Blood Supply: Transfusion-Associated Risks

Published by the Government Accountability Office on 1997-02-25.

Below is a raw (and likely hideous) rendition of the original report. (PDF)

                United States General Accounting   Office
                Reportto the RankingMinorityMember,
GAO             Committeeon Commerce, House of

February 1997

                 United States
~GAO             General Accounting OffIce
                 Washington, D.C. 20548

                 Program Evaluation and
                 Methodology Division
I                B-274942

I                February 25, 1997

                 The Honorable John D. Dingell
                 Ranking Minority Member
                 Committee on Commerce
                 House of Representatives

I                Dear Mr. Dingell:

                 Widespread concern about the safe~ of the blood supply has led to many
                 changes in the way blood is collected, processed, and transfused.
                 Consequently, the risks of contracting certain diseases, such as AIDSand
                 hepatitis, are lower today than they were in the mid-1980s,when the
                 public became increasingly aware that blood transfusions are not risk free.

                 You expressed concern about disparate estimates of
                 transfusion-associated AIDSand hepatitis cases artd asked that we
                 determine the current risks, evaluating the content and quality of data
                 collected to assess these risks. In this report, we address the risks of
                 contracting AIDSand hepatitis from blood as well as other known risks of
                 blood transfusion.

                 You also asked us to evaluate the Food and Drug Administration’s (FDA’S)
                 layers of safety and its ability to ensure the safety of the blood supply in
                 light of changes in the blood industry. We provide that information in our
                 report entitled Blood Supply: FDA Oversight and Remaining Issues of

                 On June 30, 1992,4,619persons had been reported with suspected
    Background   transfusion-associated AIDS,representing about 2 percent of the 222,418
                 U.S. residents reported with AIDS.The number of suspected
                 transfusion-associated AIDScases rose every year from 56 for patients
                 transfused in 1978to 714for patients transfused in 1984(Selik, Ward, and
                 Buehler, 1993).Then, in 1985,when HN antibody screening of donors
                 began, the number declined sharply to 288 cases, and it fell below 20 cases
                 per year from 1986through 1991.ZThe number of new Hrv infections
                 definitively associated with transfusions is even smaller. Only 38 cases of
                    S. General AccountingOffice, BloodSupply:FDAOversightand RemainingIxues of SafetY,
                 GAO/PEMD-97-l(Washington,D.C.: 1997).

                 ‘Withinthe human body’sdisease-fightingcapabilities, it can develop antibodies that are specific to
                 each viral infection. The initial HfV-1tesk detected the HIVantibody in blood donated by infected

                 Page 1                             GAO/PEMD-97-2Blood Supply:Transfusion-AssociatedRisks


                      AIDShave been attributed to transfusions of blood screened negative after
                      March 1985.

MeasuringRisk         Memwhile, researchers at the Centers for Disease Control and Prevention
                      (cDc)and within the blood industry were developing and implementing
                      new methods to measure tr~fusion-associated risks. As a result, the risk
                      estimates that have been presented in the literature vary considerably,
                      depending on when a study was published, the area of the country it
                      considered, and the assumptions underlying its methods. For instance,
                      early studies employed less-sensitive tests than are currently available,
                      were conducted in high-risk areas rather than nationally, and used
                      measurements that were less precise than those used today.

                      Moreover, the donor pool is safer today than when early studies were
                      conducted because donors who have tested positive for certain viruses or
                      who have acknowledged risk factors for disease have been removed from
                      the donor pool. Indeed, testing may be the mostly widely cited, and is
                      perhaps the most important, step in protecting the public from the risks of
                      blood transfusions. Tes@performed on every unit of blood include tesk
                      for antibody to hepatitis B core arttigen (anti-HBC),
                                                                         hepatitis B surface
                      antigen (HBsAg),antibody to hepatitis C virus (anti-Hcv),human
        ,,            immunodeficiency virus (antibody for HIV-1and HIV-2, and antigen for
                      HIV-l),human T-lymphotropic virus type I (HTLV-1), and syphilis.3

                      Because the scientflc community has focused primarily on the risks of
                      contracting specfilc diseases from blood transfusion, the state of
                      knowledge is quite advanced for some risks such as hepatitis md HIV. Less
                      is known about bacterial contamination and some noninfectious risks
                      such as circulatory overload. No systematic analysis has been published
                      regarding the overall risks of blood transfusion compared to its potential

DonatedBlood and I@   About 8 million people donate approximately 14million units of whole
Products              blood each year. This blood—blood in its natural stat~is rarely
                      transfused into patients. Instead, the blood industry separates each unit of

                      ‘]Antibodytests detect antibodies that the human body produces in its immune response to a virus,
                      whereas antigen tests detect a component of the actual virus. Because it takes time to develop
                      antibodies, antigen tests detect infection earlier than antibody tests. HTLVis a retrovirus that can lead
                      to necrologic disease or adult T-cell leukemia and lymphoma.Tests cumentlyavailable are specific for
                      antibodies to HTLV-1,   although there are varying degrees of cross-reactivity with antibodies to HTLV-11.
                      Nevertheless, it is the closest test for HTLV-11at this time. Wediscuss transfusion-associated diseases
                      further in appendix 1.

                      Page 2                             GAO/PEMD-97-2Blood Supply:Trmsfuaion-AssociatedRisks
                       whole blood into an average of 1.9specialized products that, in
                       blood-banking terminology, are “components” consisting of various types
                       of blood cells, plasma, and special preparations of plasma.4 Health care
                       facilities transfuse these components-usudy 4 to 5 units at a time-into
                       as many as 4 million patients to treat anemia, bleeding disorders, and low
                       blood volume. Donors give an additional 12million units of plasma each
                       year, for a total of approximately 26 million annual blood and plasma
                       donations prior to testing for viral infections.

                       In an increasingly common procedure called apheresis, specifically
                       desired components of a donor’s blood are removed and the undesired
                       components are given back to the donor. Whole-blood donors must wait 8
                       weeks between donations to allow the body to replenish its red blood
                       cells. Apheresis collection of plasma, platelets, or white blood cells
                       (leukocytes) may be performed more frequently, however, if red blood
                       cells are returned to the donor. As we discuss later in our report, apheresis
                       often minimizes transfusion risks for the recipient without compromising
                       safety for the donor.

                       The blood supply is safer today than any time in recent history. Improved
    Results in Brief   donor screening and education have removed from the donor pool many
                       persons who are at high risk for disease. Tests used to screen blood for
                       viruses are considerably more sensitive than previous versions. Repeat
                       donors constitute most of the donor pool, which means that they have
                       been tested for viruses on earlier donations. Thus, the window of
                       opportunity for infection is considerably smaller than for fwst-time donors
                       who have never been tested. Viralinactivation techniques for plasma
                       derivatives eliminate most viruses that may escape detection on testing.
                       And changes in transfusion practices have eliminated some of the
                       circumstances that may have led to unnecessary transfusions in the past.

                       Nevertheless, because blood is a biological product, some risk remains.
                       Eight of every 10,000donated uni~ of blood carry some kind of potentially
                       serious risk to the recipient, including allergic reactions, bacteria,
                       reactions to incompatible blood transfusions, and viruses. We calcdated

                       ‘In addition to separating whole blood into component products, other facilities manufacture plasma
                       derivatives by fractionating plasma chemically into concentrated proteins. These include dburnin,
                       used for blood volume expansion; immune globulin,used to prevent certain infectious diseases and to
                       treat deficiencies of protein; clotting factor concentrates, used to control bleeding in patients with
                       clotting factor deficiencies, such as hemophilia;and specific immune globulins,prepared from plasmas
                       collected from donors with antibodies to specific diseases and then used to prevent those diseases in
                       others. Derivatives are commonlymade by commercial manufacturers from plasma collected from
                       paid donors. Dependingon the product, they may pool plasma from as many as 60,000donors for
                       fractionation in order to produce sufficient amounts of the final concentrated material cost-effectively.

                       Page 3                              GAO/PEMD-97-2Blood Supply:Transfusion-AssociatedRisks

that 4 of every 1,000patienk who receive the average transfusion of 5
units of blood are at risk of receiving an implicated unit amd thus maybe
exposed to conditions with the potential for the development of serious
(chronic, disabling, or fatal) outcomes.5 Whilethese risks may appear to
be substantial when considered oubide a medical context, it is commordy
understood that transfusion provides substantial benefits. We reasoned
that w many as 50 percent, or 500,of the 1,000recipients would be at
serious risk of dying immediately if they did not receive trmsfusions.G

Not all recipien~ of a contaminated unit acquire the disease it contains.
Moreover, many recipienh die soon after transfusion from the underlying
condition for which the blood was prescribed. Finally, the likelihood that a
patient will develop chronic disease or die is small for some diseases. We
determined that the overall risk of developing chronic disease or dying as
a direct resdt of a blood transfusion is about 4 in 10,000,which translates
into about 1,525of the 4 million patients who receive transfusions each

The risk that a general surgery patient will require blood md develop a
chronic disease or die as a resdt of that blood is 5 in 100,000.For the
average person in the United States who has no foreseeable plans for
surgery, the annual risk of developing a need for surgery, requiring blood,
ad developing a chronic disease or dying from the transfusion is 5 in
1 million.

We concluded Mat in context these risks are very small, particularly
considering that many patienk wotid die without blood trmsfusion. The
risks from trmfusing blood to recipients in general and surgeW patients
specifically are considerably smaller than other hospital-related risks.
~ermore,       the annual risk to an average person in the United States
with no foreseeable plm for surgery is more than 250 times less than the
artrtualrisk of hospitiization from accidental poisoning by drugs and
other medicines and nearly 600 times less than that of other diseases or
events of high public concern, such as heart disease.

‘Wepresent an overall risk for afl types of blood components. Strictly speaking, different blood
components carry different risks. This is especially true for a therapeutic dose of apheresis platelets,
which, because it contains only 1donor’splatelets, carries a much lower risk to the patient than a
typical therapeutic dose of random donor platelets (6 donors) or red blood cells (5 donors). See
appendix 11for a detailed discussion of these differences.

%e ethical concerns surrounding a study of differences in survival rates between groups of patients
who have and have not received blood make collecting such data difficult. However,Jehovah’s
Witnesses who refuse blood on religious grounds are natural case study controls. Research on this
population suggests that the mortality rate is between 38 and 53percent amongseverely anemic
patients who refuse transfusion (Spence et al., 1990and 1992).Mortalityis higher (75 percent) for
those with active bleeding who require emergency surgery (Carson et al., 1988).

Page 4                              GAO/PEMD-97-2Blood Supply:Transfusion-AssociatedRisks

                     We took a worst case approach in our analysis. That is, we used the most
                     conservative risk estimates among current comprehensive studies
                     published in the scientific literature. Consequently, the actual risks of
                     transfusion may be somewhat lower, but are not likely to be higher, than
                     the risks we present.

                     Our objective in this report was to quantify the current risks associated
Objectives, Scope,   with blood transfmion. To respond to your request, we reviewed data on
and Methodology      the current risks of blood transfusion in the United States, evaluating the
                     content and quality of the data. We analyzed the theoretical and research
                     foundations underlying current and past risk estimates and held extensive
                     interviews with industry and government epidemiological experts.

                     Our analysis assumed that W the layers of safe~ are working properly.
                     That is, our risk estimates are for units of blood from donors who were
                     properly screened, who were checked on the deferral registry, whose
                     blood was tested for viruses, ad so on.

                     We included risks of receiving units contaminated by eight viruses (HAv,
                     HBV,HCV,HIV-1md HIV-2,HTLV-I     and HTLV-11,
                                                                 non-ABChepatitis), various
                     bacteria, and one parasite-transmitted disease (Chagas’), as well as four
                     complications of transfusion i@eH(ABOincompatibility, acute lung imury,
                     allergic reaction, and circtiatory overload). We did not include the risks of
                     some diseases that are known to be present in blood but that have very
                     low prevalence rates (such as Leishmaniasis), that have already high
                     prevalence rates in the general popdation with few complications (such
                     as cytomegalovirus, or CMV,   and B19parvovirus), or that have no scientific
                     proof of transfusion transmission (CreutzfeldtJakob disease, or CJD).7

                     ‘Nocases of transfusion-transmitted Leishmaniasishave been documented in the United States. In
                     1991,a new fore?of the disease, Leishmaniasis tropica, was detected in seven Desert Storm veterans,
                     leading to deferral of individualswho had been in the Persian Gulfin or after 1990.Withthe absence of
                     any data substantiating transmission of this parasite, the ban was lifted in January 1993.CMVis a type
                     of herpes virus. Estimates suggest that between 60 and 90percent of the general population have been
                     infected by the time they are adults. Primary infection is usuallythe result of respiratory or sexual
                     contact, and the acute phase of the virus usually passes without symptoms. Once infected, however,
                     blood carries antibodies for a lifetime. Onlyblood transfusion recipients with weakened immune
                     systems (such as leukemia patients) and newborns are thought to be at risk for severe complications
                     from c~n”-positiveblood. Therefore, units for these types of patients are routinely screened for CMV
                     antibodies. Parvovirus, like CMV,causes a clinicallymild,short disease state in all but severely
                     immunocompromisedpatients. It can be severely detrimental to fetuses. About 50percent of adults
                     show evidence of past infection and no licensed screening testis available. The neurological disease
                     CJDis caused by an unidentified infectious agent and has no cure. However,there is no evidence at
                     this time that it can be transmitted by transfusion.

                     Page 5                             GAO/PEMD-97-2Blood Supply:Transfusion-AssociatedRisks

Urdess otherwise noted, our risk estimates are for whole-blood products
from unpaid tiogeneic donors. Allogeneic donors include volunteer
donors for the general supply and directed donors for friends and family.8
Autologous donors, who donate their blood for their own use, can be
infectious but cannot transmit a virus to themselves. A small portion of
unused autologous blood is “crossed-over” into the general supply. We
included these units.

Limited data are available concerning the risks posed by paid donors of
plasma; therefore, we did not include plasma derivatives in our analysis.
Although the disease rates of paid donors are thought to be higher than
those of volunteer donors, most plasmaderived products undergo viral
inactivation processes during manufacturing, which eliminates most but
not all viruses. Few cases of disease transmission have been reported
since testing and inactivation began. We discuss relevant issues in
appendix III.

