Parvovirus B19 infection transmitted by transfusion of red blood cells confirmed by molecular analysis of linked donor and recipient samples
Mei-ying W. Yu
From the Division of Hematology, Center for Biologics Evaluation and Research (CBER), FDA, and the Department of Transfusion Medicine, Warren Grant Magnuson Clinical Center, NIH, Bethesda, Maryland; and the Division of Laboratory Medicine, Children's National Medical Center, Department of Pediatrics, George Washington University School of Medicine and Health Sciences, Washington, DC.
Search for more papers by this authorHarvey J. Alter
From the Division of Hematology, Center for Biologics Evaluation and Research (CBER), FDA, and the Department of Transfusion Medicine, Warren Grant Magnuson Clinical Center, NIH, Bethesda, Maryland; and the Division of Laboratory Medicine, Children's National Medical Center, Department of Pediatrics, George Washington University School of Medicine and Health Sciences, Washington, DC.
Search for more papers by this authorMaria Luisa A. Virata-Theimer
From the Division of Hematology, Center for Biologics Evaluation and Research (CBER), FDA, and the Department of Transfusion Medicine, Warren Grant Magnuson Clinical Center, NIH, Bethesda, Maryland; and the Division of Laboratory Medicine, Children's National Medical Center, Department of Pediatrics, George Washington University School of Medicine and Health Sciences, Washington, DC.
Search for more papers by this authorYansheng Geng
From the Division of Hematology, Center for Biologics Evaluation and Research (CBER), FDA, and the Department of Transfusion Medicine, Warren Grant Magnuson Clinical Center, NIH, Bethesda, Maryland; and the Division of Laboratory Medicine, Children's National Medical Center, Department of Pediatrics, George Washington University School of Medicine and Health Sciences, Washington, DC.
Search for more papers by this authorLi Ma
From the Division of Hematology, Center for Biologics Evaluation and Research (CBER), FDA, and the Department of Transfusion Medicine, Warren Grant Magnuson Clinical Center, NIH, Bethesda, Maryland; and the Division of Laboratory Medicine, Children's National Medical Center, Department of Pediatrics, George Washington University School of Medicine and Health Sciences, Washington, DC.
Search for more papers by this authorCathy A. Schechterly
From the Division of Hematology, Center for Biologics Evaluation and Research (CBER), FDA, and the Department of Transfusion Medicine, Warren Grant Magnuson Clinical Center, NIH, Bethesda, Maryland; and the Division of Laboratory Medicine, Children's National Medical Center, Department of Pediatrics, George Washington University School of Medicine and Health Sciences, Washington, DC.
Search for more papers by this authorCamilla A. Colvin
From the Division of Hematology, Center for Biologics Evaluation and Research (CBER), FDA, and the Department of Transfusion Medicine, Warren Grant Magnuson Clinical Center, NIH, Bethesda, Maryland; and the Division of Laboratory Medicine, Children's National Medical Center, Department of Pediatrics, George Washington University School of Medicine and Health Sciences, Washington, DC.
Search for more papers by this authorNaomi L.C. Luban
From the Division of Hematology, Center for Biologics Evaluation and Research (CBER), FDA, and the Department of Transfusion Medicine, Warren Grant Magnuson Clinical Center, NIH, Bethesda, Maryland; and the Division of Laboratory Medicine, Children's National Medical Center, Department of Pediatrics, George Washington University School of Medicine and Health Sciences, Washington, DC.
Search for more papers by this authorMei-ying W. Yu
From the Division of Hematology, Center for Biologics Evaluation and Research (CBER), FDA, and the Department of Transfusion Medicine, Warren Grant Magnuson Clinical Center, NIH, Bethesda, Maryland; and the Division of Laboratory Medicine, Children's National Medical Center, Department of Pediatrics, George Washington University School of Medicine and Health Sciences, Washington, DC.
Search for more papers by this authorHarvey J. Alter
From the Division of Hematology, Center for Biologics Evaluation and Research (CBER), FDA, and the Department of Transfusion Medicine, Warren Grant Magnuson Clinical Center, NIH, Bethesda, Maryland; and the Division of Laboratory Medicine, Children's National Medical Center, Department of Pediatrics, George Washington University School of Medicine and Health Sciences, Washington, DC.
