Parvovirus B19 Causes Fetal Loss

Another example of how confounding by infection leads to false blame of smoking; and of how investigation of "lifestyle" factors (even including video display terminals!) has had priority over the role of infection.

Parvovirus B19 in pregnancy

Infectious causes of hydrops fetalis. SD Barron, RF Pass. Semin Perinatol 1995 Dec;19(6):493-501. "A variety of infectious agents have been associated with nonimmune hydrops fetalis, most notably parvovirus B19, cytomegalovirus, herpes simplex virus, Toxoplasma gondii, and Treponema pallidum. These agents produce hydrops through effects on fetal bone marrow, myocardium, or vascular endothelium...."

Parvovirus B19 infection in pregnancy. AM Eis-Hubinger, D Dieck, R Schild, M Hansmann, KE Schneweis. Intervirology 1998;41(4-5):178-184. "Transplacental transmission of human parvovirus B19 (B19 virus) to the fetus is an important cause of intrauterine death, abortion, stillbirth, and nonimmune hydrops fetalis. Adverse outcome of pregnancy can occur after symptomatic and asymptomatic maternal infection. Only rare cases of congenital malformations and fetal disease in live-born infants have been associated with intrauterine B19 virus infection. Laboratory results obtained from paired maternal and fetal cord blood samples indicate that a reliable diagnosis of fetal B19 virus infection should be based on detection of parvovirus B19 DNA."

Feto-placentary pathology in human parvovirus B19 infection. AG Garcia, CS Pegado, Rd Cubel, ME Fonseca, I Sloboda, JP Nascimento. Rev Inst Med Trop Sao Paulo 1998 May-Jun;40(3):145-150. In six autopsies, "All fetuses showed a similar pathology--hydrops, hepato-splenomegaly, lung hypoplasia and erythroblastemia, the specific histological feature being the presence of intranuclear inclusions in the erythroid progenitors, in the erythropoietic visceral tissue and in blood marrow. Complex cardiopathy allied to abnormal lung lobulation and polisplenia were observed once; in 2 cases endocardial fibroelastosis was diagnosed. The pulmonary lesions were represented by dysmaturity allied to interstitial mononuclear infiltration. The hepatic consisted of cholestasis, portal fibrosis, canalicular proliferation, hemossiderosis, focal necroses and giant cell transformation. The central nervous system lesions were predominantly anoxic although the autolysis impaired a correct diagnosis."

Risk factors for parvovirus B19 infection in pregnancy. AK Valeur-Jensen, CB Pedersen, T Westergaard, IP Jensen, M Lebech, PK Andersen, P Aaby, BN Pedersen, M Melbye. JAMA 1999 Mar 24-31;281(12):1099-1105. "Based on 30 946 serum samples, 65.0% of pregnant women had evidence of past infection. Annual seroconversion rates among susceptible women during endemic and epidemic periods were 1.5% (95% confidence interval [CI], 0.2%-1.9%) and 13.0% (95% CI, 8.7%-23.1 %), respectively. Baseline seropositivity was significantly correlated with increasing number of siblings, having a sibling of the same age, number of own children, and occupational exposure to children. Risk of acute infection increased with the number of children in the household as follows: 0 children odds ratio (OR), 1 (reference); 1 child OR, 3.17 (95% CI, 2.24-4.49); 2 children OR, 5.47 (95% CI, 3.55-8.45); 3 or more children OR, 7.54 (95% CI, 3.80-14.94). Having children aged 6 to 7 years resulted in the highest rate of seroconversion among mothers (6.8%; OR, 4.07; 95% CI, 1.89-8.73). Compared with other pregnant women, nursery school teachers had a 3-fold increased risk of acute infection (OR, 3.09; 95% CI, 1.62-5.89). Population-attributable risk of seroconversion was 55.4% for number of own children and 6.0% for occupational exposure.... Nursery school teachers have the highest occupational risk, but most infections seem to be the result of exposure to the woman's own children."

Investigation of parvovirus B19 in cardiac tissue from patients with congenital heart disease. X Wang, G Zhang, M Han, Q Chao, D Xu. Chin Med J (Engl) 1999 Nov;112(11):995-997. 29 cases of CHD and 30 controls. "Five of 29 (17.2%) CHD cases were positive for HPV-B19, while all the 30 controls were negative for HPV-B19 (P=0.0237). All cases studied were negative for both HSV and TOX. Three cases in each group were positive for CMV, with presence of HPV-B19 DNA in 2 cases in the CHD group. Only two cases in the CHD group showed positive reaction for RV."

Seroprevalence of parvovirus B19 NS1-specific IgG in B19-infected and uninfected individuals and in infected pregnant women. A Hemauer, A Gigler, K Searle, K Beckenlehner, U Raab, K Broliden, H Wolf, G Enders, S Modrow. J Med Virol 2000 Jan;60(1):48-55. "IgG against the NS1 protein was present in 22% of healthy individuals with past B19 infection. In cases of persistent or prolonged B19 infections, the prevalence of NS1-specific antibodies was as high as 80%. It is concluded that NS1-specific IgG may be used as an indicator of chronic or more severe courses of parvovirus B19 infections."

