Human Parvovirus B19 in Solid Organ Transplantation

Abstract

The Parvoviridae family includes the genus erythrovirus with human parvovirus B19 being the classic type member. The virus is 25 nm in diameter, nonenveloped and consists of a single-strand linear DNA that is approximately 5 kb in length. The viral genome encodes three main proteins, a nonstructural protein (NS1) and two structural proteins (VP1 and VP2; Ref. 1Berns KP Colin R Parvoviridae.in: Knipe DHP Fields Virology.5th ed. Lippincott Williams and Wilkins, Philadelphia2007: 2438Google Scholar). The nonstructural protein is cytotoxic to host cells (2Moffatt S Yaegashi N Tada K Tanaka N Sugamura K. Human parvovirus B19 nonstructural (NS1) protein induces apoptosis in erythroid lineage cells.J Virol. 1998; 72: 3018-3028Crossref PubMed Google Scholar,3Ozawa K Ayub J Kajigaya S Shimada T Young N The gene encoding the nonstructural protein of B19 (human) parvovirus may be lethal in transfected cells.J Virol. 1988; 62: 2884-2889Crossref PubMed Scopus (173) Google Scholar). Parvovirus B19 is classified into three different genotypes (genotype 1, 2, 3), but there is no definitive association of genotypes with specific clinical manifestations. Parvovirus B19 was first detected in a healthy blood donor’s serum in 1974 (4Cossart YE Field AM Cant B Widdows D Parvovirus-like particles in human sera.Lancet. 1975; 1: 72-73Abstract PubMed Scopus (773) Google Scholar). It was subsequently linked to disease in children with sickle cell anemia experiencing transient aplastic crisis (5Pattison JR Jones SE Hodgson J et al.Parvovirus infections and hypoplastic crisis in sickle-cell anaemia.Lancet. 1981; 1: 664-665Abstract PubMed Scopus (447) Google Scholar) and then in children with a contagious exanthem, called erythema infectiosum, or fifth disease (6Anderson MJ Lewis E Kidd IM Hall SM Cohen BJ An outbreak of erythema infectiosum associated with human parvovirus infection.J Hyg (Lond). 1984; 93: 85-93Crossref PubMed Scopus (271) Google Scholar). Parvovirus B19 has particular tropism for human erythroid progenitor cells, which is the natural host cell (7Mortimer PP Humphries RK Moore JG Purcell RH Young NS A human parvovirus-like virus inhibits haematopoietic colony formation in vitro.Nature. 1983; 302: 426-429Crossref PubMed Scopus (232) Google Scholar,8Potter CG Potter AC Hatton CS et al.Variation of erythroid and myeloid precursors in the marrow and peripheral blood of volunteer subjects infected with human parvovirus (B19).J Clin Invest. 1987; 79: 1486-1492Crossref PubMed Scopus (136) Google Scholar). The cellular receptor is globoside (also called erythrocyte P antigen; Ref. 9Brown KE Anderson SM Young NS Erythrocyte P antigen: Cellular receptor for B19 parvovirus.Science. 1993; 262: 114-117Crossref PubMed Scopus (738) Google Scholar), which is found on erythroid cells, erythroid precursors and red cells of the placenta and fetal myocardium, fetal liver and some megakaryocytes and endothelial cells. Viral replication induces a distinctive cytopathic effect by light microscopy, represented by giant pronormoblasts (10Caul EO Usher MJ Burton PA Intrauterine infection with human parvovirus B19: A light and electron microscopy study.J Med Virol. 1988; 24: 55-66Crossref PubMed Scopus (63) Google Scholar), and productive infection has only been described in erythroid precursors (11Ozawa K Kurtzman G Young N Replication of the B19 parvovirus in human bone marrow cell cultures.Science. 1986; 233: 883-886Crossref PubMed Scopus (267) Google Scholar). Although P antigen receptors are found on nonerythroid cells, there is evidence that a region of the viral genome is responsible for inhibiting viral replication in nonpermissive cells (12Pallier C Greco A Le Junter J Saib A Vassias I Morinet F The 3’ untranslated region of the B19 parvovirus capsid protein mRNAs inhibits its own mRNA translation in nonpermissive cells.J Virol. 1997; 71: 9482-9489Crossref Scopus (49) Google Scholar). Parvovirus B19 is ubiquitous and a common illness of childhood so that half of the population have detectable IgG antibody by 15 years of age (13Risks associated with human parvovirus B19 infection.MMWR Morb Mortal Wkly Rep. 1989; 38 (93–97.): 81-88PubMed Google Scholar,14Anderson LJ Tsou C Parker RA et al.Detection of antibodies and antigens of human parvovirus B19 by enzyme-linked immunosorbent assay.J Clin Microbiol. 