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1. Oliver C, Blake D, Henry S. Modeling transfusion reactions

and predicting in vivo cell survival with kodecytes. Trans-

fusion 2011;51:1723-30.

2. Mock DM, Matthews NI, Zhu S, Strauss RG, Schmidt RL,

Nalbant D, Cress GA, Widness JA. Red blood cell (RBC) sur-

vival determined in humans using RBCs labeled at mul-

tiple biotin densities. Transfusion 2011;51:1047-57.

3. Franco RS. The measurement and importance of red cell

survival. Am J Hematol 2009;84:109-14.

4. Franco RS, Yasin Z, Palascak MB, Ciraolo P, Joiner CH,

Rucknagel DL. The effect of fetal hemoglobin on the sur-

vival characteristics of sickle cells. Blood 2006;108:1073-6.

5. Cohen RM, Franco RS, Khera PK, Smith EP, Lindsell CJ,

Ciraolo PJ, Palascak MB, Joiner CH. Red cell life span het-

erogeneity in hematologically normal people is sufficient

to alter HbA1c. Blood 2008;112:4284-91.

6. Cordle DG, Strauss RG, Lankford G, Mock DM. Antibodies

provoked by the transfusion of biotin-labeled red cells.

Transfusion 1999;39:1065-9.

Assessing causality in the transmission ofviruses by blood products_3614 1598..1604

Sharp and colleagues1 present data on a group of patientswith hemophilia of unspecified type, sampled between1989 and 1992 and tested at an unspecified time after theend of the study period for evidence of infection with par-vovirus 4 (PARV4). The study period precedes the modernera of coagulation factor manufacture, which since themid 1990s has been required by regulatory agencies toinclude two viral inactivation steps, one of which mustspecifically eliminate nonenveloped viruses.2 A succes-sion of studies has shown that the presence of PARV4 DNAhas progressively decreased over the past 40 years as morestringent donor selection procedures and improvedmanufacturing methods, in the form of purification andviral inactivation techniques, have been introduced.3,4 Themost recently manufactured products do not have detect-able PARV4 DNA.5 The study by Sharp and colleaguescannot discount the possibility that transmission couldhave occurred through contact in the treatment center,given the close temporal proximity of some of the infec-tions as detected by nucleic acid testing. We suggest thatnucleic acid matching between product and patientsamples in an algorithm may assist in evaluating reportsof suspected virus transmission.6 We agree with Sharp andcolleagues that the clinical signs manifested by theirinfected patients are potentially explained by their viralcomorbidities, and we suggest that data on the prevalenceof these signs in the patients not exhibiting PARV4 infec-tion would have continued to add to the usefulness of thishistorically interesting study.

CONFLICT OF INTEREST

The authors provide services to the commercial plasma protein

therapeutics industry.

Albert Farrugia, PhDe-mail: afarrugia@pptaglobal.org

Mary Gustafson, MS, MT(ASCP)SBBPlasma Protein Therapeutics Association

Annapolis, MD

REFERENCES

1. Sharp CP, Lail A, Donfield S, Gomperts ED, Simmonds P.

Virologic and clinical features of primary infection with

human parvovirus 4 in subjects with hemophilia: frequent

transmission by virally inactivated clotting factor concen-

trates. Transfusion 2012;52:1482-9.

2. European Agency for the Evaluation of Medicinal Products.

Note for guidance on plasma-derived medicinal products

1996. 1996. [cited 2012 Mar 8]. Available from: URL: http://

www.emea.europa.eu/docs/en_GB/document_library/

Scientific_guideline/2009/09/WC500003613.pdf

3. Fryer JF, Hubbard AR, Baylis SA. Human parvovirus PARV4

in clotting factor VIII concentrates. Vox Sang 2007;93:341-7.

4. Schneider B, Fryer JF, Oldenburg J, Brackmann HH, Baylis

SA, Eis-Hübinger AM. Frequency of contamination of

coagulation factor concentrates with novel human parvovi-

rus PARV4. Haemophilia 2008;14:978-86.

5. Modrow S, Wenzel JJ, Schimanski S, Schwarzbeck J, Rothe

U, Oldenburg J, Jilg W, Eis-Hübinger AM. Prevalence of

nucleic acid sequences specific for human parvoviruses,

hepatitis A and hepatitis E viruses in coagulation factor

concentrates. Vox Sang 2011;100:351-8.

6. Schosser R, Keller-Stanislawski B, Nübling CM, Löwer J.

Causality assessment of suspected virus transmission by

human plasma products. Transfusion 2001;41:1020-9.