Parvovirus B19 infection: association with third-trimester intrauterine fetal death. L Skoldebrand-Sparre, T Tolfvenstam, N Papadogiannakis, B Wahren, K Broliden, M Nyman. BJOG 2000 Apr;107(4):476-480. 5/7 cases of third trimester intrauterine fetal death without hydrops had delayed or absent IgG responses; 2 "had unusual infection patterns; persistent viraemia for at least five months before birth in one case and likely persistence or re-infection by B19 in the other."

Frequency of human parvovirus B19 infection in intrauterine fetal death. T Tolfvenstam, N Papadogiannakis, O Norbeck, K Petersson, K Broliden. Lancet 2001 May 12;357(9267):1494-1497. "Of 14147 deliveries in three hospitals in the major Stockholm area of Sweden, all cases of intrauterine fetal death (>22 gestational weeks) that occurred between January, 1998, and May, 1999 (n=47), referred cases of miscarriage (<22 gestational weeks, n=37), and induced abortions (n=29), were included in the study," plus 53 normal pregnancies at term. "Significantly more cases of intrauterine fetal death were positive for parvovirus B19 DNA (seven [15%]) than were normal pregnancies at term (zero, p=0.049). Furthermore, parvovirus B19 DNA was found in two (5%) of the miscarriages but not in any of the cases of induced abortion. Only three of nine DNA-positive cases had parvovirus-B19-associated inclusions and stained positive for viral proteins. All but one of the DNA-positive cases of intrauterine fetal death were non-hydropic."

Etiology and outcome of hydrops fetalis. KM Ismail, WL Martin, S Ghosh, MJ Whittle, MD Kilby. J Matern Fetal Med 2001 Jun;10(3):175-181. A retrospective review of 63 consecutive cases of hydrops fetalis. "Of the pregnancies, 12.7% (n = 8) were associated with an 'immune' etiology. Of these, 62.5% (n = 5) had fetal anemia due to anti-D, 25% (n = 2) anti-Kell and 12.5% (n = 1) anti-c antibodies. The remaining 55 cases (87.3%) had a non-immune cause. Eight (14.5%) were due to human parvovirus B19 infection. Fourteen cases (25.5%) were associated with aneuploidy and, in four (7.3%), a primary hydrothorax was the cause of the non-immune hydrops fetalis. A cardiac cause was found in five (9.1%) cases. Three of these had supraventricular tachycardia and one had congenital complete heart block. Cystic hygroma was associated with hydrops fetalis in six cases. Twin-twin transfusion syndrome was the cause for hydrops in two cases. Massive transplacental hemorrhage was identified in one case. Fetal akinesia and muscular dystrophy caused hydrops in one case each. In 14.5% (8/55) of cases no obvious cause was identified and these were classified as 'idiopathic'. Three other cases could not be classified because parents declined investigations (unclassified). In the pregnancies with non-immune hydrops fetalis, the outcome was favorable in 27.3% (15/55) of cases."

Fetal parvovirus B19 infection. CS Von Kaisenberg, W Jonat. Ultrasound Obstet Gynecol 2001 Sep;18(3):280-288. ""Parvovirus B19 infection during pregnancy causes up to 27% cases of non-immune hydrops in anatomically normal fetuses. The virus is believed to cause arrest of maturation of red blood cell precursors at the late normoblast stage and also causes a decrease in the number of platelets. Fetal anemia is presently thought to be responsible for the development of skin edema and effusions. Myocarditis leading to heart failure may contribute to the development of fetal hydrops." In a review of 82 studies involving 230 invasively and 435 conservatively managed pregnancies, "the proportion of seronegative susceptible mothers ranged from 19 to 65%, seroconversion with an incubation time of up to 20 days occurred in 5.7-12.1%, and 188/230 (82%) who were transfused infected fetuses had a normal outcome as opposed to only 239/435 (55%) in the conservatively managed group."

Relevance of parvovirus B19, herpes simplex virus 2, and cytomegalovirus virologic markers in maternal serum for diagnosis of unexplained recurrent abortions. M el-Sayed Zaki, H Goda. Arch Pathol Lab Med 2007 Jun;131(6):956-960. "There was a statistically significant difference between the RSA group and the pregnant women without RSA group in frequency of parvovirus IgM (84% and 16.7%, respectively) (P < .001) and herpes simplex IgM (40% for RSA) (P = .001). Parvovirus B19 viremia was positive in 48% RSA, herpes simplex virus 2 was positive in 32% RSA, and cytomegalovirus was positive in 12% RSA patients. For RSA patients with parvovirus viremia, the mean +/- SD of IgM value was 78.5 +/- 30.12 IU/mL, and for RSA patients with negative viremia it was 30.02 +/- 17.64 IU/mL with statistically significant difference between both levels (P < .001)."