1986; 24: 522-526Crossref PubMed Scopus (239) Google Scholar). Most infections occur in the spring in temperate climates with small epidemics regularly occurring several years apart (15Human parvovirus B19 infections in United Kingdom 1984–86.Lancet. 1987; 1: 738-739Abstract Scopus (60) Google Scholar). The incidence of parvovirus infection in solid organ transplant patients is unknown because of the lack of surveillance studies. Based on detection of parvovirus DNA in peripheral blood, one study reported a single institution incidence of 12% in kidney transplant patients who had anemia (16Ki CS Kim IS Kim JW et al.Incidence and clinical significance of human parvovirus B19 infection in kidney transplant recipients.Clin Transplant. 2005; 19: 751-755Crossref PubMed Scopus (49) Google Scholar). Transmission of parvovirus B19 appears to be via respiratory secretions (6Anderson MJ Lewis E Kidd IM Hall SM Cohen BJ An outbreak of erythema infectiosum associated with human parvovirus infection.J Hyg (Lond). 1984; 93: 85-93Crossref PubMed Scopus (271) Google Scholar,17Serjeant GR Topley JM Mason K et al.Outbreak of aplastic crises in sickle cell anaemia associated with parvovirus-like agent.Lancet. 1981; 2: 595-597Abstract Scopus (313) Google Scholar). Direct intranasal inoculation of parvovirus B19 into healthy volunteers resulted in viremia and clinical manifestations (18Anderson MJ Higgins PG Davis LR et al.Experimental parvoviral infection in humans.J Infect Dis. 1985; 152: 257-265Crossref PubMed Scopus (624) Google Scholar). Transmission can also occur to the fetus via transplacental infection and rarely through blood products (19Anand A Gray ES Brown T Clewley JP Cohen BJ Human parvovirus infection in pregnancy and hydrops fetalis.N Engl J Med. 1987; 316: 183-186Crossref PubMed Scopus (361) Google Scholar,20Parsyan A Candotti D Human erythrovirus B19 and blood transfusion—an update.Transfus Med. 2007; 17: 263-278Crossref PubMed Scopus (66) Google Scholar). No FDA approved test is available for parvovirus B19 screening in blood donors. However, nucleic acid testing (NAT) is available for plasma units in process of being fractionated (21Stramer SL Hollinger FB Katz LM et al.Emerging infectious disease agents and their potential threat to transfusion safety.Transfusion. 2009; 49: 1S-29SCrossref PubMed Scopus (303) Google Scholar). There is evidence that transmission of parvovirus B19 infection may occur at the time of transplantation (22Barzon L Murer L Pacenti M et al.Detection of viral DNA in kidney graft preservation and washing solutions is predictive of posttransplant infections in pediatric recipients.J Infect Dis. 2009; 200: 1425-1433Crossref Scopus (16) Google Scholar, 23Heegaard ED Laub Petersen B Parvovirus B19 transmitted by bone marrow.Br J Haematol. 2000; 111: 659-661Crossref PubMed Scopus (48) Google Scholar, 24Yango Jr., A Morrissey P Gohh R Wahbeh A Donor-transmitted parvovirus infection in a kidney transplant recipient presenting as pancytopenia and allograft dysfunction.Transpl Infect Dis. 2002; 4: 163-166Crossref PubMed Scopus (49) Google Scholar). Barzon et al. showed that in the majority of 10 pediatric kidney transplant patients (pretransplant parvovirus serology D+/R−), positive detection of parvovirus B19 DNA in the allograft kidney biopsy sample, preservation solution or washing solution (which contain circulating donor cells and resident kidney cells) was associated with posttransplant detection of parvovirus DNA in the blood of the recipient (22Barzon L Murer L Pacenti M et al.Detection of viral DNA in kidney graft preservation and washing solutions is predictive of posttransplant infections in pediatric recipients.J Infect Dis. 2009; 200: 1425-1433Crossref Scopus (16) Google Scholar). The incubation period ranges from 4–14 days, and individuals with erythema infectiosum are contagious before onset of rash but rarely afterwards. Individuals with aplastic crisis can be contagious before symptoms until about one week after onset of symptoms (25Bell LM Naides SJ Stoffman P Hodinka RL Plotkin SA Human parvovirus B19 infection among hospital staff members after contact with infected patients.N Engl J Med. 1989; 321: 485-491Crossref PubMed Scopus (156) Google Scholar). Secondary infection rates are 50% for susceptible household members (26Chorba T Coccia P Holman RC et al.The role of parvovirus B19 in aplastic crisis and erythema infectiosum (fifth disease).J Infect Dis. 1986; 154: 383-393Crossref PubMed Scopus (194) Google Scholar) and 20% for school and childcare personnel (27Gillespie SM Cartter ML Asch S et al.Occupational risk of human