Our analysis consisted of several estimates for each of the diseases above
or complications: (1) risks per donated unit, (2) annual number of
infectious or otherwise implicated component uni& released for
transfusion, (3) risks that the transfusion recipient would receive an
implicated unit, (4) number of recipients who wotid contract the disease
present in the blood transfusion, (5) number of recipien@who would not
die from the underlying disease or trauma necessitating the transfusion
before problems associated with the blood transfusion manifest, and
(6) the number of recipients who would die or develop chronic disease as
a result of the disease or other transfusion complication. These numbers
are for patients who have a blood transfusion. We also considered the
risks for general surgery patients who may or may not require a
transfusion and the annual risks for a person in the general population
who does not foresee a plan for surgery. In appendix II we provide
information on the studies used in our analysis and explain our

No risk estimate can be properly interpreted in isolation. Therefore, we
compared our risk estimate for death or chronic disease from a blood
transfusion with other known hospital-related risks, as well as with those
for death by other common diseases.

8Directeddonors are donors who are, for example, relatives or friends of a patient and who donate
blood because the patient has asked them to.

Page 6                             WO/PEMD-97-2Blood Supply:Transtilsion-AssociatedRiaks


I                        FindY) we reviewed means currently or soon to be available by which the
                         risks of blood transfusion maybe further reduced.

                         Wherever possible, we included in our analysis the most recent, nationally
                         representative studies that used state-of-the-art viral tests. For example,
                         we did not include some of the older studies on HfVrisk that employed
                         donors from geographical areas that at the time were of high risk and are,
                         therefore, less useful as predictors of current risk at a national level.
                         However, we do recognize their value as the fwst controlled studies of Hfv
                         risk and we note that they are the models upon which newer, more
                         relevant studies are conducted. In appendix I, we discuss the details of the
                         major studies we reviewed, including their relative strengths and

                         We used one overarching principle when choosing between studies that
                         we considered equally sound and that were a matter of continuing debate
                         in the research community: we chose to include the studies with the
                         higher risk estimates. In other words, ours is a worst-case analysis. Thus,
                         the actual risks for some of the agents and activities we discuss maybe
                         somewhat lower but are not likely to be higher given the available
                         research. Using some of the more variable estimates, we conducted
                         sensitivity analyses for our final analysis of the number of recipients likely
                         to die or develop chronic disease; we found the resdh to be highly robust.
                         That is, even when using different estimates for individual diseases or
                         complications, the resulting final estimate changed very little.g

I                        We conducted our review in accordance with generally accepted
                         government auditing standards.

                         In the context of other health-related risks, the risks of blood transfusion
    Principal Findings   are extremely small, especially considering the often fatal consequences of
                         refusing a medically necessary transfusion. Moreover, these risks are
                         continually decreasing as a result of advances in donor screening,
                         improved viral tests, viral inactivation techniques, and chmges in
                         transfusion medicine practices.

                         “Forexample, we used a risk estimate of 1in 4,100units for HCV    based on research suggestingthat the
                         anti-HCVscreening test misses some infected donors. L1singthis estimate, we predict that 4 in 10,000
                         patients will develop serious chronic disease or die. Someresearchers do not accept this theory,
                         believingthat the risk is closer to 1in 103,000.Usingthis estimate changes the prediction onlyslightly
                         to 2 of every 10,000patients.

                         Page 7                             GAO/PEMD-97-2Blood Supply:Transfusion-AssociatedRisks


Five FactorsThatHelp   The risk of contracting a disease from blood transfusion continues to
Reduce Risk            decrease. We identified five factors that have helped reduce the risk of
                       contacting viral diseases from blood transfusions.

                       First, better donor screening and education efforts have refined the
                       volunteer whole-blood donor pool b one comprising primarily persons
                       with lower risk than those who donated blood before such screening was
                       introduced. The frequency of positive HIV test restits among blood donors
                       is now much lower than tiat of other tested groups, such as military
                       recrui~, inner-city emergency room patients, and randomly selected
                       newborns. Moreover, the current rate of positive HIV test restits is about 8
                       per 100,000blood donors, which is 50 times lower than the rate of 400 per
                       100,000in the general popdation.

                       Second, state-of-the-art viral screening tests can detect infected blood
                       donations. For example, before anti-Hcvtesting, the rate of
                       transfusion-associated hepatitis was 4.4 percent. After first-generation
                       SrIti-HCV tests were introduced, the rate fell to about 1 percent—nearly an
                       80-percent reduction. Second-generation tests identified an additional
                       10percent of infected donors for an overall reduction of 90 percent in
                       transfusion-associated hepatitis C.

                       Third, because FDA regdations and industry practices prevent the use of
                       blood from infected, behaviorally ris~, or test-positive donors, the donor
                       pool comprises p ~y
                                         “      repeat donors who have been deemed safe.
                       These repeat donors have a narrower window of opportunity of infection
                       (defied by the interval between tested donations) compared to first-time
                       donors whose blood has never been tested and who, therefore, have a
                       substantially longer window of opportunity of infection.

                       Indeed, a recent collaborative study by the CDCand the American Red
                       Cross (MC) revealed that 7 million donations, or 80 percent of all
                       donations collected by ARCin 1991through 1993,were from repeat donors
                       (Lackritz et al., 1995).Of these donations from repeat donors, less tha 2
                       of every 100,000donations (142) tested positive for HIV.The remaining 20
                       percent of the donor pool were first-time donors who provided ordy about
                       a fourth as much blood, or 2 million donations. Donations from first-time
                       donors were 9 times more likely to be Hrv-positivethan those of repeat
                       donors: 18 of every 100,000donations (349) from first-time donors tested
                       positive for HIV.

                       Page 8                    GAO/PEMD-97-2
                                                             Blood Supply:Transfusion-AaaociatedRisks

                             Fourth, ~ainWtiyatiop kchniques are used whenever possible in the
                             manufacture of plasma derivatives. This is particdarly impotit for the
                             plasma derivatives that hemophiliacs routinely use (see appendix III).
                             Recent research suggests that new inactivation techniques may be
                             available in the future for other blood products, such as red blood cells,
                             that are too fragile to withstand most heat or chemic~y based

                             And fifth, as physicians have become more aware of changes in the
                             practice of transfusion medicine, they have moved away from routinely
                             prescribing whole blood. Instead, they have moved towmd prescribing
                             specific blood componen~ to alleviate specflc complications, using
                             plasma volume expanders wherever appropriate, collecting a patient’s
                             own blood before w operation, and salvaging and reinfusing a patient’s
                             own blood during surgery. See appendix IVfor additional discussion of
                             new technology and medical practice changes that could ~her reduce

Risks of Blood Transfusion   We evaluated the overall risk of blood transfusion by synthesizing the risks
                             of a number of different adverse outcomes that codd restit from receiving
                             blood (see table 1).10Because estimates of risk are better understood in
                             context, we compared them to other known health-related risks.

                             Appendix II discusses the method of our malysis in detail, including
                             citations for the estimates in table 1.

                             )~}our~nalysjsdid not inc]ude risks associated with plasma products. See appendix III for a discussion
                             of plasma

                             Page 9                             GAO/PEMD-97-2
                                                                            Blood Supply:Trans*ion-Associated Risk

Table1: IndividualandOverallRisksof
                                                                             1. Riskestimateper
                                                                              unit(12.057million        2. Patientriskper
                                      Agentor activity                            unitsdonated)     transfusionof 5 units
                                      HAV                                            1:1 ,000,000              1:200,000
                                      HBV                                              1:63,000                 1:12,600
                                      HCV                                               1:4,100                    1:820
                                      HIV-1 and -2                                    1:450.000                 1:90,000
                                      HTLV-I and -11                                   1:50,000                 1:10,000
                                      Non-ABC hepatitis                                 1:5,900                  1:1
                                      Platelet contamination
                                        Random donor                                   1:10,200                    ,700
                                        Apheresis                                      1:19,500                 1:19,500
                                      Yersiniaf                                       1:500,000                1:100,000
                                      T. cruzi                                         1:42,000                  1:8,400
                                      Subtotalriskof infection                         5:10,0009              2.7:1,0009
                                      ABO incompatible                                 1:12,000                  1:2,400
                                      Acute lung injury                                1:10,000                  1:2,000
                                      Anaphylaxis                                     1:150,000                 1:30,000
                                      Circulatory overload                             1:10,000                  1:2,000
                                      Subtotalriskof transfusion                       3:10,000                1.5:1 ,000
                                      Risk                                             8:1O,OOOI               4.2:1,0001

                                      Page 10                      GAO/PEMD-97-2
                                                                               Blood Supply:Transfusion-AssociatedRisk

  3. Annualnumberof                                                  5. Numberof
implicatedcomponent                                        recipient whodo not
  unitaif 23.19million                                           die of underlying 6. Numberof recipientswhodevelop
componentsavailable      4. Numberof recipientsaffected        di=ase or tmuma chronicdiseaseor die as a resultof
      and 19.23million    (likelihoodof seroconversion)    first (30%diewithin2          transfusion(likelihood)
          transfusions            Number           Percent                 years)           Number             Percent

                  23                 21                   90~o                      15                     0                  0.2Y0
                 368                258                   70                       181                    18                      10
                5,656             5,090                   90                     3,563                  713                       20
                  52                 47                   90                        33                   33                   100
                 464                125                   27                        88                     4                 4.75
                3,931             3,538                   90                     2,477                  372                       15

                 460                460*                                           460e                 120                       26
                  31d                Sld                                            31e                    8
                  24                 24d                                            24e                    6                      26

                 552                 55                   10                        39                    12                      30
              11,561              9,649                                          6,911                1,286

                 8951               322k                                           322e                   19                       6
                1,923             1,923d                                         1,923e                  96                        5
                 128                128d                                           128e                  26                       20
                1,923             1,923*                                         1,923’                  96                        5
               4,869              4,296                                          4,296                  237

              16,430             13,945                                         11,207                1,523
                               3.5:1.000m                                    2.8:1.000M           4 :lO.OOOM
                                      Althoughdonorsmaycarrymorethanonedisease,the likelihoodthat a unitwill escapedetection
                                      by multipletestsis almostnonexistent.Therefore,the individualriskspresentedhereare
                                      independent,and the totalrisk is calculatedby summingindividualrisks.Numbersmaynot be
                                      exactbecauseof rounding.An exampleusingHIVacrosscolumns1-6is as follows:
                                      1:Theriskof HIVis 1 in every450,000donatedunits.Thatis, of the 12.057millionunitsdonated,
                                      27 will be HIVpositive(12.057million/450,000

                                      2: Assumingeachpatientreceivesanaverageof about5 unitsof blood(exceptplateletsnoted
                                      below),thenthe riskto the patientis 450,000/5,or 1 in 90,000.

                                      3: Eachallogeneicunit is madeintoan averageof 1.87transfusedcomponents.Hence,
                                      12.057millionunits= 22,583,000componentsplus607,000apheresisplatelets= 23,190,000
                                      totalcomponents.The27 unitsof HIV-positivebloodbecome52 differentcomponents.

                                      Page 11                                     Blood Supply:Trmsfusion-AssociatedRisks

     4: Notall recipientswill developthe diseasepresentin the blood(seroconvert);90 percentof the
     52 recipientsof HIVbloodwill seroconvert(47 patients).Thisconceptappliesonlyto viruses.

     5: Mostpatientsreceivingbloodareat great riskof dyingfromtheirunderlyingconditions;
     30 percentdiewithin2 years.ForHIV,33 of the 47 patientswill survive.

     6: Notall agentsandactivitiesleadto chronicdiseaseor death.ThelikelihoodthatHIVwill is
     nearly100percent,so all 33patientswho survivetheirunderlyingconditionswill die.

     bThenumberof virus-andparasite-contaminated
                                               unitsis basedonthe numberof allogeneicunits
     donated(12.057million)andthe numberof componentsmade(23.190million).

     CAtotalof 6.330millionindividualunitsof plateletsweretransfused.Patientriskand available
     componentsare basedon 4.688millionrandomdonorplateletstransfused(56percentof total
     unithas6 individualunitscollectedfrom 1 donor,totaling3.642millionplatelets,or 44 percentof
     totalplatelettransfusions).Forexample,patientriskfor a randomdonorunitis the riskfor each
     donorunitdividedby the averagenumberof unitspooledintoa therapeuticdose,10,200/6,or 1
     in 1,700in Morrow’s(1991)researchon plateletcontamination.Thenumberof implicatedrandom
     donorunitsis 4.688million/10,200,or 460units.Thepatientriskfor apheresisplateletsis the
     sameas the per-unitrisk(1:19,500)becausethe plateletsarecollectedat the sametimefroma
     singledonor.Numberof implicatedapheresisunitsis 607,000/19,500,   or 31 units.

     *Notrelevantfor bacterialcontaminationor transfusion-related
                                                                outcomesthat arenear-term
     ‘Riskis basedon 12.057millionred bloodcell unitsbecauseYersiniaoccursonlyin theseunits.

     QRiskis basedon sumof viralrisksplusYersiniariskplus a weightedsumof plateletrisksbased
     on proportiontransfused((randomplateletriskx 0.56)+ (apheresisplateletriskx 0.44)).
     ‘The numberof unitsassociatedwithtransfusionproblemsis basedon the numberof units
     10.741millionwholebloodandred bloodcells,and 3.194millionothercomponents),Riskis
     basedon 19,230,000totaltransfusions.SeeappendixII for supplyandtransfusioncalculations,
     ‘Riskis basedon 10.741millionred bloodcells andwholebloodtransfusedbecause
     compatibilityis an issueonlyfor theseunits,
1’   IAssumesa 64-percentchancethat a randomtransfusionto an unintendedrecipientwouldbe
     compatibleand 100-percentreportingof incompatibleerroneoustransfusions.

     ‘Riskis basedon sumof viralrisksplusYersiniariskplusa weightedsumof plateletriskbasedon
     proportiontransfused((randomplateletriskx 0,56)+ (apheresisplateletriskx 0,44))plus

     ‘Number of affectedpatients/totalnumberof transfusionrecipients(4 million).

