Strategies for the Prevention of Post-Transfusion Hepatitis PAUL D

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Strategies for the Prevention of Post-Transfusion Hepatitis PAUL D. MINTZ, M.D. Blood Bank and Transfusion Service, University of Virginia Medical Center, Charlottesville, VA 22908

ABSTRACT Hepatitis is a common and potentially serious adverse effect of blood transfusion. A large number of strategies have been developed or proposed to reduce the incidence of post-transfusion hepatitis (PTH). The education of physicians regarding the risks of hemotherapy and the judicious use of blood must be the cornerstone of any substantial reduction in PTH. The use of volunteer rather than paid donors is associated with a much reduced incidence of PTH. Deferral of donors implicated in PTH is also helpful. Other proposed strategies include donor alanine amino-transferase levels, donor anti-HBc testing, the provision of immune globulin to recipients, and the inactivation, removal, or immune neutralization of the virus from blood products. In the absence of a blood substitute, au tologous transfusion is an excellent means of improving transfusion safety. The incidence of PTH type B should decrease as an increasing proportion of donors and recipients are immunized by vaccine and as increasingly sensitive tests for HBsAg become available. The development of a sero logic test and vaccine for non-A, non-B hepatitis would be outstanding accomplishments, but their absence underscores the need to pursue vig orously other means of reducing the incidence of the disease. Introduction from blood transfusion at all.49 In any event, efforts at reducing the incidence Post-transfusion hepatitis (PTH) de of PTH will be successful only if they are velops in approximately seven percent of directed at preventing the transmission the recipients of blood transfusions.1 of NANB hepatitis. Unfortunately, spon Non-A, non-B (NANB) hepatitis accounts taneous resolution of acute NANB hep for approximately 90 percent of these atitis fails to occur in as many as 60 per cases; type B hepatitis is responsible for cent of patients.812 The development of the remainder.138 Aach has estimated a chronic, asymptomatic infectious car that 230,000 new cases of NANB PTH rier state in association with the fact that may occur annually in the United States most patients who develop NANB hep alone.1 It has been suggested that pa atitis are never symptomatic or icteric tients with apparent PTH type B may in and never know that they have had the fact not have acquired their hepatitis disease creates a pool of apparently 198 0091-7370/84/0500-0198 $01.50 © Institute for Clinical Science, Inc. STRATEGIES TO REDUCE PTH 199 healthy blood donors capable of trans cent of apparently healthy blood donors. mitting NANB hepatitis. This report will These donors will want to know the sig review specific strategies that have been nificance of the abnormal result detected developed to try to reduce the incidence in their blood and what to do about it as of PTH. well as who will pay for a subsequent medical evaluation. In addition, the cost Alanine Amino-transferase Testing of performing the ALT determinations is of concern. One center that has per There have been two prospective formed such testing for more than two studies that have demonstrated an asso years calculates a cost of $1.22 per unit ciation between the risk of NANB PTH when considering the cost of both the and the serum alanine amino-transferase testing and the loss of income from dis (ALT) in a donor’s blood.2,6 The transfu carded blood.60 An ad hoc committee of sion-transmitted viruses study followed the American Association of Blood Banks 1,513 transfusion recipients for five (AABB) concluded that “at this time we years.2 The incidence of hepatitis was di do not advise routine donor testing for rectly correlated with the serum ALT ALT as a means for reducing the inci level in the blood donors. This relation dence of NANB hepatitis”.41 The con ship was observed among recipients of cerns specified included the fact that single or multiple transfusions of blood. ALT is not a specific test for NANB hep In fact, approximately 40 percent of the atitis, that no study has shown that the cases of NANB PTH were associated actual elimination of donors with ele with blood donor units that had an ALT vated levels of ALT in fact does reduce value equal to or greater than 45 IU per the incidence of elevated levels of ALT, 1. The data indicate that provision of “much less hepatitis”, post-transfusion, units