In reply:_3664 1598..1604

We thank Farugia and Gustafson1 for their comments thathelp to open discussion regarding PARV4 transmissionvia the parenteral route. They are certainly justified tohypothesize that both the degree of PARV4 contaminationin clotting factor concentrates and their infectivity mayhave changed considerably between the early 1990s whenthe study samples were collected and currently adminis-tered plasma-sourced Factor (F)VIII and F IX. Indeed, inour discussion we list several relevant but largely undeter-mined factors that contribute to PARV4 transmission risk,some of which may have changed substantially in the past20 years. Of these, the most important arises from sharedinfection risk factors with hepatitis C virus (HCV), wherethe adoption of antibody and more recently nucleic acid

LETTERS TO THE EDITOR

1598 TRANSFUSION Volume 52, July 2012

screening of plasma donors for HCV infections hasundoubtedly also greatly reduced the number of PARV4viremic donations entering the manufacturing process.This is consistent with low or absent detection frequenciesof PARV4 DNA by polymerase chain reaction (PCR)-basedtesting of more recently manufactured products.2-4

However, in contrast to what Farugia and Gustafsonassert, PCR negativity in tested lots does not necessarilyequate to noninfectivity in all lots. Furthermore, pools willlack other PARV4-seropositive plasma components. Forthe related parvovirus, B19V, the presence of anti-B19V ina high proportion of donations in manufacturing pools isa likely major factor that eliminates infectivity in bloodproducts with low titers of B19 DNA.5,6

Their second alternative hypothesis they advanced todismiss the potential risk of PARV4 exposure from plasma-derived blood products was that infections in the studypatients with hemophilia originated through someunspecified “contact in the treatment center” rather thanadministration of clotting factor. This supposition flies inthe face of a very clear consensus from previous studiesfor the restriction of PARV4 infections to those with pastparenteral exposure, at least in Western countries(reviewed in Brown and Simmonds7). Furthermore, in ourprevious study of the same well-characterized studygroup,8 we showed that PARV4 infections were almostentirely absent among siblings of infected patients withhemophilia. Thus, and in marked contrast to other par-voviruses, close ongoing daily household contact is not atransmission route for PARV4 in the absence of specificparenteral exposure.

In conclusion, we stand by our assertion that PARV4infections in persons with hemophilia were acquiredthrough treatment with plasma-sourced clotting factors.We additionally believe that investigation of a number offactors that are potentially contributory to ongoing trans-mission should be urgently pursued. Neither its infrequentdetection by PCR in more recently manufactured productsnor the adoption of two viral inactivation procedures guar-antee an absence of the nonenveloped PARV4 infection riskin currently used blood products. We agree with the con-clusions in the study by Modrow and colleagues4 for the“necessity for screening methods that detect all variants ofcontaminating virus in donor plasma . . . to remove orinactivate nonenveloped virus pathogens from bloodproducts.”We believe that our research should encourage aless complacent attitude toward a parvovirus of undeter-mined pathogenicity that we have shown to have beentransmitted by plasma-derived therapeutic agents.

CONFLICT OF INTEREST

The authors declare no conflict of interest with the contents of

this letter.

Peter Simmonds, BM, PhD, FRCPathe-mail: peter.simmonds@ed.ac.uk

Colin P. Sharp, BSc, PhDInfection and Immunity Division

Roslin InstituteUniversity of Edinburgh

Easter BushMidlothian, Scotland

Sharyne Donfield, PhDDepartment of Biostatistics

Rho, Inc.Chapel Hill, NC

Edward D. Gomperts, MDChildren’s Center for Cancer and Blood Diseases

Children’s Hospital Los AngelesLos Angeles, CA

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1. Farugia A, Gustafson A. Assessing causality in the transmis-

sion of viruses by blood products. Transfusion 2012;52:

1598.

2. Schneider B, Fryer JF, Oldenburg J, Brackmann HH, Baylis

SA, Eis-Hübinger AM. Frequency of contamination of

coagulation factor concentrates with novel human parvovi-

rus PARV4. Haemophilia 2008;14:978-86.

3. Fryer JF, Delwart E, Hecht FM, Bernardin F, Jones MS,

Shah N, Baylis SA. Frequent detection of the parvoviruses,

PARV4 and PARV5, in plasma from blood donors and

symptomatic individuals. Transfusion 2007;47:1054-61.

4. Modrow S, Wenzel JJ, Schimanski S, Schwarzbeck J, Rothe

U, Oldenburg J, Jilg W, Eis-Hübinger AM. Prevalence of

nucleic acid sequences specific for human parvoviruses,

hepatitis A and hepatitis E viruses in coagulation factor

concentrates. Vox Sang 2011;100:351-8.

5. Doyle S, Corcoran A. The immune response to parvovirus

B19 exposure in previously seronegative and seropositive

individuals. J Infect Dis 2006;194:154-8.

6. Davenport R, Geohas G, Cohen S, Beach K, Lazo A, Luc-

chesi K, Pehta J. Phase IV study of Plas+SD: hepatitis A

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96:1942.

7. Brown KE, Simmonds P. Parvoviruses and blood transfu-

sion. Transfusion 2007;47:1745-50.

8. Sharp CP, Lail A, Donfield S, Simmons R, Leen C, Klener-

man P, Delwart E, Gomperts ED, Simmonds P. High fre-

quencies of exposure to the novel human parvovirus,

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by a serological assay for PARV4 antibodies. J Infect Dis

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LETTERS TO THE EDITOR

Volume 52, July 2012 TRANSFUSION 1599