parvovirus B19 infection for school and day-care personnel during an outbreak of erythema infectiosum.JAMA. 1990; 263: 2061-2065Crossref PubMed Scopus (133) Google Scholar). Transmission to hospital personnel can occur. The clinical manifestations of parvovirus B19 infection in immunocompromised patients are atypical (Table 1). Among SOT recipients, fever, arthralgia and rash were observed in 25%, 7% and 6% of patients with parvovirus B19 infection, respectively. Anemia, however, was present in 99% of the patients (28Eid AJ Brown RA Patel R Razonable RR Parvovirus B19 infection after transplantation: A review of 98 cases.Clin Infect Dis. 2006; 43: 40-48Crossref PubMed Scopus (167) Google Scholar). Therefore, parvovirus B19 infection should be suspected in SOT recipients with erythropoietin-resistant anemia since the reported incidence in this group of patients is relatively high (29Bertoni E Rosati A Zanazzi M et al.Unusual incidence of aplastic anaemia due to B-19 parvovirus infection in renal transplant recipients.Transplant Proc. 1997; 29: 818-819Crossref Scopus (24) Google Scholar).Table 1:Clinical manifestations of parvovirus B19 in immunocompromised hostsPersistent anemiaSevere anemia• Lack of reticulocyte response• Lack of response to erythropoietinFever• Observed in 25% of solid organ transplant patients.Lacy skin rash• Not always present because of lack of antigen-antibody complexes (30Young NS Brown KE Parvovirus B19.N Engl J Med. 2004; 350: 586-597Crossref PubMed Scopus (739) Google Scholar,33Kurtzman GJ Cohen BJ Field AM Oseas R Blaese RM Young NS Immune response to B19 parvovirus and an antibody defect in persistent viral infection.J Clin Invest. 1989; 84: 1114-1123Crossref PubMed Scopus (294) Google Scholar)Arthropathy• Not always present because of lack of antigen-antibody complexes (30Young NS Brown KE Parvovirus B19.N Engl J Med. 2004; 350: 586-597Crossref PubMed Scopus (739) Google Scholar,33Kurtzman GJ Cohen BJ Field AM Oseas R Blaese RM Young NS Immune response to B19 parvovirus and an antibody defect in persistent viral infection.J Clin Invest. 1989; 84: 1114-1123Crossref PubMed Scopus (294) Google Scholar)Pancytopenia• A subset of patients will manifest concomitant leukopenia or thrombocytopenia with the anemia (8Potter CG Potter AC Hatton CS et al.Variation of erythroid and myeloid precursors in the marrow and peripheral blood of volunteer subjects infected with human parvovirus (B19).J Clin Invest. 1987; 79: 1486-1492Crossref PubMed Scopus (136) Google Scholar,18Anderson MJ Higgins PG Davis LR et al.Experimental parvoviral infection in humans.J Infect Dis. 1985; 152: 257-265Crossref PubMed Scopus (624) Google Scholar,51Saunders PW Reid MM Cohen BJ Human parvovirus induced cytopenias: A report of five cases.Br J Haematol. 1986; 63: 407-4010Crossref PubMed Scopus (61) Google Scholar).• The pathogenesis is speculated to be non-specific cytopathic effects in the bone marrow (8Potter CG Potter AC Hatton CS et al.Variation of erythroid and myeloid precursors in the marrow and peripheral blood of volunteer subjects infected with human parvovirus (B19).J Clin Invest. 1987; 79: 1486-1492Crossref PubMed Scopus (136) Google Scholar) or restricted non-structural protein expression in megakaryocytes, which leads to cytotoxicity but not viral progeny (52Srivastava A Bruno E Briddell R et al.Parvovirus B19-induced perturbation of human megakaryocytopoiesis in vitro.Blood. 1990; 76: 1997-2004Crossref PubMed Google Scholar). Open table in a new tab Many clinical manifestations have been associated with parvovirus B19 (30Young NS Brown KE Parvovirus B19.N Engl J Med. 2004; 350: 586-597Crossref PubMed Scopus (739) Google Scholar). However, the association with parvovirus is predominantly based on finding DNA in tissue, which may not be proof of causation. Parvovirus DNA has been found persistently in a number of tissues including bone marrow, synovium, heart tissue and skin from individuals who are asymptomatic (31Corcioli F Zakrzewska K Rinieri A et al.Tissue persistence of parvovirus B19 genotypes in asymptomatic persons.J Med Virol. 