     Page 12                          GAO/PEMD-97-2Blood Supply:Transfusion-AssociatedRisks

Although the tik of receiving Hrv-contaminatedblood is the public’s
greatest fear, other diseases transmitted through blood are far more
common thm HIV.For example, we found that the risk of contracting HCV
infection is more thari 100times greater than that of contracting HIV. After
screening and testing, the likelihood that a unit of blood infected with
hepatitis C virus would remain undetected and be released for trartsfusion
is 1 in every 4,100units of blood; for HIV,the likelihood is 1 in every
450,000units.ll A more sensitive ~ti-HCVtest that detects more infected
units is available in Europe md has been licensed in the United States
during the past year. I& use is widespread but not universal.

The likelihood that a unit of blood may become contaminated by bacteria
ranges from 1 in 500,000for red blood cells to 1 in 10,200for random
donor platelets, the blood component used to heat certain bleeding
disorders. As we discuss in Blood Supply: FDA Oversight and Remaining
Issues of Safety, cited above, bacteria can enter a unit during collection as
a result of either poor aseptic technique or donor bacteremia. Bacteria
present in a unit can proliferate during storage. Platele@ are at high risk
because they are stored at room temperature; tie risk of their
contamination greatly increases over their storage life of 5 days. Bedside
tests for bacterial contamination codd greatly mitigate this problem and
may soon be presented to FDA for approval.

We estimated that about 1 in every 2,000units may be infected by a virus,
bacterium, or parasite. 12Cetin no~~ectioW risks are also associated
with blood transfusion. One such problem is the immune reaction
associated with the inadvertent transfusion of blood that contains red
blood cells that are incompatible with those in the recipient’s blood. Other
risks include acute lung injury, circdatory overload, and allergic reactions
to certain blood proteins. Some of these risks (for example, acute lung
injury) cannot be eliminated without advances in the state of knowledge

llpre~i~e~umbe~ such ss these me known as point estimates. Their precision is necessary for
calculating purposes but should not be construed as definitive.Scientists know that statistical
measurement is not perfectly precise. Thus, they calculate a range, or confidence interval, of estimates
that is wide enough that they are confident in believingthat the real number is somewhere between
the two endpoints of the range. For example, the confidence interval for HBVrisk ranges from 1in
31,279to 1in 146,662,meaningthat the real risk almost certainly lies somewhere in the middle.In the
case of HBV,the point estimate is I in 63,171units. We used point estimates in our analyses. We
include confidence intervals in appendix I wherever they are available.
l~see~ble 1,note g, for calculation method.

Page 13                             GAO/PEMD-97-2
                                                Blood Supply:Trmsfusion-AssociatedRiska

about how they occur. 13me over~ ~kelihood of noninfectious
complications is difflcdt to ascertain, because estimates are based on
voluntary hospiti reports and because they are likely to remain
undiagnosed in the hospital setting. We estimated that some type of
noninfectious complication may occur in 1 of every 3,448units of blood.l~

Using current risk estimates for individual adverse outcomes, we
determined that as many as 8 of every 10,000units of blood carry a
potentially serious risk to the patient, including incompatibility, allergic
reactions, bacteri~ and viruses. About 11,560of the 23.19million
components available are infected by bacteria, viruses, or parasites, and
about 4,870of the 19.23million components that are transfused may lead
to a adverse, noninfectious outcome, such as circulatory overload. We
calculated that an individual patient’s risk of receiving art implicated unit
is 4.2 in 1,000,or 1 in 238 patients.15

In order to fully understand the risks of blood transfusion, one must
consider three additional factors. First, even if a unit of blood is
contaminated, the like~ood of acquiring the disease it contains is less
than 100percent, ranging from 10to 90 percent. Second, blood is typically
prescribed for patients who have very serious trauma or disease. Indeed,
there is a 30-percent chance that a patient will die within 2 years from the
underlying condition for which the blood is prescribed and, therefore,
never experience some of the possible negative consequences from the
blood transfusion i@elf.lG

lsGr~-w.host disesse is one exsmp]e   of a problem that has been virtusflyeliminated M SClentlStS
discovered how it acts. Donor lymphocytes engraft and multiplyin the recipient, who is usually
immunocompromised.The donor cells react against the “foreign”tissues of the recipient. The reaction
occurs most ofien in blood received from tirstdegree familymembers. These blood donations are now
irradiated, thus makinggrsft-vs-hostdisease from blood transfusion very rare in the [jnited States.
IiEstimated by summingtransfusion-related, noninfectious risks from the second column of table 1:
1/12,000+ 1/10,000+ 1/150,000+ 1/10,000= 0.00029,or 2.9in 10,000units, or 1in 3,448units.
l~e average patient risk is calculated by dividingthe per-unit risk by the average number of units in a
transfusion. But it must be noted that patient risk depends on the number of units transfused. fi’or
example, if tie risk per unit for a disease is 1in 500,000,then a patient who has received an average
transfusion of 5 units would have a risk of 1in 100,000(500,000dividedby 5). That is, if 1 of every
500,000units is contaminated, then 1of every 100,000patients who receive 5 units could receive a
contaminated unit. Similarly,1of every 5,000patients who receive 100units could receive a
contaminated unit (500,000dividedby 100).

“~is is to say not thatthere is a causal relationship between receiving blood and dyingbut, rather,
that those who receive a blood transfusion are typically quite ill or traumatized and, consequently, may
die from the underlyingreason for which the transfusion was administered. The mortality rate may be
even higher for platelet recipients, who are often extremely ill with cancer or other life-threatening

Page 14                             GAO/PEMD-97-2Blood Supply:Transfusion-AssociatedRisks

                                   Third, ordy Hfv-contaminatedblood leads to nearly certain fatal outcomes;
                                   the likelihood that a patient would develop clinically serious chronic
                                   disease or die as a result of blood transfusion ranges from 0.2 to 30
                                   percent for all other possible complications. When we included all these
                                   facts in our analysis, we determined that only 10percent of exposed
                                   recipients are dtimately harmed seriously by their blood transfusions.
                                   Indeed, the overall risk of developing chronic disease or dying as a direct
                                   result of a blood transfusion is about 4 in 10,000,which trmlates into
                                   1,523of the 4 million patien~ who receive transfusions each year.17

                                   Surgery patients numbered 23 million in 1993.Given that there are
                                   3 million surgical transfusion patients annually, we estimated that 13
                                   percent of the surge~ patients received blood. Therefore, discounting the
                                   fact that some patienti had multiple surgeries, a maximum of 9 percent
                                   underwent surgery and 1 percent both underwent surgery and received
                                   blood among the 260 tiion in the general U.S. popdation.l*

                                   Given these estimates, we calcdated that the risk of a general surgery
                                   patient’s requiring blood and then developing a chronic disease or dying as
                                   a resdt of that blood is 5 in 100,000(see table 2). For an average person in
                                   the general popdation who does not foresee a plan for surgery, the annual
                                   risk that he or she would develop a need for surgery, require blood, and
                                   develop a chronic disease or die as a resdt of that blood is 5 in 1 million.

Table2: Riskaof Surgeryend Blood
Transfusion’                       Likelihoodof problemif patient                                                                 Risk
                                   Receives blood                                                                         40: 100,000
                                   Is a surgery candidate                                                                   5:100,000
                                   Has no ~lans for suraerv                                                               5:1 ,000,000
                                   aAssumes23 millionsurgeriesin 1993,or 9 percentof the U.S.population,withan estimated13
                                   percentof the surgeriesusingbloodand0.012probabilityof surgeryandbloodtransfusion
                                   occurringtogether.Assumesfurtherthatonly3 millionof the 4 millionpatientswhoreceived
                                   transfusedbloodweresurgerypatients;the remaining1 millionreceivedtransfusionsfor cancer
                                   therapy,hemophilia,and otherdisorders.

                                   ‘iTherisk for HfVwe present does not include tie expected reduction resulting from the introduction
                                   of the new p24 antigen HIVtest. Althoughno confirmatory data have been collected, it is estimated
                                   that the risk of HfVin blood screened by the new test will be 1 in 700,000.Whenwe used this risk
                                   estimate in our analysis, we concluded that it would detect an additional 19of the 52conmminated
                                   components in the supply and ultimately prevent 12~essthan 1percent) of the 1,523cases of chronic
                                   disease and death associated with transfusion.
                                   la~ong the estima~d ZGOmillion U.S. population, 9 percent underwent surgery (23million dividedby
                                   200million). furthermore, 13percent of thow surgery patients received blood (3 millionestimated
                                   surgery transfusions divided by 23 millionsurgeries). The likelihoodthat an average U.S.citizen with
                                   no plans for surgery would undergo surgery and receive blood is 1 in 100(probability of surgery and
                                   blood = 0.09X0.13= 0.01).

                                   Page 15                           GAO/PEMD-97-2
                                                                                 Blood Supply:Transfusion-AssociatedRisks

Blood fiansfusion Risks in           In order to determine whether these risks are small or large, we compared
Perspective                          them to other health-related risks. Data from the Medical Practice Study
                                     suggest that more than 1 million patienk are iqjured in hospit~ each
                                     year, and approximately 180,000die annually as a restit of these injuries
                                     (Brennan et al., 1991;Leape et al., 1991).A recent study at two large
                                     Massachusetts hospitals found that 6.5 percent of admitted patients
                                     suffered an injury resdting from medical intervention related to a
                                     prescribed drug during their hospiti stay (Bates et al., 1995).

                                     The risks to blood transfusion recipients and general surgery patients are
                                     considerably smaller thw the risk of dying as a direct resdt of surgery, the
                                     risk that a hospital stay will restit in death or chronic disability, the risk of
                                     suffering a injury from hospiti drug therapy, and the risk of developing
                                     an infection of unknown cause in intensive care (see table 3).
Table3: LikelihoodM VariousHealth
Outcomes                                                                                                          Per 100,000
                                     Outcome                                                                  hospitsiizetionsa
                                     Chronic disease or death from blood if
                                       General surgery patient                                                                   5
                                       Received blood transfusion                                                               40
                                     Hospital stay ends in death or disability                                                 600b
                                     Death as direct result of surgery                                                     1,333’
                                    ~njury related to drug therapy during hospital stay                                    6,500d
                                     Infection of unknown cause in intensive care                                          7,500’
                                     aWewereunableto determinewhethersomeof thesefiguresincludethe riskof dyingfrom
                                     transfusion.However,that riskis a verysmallproportionof the otherrisks,

                                     bT.A. Brennanet al., “Incidenceof AdverseEventsand Negligencein HospitalizedPatients:
                                     Resultsof the HarvardMedicalPracticeStudyl,” NewEnglandJournalof Medicine,324:6(1991),

                                     CC.B. Inlanderet al., TheConsumer’sMedicalDeskReference(NewYork:StonesongPress,

                                     ‘D. W.Bateset al,, “Incidenceof AdverseDrugEventsand PotentialAdverseDrugEvents:
                                     implicationsfor Prevention,”Journalof the AmericanMedicalAssociation,274:1(1995),29-34.

                                     ‘B, N.Doebbelinget al., “ComparativeEfficacyof AlternativeHand-Washing
                                     ReducingNosocomialInfectionsin IntensiveCareUnits,”NewEnglandJournalof Medicine,327

                                    Furthermore, the annual risk from trufusion to arI average person in the
                                    United States who foresees no plarI for surgery is the same as or lower
                                    than the annual risk of dying from tuberculosis or from accidental

                                    Page 16                          GAO/PEMD-97-2
                                                                                 Blood Supply:Transtiion-Associated Risks

                                electrocution or drowning, and it is as much as nearly 600 times less than
                                the annual risk of dying from other diseases or eventi of great public
                                concern (see table 4). These differences are partictiarly striking
                                comidering that the risk estimate for blood transfusion includes both
                                chronic disease and death, whereas some of the other risk estimates
                                include only death; estimates that included chronic disease wodd be
                                substantially higher. Perhaps most importantly, the risks associated with
                                blood trmsfusion must be compared to the risk of dying from having
                                refused a blood transfusion that physicim believed to be medically
                                necessary-a risk that could approach 100percent in some cases.

Table4: AnnualRatesof Various
HealthOutcomea                                                                                          Per 100,000
                                Outcome                             Condition                            population
                                Chronic disease or death by
                                transfusion without surgery plans                                              0.5
                                Hospitalization for                 Septicemia (bacteria infection in
                                                                    bloodstream)                               105
                                                                    Accidental poisoning by drugs,
                                                                    medicines, and bioloaicals                 128
                                                                    Drugs and other
                                                                    pharmaceuticals causing
                                                                    adverse effects in therapeutic
                                                                    use                                        142
                                                                    Infections or parasitic diseases           311
                                                                    Cerebrovascular disease                    328
                                                                    Pneumonia                                  462
                                                                    Malianant tumor                            578
                                                                    Injury and poisoning                     1,060
                                                                    Heart disease                            1,541
                                Death from                          Electrocution                              0.5
                                                                    Tuberculosis                               0.8
                                                                    Drowning                                   2.8
                                                                    Hardening of arteries                        9
                                                                    Motor vehicle crash                         15
                                                                    Pneumonia or influenza                      32
                                                                    Stroke                                      59
                                                                    Cancer                                     206
                                                                    Heart disease                              296

                                Page 17                        GAO/PEMD-97-2
                                                                           Blood Supply:Transfusion-AssociatedRisk

                  We found that the current risks from blood trmsfusion are small
Conclusions       compared to transfusion’s overwhelming benefits in saving lives. Blood
                  transfusion is the most common therapy using human tissue in the world.
                  As a tissue, blood retains the medical history of its donor. Because it is a
                  biological product, the risks can approach but may never reach zero.

                  Medical testing and manufacturing technologies continue to improve
                  blood safety. Medicalpractice is being transformed to accommodate new
                  knowledge about the risb and benefits of blood transfusion. Ultimately,
                  each patient benefik from these advances. However, because the risks are
                  already so low, incremental increases in safety maybe difficdt to achieve.
                  Therefore, the potential outcomes of alternatives for reducing blood
                  transfusion risks may require care~ consideration in order to identify
                  areas of improvement &at would maximize safety with reasonable costs.

                  The analysis we present here incorporates what is known today about
                  infectious agents in the blood supply. New infectious agents are always
                  emerging, and there is always the possibility that they could be trmsmitted
                  by blood. Continued safety, therefore, depends on the scient~lc and
                  medical communities’ detecting and identifying new threats to the blood

                  The Department of Health and Human Services (HHS) generally agreed
Agency Commenti   with the findings and conclusions of our study (see appendix V). HHSalso
                  provided technical commenb that we have incorporated in the body of the
                  report where appropriate.