with ALT values less than 45 IU the significance of elevations of ALT after per 1 could result in a reduction of transfusion are in fact unknown, that NANB PTH of 31 percent among multi there is insufficient information to estab donor recipients and 23 percent among lish what the cut off level for acceptable single unit recipients.3 However, approx donors should be, and that the effect of imately three percent of donors had ALT losing approximately three percent of levels above 45 IU and would have to be blood donors may seriously stress the na deferred. This study concluded that “the tion’s blood supply. high correlation between an elevated It is important to point out that the two ALT level and infectivity of transfused prospective studies reviewed also dem blood provides a compelling argument onstrated 70 percent of PTH would not that such screening should be insti be prevented by ALT testing and that tuted”. A second study by Alter et al6 transfusion of 70 percent of the donor also determined that the risk of PTH was blood with an elevated ALT level did not significantly associated with the level of result in PTH. These two numbers have donor ALT. They calculated that if do been likened to a 70 percent false-nega- nors with ALT levels greater than 53 IU tive rate and a 70 percent false-positive were excluded, 29 percent of the cases rate, respectively.21 of PTH could be prevented with the loss While some blood centers have of 1.6 percent of donor units. elected to initiate ALT testing and seek Several considerations have prevented answers to the issues raised with addi the widespread introduction of donor tional data,22,37,60 most blood collection ALT testing. First, such testing would centers have not initiated ALT testing of result in the rejection of two to three per donors. 200 MINTZ This issue is under active debate. This anti-HBc test clarifies the reason of the reviewer shares the concerns of the ad exclusion for the donor. Obviously, this hoc committee on ALT testing and finds testing could not be utilized without sur- it prudent not to initiate such testing of face-antigen testing as well since some all blood donors at this time. Those cen infectious donors may be surface-antigen ters currently performing ALT testing positive and negative for anti-HBc. may provide additional and compelling A recent survey of more than 20,000 evidence for its role in donor evaluation. volunteer blood donors found a preva lence of anti-HBc of 2.2 percent.36 How Anti-HBc Testing ever, more than 96 percent of donors positive for anti-HBc were also positive Blood donors capable of transmitting for anti-HBs. Thus, only 16 donors (0.08 hepatitis B may have anti-HBc as the percent) had anti-HBc in the absence of only serologic marker of this dis detectible HBsAg and anti-HBs. In ad ease. 23>29>40 The transfusion-transmitted dition, Tabor et al54 reported that 0.4 per viruses study noted that of the 15 pa cent of 1,086 volunteer blood donors tients who developed transfusion associ with no history of hepatitis had anti-HBc ated hepatitis B, eight had received at alone. Thus, screening volunteer blood least one unit of blood that was positive donors for anti-HBs as well as anti-HBc for anti-HBc.20 Assuming that these units would greatly reduce the number of do were responsible for causing the hepa nors eliminated since those who are pos titis B infection, then the majority of itive for both anti-HBs and anti-HBc are such infections might have been pre presumably not potentially infectious. vented by rejecting those donors positive Donors with an elevated ALT are for anti-HBc. However these units would more likely to have anti-HBs and, pre have to be replaced with anti-HBc neg sumably, anti-HBc.6 Therefore, the com ative units which also carry their own bined effects of ALT and anti-HBc hepatitis risk. testing would not be additive. Despite While the prevention of one half the the cost of testing and the exclusion of cases of PTH type B certainly seems de donors, careful consideration should be sirable, the fact that 90 percent of PTH given to this specific test that could pre is NANB means the overall effect would vent as many as one in six cases of PTH. be small unless anti-HBc testing could The Technical Manual of the AABB states also reduce the incidence of NANB PTH. that “routine testing of blood donors for Vyas and Perkins59 presented evidence anti-HBc is not recommended at this that the incidence of NANB PTH is time”.55 The expense of performing all higher in recipients of anti-HBc positive three