Search for more papers by this authorMaria Luisa A. Virata-Theimer
From the Division of Hematology, Center for Biologics Evaluation and Research (CBER), FDA, and the Department of Transfusion Medicine, Warren Grant Magnuson Clinical Center, NIH, Bethesda, Maryland; and the Division of Laboratory Medicine, Children's National Medical Center, Department of Pediatrics, George Washington University School of Medicine and Health Sciences, Washington, DC.
Search for more papers by this authorYansheng Geng
From the Division of Hematology, Center for Biologics Evaluation and Research (CBER), FDA, and the Department of Transfusion Medicine, Warren Grant Magnuson Clinical Center, NIH, Bethesda, Maryland; and the Division of Laboratory Medicine, Children's National Medical Center, Department of Pediatrics, George Washington University School of Medicine and Health Sciences, Washington, DC.
Search for more papers by this authorLi Ma
From the Division of Hematology, Center for Biologics Evaluation and Research (CBER), FDA, and the Department of Transfusion Medicine, Warren Grant Magnuson Clinical Center, NIH, Bethesda, Maryland; and the Division of Laboratory Medicine, Children's National Medical Center, Department of Pediatrics, George Washington University School of Medicine and Health Sciences, Washington, DC.
Search for more papers by this authorCathy A. Schechterly
From the Division of Hematology, Center for Biologics Evaluation and Research (CBER), FDA, and the Department of Transfusion Medicine, Warren Grant Magnuson Clinical Center, NIH, Bethesda, Maryland; and the Division of Laboratory Medicine, Children's National Medical Center, Department of Pediatrics, George Washington University School of Medicine and Health Sciences, Washington, DC.
Search for more papers by this authorCamilla A. Colvin
From the Division of Hematology, Center for Biologics Evaluation and Research (CBER), FDA, and the Department of Transfusion Medicine, Warren Grant Magnuson Clinical Center, NIH, Bethesda, Maryland; and the Division of Laboratory Medicine, Children's National Medical Center, Department of Pediatrics, George Washington University School of Medicine and Health Sciences, Washington, DC.
Search for more papers by this authorNaomi L.C. Luban
From the Division of Hematology, Center for Biologics Evaluation and Research (CBER), FDA, and the Department of Transfusion Medicine, Warren Grant Magnuson Clinical Center, NIH, Bethesda, Maryland; and the Division of Laboratory Medicine, Children's National Medical Center, Department of Pediatrics, George Washington University School of Medicine and Health Sciences, Washington, DC.
Search for more papers by this authorThe findings and conclusions in this article have not been formally disseminated by the FDA and should not be construed to represent any Agency determination or policy.
The study was funded in part by a grant from the NIH and in part by the Intramural Research Program of the NIH Clinical Center and that of CBER, FDA.
Abstract
BACKGROUND: Extremely high viremic levels of parvovirus B19 (B19V) can be found in acutely infected, but asymptomatic donors. However, reports of transmission by single-donor blood components are rare. In this prospective study, paired donor-recipient samples were used to investigate the transfusion risk.
STUDY DESIGN AND METHODS: Posttransfusion plasma or blood samples from recipients were tested for B19V DNA by polymerase chain reaction, generally at 4 and 8 weeks, and for anti-B19V immunoglobulin (Ig)G by enzyme immunoassay, at 12 and 24 weeks. To rule out infection unrelated to transfusion, pretransfusion samples and linked donor's samples for each B19V DNA–positive recipient were assayed for B19V DNA and anti-B19V IgG and IgM. To confirm transmission, sequencing and phylogenetic analysis were performed.
RESULTS: A total of 14 of 869 (1.6%) recipients were B19V DNA positive, but only 1 of 869 (0.12%; 95% confidence interval, 0.0029%-0.6409%) was negative for B19V DNA and anti-B19V IgG before transfusion and seroconverted posttransfusion. This newly infected patient received 5 × 1010 IU B19V DNA in one red blood cell (RBC) unit from an acutely infected anti-B19V–negative donor in addition to RBCs from three other donors that cumulatively contained 1320 IU of anti-B19V IgG. DNA sequencing and phylogenetic analysis showed that sequences from the linked donor and recipient were identical (Genotype 1), thus establishing transfusion transmission.