2008; 80: 2005-2011Crossref PubMed Scopus (72) Google Scholar). The reason for the persistence is unclear but may be related to inhibition of viral replication in nonpermissive cells. Furthermore, normal healthy blood donors have been found to have circulating parvovirus B19 DNA in peripheral blood (32Kooistra K Mesman HJ de Waal M Koppelman MH Zaaijer HL Epidemiology of high-level parvovirus B19 viraemia among Dutch blood donors, 2003–2009.Vox Sang. 2011; 100: 261-266Crossref PubMed Scopus (41) Google Scholar). Antibody response to parvovirus B19 appears to confer life-long protective immunity for the individual. Lack of an antibody response is observed in patients with persistent infection (33Kurtzman GJ Cohen BJ Field AM Oseas R Blaese RM Young NS Immune response to B19 parvovirus and an antibody defect in persistent viral infection.J Clin Invest. 1989; 84: 1114-1123Crossref PubMed Scopus (294) Google Scholar). “Recurrences” of parvovirus B19 infection may be more related to poor initial neutralizing antibody production in immunocompetent and immunocompromised hosts. T cell responses to parvovirus B19 have been detected (34Tolfvenstam T Oxenius A Price DA et al.Direct ex vivo measurement of CD8(+) T-lymphocyte responses to human parvovirus B19.J Virol. 2001; 75: 540-543Crossref PubMed Scopus (39) Google Scholar) but their role in protective immunity is not clear (35Isa A Norbeck O Hirbod T et al.Aberrant cellular immune responses in humans infected persistently with parvovirus B19.J Med Virol. 2006; 78: 129-133Crossref PubMed Scopus (24) Google Scholar). Parvovirus B19 infection can be diagnosed by serology or direct viral detection in clinical specimen such as blood, bone marrow and other organs (i.e. liver, lung, kidney). In highly viremic patients following acute parvovirus B19 infection, serology might be falsely negative because antibodies could be complexed by viral particles (36Bredl S Plentz A Wenzel JJ Pfister H Most J Modrow S False-negative serology in patients with acute parvovirus B19 infection.J Clin Virol. 2011; 51: 115-120Crossref PubMed Scopus (39) Google Scholar). In addition, parvovirus B19 serology is not reliable in immunocompromised patients due to inadequate or delayed antibody-mediated immune response (37Broliden K Parvovirus B19 infection in pediatric solid-organ and bone marrow transplantation.Pediatr Transplant. 2001; 5: 320-330Crossref PubMed Scopus (82) Google Scholar,38Kurtzman GJ Ozawa K Cohen B Hanson G Oseas R Young NS Chronic bone marrow failure due to persistent B19 parvovirus infection.N Engl J Med. 1987; 317: 287-294Crossref PubMed Scopus (396) Google Scholar). Parvovirus B19 IgM antibody was present in only 75% of SOT recipients at the time of disease onset. The detection of parvovirus B19 IgG antibody alone is suggestive of remote infection and is uncommonly seen (7% of patients) among transplant recipients with parvovirus B19 infection (28Eid AJ Brown RA Patel R Razonable RR Parvovirus B19 infection after transplantation: A review of 98 cases.Clin Infect Dis. 2006; 43: 40-48Crossref PubMed Scopus (167) Google Scholar). The current use of polymerase chain reaction (PCR) assays significantly improved the detection of viral DNA (39Manaresi E Gallinella G Zuffi E Bonvicini F Zerbini M Musiani M Diagnosis and quantitative evaluation of parvovirus B19 infections by real-time PCR in the clinical laboratory.J Med Virol. 2002; 67: 275-281Crossref PubMed Scopus (59) Google Scholar). However, one should keep in mind that some PCR assays are unable to detect non-B19 strains (genotypes and SA A testing study to for the detection of different genotypes of parvovirus Sang. 2009; PubMed Scopus Google Scholar, SA N of different assays for the detection of parvovirus B19 DNA in human 2004; PubMed Scopus Google Scholar, M K et PCR for and of parvovirus B19 DNA in Clin Microbiol. 2001; PubMed Scopus Google Scholar), and real-time PCR can be falsely negative in of high-level viremia P A M et and of acute infection with parvovirus B19 in immunocompromised patients in Med Virol. 2011; PubMed Scopus Google Scholar). Furthermore, parvovirus B19 DNA can be detected by PCR in the serum of some patients for time after the acute of infection P G evidence for persistence of human parvovirus B19 DNA in an immunocompetent J Clin Infect Dis. 2000; 19: PubMed Scopus (66) Google Scholar). a positive PCR for parvovirus B19 not acute However, the positive predictive of positive PCR in an immunocompromised host with red cell is marrow associated with in or could be in the the clinical is suggestive of parvovirus B19 infection but the PCR and serology are negative (28Eid AJ Brown RA Patel R Razonable RR Parvovirus B19 infection after transplantation: A review of 98 cases.Clin Infect Dis. 2006; 43: 40-48Crossref PubMed Scopus (167) Google Scholar). bone marrow and the of giant pronormoblasts with and with a clear and B19 infection should be suspected in