serologic tests seems prohibitive. blood. Holland has calculated that per forming anti-HBc screening of blood do Immune Serum Globulin nors could result in a 12 percent reduc tion in the frequency NANB PTH.20 The value of immune globulin prepa Thus, he concluded that 17 percent of rations for the prevention of PTH is un cases of PTH might be prevented by the certain. Most studies designed to con inclusion of donor anti-HBc testing with sider this question were performed prior a loss of approximately five percent of do to the availability of serologic tests for nors. He also noted that a 17 percent re hepatitis B. Approximately one-half of duction with a five percent donor loss is such studies showed some protective ef not so beneficial as that calculated for the fect while the remainder did not.10 Three ALT test. However, the specificity of the more recent randomized studies have ad STRATEGIES TO REDUCE PTH 201 dressed the efficacy of immune serum cumstances, it seems prudent to admin globulin in preventing NANB PTH. ister HBIG. Knodell et al25 studied 279 cardiac sur gery patients. Patients who received Freezing/Washing or Washing Blood “normal gamma-globulin” or hepatitis B immune globulin had less icteric hepa Freezing, deglycerolizing, and subse titis and a decrease in subsequent quent washing of red blood cells does chronic active hepatitis than patients re not prevent transfusion associated ceiving a placebo.26 The protective ef hepatitis.5,18 Alter et al5 demonstrated fects of the two gamma-globulin prepa hepatitis B infection in chimpanzees rations were not significantly different. transfused with infectious, frozen-degly- Both the severity and frequency of PTH cerolized red blood cells. Haugen18 re in the patients were reduced. The inci ported 56 cases of “overt” hepatitis of dence of type B PTH was too low for any whom 16 had received only frozen red conclusions to be drawn regarding the ef blood cells, 13 only washed red cells, and fectiveness of the preparations in re eight only frozen and washed cells. Mer- ducing its occurence. The patients in this yman et al34 also noted that neither study received a mean of 12 transfusions. freezing nor saline washing prevented Whether or not such prophylaxis would PTH. The incidence of hepatitis ap be effective in patients receiving fewer peared comparable in the control and sa transfusions was not addressed. How line washed groups and appeared to be ever, Kuhns et al27 found no effect on the reduced in patients receiving frozen de- frequency of type B or NANB hepatitis glycerolized blood.35 Others have sug despite the fact the immune serum glob gested that washed blood may reduce the ulin they administered was obtained incidence of PTH.30,56 There is insuffi from the plasma of donors giving a his cient evidence at this time to recom tory of overt viral hepatitis two or more mend the costly procedures of washing years earlier. Seeff et al43 did find a re or freezing and washing blood routinely duction in icteric NANB PTH in recipi as a means of reducing the incidence of ents of an immune serum globulin pre PTH. It is not unreasonable to assume pared from World War II volunteer do that the risk may be reduced by the re nors compared to placebo. However, this moval of viruses but the extent of this effect appeared to be confined to patients reduction is not known. receiving three or more units of com- mericial blood. They concluded that Coagulation Factor Concentrates even greater benefit was achieved by Patients who receive coagulation factor eliminating paid donor blood. It is gen concentrates are at high risk of devel erally not recommended that transfusion oping PTH. There is an increased risk of recipients be given an immune serum acquiring NANB and type B hepa globulin preparation prior to transfu titis.48,58 A variety of strategies have been sion.44 developed in an attempt to reduce this The inadvertant administration of risk. Coagulation factor concentrates are HBsAg-positive blood poses a different prepared from pools of hundreds to thou problem. There are reports of the ap sands of donors; therefore, patients with parent effectiveness of hepatitis B im hemophilia A who require infrequent munoglobulin (HBIG) and the apparent treatment should receive cryoprecipitate ineffectiveness of HBIG in preventing to reduce the number of donor expo PTH in this situation.42,57 In these cir sures. However, a retrospective analysis 202 MINTZ of patients with severe hemophilia reported that an average of 730 units of treated with small pools of