department of Rheumatology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
Mojtaba Habibagahi, PhD; Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Zand Blvd, Shiraz, Iran
Tel/Fax: +98 71 32351575
Received: 12 October 2013
Revised: 27 November 2013
Accepted: 12 January 2014
Table 1: Distribution of patients with different clinical manifestations among sub-groups of the disease activity Clinical No % Inactive Mild Moderate Severe presentation Mucocutaneous - 4 1 1 0 7.28 1.82 1.82 0 + 4 17 15 13 7.28 30.9 27.3 23.6 Ocular - 8 18 8 5 14.6 32.5 14.6 9.1 + 0 0 8 8 0 0 14.6 14.6 Vascular - 8 16 16 12 14.6 29.1 29.1 21.85 + 0 2 0 1 0 3.65 0 1.82 Articular - 8 17 13 11 14.6 30.9 23.7 20 + 0 1 3 2 0 1.82 5.46 3.65 CNS - 8 18 15 8 14.6 32.76 27.3 14.6 + 0 0 1 5 0 0 1.82 9.1 Intestinal - 8 18 16 12 14.6 32.76 29.1 21.85 + 0 0 0 1 0 0 0 1.82 Pulmonary - 8 18 16 12 14.6 32.76 29.1 21.85 + 0 0 0 1 0 0 0 1.82 Fatigue - 6 4 7 2 10.92 7.28 12.74 3.64 + 2 14 9 11 3.64 25.5 16.4 20
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|Title Annotation:||Original Article|
|Author:||Habibagahi, Mojtaba; Habibagahi, Zahra; Saidmardani, Said-Mostafa; Sadeghian, Faezeh|
|Publication:||Iranian Journal of Medical Sciences|
|Date:||Nov 1, 2015|
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