CONCLUSIONS: The 0.12% transmission rate documented here, although low, could nonetheless result in hundreds or thousands of infections annually in the United States based on calculated confidence limits. Although most would be asymptomatic, some could have severe clinical outcomes, especially in neonates and those with immunocompromised or hemolytic states.
REFERENCES
- 1 Young NS, Brown KE. Mechanisms of disease: parvovirus B19. N Engl J Med 2004; 350: 586-97.
- 2 Siegl G, Cassinotti P. Presence and significance of parvovirus B19 in blood and blood products. Biologicals 1998; 26: 89-94.
- 3 Yee TT, Cohen BJ, Pasi KJ, Lee CA. Transmission of symptomatic parvovirus B19 infection by clotting factor concentrate. Br J Haematol 1996; 93: 457-9.
- 4 Santagostino E, Mannucci PM, Gringeri A, Azzi A, Morfini M, Musso R, Santoro R, Schiavoni M. Transmission of parvovirus B19 by coagulation factor concentrates exposed to 100 degrees C heat after lyophilization. Transfusion 1997; 37: 517-22.
- 5 Matsui H, Sugimoto M, Tsuji S, Shima M, Giddings J, Yoshioka A. Transient hypoplastic anemia caused by primary human parvovirus B19 infection in a previously untreated patient with hemophilia transfused with a plasma-derived, monoclonal antibody-purified factor VIII concentrate [case report]. J Pediatr Hematol Oncol 1999; 21: 74-6.
- 6 Azzi A, Morfini M, Mannucci PM. The transfusion-associated transmission of parvovirus B19. Transfus Med Rev 1999; 13: 194-204.
- 7 Blümel J, Schmidt I, Effenberger W, Seitz H, Willkommen H, Brackmann HH, Löwer J, Eis-Hubinger AM. Parvovirus B19 transmission by heat-treated clotting factor concentrates. Transfusion 2002; 42: 1473-81.
- 8 Wu CG, Mason B, Jong J, Erdman D, McKernan L, Oakley M, Soucie M, Evatt B, Yu MW. Parvovirus B19 transmission by a high-purity factor VIII concentrate. Transfusion 2005; 45: 1003-10.
- 9 Blood Products Advisory Committee. Nucleic acid testing of blood donors for human parvovirus B19 [Internet]. Rockville (MD): U.S. Food and Drug Administration; 1999. p. 144-222. [cited 17 Jan 2010]. Available from: http://www.fda.gov/ohrms/dockets/ac/99/transcpt/3548t1b.pdf and http://www.fda.gov/ohrms/dockets/ac/99/transcpt/3548t1c.pdf
- 10 Brown KE, Young NS, Alving BM, Barbosa LH. Parvovirus B19: implications for transfusion medicine, summary of a workshop. Transfusion 2001; 41: 130-5.
- 11 Geng Y, Wu CG, Bhattacharyya SP, Tan D, Guo ZP, Yu MW. Parvovirus B19 DNA in factor VIII concentrates: effects of manufacturing procedures and B19 screening by nucleic acid testing. Transfusion 2007; 47: 883-9.
- 12 Anderson MJ, Tsou C, Parker RA, Chorba TL, Woffe H, Tattersall P, Mortimer PP. Detection of antibodies and antigen of human parvovirus B19 by enzyme-linked immunosorbent assay. J Clin Microbiol 1986; 24: 522-6.
- 13 Cohen BJ, Buckley MM. The prevalence of antibody to human parvovirus B19 in England and Wales. J Med Microbiol 1988; 25: 151-3.
- 14 Wong S, Brown KE. Development of an improved method of detection of infectious parvovirus B19. J Clin Virol 2006; 35: 407-13.
- 15 Modrof J, Berting A, Tille B, Klotz A, Forstner C, Rieger S, Aberham C, Gessner M, Kreil TR. Neutralization of human parvovirus B19 by plasma and intravenous immunoglobulins. Transfusion 2008; 48: 178-86.
- 16 Jordan J, Tiangco B, Kiss J, Koch W. Human parvovirus B19: prevalence of viral DNA in volunteer blood donors and clinical outcomes of transfusion recipients. Vox Sang 1998; 75: 97-102.
- 17 Aubin JT, Defer C, Vidaud M, Maniez Montreuil M, Flan B. Large-scale screening for human parvovirus B19 DNA by PCR: application to the quality control of plasma for fractionation. Vox Sang 2000; 78: 7-12.