cryoprecipi- factor VIII could be collected from a tate actually showed a similar prevalence single donor during an apheresis proce of abnormal liver enzyme levels and hep dure. They concluded that this product atitis B markers compared to patients could reduce donor exposure in factor treated with coagulation factor concen VIII replacement therapy. trates.11 Thus, cryoprecipitate need be Several strategies to inactivate hepa reserved only for patients requiring in titis virus have been developed. One frequent treatment. Similarly, patients manufacturer of coagulation factor con with hemophilia B may be treated with centrates* has recently received approval plasma instead of the commercial factor to provide a heat treated factor VIII con IX concentrates. Because of the large centrate. The clinical efficacy of this volumes required, a modified plasma ex product in reducing abnormal liver func change might have to be performed. tion tests and hepatitis in human recipi Nevertheless, in patients requiring rela ents is not known publicly at this time. tively infrequent treatment, this would Comparable in vivo recovery, half-life, appear to be preferable than the provi and safety compared to unheated prod sion of the concentrate. Thankfully, the ucts has been demonstrated.13 Prelimi availability of an efficacious vaccine to nary work in chimpanzees suggests the hepatitis B should reduce the risk to risk of PTH may be reduced.13 these patients of this agent. Very promising results have been Alternative means of treating bleeding obtained by using beta-Propiolactone/ulin patients with hemorrhagic disorders traviolent irradiated factor IX concen have been developed. The role of Ep- trates.19,39 This method appears to pro silon-aminocaproic acid as a means of re vide a means for substantially decreasing ducing the coagulation factor require the risk of PTH from these concentrates. ment for patients with hemophilia A and The stability of a number of plasma pro B undergoing dental procedures has teins in similarly treated pooled human been proven.61,62 Deamino-d-arginine plasma has been demonstrated.47 The ad vasopressin has been shown to raise dition of HBIG to plasma derivitives has factor VIII levels in patients with mod been demonstrated to reduce the inci erate hemophilia A and Von Willebrand’s dence of hepatitis B transmission in disease thus reducing their coagulation chimpanzees.9,51 It has been suggested factor requirements.32,63 Recently, Dan- that anti-HBs could be added to the lots azol, an attenuated androgen was dem of products in which anti-HBs was not onstrated to increase modestly factor detectable.15 However, concerns re VIII and factor IX activities in four pa garding the regular exposure of patients tients with hemophilia A and one with to immunoglobulins have been raised.45 hemophilia B.16 An alternative strategy has been to re Donor Deferral duce the number of donors to whom such The American National Red Cross patients are exposed through directed policy is to defer any donor who has pro apheresis collections. One report de vided blood which was the sole source scribed total support for a patient with product to a patient who has developed congenital afibrinogenemia through plas PTH. Such a donor is placed in a national mapheresis of the patient’s parents with registry. If two to ten donors have pro return of cryoprecipitate-depleted * Hyland, Glendale, CA. (Several manufacturers plasma to the donors. McCleod et al33 have now received approval.) STRATEGIES TO REDUCE PTH 203 vided blood products to a patient who fusion service have “a system for identi has developed PTH, a record is main fying and recording all cases of suspected tained. Any donor who has twice been PTH and for reporting such cases to the among two to ten donors who have pro supplier of the blood. . . . ”4B This man vided products to a patient who has de date may be of great benefit in helping veloped PTH is permanently deferred. to identify potentially infectious donors. No formal record of donors is mandated for patients who have developed PTH General Considerations and who have received blood products from more than 10 donors. Some blood One of the most successful steps that centers have a policy of calculating prob may be taken to reduce PTH is the ex ability values for donors who have pro clusion of paid donors. It has been esti vided blood to patients who have devel mated that exclusion of these donors by oped PTH. The probability value for a itself can lead to a 70 percent reduction multiply implicated donor has been cal