Detection of cytomegalovirus, parvovirus B19 and herpes simplex viruses in cases of intrauterine fetal death: association with pathological findings. G Syridou, N Spanakis, A Konstantinidou, ET Piperaki, D Kafetzis, E Patsouris, A Antsaklis, A Tsakris. J Med Virol 2008 Oct;80(10):1776-1782. 62 fetal deaths and 35 controls. "Thirty-four percent of placental specimens taken from intrauterine fetal deaths were positive for any of the three viruses (16%, 13%, and 5% positive for CMV, PB19, and HSV-1/2, respectively), whereas only 6% of those taken from full term newborns were positive (P = 0.0017)... Intrauterine death and the control groups differed in the detection rate of CMV DNA (16% and 3%, respectively; P = 0.047), which was more pronounced in a gestational age >20 weeks (P = 0.03). Examination of the pathological findings among the PCR-positive and PCR-negative fetal deaths revealed that hydrops fetalis and chronic villitis were more common among the former group (P = 0.0003 and P = 0.0005, respectively)."

Infection with Parvovirus B19 and Herpes viruses in early pregnancy and risk of second trimester miscarriage or very preterm birth. S Johansson, S Buchmayer, S Harlid, A Iliadou, M Sjöholm, L Grillner, M Norman, P Sparén, J Dillner, S Cnattingius. Reprod Toxicol 2008 Nov-Dec;26(3-4):298-302. "Viremia was found in blood samples of 11 (4.7%) women with second trimester miscarriage and 10 (3.7%) women with very preterm birth, compared to 5 (1.7%) women who delivered at term, corresponding to adjusted odds ratios [95% CI] of 3.32 [0.93, 11.8] and 2.21 [0.71, 6.84], respectively. In stratified analyses, Parvovirus B19 viremia was associated with adjusted odds ratios of 3.76 [0.77, 18.3] for second trimester miscarriage and 2.66 [0.64, 11.1] for very preterm birth. Corresponding odds ratios for Human Herpes virus 6 viremia was 2.52 [0.33, 19.5] and 1.08 [0.14, 8.08], respectively."

Parvovirus b19 infection in fetal deaths. A Riipinen, E Väisänen, M Nuutila, M Sallmen, R Karikoski, ML Lindbohm, K Hedman, H Taskinen, M Söderlund-Venermo. Clin Infect Dis 2008 Dec 15;47(12):1519-1525. 535 unborn fetuses, including 120 fetuses from miscarriages and 169 from IUFDs; and 246 controls from induced abortions. "Parvovirus B19 DNA was detected in 5 fetuses with gestational ages of 14, 22, 23, 30, and 39 weeks; these included fetuses from 4 (2.4%) of the 169 IUFDs and 1 (0.8%) of the 120 miscarriages. During the epidemic year 1993, the prevalence of parvovirus B19 DNA-positive fetal deaths was 6 times the prevalence during nonepidemic years. All 5 mothers of the parvovirus B19 DNA-positive fetuses had serological signs of acute parvovirus B19 infection close to the time of fetal death. The only nonhydropic fetus was full-term."

Placental endothelial cells can be productively infected by Parvovirus B19. G Pasquinelli, F Bonvicini, L Foroni, N Salfi, G Gallinella. J Clin Virol 2009 Jan;44(1):33-38. "Foetal capillary endothelium in placental villi can be an additional target of productive B19 virus infection. Infection of placental endothelial cells may lead to a structural and functional damage critical both for altering maternal-foetal blood exchanges and for spreading the infection to the foetus, possibly concurring to the development of foetal hydrops and intrauterine foetal death."

Detection of the human Parvovirus B19 in nonimmune hydrops fetalis using immunohistochemistry and nested-PCR in formalin-fixed and paraffin-embedded placenta and fetal tissues. H Landolsi, MT Yacoubi, L Bouslama, A Lahmar, A Trabelsi, S Hmissa, M Aouni, S Korbi. Pathol Biol (Paris) 2009 May;57(3):e1-7. 5 of 29 samples of various tissues from cases of hydrops fetalis were positive for Parvovirus B19 by nested PCR.

No detection of human bocavirus in amniotic fluid samples from fetuses with hydrops or isolated effusions. M Enders, J Lindner, JJ Wenzel, C Baisch, G Schalasta, G Enders, S Modrow. J Clin Virol 2009 Aug;45(4):300-303. "None of 87 amniotic fluid samples tested was HBoV DNA positive. Twelve of 60 fetuses with hydrops or anemia were found B19 DNA positive. Anti-HBoV IgG antibodies were detected in 100% (19/19) and 94% (47/50) of serum samples from pregnant women with fetal hydrops and normal ultrasound findings, respectively."