SOT recipients anemia or anemia with reticulocyte response with or arthralgia or disease such as disease or initial for suspected parvovirus B19 infection should serology and and blood PCR for parvovirus B19 not bone marrow should be parvovirus B19 infection is suspected and the serology and serum PCR are In addition, in or should be are not available for the of parvovirus B19 However, has to be in a number of SOT recipients with parvovirus B19 infection (28Eid AJ Brown RA Patel R Razonable RR Parvovirus B19 infection after transplantation: A review of 98 cases.Clin Infect Dis. 2006; 43: 40-48Crossref PubMed Scopus (167) Google aplastic anemia by parvovirus B19 infection in a heart transplant Transplant. Google M J of use in solid organ transplant J Transplant. 2011; PubMed Scopus (136) Google Scholar). The and of for parvovirus B19 infection has not been and some patients have been reported to have of the infection (28Eid AJ Brown RA Patel R Razonable RR Parvovirus B19 infection after transplantation: A review of 98 cases.Clin Infect Dis. 2006; 43: 40-48Crossref PubMed Scopus (167) Google Scholar). Most patients are with for 5 days, have been for of In one the of was not different among transplant recipients who a of or (28Eid AJ Brown RA Patel R Razonable RR Parvovirus B19 infection after transplantation: A review of 98 cases.Clin Infect Dis. 2006; 43: 40-48Crossref PubMed Scopus (167) Google Scholar). in the to of SOT recipients after The of PCR use to the response to is not that persistent viremia for clinical response to is not J MJ S of associated anemia in a renal transplant recipient induced by with and positive Infect Dis. 2005; PubMed Scopus Google Scholar). Therefore, be to measurement and parvovirus B19 PCR in of of with of parvovirus B19 infection have been with of J MJ S of associated anemia in a renal transplant recipient induced by with and positive Infect Dis. 2005; PubMed Scopus Google Scholar). there is a in the clinical in of and of The effects of fever, and renal The of is to to the of however, the of such an (i.e. before or after is a of with parvovirus B19 infection may be with of for 5 of should be at at the time of of to the first or in of of for 5 may be In the SOT no specific parvovirus B19 infection is screening of donor and recipient for parvovirus B19 is not In one donor and recipient and more the detection of viral DNA in renal allograft tissue, preservation solution or washing solution were to the risk of posttransplant viremia (22Barzon L Murer L Pacenti M et al.Detection of viral DNA in kidney graft preservation and washing solutions is predictive of posttransplant infections in pediatric recipients.J Infect Dis. 2009; 200: 1425-1433Crossref Scopus (16) Google Scholar). However, only a patients disease in this which the of of such Furthermore, to parvovirus B19 infection are to be at of transplant recipients to children or with parvovirus B19 have not been by group because patients are no In addition, the of this in transplant recipients, among pediatric transplant recipients, not the of such a and should be a has an in bone marrow transplant recipients have the of parvovirus B19 disease in of patients who for other A R S Zakrzewska K A Human parvovirus B19 infection in bone marrow transplantation J 1993; PubMed Scopus Google Scholar). However, the incidence of parvovirus infection among bone marrow transplant recipients who and who not are not Furthermore, the lack of evidence of in the SOT the incidence of parvovirus B19 infection and the high and potential associated with not its the of human parvovirus B19 of and capsid proteins is volunteers who or 25 of parvovirus B19 with the at and neutralizing antibody that after the and were through study Young NS S and of a parvovirus B19 with Infect Dis. PubMed Scopus Google Scholar). A clinical of the and of of a human parvovirus B19 by the of and was because of three the of the recipients and neutralizing antibody to parvovirus B19 et and of a parvovirus B19 2011; 29: PubMed Scopus (66) Google Scholar). a will be available in the for clinical use in However, will be to its use in the SOT and should be a has an should the of parvovirus B19 in SOT The significance of parvovirus B19 DNA detection in the blood or tissue from immunocompetent patients and SOT recipients should be are in to current and for parvovirus B19 are to new parvovirus B19 and the of their use among SOT and was from a by AJ in of 2009; and by the of of The of this have no of to as described by the of