in the incidence of PTH.4 The risk of culated as the sum of the fraction of the both type B and NANB PTH has been total donor pool he represents for each shown to be greater with the use of paid hepatitis case. When a predesignated donors.1 Attack rates of PTH in studies probability value, e.g., 0.2 or 0.3 is with transfusions of blood from paid do reached, that donor is permanently re nors indicate a range of 17 to 54 percent jected. The problem with such a system compared to the approximately seven is that each donor involved in a case of percent incidence seen in recipients of hepatitis has been assumed to be equally volunteer blood. Tabor et al52 found an likely to be the infective source regard incidence of HBeAg in 15 percent of paid less of that donor’s prior implication. blood donors and five percent of volun Such probabilities need to be calculated teer blood donors. This evidence sup taking the donor’s past history into ac ports the role of the paid donor in trans count.28 Certainly deferral of implicated mitting hepatitis B virus. No single step donors is a productive means of reducing has been more important than the com PTH. mitment to providing blood from volun Tabor et al50 studied donors implicated teer donors. in cases of clinically recognized PTH and In July 1972, HBsAg was mandated by determined that they could not be dis federal regulations. Alter et al4 have es tinguished by age, race, sex, history of timated that excluding HBsAg-positive clinical hepatitis, or of prior blood trans blood alone may lead to a 25 percent re fusion. duction in PTH. The fact that a greater A key component of identifying donors reduction has not been achieved is prob who may transmit hepatitis is reporting ably due to the prevalence of NANB cases of PTH to the blood collection PTH prior to the introduction of HBsAg center. Efforts at increasing such re testing. In fact, the prevalence of PTH porting by mailed inquiries to the phy does not seem to have declined signifi sicians of transfused patients has met cantly despite the apparent decrease in with mixed success.17,64 The suggestion type B PTH1. This suggests that NANB that all hospitals be mandated to publi PTH may have increased recently or that cize the incidence of PTH in their trans because of better investigation of this fre fused patients14 is unworkable, given the quently asymptomatic and anicteric dis latency of infection and large number of ease, a larger number of cases are now asymptomatic cases. However, the stan being detected. In addition, the overall dards of the AABB require that a trans role of type B PTH may have been 204 MINTZ simply insufficient even prior to HBsAg blood supply and preventing unneces screening to affect significantly the inci sary risks. dence of PTH, even when most cases of The development of a safe and effec type B PTH are precluded by HBsAg tive vaccine for hepatitis B will indirectly testing. The finding of Seeff et al43 that lead to a reduction in the incidence of an immune serum globulin prepared type B PTH. As an increasing proportion from World War II volunteer donors re of donors and recipients are immunized, duced icteric NANB PTH substantiates the incidence of this disease will de the longstanding presence of this dis crease. Increasingly sensitive tests for ease. HBsAg will also serve this purpose. The Autologous transfusion has been dem protective efficacy of the hepatitis B vac onstrated to be an efficient and safe way cine against infections from transfusions of reducing the risk of blood transfusion. of large volumes of highly infective blood Patients scheduled for elective surgery has been demonstrated in chimpan may donate blood prior to their operative zees.24 procedure, and it may be stored in the Future efforts must be directed at the refrigerated or frozen state until they re reduction of NANB PTH. The develop ceive the units in return. This procedure ment of a serologic test to detect present may be performed in patients who would or past infection is a high priority. Un not otherwise qualify for blood donation fortunately, it may be that a sufficient and has been shown to be quite safe.31 number of circulating virus particles are Furthermore, techniques are available not present to be detected by any of the for salvaging blood intraoperatively and known techniques. It is hoped that a vac returning it to the patient during the cine could be eventually developed for course of the operation. NANB PTH. Tabor and Gerety53 have An important consideration in re shown that formalin treatment