                  &we arranged with your office, unless you publicly announce the report’s
                  contents earlier, we plan no further distribution until 15 days after the date
                  of this letter. We will then send copies of the report to the Secretary of
                  Health and Human Services, the Commissioner of the Food and Drug

                  Page 18                    GAO/PEMD-97-2
                                                         Blood Supply:Transfusion-AssociatedRisks

Administration, md others who are interested. We will also make copies
available to others upon request. If you have any questions or would like
additional information, please cti me at (202) 512-3652.M@or
contributors to this report are listed in appendix VI.

Sincerely yours,

Director for Program Evaluation
  in Physical Systems Areas

Page 19                   GAO/PEMD-97-2
                                      Blood Supply:Transfusion-AssociatedRisks

Letter                                                                                       1

Appendix I                                                                                  24
                   HIV-I and HTV-2                                                          24
Transfusion-       Hepatitis A                                                              29
Associated         Hepatitis B                                                              30
                   Hepatitis C                                                              32
Complications      Other Hepatitis Viruses                                                  35
                   HTLV-Itid HTLV-11                                                        36
                   Parasites                                                                39
                   Bacteria                                                                 41
                   Noninfectious Complications of Transfusion                               44

Appendix II                                                                                 48
                   The Evaluation of Transfusion-Risk Studies                               48
Our Methods ad     The United States Blood Supply                                           51
Analysis           Risk Estimates and Their Cordidence Intervals                            58

Appendix III                                                                                60
                   Plasma Product Uses                                                      60
Plasma Products    Plasma Donors                                                            61
                   Plasma Fractionation and Product Manufacture                             62
                   History of Disease Transmission From Plasma Products                     63
                   Rates of Vti Test Positivity Among Commercial and Volunteer              64
                   summary                                                                  69

Appendix W                                                                                  70
                   Drug Therapies to Reduce the Need for Blood Transfusion                  70
Further Reducing   Alternatives to Blood                                                    70
Risk               Reducing the Use of Transfusions                                         71
                   Controlling the Sources of Donation                                      72
                   Extending ViralInactivation to Celldar Components                        73
                   Closing the Window Period                                                73
                   summary                                                                  74

                   Page 20                  GAO/PEMD-97-2
                                                        Blood Supply:Trmstiion-Associated Risks

Appendix V
Comments From the
Department of Health
and Human Services
Appendix VI
Major Contributors to
This Report
Tables                  Table 1:Individual and Ovedl RiBksof AdverseOutcomes From                 10
                          Allogeneic Blood Trmfusion
                        Table 2: Risks of Surgery and Blood Transfusion                          15
                        Table 3: Likelihood of Various Health Outcomes                           16
                        Table 4: Annual Rates of Various Health Outcomes                         17
                        Table 11.1:Scientific Studies Used as Source of Our Risk                 49
                        Table 11.2:Estimate of Toti Allogeneic Blood Supply and                   52
                        Table 11.3:Calcdations for Individud and Overall Risks of                 54
                          Adverse Outcomes Prom Allogeneic Blood Transfusion
                        Table 11.4:Estimated Risks for Specific Blood Componen@                   58
                        Table 11.5:Test Sensitivity ad Specificity Rates and Window               59
                          Period Estimates
                        Table 111.1:Uses for Plasma Componenk                                     60
                        Table 111.2:Viral Test Antibody Positivity Rates: ClinicalTrial           68

                        Figure 111.1:Reported Confirmed HIVPrevalence Rates Among                 66
Figure                    Donations in California, 1989-94

                        Page 21                  GAO/PEMD-97-2
                                                             Blood Supply:Transtiion-Associated Risks


ABRA       American Blood Resources Association
Me         American Red Cross
ATL        Addt T-cell leukemia and lymphoma
CDC        Centers for Disease Control and Prevention
m          Creutzfeldt-Jakob disease
CMV        Cytomegalovirus
FDA        Food and Drug Administration
WSP        HTLV-I-associatedmyelopathy and tropical spastic
HAv        Hepatitis A virus
HBc        Hepatitis B core
HBV        Hepatitis B virus
HBsAG      Hepatitis B surface antigen
HCV        Hepatitis C virus
HDV        Delta hepatitis
HEV        Hepatitis E virus
HGV        Hepatitis G virus
HHS        Department of Health and Human Services
HIV        Human immunodeficiency virus
HTLv       Human T-lymphotropic virus
IGIV       Immune Globtin Intravenous
NIH        National Institutes of Health
TRALI      Transfusion-related acute lung iqjury

Page 22                GAO/PEMD-97-2
                                   Blood Supply:Tra.nstiion-Associated Risks


        Page 23   GAO/PEMD-97-2
                              Blood Supply:Transfusion-AssociatedRisks
Appen& I


                  In this appendix, we discuss factors important for understanding the
                  nature of blood transfusion risks. Specifically, we highlight
                  epidemiological disease factors, present and evaluate the data from
                  blood-supply-risk and transmission-by-transfusion studies, and discuss
                  what is known about the clinical prognosis for each virus, bacterium, and
                  transtiion complication we include in our risk analysis.

HN-1 and HIV-2

Disease Factors   HIV-1is widely distributed throughout the world, 21.8 million cases having
                  been repo~d by July 1996.Sub-Saharan Africa is home to 63 percent,
                  South Asia and Southeast Asia to 23 percent, and North America to
                  3.7 percent of all reported cases. HIV-2is endemic only in West Africa,
                  although cases have appeared in other pm of Africa and in Europe,
                  North America, and South America.

                  The mode of transmission and the course of immunological destruction
                  are similar in HIV-1and HIV-2.The rate of disease progression, however,
                  may be substantially slower in HIV-2,as may be the likelihood of secondary
                  transmission. HIV-2is rare in the United States: by 1991,CDChad confirmed
                  ordy 17 cases, of which 13had migrated from West Africa, where it was
                  first identtiled.

                  HIVcases in the United States were initially clustered among homosexual
                  males, intravenous drug users, prostitutes, and transfusion recipients.
                  However, distribution patterns have changed in the past 10years to
                  include more cases of infection acquired from heterosexual sex and from
                  perinatal transmission to newborns. CDCreported in July 1996that 1 in
                  every 300Americans carries the HIVvirus. According to its most recent
                  data, 650,000to 900,000Americans were infected by 1992,and 40,000more
                  become infected each year. More than 325,000persons had died of AIDSin
                  the United States through 1994;50,000more die each year. Experts point
                  to five factors that contribute to HIV’S
                                                         emergence: urbanization, changes in
                  lifestyles, increased intravenous drug abuse, international travel, and
                  blood and tissue transplantation.

                  In July 1996,CDCannounced the discovery in California of the first person
                  in the United States known to carry a rare strain of HIV(group O) that is
                  not consistently detected by current HI\rscreening tests. Fewer than 100

                  Page 24                   GAO/PEMD-97-2Blood Supply:Transfusion-AssociatedRisk
                           Appendix I

                           cases of this virus have been reported worldwide from West and Central
                           Africa, Belgium, France, and Germany. The source of infection of the
                           patient in Los Angeles is not known, but she is originally from Central
                           Africa, and CDCofficials believe that she contracted the disease before
                           coming to the United States. The patient has never donated blood, and FDA
                           is working with industry to improve HNscreening tests to detect HIVgroup
                           O reliably. A second case of HIV-1group O infection has been identified in
                           the United States under CDC’S  surveillance activities for unusual HIV-1

                           The incubation period from exposure to antibody seroconversion for HIV
                           ranges from days to months before the virus is detectable in blood. It is
                           thought that the average time between infectiousness (when a recently
                           infected blood donor can transmit disease) and seroconversion is 22 days,
                           with a 95-percent cotildence interval of 6 to 38 days. It takes an average of
                           10years after infection for clinical signs of HIVdisease to emerge.

                           The period of communicabili~ is not well established but is presumed to
                           begin early after the onset of HIVand to extend throughout life. Recent
                           advances in treatment using a combination therapy, which may include
                           new “protease-inhibitors,” appear promising. The drugs work by blocking
                           an enzyme critical to HIVreplication md cm reduce the amount of HIVin
                           the blood to levels that cannot be detected by even the most sensitive tests
                           avtilable. However, success depends on strict compliance with the
                           treatment program.

                           Prevention and control measures include blood and tissue screening,
                           avoidance of any form of sexual intercourse with persons known or
                           suspected of infection, use of latex condoms md spermicide to reduce
                           risk of sexual transmission, avoidance of shared needles by intravenous
                           drug users, and universal precautions by health care workers.

Blood-Supply-RiskStudies   In a study carried out between 1985and 1991in Baltimore and Houston
                           (both areas of high HIVrisk), Nelson and colleagues (1992) directly tested
                           the blood of patients before and after cardiac surgery to determine their
                           risk of acquiring HIVfrom blood donations screened negative for the
                           antibody to HIV.Two cases of HIVwere documented in 11,532recipienfi
                           after the transfusion of 120,312units of blood, for an estimated risk of 1
                           per 60,000units (upper limit of cotildence interval 1 in 19,000).A direct
                           approach was also taken in San Francisco, another high risk area, using
                           donations made between November 1987and December 1989.Busch and

                           Page 25                     GAO/PEMD-97-2
                                                                   Blood Supply:Transfusion-AssociatedRisk
    Appendix I

    colleagues (1991)fmt pooled units of blood that had been screened for HIV
    antibodies and issued for tr~fusion and then they tested for evidence of
    the actual virus. This study estimated the risk of Hfv-1as 1 per 61,171units,
    with a 95-percent upper confidence bound of 1 in 10,695.In a subsequent
    analysis of pools of screened blood donated between October 1990and
    June 1993,researchers reported a risk of 1 in 160,000units (upper bound
    of 95-percent confidence interval, 1:128,000)(Vyas et al., 1996).

    Statistical modeling techniques have replaced most of the direct
    measurement methods of collecting transfusion risk data. The first such
    method estimated risk based on data on the incidence of seroconversion
    among donors (the total number of new infections in a given time period)
    and assumptions about the sensitivity of tests and the length of the
    wirtdow period. Using this method, Ward and colleagues (1988)estimated
    the HfVrisk at about 1 per 40,000units.1 Ward’s groundbreaking reasoning
    was as follows.

    from May 1986to May 1987,0.012percent of repeat blood donors md
    0.041 percent of fwst-time donors in the United States had HIVantibody.2If
    we assume that all HIVinfections detected in repeat blood donors are new,
    or incident, infections and that those in firsttime donors are preexisting, or
    prevalent, infections, then we can estimate the number of persons who are
    infected with HIV after they have received transfusions screened as
    negative for antibody. We can do this by assuming the following:a test
    sensitivity of 99 percent, the development of detectable HIV antibody 8
    weeks after infection, m equal probability of infection throughout time, a
    repeat donation rate of 1.5times per year (about every 32 weeks), and the
    collection of 14.4million of the 18 million components trasfused annually
    (or 80 percent) from repeat donors.In other words,

●   for repeat donors, (14,400,000x [0.00012x (8/32)])+ (14,400,000x [0.00012
    X (24/32) X 0.01]) = 445.3
●   For firsttime donors: 3)600,000x (0.00041x 0.01)= 15.
●   Transmission by HIVseronegative blood: 445 + 15.460 units of 18 million
    = 1 per 39,130,or about 1 per 40,000.

    ‘Warddid not report confidence intervals.

    ‘Personal communication from Roger Doddof the American Red Cross.

    ‘mat is, [number of donors x (the HfVpositivity rate x the proportion of the time between donations
    when the donor could be in the window period)] + [number of donors x (the HIVpositivityrate x the
    proportion of the time between donations when the donor would be outside the windowperiod x the
    probability that the test result is false negative)], the latter probability being 100percent minus

    Page 26                            GAO/PEMD-97-2Blood Supply:Transfusion-AssociatedRisks
Appendix I

cumming and colleagues (1989) used similar methods but with more
refined rates of donor infectivity tiat accounted for differences between
males and females and between firstie and repeat donors and a lower
estimate of test error (0.1 percent). They reported the risk of an w
positive unit at 1 per 153,000uni~ if the window period was 8 week (as
was then thought, using f-t-generation Hrv tesb), a l-in-300,000risk with
a 4-week window period, and 1 in 88,000with a 14-week window period.

Kleinmm and Secord (1988) improved the mathematical model by
employing “look-back techniques” to estimate the number of m-infected
units that wotid be donated by repeat donors in the window period. That
is, they looked back at recipien@who had received test-negative
donations from repeat donors who later gave test-positive donations. With
this technique, Kleinman and Secord calcdated the rate of recipient
infection from these preseroconversion donations, estimated the duration
of the window period, artd found the Hrv risk in Los Angeles in 1987to be 1
per 68,000.

Petersen and colleagues (1994)used the lookback method to refine the
estimate of the window period. They evaluated the HIV status of recipients
who had received screened negative donations from 182repeat donors
who later tested positive for HIV. The study reflected donations from a
large portion of the United States and conditions from 1985to 1990.These
researchers found 20 percent of recipients of preseroconversion units
infected. Moreover, the rate of disease transmission in recipienk was
found to be higher as the interval between the negative and positive
donations decreased. Mathematical modeling showed that the infectious
window period averaged 45 days (95-percent cotildence interval, 34 to 55
days).~Subsequently, Petersen combined the 45-daywindow period with
measures of the rate of seroconversion among repeat donors in a large
donor population with estimates of seroconversion rates for f~sttime
donors to tive at the fwst national Hrv risk estimate of 1 in 225,000.

Today, newer HN antibody tests have reduced the window period to
between 22 and 25 days. Using the 25-daywindow estimate and nationally
representative data from a total of 9 million MCdonations in 1992ad
1993,Lackritz ad colleagues (1995)used a laboratory error rate of 0.5

‘By95-percent confidence interval, we mean that the researchers have established a range of values
for which they are confident that in 95out of every 100measurements (in this case of the window
period), the true value would fall somewhere between tie two endpoints of the stated interval. These
researchers found preliminary evidence suggestingthat antibody tests used after March 1987had a
smaller window period of 42 days, a findingthat was later confirmed.