Management and outcome of pregnancies with parvovirus B19 infection over seven years in a tertiary fetal medicine unit. RA Simms, RE Liebling, RR Patel, ML Denbow, SA Abdel-Fattah, PW Soothill, TG Overton. Fetal Diagn Ther 2009;25(4):373-378. 12 / 46 fetuses of pregnant women with parvovirus B19 infection showed signs of fetal anemia, and eight of these developed hydrops.

Exposure to fifth disease in pregnancy. A Staroselsky, C Klieger-Grossmann, F Garcia-Bournissen, G Koren. Can Fam Physician 2009 Dec;55(12):1195-1198. REVIEW. "Parvovirus infection is transmitted across the placenta to the fetus in approximately 30% of pregnant women who contract the infection, with a mean interval of 6 to 7 weeks between maternal exposure and fetal infection. For women who contract parvovirus in the first trimester, the rate of fetal loss can be as high as 10%. The highest risk is between 9 and 16 weeks of gestation. The risk is reduced in the second trimester, and fetal complications are rare during the last 2 months of pregnancy. When hydrops develops, it most frequently occurs 2 to 4 weeks after maternal infection. Most of the time clinical signs of hydrops are evident in the second trimester (mean gestational age of 22 to 23 weeks)."

Risk of fetal hydrops and non-hydropic late intrauterine fetal death after gestational parvovirus B19 infection. M Enders, K Klingel, A Weidner, C Baisch, R Kandolf, G Schalasta, G Enders. J Clin Virol 2010 Nov;49(3):163-168. 228 live births and 8 fetal losses among pregnant women with serologic evidence of acute B19 infection. "The observed rate of fetal hydrops for all pregnant women was 4.2% (10/236) (95% confidence interval [CI], 2.1-7.7) and 10.6% (10/94) (95% CI, 5.2-18.7) for those infected between 9 and 20 weeks gestation. Tissue samples from 8 hydrops cases were investigated by PCR or ISH and all were B19 DNA positive. Fetal death occurring during or after gestational week 22 was only observed in one case which was associated with B19-derived fetal hydrops."

Viral detection in hydrops fetalis, spontaneous abortion, and unexplained fetal death in utero. M Al-Buhtori, L Moore, EW Benbow, RJ Cooper. J Med Virol 2011 Apr;83(4):679-684. "Tissue specimens including heart, kidney, liver, lung, and placenta of 73 cases of fetal death were examined with 27 cases of elective termination of pregnancy as a control group... Viral DNA was found in one or more tissue samples from 25/73 cases (34%): CMV in 20, HSV in 5, parvovirus B19 in 5, HHV-7 in 3, and HHV-6 in 2... Viral DNA was not found in any of the termination of pregnancy samples."

Gestational and fetal outcomes in B19 maternal infection: A problem of diagnosis. F Bonvicini, C Puccetti, NC Salfi, B Guerra, G Gallinella, N Rizzo, M Zerbini. J Clin Microbiol 2011 Aug 17 [Epub ahead of print]. 72 pregnancies. "The analysis of serological/virological maternal B19 markers of infection demonstrated that neither B19 IgM nor B19 DNA detected all maternal infections; IgM serology correctly diagnosed 94.1% of the B19 infections, while DNA testing correctly diagnosed 96.3%. The maximum sensitivity was achieved with the combined detection of both parameters. B19 vertical transmission was observed in 39% of the pregnancies with an overall 10.2% rate of fetal deaths. The highest rates of congenital infections and B19-related fatal outcomes were observed when maternal infections occurred by the gestational week 20. B19 fetal hydrops occurred in 11.9% of the fetuses, and 28.6% resolved the hydrops with a normal neurodevelopment outcome at 1- to 5- year follow-up."

Parvovirus B19 and Arthritis

[Research on Parvovirus B19 infections and chronic articular manifestations in a Tunisian hospital]. F Regaya, R Khelifa, R Zouari, M Kchir, M Karoui, R Essid. Arch Inst Pasteur Tunis 2003;80(1-4):9-15. 100 patients with different chronic inflammatory rheumatismal affections vs 100 controls. specific anti-Parvovirus B19 IgG was detectable in the sera of 80.7% of patients and 43% of controls. No synovial fluid samples were positive.

Frequent infection with a viral pathogen, parvovirus B19, in rheumatic diseases of childhood. HW Lehmann, A Knöll, RM Küster, S Modrow. Arthritis Rheum 2003 Jun;48(6):1631-1638. 74 children with rheumatic disease vs. 124 controls. "Twenty-six of the 74 patients (35%) had detectable amounts of parvovirus B19 DNA in the serum (n = 22 [30%]) and/or the synovial fluid (n = 16 [22%]), whereas only 9 of the 124 control sera (7%) were positive for the viral DNA (P < 0.0001). Forty-six patients (62%) had serum IgG against the structural proteins, indicating past infection with B19. NS1-specific antibodies were detected in sera from 29 patients (39%) and 27 controls (22%) (P < 0.001)."