- 18 Weimer T, Streichert S, Watson C, Gröner A. High-titer screening PCR: a successful strategy for reducing the parvovirus B19 load in plasma pools for fractionation. Transfusion 2001; 41: 1500-4.
- 19 Schmidt M, Themann A, Drexler C, Bayer M, Lanzer G, Menichetti E, Lechner S, Wessin D, Prokoph B, Allain JP, Seifried E, Hourfar MK. Blood donor screening for parvovirus B19 in Germany and Austria. Transfusion 2007; 47: 1775-82.
- 20 Kleinman SH, Glynn SA, Lee TH, Tobler L, Montalvo L, Todd D, Kiss JE, Shyamala V, Busch MP, National Heart, Lung, and Blood Institute Retrovirus Epidemiology Donor Study (REDS-II). Prevalence and quantitation of parvovirus B19 DNA levels in blood donors with a sensitive polymerase chain reaction screening assay. Transfusion 2007; 47: 1756-64.
- 21 Kerr JR, Curran MD, Moore JE, Coyle PV, Ferguson WP. Persistent parvovirus B19 infection. Lancet 1995; 345: 1118.
- 22 Cassinotti P, Siegl G. Quantitative evidence for persistence of human parvovirus B19 DNA in an immunocompetent individual. Eur J Clin Microbiol Infect Dis 2000; 19: 886-95.
- 23 Lefrère JJ, Servant-Delmas A, Candotti D, Mariotti M, Thomas I, Brossard Y, Lefrère F, Girot R, Allain JP, Laperche S. Persistent B19 infection in immunocompetent individuals: implications for transfusion safety. Blood 2005; 106: 2890-5.
- 24 Matsukura H, Shibata S, Tani Y, Shibata H, Furuta RA. Persistent infection by human parvovirus B19 in qualified blood donors. Transfusion 2008; 48: 1036-7.
- 25 Blood Products Advisory Committee. Human parvovirus B19 NAT testing for whole blood and source plasma [Internet]. Rockville (MD): U.S. Food and Drug Administration; 2002. p. 299-440. [cited 17 Jan 2010]. Available from: http://www.fda.gov/ohrms/dockets/ac/02/transcripts/3913t1.pdf
- 26 Zanella A, Rossi F, Cesana C, Foresti A, Nador F, Binda AS, Lunghi G, Cappellini MD, Furione M, Sirchia G. Transfusion-transmitted human parvovirus B19 infection in a thalassemic patient. Transfusion 1995; 35: 769-72.
- 27 Yoto Y, Kudoh T, Haseyama K, Suzuki N, Oda T, Katoh T, Takahashi T, Sekiguchi S, Chiba S. Incidence of human parvovirus B19 DNA detection in blood donors. Br J Haematol 1995; 91: 1017-8.
- 28 Cohen BJ, Beard S, Knowles WA, Ellis JS, Joske D, Goldman JM, Hewitt P, Ward KN. Chronic anemia due to parvovirus B19 infection in a bone marrow transplant patient after platelet transfusion. Transfusion 1997; 37: 947-52.
- 29 Shade RO, Blundell MC, Cotmore SF, Tattersall P, Astell CR. Nucleotide sequence and genome organization of human parvovirus B19 isolated from the serum of a child during aplastic crisis. J Virol 1986; 58: 921-36.
- 30 Saldanha J, Lelie N, Yu MW, Heath A, B19 Collaborative Study Group. Establishment of the first World Health Organization International Standard for human parvovirus B19 DNA nucleic acid amplification techniques. Vox Sang 2002; 82: 24-31.
- 31 Ferguson M, Walker D, Cohen B. Report of a collaborative study to establish the international standard for parvovirus B19 serum IgG. Biologicals 1997; 25: 283-8.
- 32 Dorsch S, Kaufmann B, Schaible U, Prohaska E, Wolf H, Modrow S. The VP1-unique region of parvovirus B19: amino acid variability and antigenic stability. J Gen Virol 2001; 82: 191-9.
- 33 Parsyan A, Addo-Yobo E, Owusu-Ofori S, Akpene H, Sarkodie F, Allain JP. Effects of transfusion on human erythrovirus B19-susceptible or -infected pediatric recipients in a genotype 3-endemic area. Transfusion 2006; 46: 1593-600.