Page 27                            GAO/PEMD-97-2Blood Supply:Transtiion-Associated Risb
Appendix I

percent, which predicted the erroneous release of 1 in every 2.6 million
po~tive donations. An additional factor in this model was the elimination
of the window period unik that would have been discarded because they
were positive on other test resdts, such as hepatitis, syphilis, and liver
enzymes. Indeed, 15percent OfHIV preseroconversion (HIV test-negative)
donations from repeat donors ad 42 percent of HIV test-positive donations
were positive ofi’other tests. This study concluded that there was a
residual risk of HIV transmission in 1 of every 450,000to 660,000
t-fusions     of a unit of screened blood.5

h discussing tie implications of their findings, the researchers noted
several limitations. First, scientists are unable to measure directly the
number of window-period donations that are discarded for positive restits
on other screening tests, and it is not known what pattern of positivity on
other tests window-period donors might display. Second, because current
data on the incidence of HIV among firsttime donors is unavailable,
researchers must rely on 1985data collected when HIV testing begart that
showed that the prevalence among firsttime donors was 1.8times higher
thsrI the prevrdence among repeat don~rs. It was assumed that the
incidence rates wotid show a similar relationship. Whether this has
changed in the past 11years is a question sti~’outstanding. Third, although
the study is based on a large sample of donations from 42 different ARC
regions that together collect nearly half of the nation’s blood, it is not
certain that they represent non-~c centers.

Schreiber and colleagues (1996) studied the donations of 586,507repeat
donors who donated 2,318,356units at five metropolitan blood centers
between 1991and 1993.Using a window estimate of 22 days, the
researchers estimated the likelihood that a repeat blood donor would
donate a unit in the window period at 1 in 493,000(95-percent confidence
interval, 202,000to 2,778,000).6Schreiber did not adjust for the firsttime
donors who constituted 20 percent of the donor pool or for laborato~
error. When we did so, using the method that Lackritz and colleagues
published, we calculated the risk at 1 in 412,000.Our revised estimate is
higher than Lackritz’s.However, the study population for Schreiber’s
research is in Baltimore, Detroit, Los Angeles, Oklahoma City,and San
Francisc&metropolitan areas that collect only 9 percent of the nation’s

‘No point estimate is reported.

%chreiber’s calculation of the windowperiod is 3 days less thanthatof Lactitz. Theyare considered
equaflyvalid estimates. The choice of one over the other does not significantlychange the outcome of
the csfculations.

Page 28                            GAO/PEMD-97-2Blood Supply:Transfusion-A..sociatedRisks

                     blood and that wodd be expected to pose higher risks thm the national

                     To date, no cases of transfusion recipienk infected with HIV-2have been
                     reported in the United States and ordy 2 HIV-2positive units have been
                     detected among nearly 60 mi~on screened units. In Europe, however, a
                     sizable number of infected blood donors have been detected on screening,
                     and some cases of transfusion transmission have been documented. Thus,
                     the United States may see cases of transfusion-transmitted HIV-2in the

Transmission-by-     Donegan and colleagues (1990) retrospectively tested 200,000blood
TransfusionStudies   component specimens stored in late 1984and 1985for HIV antibody and
                     contacted recipients of positive donations to de~rmine their status. Of the
                     124recipients with no known risk factors for HIV, 111(89.5 percent) were
                     positive for HIV.The recipien~’ gender, age, underlying condition, and type
                     of component did not intluence infection rates. The rate of progression to
                     AIDSwithin the first 38 months after infection was similar to that reported
                     for homosexual men and hemophiliacs. A later study by Donegan and
                     Lenes (1990) suggested that washed red blood cells and red blood cell
                     uni~ stored more than 26 days had lower transmission rates than other
                     components. Rawal and Busch (1989) have demonstrated that faltering
                     leukocytes from blood componen~ reduces HIVinfectivity.

ClinicalPrognosis    Despite the encouraging findings of recent research on AIDStreatment, it
                     is currently believed that 50 percent of persons testing positive for HIVwill
                     develop AIDSwithin 10years after contracting the virus and, because
                     AIDSis currently incurable, it is expected that all will succumb to it

                     HAV is almost always transmitted by the fecal-oral route. Commonly
Hepatitis A          reported risk factors among patients with HAV    include household exposure
                     (about 24 percent of all patients), contact with young children in daycare
                     (18 percent), homosexual activity (11 percent), foreign travel in endemic
                     areas (4 percent), and illicit drug use (2 percent), but in about 40 percent
                     of cases no risk factors can be identWled.The infection does not lead to

                     7Forsimilar reasons, we did not use Schreiber’s estimates for HTLV-Irisk (1 in 641,000,confidence
                     interval from 1 in 256,000to 1in 2,000,000)or for HCV(1 in 103,000,confidence interval from 1in
                     28,000to 1 in 2SS,000).But we did use his estimate for HBVdespite the lack of adjustment for testing
                     sensitivi~ and errors, because it was more conservative than the estimate that did.

                     Page 29                            -/PEMD-97-2        Blood Supply:Transfusion-AssociatedRisks
                 Appenti 1

                 chronic     md mortality is 0.2percent or less. A vaccine was
                 introduced in 1995.

                 HAVis very rarely found in donated blood because the virus circulates in
                 blood for ordy 7 to 10days before an infected person becomes
                 symptomatic. The risk of hepatitis A by blood transfusion is estimated at 1
                 per 1 million, and ordy 25 cases of transfusion transmission had been
                 reported in the literature by 1989.8

Hepatitis B

Disease Fac~rs   HBV, a  DNAvin.is,has a worldwide distribution. In the United States, an
                 estimated 1 to 1.25million persons have chronic HBVinfection, with
                 200,000to 300,000new infections each year. HBVis diagnosed by elevated
                 levels of certain liver enzymes and by serological antigen and antibody
                 tests, such as those used in blood donor screening. Antigen tests are
                 99.9-percent sensitive; antibody tests are 99-percent sensitive. Antibody
                 tests remain positive even after infectious viremia has subsided, and
                 positivity is considered a surrogate for persons with lifestyle behaviors
                 that place them at risk for HIV or hepatitis C.

                 Symptoms include the gradud onset of anorexia, abdominal pain, or
                 jaundice (yellowing of the skin as a restit of decreased liver function).
                 sometimes, patien~ experience joint pains, a rash, or itching. HBVis
                 acquired when the virus enters the body through breaks in the skin or
                 mucous membranes. The virus has been isolated in many different body
                 fluids but has been shown to be at infectious levels only in blood, semen,
                 ad saliva. The virus is spread by sharing contaminated needles, sexual
                 contact, occupational exposure to blood or body fluids, transmission from
                 an infected mother to her newborn during the perinatal period, and blood
                 transfusions. Although 30 percent of all infected persons have no
                 identifiable risk factor, most have other high risk characteristics (that is,
                 history of other sexu~y transmitted diseases, noninjection drug use,
                 incarceration) or belong to minority popdations of low socioeconomic

                 8HAVis a very stable virus capable of withstanding considerable heat in dry conditions. In 1$)92,
                 hemophiliacpatients receiving factor VIIIconcentrates of plasma were exposed to IWVbecause th(,
                 method used for inactivatingviruses (solventdetergent washing) did not affect HAVin the plasma, The
                 outbreak led to swift recall of this product. A heat-inactivation process should eliminate this risk,

                 Page 30                           GAO/PEMD-97-2Blood Supply:Transfusion-AssociatedRisks
                            Appendix I

Blood-Supply-RiskStudies    Transfusion-associated HBVinfection has not been studied to the same
                            extent as trmfusion-associated Hfv. Few direct measures exist. Most
                            estimates are based on statistical modeling of the window period or on
                            mathematical modeling of the incidence rates and test sensitivities.

                            The current estimate of the window period for detecting HBVis 59 days,
                            with a range of 37 to 87 days. Blood containing the virus is infective many
                            weeks before the clinical onset of symptoms and remains infective during
                            the acute phase of the disease. Chronic carriers who may exhibit no
                            symptoms are also infectious. Often, the amount of virus is too low to be
                            detected on the antigen test; therefore, positivity on antibody tests
                            (anti-HBC)also helps detect chronic carriers.g

fiansmission-by-            No direct measures of HBvtransfusion risk exist. In the ARC system, 100
TransfusionStudies         \ cases per year are reported among 2 million recipients. Surveillance
                            studies indicate prior transfusion % a factor for 1.1percent of the 23,000
                            cases of hepatitis B reported each year, or 250 cases.

                            M.J. Alter of CDC(1995) estimates the transfusion risk of HBVat about 1
                            per 200,000units. Her analysis is based on the theory that a certain
                            proportion of infectious cases of HBV(and other hepatitis viruses as we
                            discuss below) among blood donors are not detected by current tests. In
                            the case of HBV, the relevmt figures areas follows: HBVis found in
                            0.03 percent of blood donors (3 in 10,000).The antigen testis 99.9-percent
                            sensitive and the antibody test is 99-percent sensitive, meaning that as
                            many as 1 percent of infected individuals test false negative. After testing,
                            1 in 233,000units (0.00043percent) are still infectious.l” The risk from
                            transmission of missed units is 100percent.11Among patients who receive
                            4 units of blood, 1 in 58,000are at risk.

                            ‘)Deltahepatitis (HDV) is an incomplete virus that requires the help of HBVto replicate in the human
                            body. Persons confected with HBVand HDVmay have a more severe acute illness and a higher risk of
                            fulminant hepatitis than others infected only with HBV.No direct measure of the incidence of HDVis
                            available, but CDC’Smodels suggest that HDVaccounts for 7,500infections annually.Its prevalence
                            among HBVinfected donors is estimated at between 1.4and 8 percent. Hepatitis B immunizations
                            prevent HDVinfections, too.
                            II)Mer antigen screening, 0,00003 percent of units are infectious; after antibody screening,
                            0.0004percent. In sum, 0.00043percent, of afl units are infectious. Note that Alter rounds this last
                            figure to 0.00040percent in table 2 of her article. Weuse 0.00043percent, which changes the estimate
                            1l’rherisk of transmission among donom who test positive on the antibody test done is 4 Percent,
                            because in most cases a positive antibody test indicates an old, resolved infection.

                            Page 31                            GAO/PEMD-97-2
                                                                           Blood Supply:Transfusion-AssociatedRisks
                    Appendix I

                    More recentiy, Schreiber and colleagues (1996) used data on 2,318,356
                    Mogeneic blood donations from 586,507donors who had donated more
                    than once between 1991and 1993at five blood centers. Among donors
                    whose units passed all screening tesb, the risks of giving
                    HBv-contaminatedblood during the infectious window period was
     s              estimated to be 1 in 63,000units (confidence interval from 1 in 31,000to 1
                    in 147,000).

ClinicalPrognosis   M.J. Alter (1995) assumed that half of the 4 million annual transfusion
                    recipien~ die of their underlying disease.12Using these assumptions, Alter
                    predicts 34 HBVinfections among the 2 million tr%fusion rec{pienk who
                    survive long enough to develop HBV.

                    The development of chronic infection occurs in 5 percent to 10percent of
                    HBv-infectedaddts (M.J. Alter, 1995).An estimated 15percent of persons
                    with chronic HBVacquired -r      early childhood die of either cirrhosis or
                    liver cancer. There is no treatment for HBV.Factors that facilitate the
                    emergence of the virus are increased sexual activity and intravenous drug

                    Interferon treatment of addts with HBv-relatedchronic hepatitis has been
                    shown to achieve long-term clearance of infection in upward of
                    40 percent. Routine hepatitis B vaccination of infants and adolescents and
                    vaccination of adolescents md add~ in high-risk groups has begun to
                    prevent transmission of H13v.

Hepatitis C

Disease Factors     HCV,a flavi-likevirus, has a worldwide distribution and is relatively
                    common among dialysis patients, hemophiliacs, healthcare workers, artd
                    intravenous drug users. In 1995,CDCestimated that there are 35,000to

                    l~~e 50-percentfa~liW rate for transfusion is based on a study by Ward et d. (1989)that traced back
                    selected recipients of transf~ions and found that 50percent of a transfusion control group that had
                    not received ruv.infectedblood had died within a year and that 83percent of recipients of HIv-infected
                    blood had died by the time investigators could locate them. However,other researchers have noted
                    that these study participants were not representative of a general surge~ population as they were
                    often referred from a subspecialty surgical area and had a poorer prognosis for survival.[n a more
                    recent study, Vamvakasand Taswell (1994)enrolled all residenta of a U.S.county who underwent
                    transfusion in 1981.Whilethis group cannot be directly generalized to all U.S.  surgeries, the enrollment
                    of all transfusion patienta without any selection bias better characterizes actual transfusion practices.
                    These researchers found a 30-percentfatality rate within 2 yeara followingsurgery.

                    Page 32                             GAO/PEMD-97-2Blood Supply:Tranatiion-Associated Riska
                           Appendix I

                            180,000(average 120,000)new HCVinfections each year in the United
                           States. Diagnosis is by an antibody test that is 90-to 95-percent sensitive.
                           Symptoms include gradual onset of anorexia, nausea, vomiting, and
                           jaundice. Its course is similar to that of HBVbut more prolonged.

                           Most HCV is acquired in the community and much needs to be learned
                           about modes of transmission. CDC repo~ among documented cases in
                           1992that 2 percent were associated with health care occupational
                           exposure to blood, 4 percent with blood transfusion, 12 percent with
                           exposure to asexual partner or household member who had hepatitis or
                           multiple sexual partners, 29 percent with ~ection drug abuse, 46 percent
                           with low socioeconomic level, ad 6 percent with other high-risk behavior
                           (that is, nonimection illegal drug use, history of sexually trwmitted
                           diseases, imprisonment, sexual partners or household contacts who inject
                           drugs, or no identifiable risk factors).

Blood-Supply-RiskStudies   Before an antibody-specflc test for HCVwas implemented, blood donors
                           were tested for surrogate markers of the disease using tests to detect
                           antibody to HBV(ati-HBc) and elevated alanine aminotransferase, a liver
                           enzyme that, when levels are high, may indicate liver problems such as
                           those associated with HCV. Donahue, Nelson, and other colleagues in
                           Baltimore md Houston evaluated the risk of HCVat four different phases of
                           blood donor screening in 12,146cardiac surgery patients who had been
                           transfused (Donahue et al., 1992;Nelson et al., 1992,1995).Prior to
                           surrogate testing, these researchers estimated the risk of
                           transfusion-associated HCVat 1 in every 222 units of blood. When surrogate
                           testing was implemented, the risk decreased to about 1 in every 525 unik.
                           The first-generation ~ti-HCV test further reduced the risk to 1 in 3,333
                           units. When the second generation HCVtest was introduced in 1992,these
                           researchers found 15 cardiac surgery patients infected with HCV among a
                           study popdation who together had received 22,008units of blood for a
                           per-unit risk of about 1 in 1,470.