High frequency of parvovirus B19 DNA in bone marrow samples from rheumatic patients. A Lundqvist, A Isa, T Tolfvenstam, G Kvist, K Broliden. J Clin Virol 2005 May;33(1):71-74. "B19 IgG was found in 41 of 50 patients (82%) whereas none was B19 IgM positive. The serologic evaluation showed that none of the patients had acute B19 infection. However, B19 DNA was detected by PCR in 13 of 50 (26%) bone marrow samples from these patients indicating a high frequency of persistent infection compared with previous reports of patient groups and healthy controls. In the study, 22 patients had rheumatoid arthritis (RA) and 7 of these RA patients were B19 DNA positive in bone marrow. Rheumatoid factor was positive in 4 of the 7 B19 DNA positive RA patients as compared with Rheumatoid factor positivity in all of the 15 B19 DNA negative RA patients. Erosive arthritis in X-ray was less common in the B19 DNA positive group than in the B19 DNA negative group."

The relationship between arthritis and human parvovirus B19 infection. R Caliskan, S Masatlioglu, M Aslan, S Altun, S Saribas, S Ergin, E Uckan, V Koksal, V Oz, K Altas, I Fresko, B Kocazeybek. Rheumatol Int 2005 Nov;26(1):7-11. 20 patients with early synovitis, 31 with rheumatoid arthritis, 25 with SLE, 25 with osteoarthritis, and 50 healthy blood donors. "B19 IgM, B19 IgG, and B19 DNA were found in the three patients of the ES group. Subsequently, two of them were diagnosed with RA and one with SLE. B19 DNA was also detected in the synovial fluid of eight patients in the RA group. Of them, all were positive for B19 IgG and half were positive for B19 IgM. B19 IgM was not detected in either of the control groups."

Incidence and clinical significance of parvovirus b19 infection in patients with rheumatoid arthritis. SV Kozireva, JV Zestkova, HL Mikazane, AL Kadisa, NA Kakurina, AA Lejnieks, IN Danilane, MF Murovska. J Rheumatol 2008 Jul;35(7):1265-1270. 100 patients with rheumatoid arthritis and 94 controls. "IgM anti-B19-specific antibodies were detected in 24.0% of RA patients; B19 DNA was found in plasma and/or PBL, synovial fluid cells in 34.0% (34 patients); in 14.0% of the cases (14 patients) both markers were found. In blood donor controls, anti-B19 IgM antibodies were observed in 16.0% (15 donors) and B19 DNA in 6.4% (6 donors); all donors with detectable B19 genomic DNA were IgM-positive. The disease activity in patients with and without B19 infection was similar, while the frequency of clinical complications was significantly higher in the patients with anti-B19 IgM antibodies. Moreover, liver failure and sicca syndrome were observed in the viremic patients only."

Anti-human parvovirus B19 nonstructural protein antibodies in patients with rheumatoid arthritis. BS Tzang, CC Tsai, GJ Tsay, M Wang, YS Sun, TC Hsu. Clin Chim Acta 2009 Jul;405(1-2):76-82. "Significantly higher prevalence of B19-NS1 IgM and IgG antibodies in patients with recent B19 infection was observed as well as the higher prevalence of B19-NS1 IgM and IgG antibodies in RA patients with seronegative diagnostic patterns." Number of subjects not given in abstract.

Parvovirus B19 and Hemolytic Anemia

Cerebrovascular complications and parvovirus infection in homozygous sickle cell disease. KJ Wierenga, BE Serjeant, GR Serjeant. J Pediatr 2001 Sep;139(3):438-442. 346 aplastic crises. "Six cerebrovascular episodes, 5 with hemiplegia, occurred within 2 days of aplastic crises; and 4, all with features of encephalitis, occurred within 2 to 5 weeks. Hemiplegia in 2 children resolved completely, one is improving, and one persists 20 years later; one patient died from recurrent strokes. Of the 4 children whose events occurred later, all had seizure disorders and 2 had transient cortical blindness. The crude risk of cerebrovascular episodes in the 5-week interval after B19 infection was calculated as 58 times greater than expected, which is suggestive of a causal association."

Epidemiology of human parvovirus B19 in children with sickle cell disease. K Smith-Whitley, H Zhao, RL Hodinka, J Kwiatkowski, R Cecil, T Cecil, A Cnaan, K Ohene-Frempong. Blood 2004 Jan 15;103(2):422-427. 633 patients with sicle cell disease. "Sixty-eight episodes of HPV B19-induced transient red cell aplasia occurred with the following clinical events: fever (89.7%), pain (61.8%), acute splenic sequestration (19.1%), and acute chest syndrome (11.8%). Pain, fever, and acute splenic sequestration were more frequent events with acute HPV B19 infections compared with acute events in uninfected patients."