of serum ducing the risk of PTH is the education of documented infectivity for NANB of physicians regarding the judicious use PTH apparently reduced its infectivity of blood products and the associated risks for this disease in chimpanzees. This may of blood transfusion. The benefits of provide a basis for eventually preparing blood transfusion are often readily ap an inactivated NANB hepatitis vaccine. parent whereas the adverse effects are The recent finding that most patients frequently delayed. In fact, it is common with the acquired immune deficiency for the physician who confronts the pa syndrome have anti-HBc may indirectly tient with PTH not to have been the phy lead to a reduction in PTH. Blood cen sician who was caring for the patient at ters are currently asking such donors to the time of the culpable blood transfu defer from donating blood. Thus, a pool sion. Thus, it is often difficult for physi of donors who may be at higher risk of cians to give due consideration to the po transmitting both type B and NANB hep tential problems associated with blood atitis may be being removed from the transfusion. Studies are needed to deter donor population. There are no data pub mine what triggers physicians to initiate licly available regarding changes in the a blood transfusion; such data are not proportion of donors with various hepa available. Most medical school curricula titis B serologic markers since the wide do not give considerable attention to spread introduction of this policy, but it hemotherapy. Thus, the proper educa is at least theoretically possible that the tion of physicians and medical students self deferral of these donors could lead to reduce unnecessary transfusions to a reduction in the incidence of PTH. serves the dual purpose of conserving the The amount of effort and the multi STRATEGIES TO REDUCE PTH 205 plicity of strategies that have been de transfusion: Viral hepatitis and other infectious disorders. Semin. Hematol. 18:122-146, 1981. veloped to try to reduce the incidence of 11. C o u n t s , R. B.: Serum transaminase and HBsAg PTH attest to the magnitude of the antibody in hemophiliacs treated exclusively public health problem and the frustration with cryoprecipitate. Proceedings of Conference on Unsolved Problems in Hemophilia. DHEW of dealing with the elusive NANB agent Publ. No. (NIH) 77-1089, 1976, p. 77. or agents. Eliminating the current risks 12. C za ja , A. J. and D a v is, G. L.: Hepatitis non-A, of blood transfusion, including PTH, may non-B. Mayo Clin. Proc. 57:639—652, 1982. 13. D o l a n a , G ., T s e , D ., T h o m a s W., and K in g d o n , not occur until safe and effective blood H. S.: Hepatitis risk reduction in hemophilia; A substitutes are readily available. Current heated factor VIII preparation. Blood 60:210A, efforts, however, may lead to a substan 1982. 14. F in k e l s t e in , S. N. and S a p o l sk y , H. M.: Con tial reduction in this potentially devas trolling post-transfusion hepatitis: a proposal to tating disease. publicize hepatitis rates of transfusion facilities. Am. J. Law. Med. 5:51-59, 1979. 15. G e r e t y , R. J. and A r o n s o n , D. L.: Plasma de Acknowledgments rivatives and viral hepatitis. Transfusion 22:347- Thanks are extended to Ms. Lena Garrison Frazier 351, 1982. for outstanding word processing and secretarial assis 16. G r a l n ic k , H. R . and R ic k , M. E.: Danazol in tance. creases factor VIII and factor IX in classic he mophilia and Christmas disease. New Engl. J. 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V ., et al.: Type B hepatitis after transfusion with et al. : Donor transaminase and recipient hepablood containing antibody to hepatitis B core an titis. Impact on blood transfusion services. J. tigen. New Engl. J. Med. 298:1379-1383, 1978. Am. Med. Assoc. 246:630-634, 1981. 24. K a r a sa w a , T., S h ik a t a , T., A b e , K ., et al.: Effi 7. B a l l a r d , J.: Congenital afibrinogenemia: Clin cacy of hepatitis B vaccine in chimpanzees given ical presentation and management. Annual Sci transfusion of highly infective blood. J. Infect. entific Session of the Pennsylvania Association of Dis. 147:327-335, 1983. Blood Banks, Hershey, PA, April 29, 1982. 25. K n o d e l l , R. G ., C o n r a d , M. E., G in s b e r g , 8. B e r m a n , M., A l t e r , H. J., I s h a k , K. G., et al.: A. L., and B e l l , C . J.: Efficacy of prophylactic The chronic sequelae of non-A, non-B hepatitis. gamma globulin in preventing non-A, non-B Ann. Intern. 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