                           In another study, IUeinman and colleagues (1992) concluded that second
                           generation HCV tesb reduced HCV risks to between 1in 2,000and 1 in 6,000
                           component units.

                           The current estimate of the window period is 82 days with a range of 54 to
                           192days. Blood containing the virus is infective from 1 week after
                           exposure into the chronic stage. Screening is inhibited by several factors:
                           current second-generation tests may not detect 10percent of persons

                           Page 33                      GAO/PEMD-97-2
                                                                    Blood Supply:Transfusion-AssociatedRisks
                     Appendix I
                     Trmtion-Associated     Complications

                     infected with HCV; mute, chroNc, and resolved infections cannot be
                     distinguished on the basis of test resdts; the window period can be quite
                     prolonged; and in popdations with low prevalence (such as blood
                     donors), the rate of false positives is high.

                     Two factors currently contribute to the risk of HCVin the blood supply.
                     First, donors in the window period do not yet have any antibodies to be
                     detected on screening tesk. Schreiber and colleagues estimate that the
                     risk posed by tiese donors is 1 in every 103,000units (95-percent
                     confidence interval, 28,000to 288,000).

                     A much bigger risk sterns from the possibility that the relatively low
                     sensitivity of current antibody tesb results in false negative tests in 10
                     percent of donors actually infected by HCV.Assuming that the prevalence
                     of HCVamong donors is 0.244percent and test sensitivity is 90 percent, M,
                     J. Alter (1995) at CDCestimates that 0.0244percent of all units (1 in
                     4,1OO)are HCVinfectious after screening.13Using the 50-percent motiity
                     rate for transfusion, M.J. Alter predicts 1,955infections in the 2 million
                     surviving recipients.

                     M.J. Alter’s estimate is based on observations in community acquired
                     hepatitis, identtiled as a resdt of active surveillance. It has not been
                     independently confirmed, it is based on second-generation tests, and it is
                     unclear whether it applies to asymptornatic blood donors. Nevertheless,
                     because it represents the most conservative risk estimate in the current
                     literature, we chose to use it in our overall risk analysis.

Transmission-by-     Studies from around the world suggest that between 80 and 90 percent of
TransfusionStudies   transfusion recipien~ who receive antibody positive blood seroconvert to

ClinicalPrognosis    Approxirnately 25 percent of persons infected with HCVbecome acutely ill
                     with jaundice and other symptoms of hepatitis, and each year more than
                     4,000patienb require hospi-tion.     About 600 die of ~nant    disease.14

                               inteti RPO*.
                     l%eaefiguresincludeallcaaesof HCV,not tranafuaion-~   iated cases alone.

                     P~e 34                         GAO/PEMD-97-2Blood Supply l’mnatiion-hsociated   Riska
                  Appendix I

                  Much still needs to be learned about the long-term effects of HCVinfection.
                  Eighty-fivepercent or more develop persistent HCVinfection, and while
                  about 70 percent of infected individuals develop chronic hepatitis,
                  long-term follow-up studies suggest that only 10 to 20 percent develop
                  clinical symptoms of their liver disease over a 20year period following
                  trmfusion. (Farci et al., 1991;Seeff et al., 1992;Koretz et al., 1993;
                  Iwarson et al., 1995).Many persons who are affected suffer no symptoms.

                  Until recently, no treatment was available for hepatitis C. Recent evidence
                  now sugges~ that interferon maybe helpfti in treating chronic hepatitis C.
                  Studies by DiBisceglie and colleagues (1989) and Davis and colleagues
                  (1989) demonstrated marked improvement of liver enzyme activity in
                  about half of all treated patients. In mmy, the liver itself improved.
                  However, liver enzyme activity was sustained in ordy 10 to 51 percent of
                  patien@,and the effect of long-term therapy had not been determined.

Other Hepatitis

Disease Factors   Hepatitis E has been identified in developing nations around the world.
                  Like HAV, it is transmitted by the fecal-oral route (and also by
                  contaminated water) and its course of symptoms par~els that of HAV.      HEV,
                  however, is associated witi a high rate of ~nant       hepatic failure among
                  pregnant women, in whom the death rate maybe as high as 20 percent.

                  In 1995,researchers announced the discovery of a new hepatitis virus not
                  previously identified as hepatitis A, B, C, D, or E. Labeled hepatitis G virus
                  (HGV),it is not yet known if this strain is associated with acute and chronic
                  hepatitis. Between Oand 16percent of cryptogenic (non-A,B,C,Etype)
                  hepatitis patients and between 28 and 50 percent of patients with
                  fuhninant hepatitis were HGv-positive.HGVmay also lead to aplastic anemia
                  (decreased bone marrow mass); 3 of 10 such patients were HGVpositive
                  (Alter, 1996).Persistent infection has been observed for up to 9 years. h
                  1995,the National Institutes of Health (NIH)reported that 3 of 13hepatitis
                  patien- (23 percent) enrolled in an ongoing stidy had acquired HGVfrom
                  their blood transfusion. In the NIHstudy, HGVwas also detected in
                  12percent of transfusion recipien@ who had minor symptoms that were
                  not clinically identified as hepatitis, in 10percent of those with Hcv-related
                  hepatitis, in 8 percent of those with no symptoms, but in ordy 0.6 percent
                  of the 157nontransfused patien@ enrolled as study controls.

                  Page 35                      GAO/PEMD-97-2
                                                           Blood Supply:Transtiion-Associated Risks
                           Appendix I

Blood-Supply-RiskStudies   The prevalence of HGVin blood donors as measured by HGVRNAdetected
                           by PCR is higher tha tiat of HCV. The HGV virus was identified in the blood
                           of 24 of 1,478(1.6 percent) of the NIH donors, and a small study of 200
                           Midwestern blood donors found hat 4 (2 percent) were reactive for HGV
                           (“New Hepatitis G Virus,” 1995;“Abbott Announces Discove~,” 1995).
                           Although no antibody tesh have been developed to detect HGV,HGV
                           frequently coexists with HBVor HCV;  therefore, tests that detect either of
                           the latter viruses help eliminate HGVfrom the blood supply.

                           Both HBV and HCVtes@ help de@ct non-ABChepatitis in blood donors.
                           Using the same methods and assumptions as for HCV,M.J. Alter
                           (1995) estimates the risk of transfusion-transmitted non-ABChepatitis at 1
                           per 5,925units.

Transmission-by-           Despite the relatively high risk estimates of hepatitis in the blood supply,
TransfusionStudies         hepatitis researchers assert that the residual risk of hepatitis from
                           transfusion is very small and no different from the risk of background
                           hepatitis found in nontransfused hospitized patients. For example,
                           analyses from two large transfusion-related hepatitis studies conducted in
                           the United States in the late 1970sand in Canada in the 1980ssuggest that
                           the risk of non-ABChepatitis from transfusion (3.6 percent of patienk) is
                           similar to that of control groups of nontransfused hospital patients
                           (3 percent) (Aach et al., 1991).The Canadian Red Cross found the same
                           rate of non-ABChepatitis (0.6 percent) between patients receiving
                           volunteer supply blood and patienk receiving their own blood.

HTLV-Iand H~V-11

Disease Factors            HTLV-I isendemic in southern Japan, tie Caribbean basin, and Africa.
                           Popdations in Japan have rates of HTLV-I  infection ranging from a low of
                           1.1percent in Tokyo to a high of 37.5 percent in males and 44 percent in
                           females from Okinawa. Populations native to the Caribbean basin have
                           HTLV-I seroprevalence rates of 2 percent to 12percent. HTLV-11,which is
                           detected by the H’rLv-I-basedlaboratory tests currently used to screen the
                           blood supply, is endemic among Indian popdations in the Americas,
                           including popdations in Florida and New Mexico (Levine et al., 1993;
                           Hjelle et d., 1990)and among intravenous drug users in the United States
                           and Europe. The rate of infection in the United States blood donor

                           Page 36                     ~EMD-97-2   Blood Supply:l’ranafuaion-bociated Risks
                           Appendix I

                           popdation has been estimated to be between 0.009and 0.043per cent
                           (Williamset al., 1988;Lee et al., 1991;Sandier et d, 1990).Dodd reports
                           that the ARCobserves a donor seropositivity rate of 0.006percent to

                           The most common modes of transmission are from mother to child by
                           breast feeding, by transfusion of contaminated celh.darblood products, by
                           needle sharing among intravenous drug users, and through sexual activity.

Blood-Supply-RiskStudies   The current estimate of the window period for HTLV-I     and HTLV-11  is 51 days
                           with a range of 36 to 72 days (Manns et al., 1992).When blood screening
                           for HTLV was introduced in 1988,nearly 2,000U.S. donors were found to be
                           positive. The HTLV infections among blood donors in the United States are
                           nearly evenly divided between types I and 11.15   Most HTLV-I  positive donors
                           were born in or report sexual contact with a person from the Caribbean or
                           Japan, while nearly all HTLV-11 positive blood donors report a past history
                           of intravenous drug use or sex with an intravenous drug-using partner.
                           Because the current blood screening tests use HTLV-I     antigens to detect
                 I         both types, the sensitivity of detection of HTLV-11 is lower than that for
                           HTLV-1 antibodies. Hjelle and colleagues (1993) reported that the screening
                           ELISAtest misses 20 percent of HTLV-1infections and 43 percent of HTLV-11
                           infections. Thus, low test sensitivity, especially for HTLV-11,is the primary
                           reason that infected blood remains in the blood supply.

                           Schreiber and colleagues (1996) estimate that the risk of receiving an
                           HTLV-Contaminated unit from a repeat donor in the infectious window
                           period is 1 in 641,000(cotildence interval from 1 in 256,000to 1 in

                           Dodd (1992)has calcdated the residual risk of transfusion transmission at
                           1 in 50,000units based on current seroprevalence rates among donors artd
                           screening t-t sertsitivity.lG

Transmission-by-           Data from the Transfusion Safety Study (Donegan et al., 1994)show that,
Trmfusion Studies          overall, 27 percent of recipients who received anti-Hmv-positiveblood
                           became infected. The rates of infectivity varied by blood product and

                           IsMorefin so percent of HTLV-IandHTLV-11               amongintravenoushg We= *~
                                                                     aeropoait.ivity                          from
                           HTLV-11infection. HTLV-11alao appeara endemicamongNorthAmericanIndiansinFloridaandNew

                                cofildenceinteti rePo~.

                           Page 37                        GAO/PEIUD-97-2
                                                                       Blood SUPPW:Tranahion-Aaaociated Riaka
                    storage time. Only celhdar blood products (red blood cells md platelets)
                    appear to transmit HTLV;  no plasma products have been implicakd in
                    disease transmission. Moreover, the longer the blood was stored, the less
                    likely it was to transmit HTLV:the transmission rate for products stored Oto
                    5 days was 74 percent; 6 to 10 days, 44 percent; 11to 14days, Opercent.
                    The transmission rate in the United States appears to be much lower than
                    in other countries, where rates of 45 to 63 percent have been reported. The
                    most likely explanation for the lower infectivity of U.S. blood is its
                    typically longer storage time.

ClinicalPrognosis   Wo diseases have been associated with HTLV-1:  addt T-cell leukemia and
                    lymphoma (ATL) and a chronic degenerative necrologic disease called
                    HTLv-I-associatedmyelopathy and tropical spastic paraparesis (~sP).

                    ATLis a malignant condition of T lymphocytes, a form of white blood cell
                    produced by the lymph nodes and impotit for immunity. The clinical
                    features of A~Linclude leukemi~ swelling lymph nodes, enlarged and
                    impaired functioning of the liver, enlarged spleen, skin and bone lesions,
                    ad increased calcium in the blood. Conventional chemotherapy is not
                    curative, and the median stival after diagnosis is 11months.

                    ATL occurs in 2 to 4 percent of individuals infected with HTLV-I in regions
                    where the disease is endemic and early childhood infection is common.
                    The typical patient is 40 to 60 years old, which suggests that several
                    decades may be required for the disease to develop. Only one case of ATL
                    has been documented as having been acquired by transfusion (cDc, 1993).

                    ~sP      is characterized by slowly progressive chronic spastic paraparesis
                    (slight paralysis of the lower limbs), lower limb weakness, urinary
                    incontinence, impotence, sensory disturbances (tingling, pins and needles,
                    and burning), low back pain,exaggerated reflexes of the lower limbs, and
                    impaired vibration sense. Fewer than 1 percent of persons infected with
                    HTLV-I develop ~sP.       The interval between infection and disease is much
                    shorter than that for ATL,and cases of ~sP      as a restit of blood
                    transfusion have been documented witi a median interval of 3.3 years
                    between transfusion and development of the disease.

                    Despite sporadic case reports, HTLV-11 had not been definitively associated
                    with Wy disease until recently. In November 1996,Lehky and colleagues
                    (1996) reported on the clinical and immunological findings of 4 HTLV-11
                    positive patients with spastic paraparesis, whose disease progression

                                              W/PEMD-97-2 Blood Supply:Transf’usion-Associa@dEisb
                           Appendix I

                           resembles that of HTLv-I-infected  patienti with HAM/1’SP.
                                                                                    HTLV-H WasfirSt
                           isolated in 2 patients with hairy cell leukemia, although no virus has been
                           isolated from additional cases of this disease.


Disease Factors            Several bloodbome parasites can be present in donated blood. Few direct
                           measures of risk exist; therefore, estimates are based on reported cases.
                           With the exception of one parasite, the risk of transfusion-associated
                           parasite transmission is less than 1 in 1 million.17

                           Chagas’’diseaseis caused by the parasite T. cruzi. Typically,humans
                           become infected following the bite of a reduviid bug, otherwise known as
                           the kissing bug. The bug favors poverty conditions, particdarly in rural
                           areas where wood and adobe housing is cracking or decaying. Infected
                           bug feces either contaminate the bite wound or enter by other mucous
                           membranes. Chagas’disease is endemic in large pm of South America,
                           Central America, and Mexico. Estimates are that as many as 100,000T.
                           cruzi-infected persons are in the United States (Shdman, 1994).