[Neutropenia and/or thrombocytopenia due to acute parvovirus B19 infection]. B Frotscher, S Salignac, L Morlon, C Bonmati, H Jeulin, V Venard, T Lecompte. Ann Biol Clin (Paris) 2009 May-Jun;67(3):343-348. "In healthy adults, most cases of infection are asymptomatic or accompanied by a flu-like syndrome like headaches and myalgia. Haematological manifestations are dominated by transient aplasia of erythroid progenitor cells which remains asymptomatic in most of non immunocompromised patients. Patients with sickle cell disease, thalassemia or other disorders associated with shortened red blood cell survival are at particular risk for marked anemia or red blood cell aplasia. In immunosuppressed patients, anemia may be chronic because of persistent viral load. Neutropenia, lymphopenia or thrombocytopenia have also been reported in acute parvovirus B19 infection."

Parvovirus B19 and Other Illness

Human parvovirus B19: relevance in internal medicine. AM van Elsacker-Niele, AC Kroes. Neth J Med 1999 Jun;54(6):221-230. "These include aplastic crisis in chronic haemolytic anaemias, exanthemathous disease and arthropathy, mainly in women, and chronic anaemia in the immunocompromised host. After initial replication, probably in the respiratory tract, the virus enters its target cells in the bone marrow, erythroid precursor cells, through its receptor, the blood group P antigen. Viral replication in these cells leads to an arrest in erythropoiesis, normally lasting approximately 1 week. In this stage, an aplastic crisis can be produced in all patients under 'erythropoietic stress'. The viraemia disappears as specific antibodies to the virus become detectable in serum, which may give rise to a rash or arthralgia, symptoms that are probably immune-mediated. In immunologically normal individuals the infection is cleared by the humoral immune system within several weeks, whereafter detectable specific IgG confers lifelong immunity to reinfection. In patients with absent or dysfunctional humoral immunity to this virus, however, persistent infection can occur, which results in chronic suppression of erythropoiesis with chronic anaemia."

Clinical and laboratory findings in immunocompetent patients with persistent parvovirus B19 DNA in bone marrow. A Lundqvist, T Tolfvenstam, J Bostic, M Soderlund, K Broliden. Scand J Infect Dis. 1999;31(1):11-6. "The clinical relevance of parvovirus B19 DNA persistence in bone marrow was examined in 10 immunocompetent individuals undergoing examinations for unexplained fever, arthralgia or chronic leukopenia. Common causes of these symptoms had been ruled out and bone marrow aspiration was indicated at this stage of investigation. In addition to morphological analysis of the bone marrow, a test for B19 DNA was performed with 2 nested PCRs. Five of these 10 selected patients had detectable B19 DNA in their bone marrow, whereas no viraemia was observed. Additional bone marrow samples were collected at least 6 months after the first sample from the B19 DNA-positive patients, of whom 3 were found to be still positive. Indeed, 2 of the patients have been positive for more than 5 y of follow-up. Sera from all patients with persistent B19 DNA in bone marrow could neutralize the virus. One patient responded to treatment with immunoglobulin but later relapsed. No other cause of the symptoms was found, despite extensive investigations, and at least some of the prolonged disease manifestations may be due to parvovirus B19."

Evidence for persistence of parvovirus B19 DNA in livers of adults. AM Eis-Hubinger, U Reber, T Abdoul-Nour, U Glatzel, H Lauschke, U Putz. J Med Virol 2001 Oct;65(2):395-401. "B19 was detected in the livers of 4/17 (24%) anti-B19 IgG-positive individuals, three of whom had also B19 DNA in their bone marrow... Further studies are needed to address whether B19 is an innocent bystander in the liver or whether the presence of B19 in liver is of biological and clinical significance." (News) Human parvovirus B19 persists in adult livers. M Greener, Doctor's Guide 2001 Oct 11.

Parvoviral infection of endothelial cells and its possible role in vasculitis and autoimmune diseases. CM Magro, AN Crowson, M Dawood, GJ Nuovo. J Rheumatol 2002 Jun;29(6):1227-1235. Parvoviral RNA was detected by in situ everse transcriptase PCR in 14 of 16 cases. 10 of 11 tested had either IgG or IgM specific antibodies against parvovirus.

Human Parvovirus B19. ED Heegaard, KE Brown. Clinical Microbiology Reviews 2002 Jul; 15(3):485-505. Review Article

Advances in the biology, diagnosis and host-pathogen interactions of parvovirus B19. A Corcoran, S Doyle. J Med Microbiol 2004 Jun;53(Pt 6):459-475. Review Article. "Tropism of productive B19 infection is mainly due to the restrictive cellular distribution of the P blood group antigen globoside (Gb4) (Brown et al., 1993, 1994), which is found most commonly on cells of the erythroid lineage, but also on platelets, tissues from the heart, liver, lung, kidney and endothelium and on synovium." An additional co-receptor is also necessary. The annual seroconversion rate among women of childbearing age has been estimated to be 1.5 % during endemic periods and 13 % during epidemics.