- 34 Plentz A, Hahn J, Knöll A, Holler E, Jilg W, Modrow S. Exposure of hematologic patients to parvovirus B19 as a contaminant of blood cell preparations and blood products. Transfusion 2005; 45: 1811-5.
- 35 Kleinman SH, Glynn SA, Lee TH, Tobler LH, Schlumpf KS, Todd DS, Qiao H, Yu MW, Busch MP, for the NHLBI Retrovirus Epidemiology Donor Study-II (REDS-II). A linked donor-recipient study to evaluate parvovirus B19 transmission by blood component transfusion. Blood 2009; 114: 3677-83.
- 36 Anderson MJ, Higgins PG, Davis LR, Willman JS, Jones SE, Kidd IM, Pattison JR, Tyrrell DA. Experimental parvoviral infection in humans. J Infect Dis 1985; 152: 257-65.
- 37 Servant A, Laperche S, Lallemand F, Marinho V, De Saint Maur G, Meritet JF, Garbarg-Chenon A. Genetic diversity within human erythroviruses: identification of three genotypes. J Virol 2002; 76: 9124-34.
- 38 Blümel J, Eis-Hübinger AM, Stühler A, Bönsch C, Gessner M, Löwer J. Characterization of parvovirus B19 genotype 2 in KU812Ep6 cells. J Virol 2005; 79: 14197-206.
- 39 Schneider B, Becker M, Brackmann HH, Eis-Hübinger AM. Contamination of coagulation factor concentrates with human parvovirus B19 genotype 1 and 2. Thromb Haemost 2004; 92: 838-45.
- 40 Baylis S. Standardization of nucleic acid amplification technique (NAT)-based assays for different genotypes of parvovirus B19: a meeting summary. Vox Sang 2008; 94: 74-80.
- 41 Candotti D, Etiz N, Parsyan A, Allain JP. Identification and characterization of persistent human erythrovirus infection in blood donor samples. J Virol 2004; 78: 12169-78.
- 42 Baylis SA, Shah N, Minor PD. Evaluation of different assays for the detection of parvovirus B19 DNA in human plasma. J Virol Methods 2004; 121: 7-16.
- 43 Rinckel LA, Buno RB, Gierman TM, Lee DC. Discovery and analysis of a novel parvovirus B19 genotype 3 isolate in the United States. Transfusion 2009; 49: 1488-92.
- 44 Ekman A, Hokynar K, Kakkola L, Kantola K, Hedman L, Bondén H, Gessner M, Aberham C, Norja P, Miettinen S, Hedman K, Söderlund-Venermo M. Biological and immunological relations among human parvovirus B19 genotypes 1-3. J Virol 2007; 81: 6927-35.
- 45 Doyle S, Corcoran A. The immune response to parvovirus B19 exposure in previously seronegative and seropositive individuals. J Inf Dis 2006; 194: 154-8.
- 46 U.S. Food and Drug Administration. Nucleic acid testing (NAT) to reduce the possible risk of parvovirus B19 transmission by plasma-derived products. Rockville (MD): FDA Center for Biologics Evaluation and Research; 2008. FDA draft guidance for industry.
- 47 Human anti-D immunoglobulin. Strasbourg, France: European Directorate for the Quality of Medicines & HealthCare; 2008. Ph Eur monograph 0557.
- 48 Human anti-D immunoglobulin for intravenous administration. Strasbourg, France: European Directorate for the Quality of Medicines & HealthCare; 2008. Ph Eur monograph 1527.
- 49 Human plasma (pooled and treated for virus inactivation). Strasbourg, France: European Directorate for the Quality of Medicines & HealthCare; 2009. Ph Eur monograph 1646.
- 50 OMCL Guideline for validation of nucleic acid amplification techniques (NAT) for quantitation of B19 virus DNA in plasma pools. Strasbourg, France: European Directorate for the Quality of Medicines & HealthCare; 2007. Official Control Authority Batch Release (OCABR) of Biological Substances guideline PA/PH/OMCL (07) 47, DEF.
- 51 Schmidt M, Mayr-Wohlfart U, Hourfar MK, Schrezenmeier H, Sireis W, Seifried E. Infectivity of B19 positive blood products. Vox Sang 2009; 96 Suppl 1: 54.
Citing Literature