Blood-Supply-RiskStudies   Four cases of transfusion-transmitted Chagas’disease have been reported
                           in the United States and Canada. Risk of blood donors infected with T.
                           cruzi varies in the United States, depending on the number of Hispanic
                           immigrants in a given area. Brashear et al. (1995) reported that 14 of 13,309
                           (10.5 percent) donors in Texas, New Mexico, and California had evidence
                           of infection. Kirchhoff et al. (1987) reported that as many as 5 percent of
                           the Salvadoran and Nicaraguan irnmigrmts in the Washington, D.C., area

                           ‘:Malariais caused by the bite of an infected mosquitoin endemic areas. An average of 3 cases a year
                           that were acquired by transfusion are reported in the United States. Donor history questions are
                           designed to defer donors who are at risk of malaria as a result of travel. Viscerotropic Leishmaniasisis
                           caused by the bite of an infected sandfly in endemic areas, such as the Persian Gulf.Viscero&opic
                           Leishmaniasisaffects the internal organs of the body.Veterans of Desert StQrrnwere deferred from
                           donating blood when 7 cases were discovered amongmilitary personnel serving in Desert Storm and
                           Desert Shield. Whileca..es of cutaneous Leishmaniaaishave been reported in Texas, this variant of the
                           disease in not thought to be a risk for blood transfusion. Nocases of transfusion-transmitted
                           viscemtropic Leishmaniasis have been reported in the United States. Babesiosis is caused by the bite
                           of an infected tick, a problemfoundmostly in endemic areas of the northeastern United States. To
                           date, CDCreports 15cases of transfusion-transmitted babesiosis in the United States. Toxoplasmosis
                           is caused by infettion with a parasite whose usual host is the domestic cat. The parasite is transmi~d
                           through handling of infected [:ats or cat litter. Other means of transmission include eating raw or
                           undercooked pork, goat, lamb, beef, or wild game. Recent preliminary data from CDCindicate that
                           about 20 to 25percent of the [!.S. population has been infected. Most cases pass unnoticed. Cases have
                           been reported as transmitted by transfusion onlyto immunocompromisedpatients.

                           Page 39                             GAOffEMD-97-2Blood Supply:Transtiion-Associated Risks
                     Appendix I
                     Tr~fusion-Aaaociated Compli~tiona

                     may be infected. In some U.S. areas, about 1 in 600 eligible blood donors
                     who have Hispanics urnames and 1 in 300 eligible blood donors who are
                     Hispanic imrnigranh or refugees might be infected (Kerndt et al., 1991;Pan
                     et d., 1992).

                     Most blood banks now ask donors whetier they have a history of Chagas’
                     disease and questions about risk factors that are linked to possible
                     infection with T. cruzi. ARCh= conducted seroepidemiological studies of
                     blood donors in Los Angele and Miami,where 8 percent and 12percent of
                     prospective donors reported having been born in or having traveled for
                     more than 4 weeks to areas in which Chagas’disease is endemic.*8
                     Additional screening questions ARC asked these donors included a history
                     of sleeping in rural areas where the bugs are prevalent, a history of
                     transfusion in an endemic are% and a history of a positive test for Chagas’
                     disease. Of those at risk, 0.1 percent tested positive for the antibody to T.
                     cruzi. Dodd estimates that 1 in about 8,500units in Miamiand Los Angeles
                     may contain T. cruzi.

                     Furthermore, about 2.4 percent of donom nationally report risk factors, or
                     about one fourth the risk in Miamiand Los Angeles, where large numbers
                     of Hispanic immigrants reside. If the same rate of seroprevalence
                     (0.1 percent) exists among all U.S. donors who report behavioral risk, then
                     Dodd estimates that the national risk for T. cruzi-contaminated blood is 1
                     in about 42,000.

Transmission-by-     Schmunis (1991) repofi that the risk of transmitting T. cruzi through
TransfusionStudies   infected blood ranges from 14 to 49 percent in South America. ARC has
                     found no evidence of transmission among 15recipients of infected blood,
                     suggesting that transmission rates in the United States are no higher than

ClinicalPrognosis    Following the bug bite, a charactefitic lesion may form but usually passes
                     unnoticed. If the bug feces falls onto mucous membranes directly, the
                     classic Romana sign (co@unctivitis md swelling of the eye area) develops.
                     During the acute phase, the parasite can be seen in the blood for a few
                     weeks. Acute infection with T. cruzi can be asymptomatic, or it can be
                     fatal. More typically, after a 10-to-14day incubation period, fever, swollen
                     lymph nodes, and erdmged spleen and liver develop.

                     lsln@fiew wi~ RogerY. Dodd,American RedCross,JeromeH. Hollandbboratow.

                     lgIn@fiew Mti Roger Y. Dodd,AmericanRedCross,Jerome H. Hollandbbomto~.

                     P~e 40                       GAO/PEMD-97-2
                                                              Blood Supply:Transfusion-AssociatedRisks
                  Appendix I
                  Transtiion-Associated Complications

                  Between 20 and 30 percent of infected individuals develop chronic Chagas’
                  disease, often years to decades following infection. Rapid md erratic heart
                  beats signify cardiac involvement. The parasite has an affinity for cardiac
                  cells and for the smooth muscle of the esophagus and colon. As the
                  disease progresses, the heart, esophagus, and colon (ad occasionally, the
                  stomach, gall bladder, and bladder) enlarge (Shulman, 1994).

                  Treatment of acute infections with the drugs nifurtimox and benznidazole
                  is successful in at least 70 percent of cases. In Jdy 1996,Venezuelan
                  scientists announced success in eradicating Chagas’disease in 70 percent
                  to 90 percent of infected laboratory mice using the antifungal drug D0870
                  (Urbina et al., 1996).


Disease Factors   Bacteria can enter donated blood at one of several points (Yomtovian,
                  1995).Bacteria can be introduced during the manufacture of the bag used
                  to collect blood. During collection, bacteria from the skin can contaminate
                  blood, especially if the donor’s arm is not disinfected properly. Donors
                  who are suffering from a bacterial disease-even common food-induced
                  digestive infections<a     unknowingly donate a contaminated blood unit.
                  In a review of the research on transfusion-associated bacterial sepsis,
                  Wagner and colleagues (1994) point to several reports of bacteria already
                  present in the collection bag proliferating during processing or storage of
                  the blood. Pinally, bacteria can be introduced while preparing for
                  transfusion, particdarly if the entry port of a thawing container for a
                  frozen blood component comes in contact with contaminated water in the
                  warming bath. Although fresh plasma and cryoprecipitate can harbor
                  bacteria, contamination of red blood cells and platelek is the most
                  significant problem. Bacterial contamination is one complication that
                  cannot be eliminated by donating blood for self use.

                  Red blood cells are refrigerated, which reduces the viability of most
                  bacteria, such as the one that causes syphilis. However, certain cold-loving
                  bacteria, such as Yersinia enterocolitica and Pseudomonas florescens,
                  thrive under refrigerated conditions. Yersinia is present in the digestive
                  tract or lymph nodes of humans and can cause diarrhea and other gastric
                  symptoms that may be mild enough to be overlooked by blood donors.

                  .’age 41                     GAO/PEMD-97-2
                                                           Blood Supply:Transfusion-AssociatedRisk
                           Appenti I

                           Pseudomonas florescens k one of several common skin bacteria that can
                           en~r blood during co~ection.

                           Plateleb run a greater risk of bacterial contamination because they are
                           stored for up to 5 days at room temperature. Skin contaminants, such as
                           staphylococcus epidermidis, are the most frequently isolated bacteria from
                           platelets. In the United States, platelets can be administered as either
                           apheresis single-donor uniti or pooled random donor uni~ collected from
                           6 to 10 donors. Bacterial sepsis can occur if any of the pooled uni~ are
   ?.                      contaminated. Indeed, Morrow and colleagues (1991)found that the rate
   ,.,,                    of sepsis was 12 times higher for pooled units than for single-donor units.
                           Today, single-donor units are increasingly replacing pooled units.

Blood-Supply-RiskStudies   Wagner and colleagues (1994) report that the frequency of bacterial
                           contamination is measured three ways—through laboratory culture,
                           hospital surveillance programs, and fatalities. Laboratory culture
                           techniques measure bacteria directly but are subject to lapses in sterile
                           techniques that can introduce bacteria into samples. In addition, many
                           qutity control studies reporting bacterial contamination have found that
                           the number of bacteria in the sample was far below the level that would be
                           expected to cause problems to the recipient. Nevertheless, culture
                           methods of bacterial detection suggest that blood component
                           uni@-partictiarly platelets-run a significant risk of contamination.

                           Most episodes of bacterial sepsis are associated with platelets late in the
                           storage period. Yomtovian (1995) conducted a 4-year hospital-based
                           surveillance program in which platelets were cultured for bacteria. The
                           reported contamination rate of platelets 4 days old or less was 1.8per
                           10,000units, whereas the contamination rate for 5-day-oldplatelets was
                           significantly higher, at 11.9per 10,000(p < .05). Morrow et al. (1991), also
                           found that the contamination rate was five times higher in 5-day-old
                           platelets than in 1-4-day-oldplatelets (Morrow et al., 1991).Earlier findings
                           such as this led FDA in 1985to reverse its 1983decision to extend the shelf
                           life of platelets from 5 to 7 days.

                           In 11percent of all reported patient fatalities (10 of 89 deaths) between
                           1986and 1988,bacteria in the patient’s blood matched that of the donated
                           units. During this period, about 60 million units of blood components were
                           transfused. Thus, about 1 death per 6 million transfused units was
                           definitively caused by bacterial sepsis. However, researchers acknowledge
                           that bacteria-induced transfusion fatiities are only rarely diagnosed and

                           Page 42                     GAO/PEMD-97-2Blood Supply:Transfusion-AssociatedRisks
Appendix I

reported, because physicians fail to attribute patients’ deaths to the
possibility of bacteria in blood transfusions.

Similarly,nonfatal outcomes of sepsis are believed to be greatly
underdiagnosed and, therefore, underreported. Common, nonthreatening
reactions of a patient’s immune system to transfusion include fever and
chills that may mask underlying bactiremia. Morrow and colleagues of
Johns Hopkins Medical Institutes (1991) reported platelet
transfusion-associated sepsis in 1 out of every 4,200platelet transfusions.
Bacterial contamination associated with fever following transfusion
occurred once in about 1,700pooled platelet uniti or once in 19,519
single-donor platelets. This is undoubtedly an underestimate because ordy
patients exhibiting clinical symptoms were evaluated.

More recently in Hong Kong, Chiu and colleagues (1994) conducted a
3-year prospective study of bone marrow transplant recipients for clinical
evidence of platelet transfusion reactions. These researchers found 10
episodes of symptomatic bacteremia with 4 leading to septic shock. A total
of 21,503random-donor platelet uni~ were pooled into 3,5S4doses
administered to 161patients. Each patient received w average of 20 pools.
The frequency of bacteremia was calculated three ways: 1 in every 2,100
platelet units, 1 in every 350 transfusions, and 1 in every 16patients.20
Again,this is probably m underestimate, because Chiu and colleagues
looked only for symptomatic bacteremia.

In sum, there is no reliable estimate of the frequency of bacterial sepsis
among transfusion recipients across the United States. Ctiture methods
probably yield overestimates while reporting mechanism probably yield
underestimates of clinically relevant bacterial contamination. CDC is
initiating a prospective incidence study in collaboration with AABB, ARC,
and the Navy in an attempt to quantify this risk. For the purpose of our
analysis, we include the Morrow estimate of documented bacterial sepsis
(not all febrile reactions) because the researchers prospectively monitored
patients and obtained bacterial cultures from implicated uni~ in the
United States.

Although it is now well documented that refrigerated red blood cells can
harbor bacteria, we cotid find no studies that directly estimated the
likelihood that red blood cells are contaminated by bacteria. Dodd

‘“NO{confidenceintervals were reported.

Page 43                           GAO/PEMD-97-2
                                              Blood Supply:Transfusion-AssociatedRisb
                            Appendix I

                            (1994) estimates that 1 in every 500)000red blood cell units maybe
                            contaminated by Yersinia or other bacteria.21

fiansmission-by-            Many surgical patien~ who are otherwise healthy can sustain a small
TransfusionStudies          amount of bacteria introduced by transfusion. However,
                            immunocompromised patienti, such as those with leukemia, are very
                            susceptible to foreign organisms. Unfortunately, these patients are the
                            primary users of platelefi.

ClinicalPrognosis           In transfwion-associated bacterial sepsis, the onset of symptoms usually
                            occurs within the first few hours following transfusion but may occur
                            during the transfusion or following an extended delay (Greene, 1995).The
                            initial signs are typically fever and chills and may include nausea,
                            vomiting, diarrhe~ chest or back pain, low blood pressure, rapid heartbeat
                            and breathing, and cyanosis from lack of blood oxygen. Patients with
                            advancing bacterial sepsis rapidly progress to acute renal failure,
                            respiratory distress, disseminated intravascular coagtiation (uncontrolled
                            internal bleeding), and death. Death may occur from 50 minutes to 17 days
                            following transfusion (Morduchowicz et al., 1991;Tipple et al., 1990).
                            Goldman and Bl~chman (1991) reported that 26 percent of identified
                            transfusion-associated sepsis cases ended in death.

                            Transfusions can result in serious or fati complications as a result of
Noninfectious               serological or clerical errors in blood typing, mismanagement of the
Complications of            transfusion, or unanticipated reactions in the recipient to elements of the
fiansfusion                 donor’s blood. Many of the unanticipated reactions are unavoidable within
                            current understanding and practice of trmsfusion medicine. Few
                            comprehensive assessmen~ of the incidence of such outcomes can be
                            found in the literature. Thus, estimates of the frequency of noninfectious
                            transfusion risks are based on studies by a small number of transfusion
                            services, summation of the number of such occurrences reported in the
                            literature, or from regulatory reports of errors, accidents, and deaths
                            (Dodd, 1994).

Transfusion-RelatedAcute    Transfusion-related acute lung injury (TRALI) has only recently been
LungInjury                  recognized as a potential complication of blood transfusion. No known
                            risk factors have been identified among recipients who develop TRALI.