Coronary vasospasm as the underlying cause for chest pain in patients with PVB19 myocarditis. Yilmaz A, Mahrholdt H, Athanasiadis A, Vogelsberg H, Meinhardt G, Voehringer M, Kispert EM, Deluigi C, Baccouche H, Spodarev E, Klingel K, Kandolf R, Sechtem U. Heart 2008 Nov;94(11):1456-1463. 85 patients who presented at hospital with atypical chest pain and demonstrated clinical signs suggestive of myocarditis. "Patients with isolated PVB19 infection (n = 22) demonstrated a significantly higher incidence of coronary vasospasm than both those with isolated HHV6 infection (86.4% vs 46.7%; p = 0.025) and those with normal biopsy results (86.4% vs 40.0%; p<0.001). Univariate and multivariate logistic regression analysis showed that only PVB19 infection was independently correlated with coronary vasospasm (OR = 4.9, 95% CI 1.56 to 15.28, p = 0.006)."

Intrahepatic long-term persistence of parvovirus B19 and its role in chronic viral hepatitis. C Wang, A Heim, V Schlaphoff, PV Suneetha, KA Stegmann, H Jiang, M Krueger, P Fytili, T Schulz, M Cornberg, R Kandolf, MP Manns, CT Bock, H Wedemeyer. J Med Virol 2009 Dec;81(12):2079-2088. "B19V DNA was amplified frequently from explanted end-stage liver tissues (37/50, 74%) and from routine biopsy samples (14/32, 44%) (P < 0.05). However, there was no significant difference in B19V copy number per cell between these two groups. B19V-specific CD4(+) T-cell responses to two dominant MHC-class-restricted epitopes were detected in a similar frequency in healthy anti-B19V-positive individuals (3/19; 16%) and patients with chronic hepatitis C (3/13; 23%). These results indicate that B19V can persist in the liver. However, there is no evidence that B19V is a "hepatitis virus" worsening liver disease in European patients with chronic hepatitis C."

Interferon beta modulates endothelial damage in patients with cardiac persistence of human parvovirus b19 infection. C Schmidt-Lucke, F Spillmann, T Bock, U Kühl, S Van Linthout, HP Schultheiss, C Tschöpe. J Infect Dis 2010 Mar 15;201(6):936-945. 9 adult patients with dpcumented B19 genome vs. 9 healthy controls. Patients with B19V persistence had significantly higher (P = .04) levels of CMAECs [dead mature endothelial cells] than did control subjects, which normalized after treatment. "Similar improvement was shown for flow-mediated dilatation (P = .04) in the treatment group only (P = .017 for the comparison with untreated patients with B19V persistence n = 5). There were significantly higher numbers of CPCs in patients with B19V persistence before therapy," which normalized after treatment.

Parvovirus B19 infection associated with Hashimoto's thyroiditis in adults. J Wang, W Zhang, H Liu, D Wang, W Wang, Y Li, Z Wang, L Wang, W Zhang, G Huang. J Infect 2010 May;60(5):360-370. 86 thyroid disase patients. "B19 DNA was significantly present in HT tissues by both PCR (29/32, 90.6%) and in-situ hybridization (23/32, 71.9%, all p < 0.01) compared with normal thyroid tissue (7/16, 43.8%; 2/16, 12.5%). Laser-capture microdissection further confirmed this difference. B19 capsid protein in HT group was significantly higher than that in all the control groups (p < 0.01), and the expression of NF-kappaB and interleukin-6 in HT tissues was up-regulated. NF-kappaB was well co-localized with B19 protein in thyroid epithelia by double-labeling immunofluorescence and confocal microscopy."

Epidemiology of parvovirus B19

The prevalence of antibody to parvovirus B19 in hemophiliacs and in the general population. AM Eis-Hubinger, J Oldenburg, HH Brackmann, B Matz, KE Schneweis. Zentralbl Bakteriol 1996 Jul;284(2-3):232-240. Rates of infection rose rapidly during childhood, to 61% at age 12 years; then increased more slowly to 77% at age 60 and over. 98% of hemophiliacs were positive, indicating that it can be transmitted by clotting factors.

Prolonged activation of virus-specific CD8+ T cells after acute B19 infection. A Isa, V Kasprowicz, O Norbeck, A Loughry, K Jeffery, K Broliden, P Klenerman, T Tolfvenstam, P Bowness. PLoS Med 2005 Dec;2(12):e343. "[R]esponses increased in magnitude over the first year post-infection despite resolution of clinical symptoms and control of viraemia, with T cell populations specific for individual epitopes comprising up to 4% of CD8+ T cells. B19-specific T cells developed and maintained an activated CD38+ phenotype, with strong expression of perforin and CD57 and downregulation of CD28 and CD27."

Rapid sequence change and geographical spread of human parvovirus B19; comparison of B19 evolution in acute and persistent infections. P Norja, AM Eis-Hübinger, M Söderlund-Venermo, K Hedman, P Simmonds. J Virology 2008 Jul;82(13):6427-6433. "These revised estimates predict a last common ancestor for currently circulating genotype 1 variants of B19 around 1956-1959, fitting well with previous analyses of the B19 "bioportfolio" for a complete cessation of genotype 2 infections and replacement by genotype 1 in the 1960s. In contrast, the evolution of B19 amplified from tissue samples was best modelled by using estimated dates of primary infection rather than sample dates, consistent with slow or absent sequence change during persistence."

The genome of human parvovirus B19 virus can replicate in non-permissive cells with the help of adenovirus genes and produces infectious virus. W Guan, S Wong, N Zhi, J Qiu. J Virol 2009 Sep;83(18):9541-9553. "[T]he replication of B19V DNA in the 293 cells and the production of infectious progeny virus were made possible by the presence of the adenovirus E2a, E4orf6, and VA RNA genes that emerged during the transfection of the pHelper plasmid."

Epidemiology of high-level parvovirus B19 viraemia among Dutch blood donors, 2003-2009. K Kooistra, HJ Mesman, M de Waal, MH Koppelman, HL Zaaijer. Vox Sang 2011 Apr;100(3):261-266. "Four hundred and eleven donations (1/15815) were identified with B19 DNA levels above 10(6) IU/ml, predominantly (83%) occurring in donors aged 18-47 years. Each year infection rates were elevated between December and July, with April accounting for 16% of infections. The years 2004 and 2009 were epidemic, with up to 1/4880 highly viraemic donations in May 2004. In a subset of 67 viraemic donations, 47/67 (70%) tested negative for IgG and IgM antibodies to B19; 16/67 (24%) showed isolated IgM and 4/67 (6%) contained IgG and IgM antibodies. The seasonal pattern of asymptomatic B19 infection in blood donors followed the notification rate of clinical cases."

New Parvoviruses

New DNA viruses identified in patients with acute viral infection syndrome. MS Jones, A Kapoor, VV Lukashov, P Simmonds, F Hecht, E Delwart. J Virol. 2005 Jul;79(13):8230-6. A parvovirus and two viruses related to TT virus (TTV) were discovered among 25 individuals with acute viral syndrome of unknown etiology.

Novel Parvovirus and Related Variant in Human Plasma. JF Fryer, A Kapoor, PD Minor, E Delwart, SA Baylis. Emerg Infect Dis 2006 Jan;12(1):05-0916. 5% of human plasma pools tested positive for the parvovirus found by Jones, which was named PARV4. "As yet, nothing is known about the prevalence of PARV4, its possible role in human disease, or whether PARV4 was transmitted to the original patient from an unidentified animal host."

Human bocavirus: clinical significance and implications. J Kahn. Curr Opin Pediatr 2008 Feb;20(1):62-66. Review. "Human bocavirus (HBoV), a parvovirus, was discovered in 2005 with the use of nonspecific genome amplification techniques. Since its discovery, HBoV has been identified worldwide.... HBoV is not confined to the respiratory tract as evidence of the virus has been detected in serum and stool, the significance of which remains unclear. Presence of the virus in respiratory secretions, serum and stool suggests that this virus may cause systemic illness."

Persistence of novel human parvovirus PARV4 in liver tissue of adults. B Schneider, JF Fryer, U Reber, HP Fischer, RH Tolba, SA Baylis, AM Eis-Hübinger. J Med Virol 2008 Feb;80(2):345-351. PARV4 DNA was detected in 13 (15%) liver tissue specimens from 87 individuals, 1 HIV+. Serum samples from 40 of these individuals all tested negative for PARV4 DNA.

Human parvovirus PARV4 DNA in tissues from adult individuals: a comparison with human parvovirus B19(B19V). F Corcioli, K Zakrzewska, R Fanci, V De Giorgi, M Innocenti, M Rotellini, S Di Lollo, A Azzi. Virol J 2010 Oct 15;7(1):272. In "individuals without suspect of acute viral infection... Low amount of PARV4 DNA was found frequently (>40%) in heart and liver of adults individuals, less frequently in lungs and kidneys (23,5 and 18% respectively) and was rare in bone marrow, skin and synovium samples (5,5%, 4% and 5%, respectively). By comparison, B19V DNA sequences were present in the same tissues with a higher frequency (significantly higher in myocardium, skin and bone marrow) except than in liver where the frequency was the same of PARV4 DNA and in plasma samples where B19V frequency was significantly lower than that of PARV4."

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cast 09-29-11