                            “NOconfidence interval was reported.

                            Page 44                          GAO/PEMD-97-2
                                                                         Blood Supply:Transfusion-AssociatedRisks
                     Appendix I
                     Tranatiion-Aaaociated Complications

                     Cases have been evenly distributed between males md females and among
                     recipients of all ages. No underlying conditions necessitating transfusion
                     have been identified, and most patients have no prior history of
                     transfusion reactions.

                     Implicated blood componenb include whole blood, red blood cells, fresh
                     frozen plasma, and cryoprecipitate. It is the plasma portion of the blood
                     that causes TW, and even red blood cells contain small residual amounts
                     of plasma.

                     In TaALI, specific white blood cell antibodies present in the donor’s blood
                     react with the entire circdation of the recipient’s white blood cells. The
                     result is the release of various components that cause severe damage to
                     lung tissue, which in turn leads to acute respiratory crisis. Most cases of
                     w     have been traced back to blood donated by women who have been
                     pregnant more than once, because pregnancy causes the mother’s blood to
                     develop specific antibodies to elements of the fetus’s blood that her body
                     considers foreign (Popovsky and Moore, 1985).

                     Walker (1987) estimated the risk OfTRALI   to be 1 in 10,000units.22
                     However, Popovsw argues that TaALI     is rarely diagnosed and reported.
                     Therefore, Walker’s figure is probably an underestimate. Popovsky et al.
                     (1992) report that, prior to 1985,only 31 cases OfTRALI  had been reported.
                     By 1992,additional repo~ involvingover 40 recipient reactions had been
                     published. At the time of their publication, Popovsky and colleagues were
                     aware of an additional 35 unreported cases.

                     TRALI presents  with acute respirato~ distress within about 2-4hours
                     following transfusion (Boyle and Moore, 1995).Fever, low blood pressure,
                     chills, cyanosis from lack of blood oxygen, nonproductive cough, and
                     shortness of breath or difflcdty breathing are common symptoms. In most
                     instances, TRALI improves within 48 to 96 hours, provided that prompt
                     diagnosis and respiratory support is initiated. For those who recover,
                     there appear to be no long-term consequences. Death may be the outcome
                     in approximately 5 percent of cases.

ABOIncompatibility   ABOincompatibility is the resuk of improper serological typing or clerical
                     recording of the major blood groups in donor or recipient blood,
                     mislabeling of donor units, or improper verification of donor or recipient
                     blood type.
                      ~zNoconfidence interval was repo~d.

                      Page 45                          GAO/PEMD-97-2
                                                                   Blood Supply:Transtiion-Associated Risks
              Appendix I
              Transtiion-Associated Complications

              A study of errors reported to New York State in 1990-91found 104cases of
              erroneous transfusions out of 1,784,641(0.006percent) red cell
              tr-fusions, over hti of these (54, or 0.003percent) related to ABO
              incompatibility (Linden, Pad, and Dressier, 1992).This is important
              because transfusion of ABO-incompatibleblood is one of the major causes
              of serious noninfectious risks for transfusion recipients. Most of the 50
              other errors were related to the transfusion of a wrong unit of blood that
              was fortuitously ABO-compatible with the recipient’s blood type and
              transfusion of ABO-incompatiblefresh-frozen plasma.

              It was also found that 61 incidents (59 percent of the 104cases) were the
              result solely of errors outside the blood establishment. The majority of
              these stemmed from the ftilure of the person administering the
              transfusion to verify the identity of the recipient or the blood unit.
              However, there were 25 incidents (25 percent) in which the errors were
              attributable to the blood establishment and 18 cases (17 percent) in which
              both the blood bank and hospital service made errors in administering
              incorrect blood or in givingblood to someone other than the intended

              Prom this information, the study’s authors calculated an incidence rate of
              ABO-incompatibleerrors of 1 in every 33,000transfusions (0.003percent).
              The study concluded that three persons died from acute transfusion
              reactions, for a death rate of 1 per 600,000red cell transfusions. The
              overall true rate of ABOerrors, accounting for instances in which errors
              were made but the blood was fortuitously compatible, was calculated at 1
              in 12,000 units.

              Transfusing ABO-incompatibleblood usually-but not always—leads to a
              hemolytic transfusion reaction (HTR), the result of the immune system’s
              destruction of red blood cells. It presents with fevers, chills, low blood
              pressure, destruction of red blood cells, kidney failure, blood in the urine,
              uncontrolled internal bleeding, shock, and death. Occasionally, initial
              symptoms are deceptively mild with the patient experiencing a vague
              sense of unease or an aching back. There are no known long-term effects.
              In the Linden study, death occurred in 6 percent of cases.

Anaphylaxis   Anaphyltis is a serious allergic reaction that can occur in recipients who
              are deficient in IgA,a type of antibody normally present in humans.
              Approximately 1 in 700 individuals are IgA-deficient,but anaphylaxis
              occurs only in those who have developed antibodies to IgAas a result of

              Page 46                     GAO/PEMD-97-2
                                                      Blood Supply:Transfusion-AssociatedRisks
                      Appendix I

                      pregnancy or prior blood transfusion and then receive a blood transfusion
                      that contains I@. Therefore, cases of transfusion-induced anaphylaxis we
                      generally unanticipated ~d unavoidable. Walker (1987) estimates that 1 in
                      150,000blood units transfused resdts in anaphylaxis in the recipient.23

                      Anaphylaxis occurs immediately after transfusion begins, sometimes after
                      the infusion of only a few mi~iliters of blood or plasma. The onset is ‘
                      characterized by coughing, bronchospasm, respiratory distress, vascdw
                      instability, nausea, abdominal pain, vomiting, diarrhea, shock, and loss of
                      consciousness. We found no estimates of the likelihood of death as a
                      result of anaphylaxis. Because of its seriousness and the possibility that it
                      can be overlooked or not diagnosed rapidly, we used a fatity rate of
                      20 percent in our analysis. Patients with a history of anaphylaxis should
                      receive plasma from an IgAdeficient donor.

CirculatoryOverload   Rapid increases in blood volume ae not toleratid well by patients with
                      poor cardiac or pdmonary functioning. Even the transfusion of small
                      amounts of blood can cause circulatory overload in infants. Patients with
                      chronic anemia or active hemorrhaging are also susceptible. Walker
                      estimates that 1 in 10,000transfused units leads to circdatory overload.24

                      Circulatory overload presents with rapid breathing, severe headache,
                      swelling of hands and feet, and other signs of congestive heart failure.
                      Other symptoms include coughing, cyanosis from lack of blood oxygen,
                      discomfort in breathing, and a rapid increase in systolic blood pressure.
                      No long-term effects have been noted when transfusion is stopped
                      promptly at the first signs of circdatory overload. We found no estimates
                      of the likelihood of death. Because the symptoms typically develop over
                      the course of the transfusion, we assume that most instances are
                      diagnosed before permanent damage ensues. We used a fatality estimate
                      of 5 percent in our analysis.

                      “N(I (,c)n!i(lt,n(t, interval was reported.

                      2JN()(,ontid~,nce int.c~nalwas   reported.

                      Page 47                                 GAO/PEMD-97-2
                                                                          Blood Supply:Transfusion-AssociatedRisk
Appendm II


                        Here we discuss the methods we used in conducting our analysis on
                        transfusion risks. We also include supporting information for the risk
                        estimates on which our m~alysisis based, as well as other information that
                        is important for understanding transfusion risks.

                        In recent years, many estimates of transfusion risks have been published
The Evaluation of       in the scient~lc literature. As more becomes known about how viruses are
Transfusion-Risk        transmitted through blood transfusion, the methods used to evaluate these
Studies                 risks continue to evolve. In this report, we sought to provide insight into
                        the changing nature of the field and how methodological developments
                        have affected estimates of transfusion risk.

                        We considered the following factors as we evaluated the scientific

                    ●   who the study participants were (donors or recipient@),
                    ●   what was measured (which generation test was used),
                    ●   when the study was conducted (before or after the widespread use of
                        screening tests),
                    ●   where the study was conducted (in a geographic srea with high disease
                        incidence or among geographic areas representative of the United States),
                    s   how risk was estimated (using direct measurement of disease status or
                        statistical modeling).

                        The studies in our analysis differ by whether they were based on positive
                        viral tests among blood donors or recipients and whether they involved
                        the direct measurement of disease or statistical modeling. IdeWy, direct
                        measurement of disease among recipients both before and after
                        transfusion yields the most vtid estimate of transfusion risks. However,
                        such studies are difficdt and costly to conduct, particdarly for diseases
                        with low incidence rates. Most of the recent studies used statistical
                        modeling of the window period and blood donor seroconversion rates.

                        By window period, we mean the period of time between viral infection and
                        when blood tests can detect either the presence of the virus itself or the
                        body’s antibody response to the virus. By seroconverting donors, we mean
                        donors who change from test-negative at one donation to test-positive at
                        the next. The risk estimate on HCVthat we used is based on the sensitivity
                        of the viral test itself and the possibility that some positive donors are

                        Page 48                   GAO/PEMD-97-2
                                                              Blood Supply:Transfnaion-AssociatedBisks
                                                  Appendix 11
                                                  Our Methodamd Analyaia

                                                  Appendix I provides detailed findings from mmy published scientific
                                                  articles. We codd select ordy one study for each part of our analysis. We
                                                  used one overarching principle when choosing between studies that we
                                                  considered equally sound and that were a matter of continuing debate in
                                                  the research community: we chose to include the studies with the higher
                                                  risk estimates. In other words, ours is a worst-case analysis. Table 11.1
                                                  provides the research citations for the risk estimates we used, including
                                                  information about the methods used in each study and their relative

Table11.1:ScientificStudiesUsedas Sourceof Our RiskEstimates
                                         Study                                                         Riskof   Riskof chronic
Complication           Source            type”         Strengthb                   Riskper unit aeroconversion diseaseor death
HAV                      Dodd (1994).                c                     6        1:1,000.000
                         GAO estimate                                                                          go~oc
                         Institute of Medicine       C                                                                           0.270
HBV                      Schreiber et al. (1996) M                  1,2,3,5            1:63,000
                         M, Alter (1995)             c                                                         70                10
HCV                      M. Alter (1995)             M              1,2,4,5              1:4,100
                         Aach et al. (1991)          R                     2                                   90
                         Koretz et al. (1993)        P                1,3,4                                                      20
HIV-1 and -2             Lackritz et al. (1995)      M              1,2,3,4           1:450,000
                         Donegan et al, (1990) R                           4                                   90
                         Merck Manual (16th          Cd                                                                         100
                         cd. )
HTLV-I and -11           Dodd (1992)                c                                  1:50,000
                         Donegan et al, (1994) R                      1,2,3                                    27
HTLV I                   CDC (1993)                 c                                                                             4
HTLV II                  CDC (1993)                 c                                                                            <1
Non-ABC hepatitis        M. Alter (1995)             M              1,2,4,6             1:5,900                90                15
Yersinia                 Dodd (1994)                c                      6          1:500,000       Not relevant
                         Goldman and                 R                     6                                                     26
                         Blajchman (1991)
Platelet contamination   Morrow et al, (1991)        P                 3,4           Random =         Not relevant
                                                                                    apheresis =
                         Goldman and                 R                     6                                                     26
                         Blaichman (1991)
T. cruzi                 Dodd (GAO interview) P                            1           1:42,000
                         Dodd (GAO interview) R                            1                                   10

                                                  Page 49                      OAO/PEMD-97-2Blood Supply:Tr-tiion-Associated   Riaks
                                                study                                                 Riskof   Riskof chronic
Complication           Souroe                   W*              Strengthe         Riskpar unit aaroconversion diseasaor death
                       Shulman(1994)            c                                                                                          30
ABO incompatibility    Linden et al. (1992)      R                    1,4,5             1:12,000        Not relevant                       6’
Acute lung injury      Walker(1987)              c                                      1:10,000        Not relevant
                       Boyle and Moore           C                                                                                          5
Anaphylaxis            Walker (1987)             c                                    1:150,000         Not relevant
                       GAO estimate                                                                                                        20’
Circulatory overload   Walker (1987)             c                                      1:lo,om          Not relevant
                       GAO estimate                                                                                                         5’

                                              % = compendiumsource:M = statisticalmodel;P = prospectivedirectmeasure;R =
    i                                         retrospectivedirectmeasure.
                                              bl = current
                                                         timeperiod; 2 = State Ofart teStS;3 = representativesample;4 = validmeasures,
                                              includingtest sensitivityand testerrorswherepossible:5 = mostconservativeestimate;6 = only

                                              Where datawerederivedfromcompendiumsources,we did notevaluatestrengths.

                                              ‘Estimatebasedon clinicalpresentationof symptomsand prognosisas discussedin R.Berkow
                                              \~d~jThe MerckManualof DiagnosisandTherapy(WhitehouseStation,N.J.:MerckandCo.,

                                               Page 50                         GAO/PEMD-97-2
                                                                                           Blood Supply:Transtiion-Associated Rish
                    Appendix II
                    Our Methodaand Andyei.Y

                    Our analysis differs on several dimensions from the mslyses in the
The United States   literature. Other studies have considered ordy volunteer donations
Blood Supply        screened in the United States to calcdate the number of implicated units
                    available for transfusion. We sought to simulate the total allogeneic blood
                    supply and delivery system as accurately and completely as possible from
                    the most recent and complete data we codd obtain. Thus, we calculated
                    the number of units donated by U.S. volunkers and directed donors,
                    subtracted the number of units rejected on testing, and then added
                    autologous unik that were crossed-over into the general supply and unik
                    imported from Europe. We also calcdated the total number of Wogeneic
                    blood produch that were available for transfusion and the total number of
                    Mogeneic blood products that were transfused (Wallace et al., 1995).(See
                    table 11.2).

                    Page 51                   GAO/PEMD-97-2
                                                          Blood Supply:Transfusion-AssociatedRisks
                                          Appendix 11
                                          Our Methodsand -~

             Estimateof TotalAllogeneic
    BloodSupplyandTrenefuelons-           Item                                                                   Totalunits      Percent
                                          Volunteerdonations                                                     12,035,000       87.3%
                                          Autoloaous donations                                                     1,117,000           8.1
                                          Directed donations                                                        436,000            3,2
                                          European imports                                                          206,000            1.5
                                            Total blood collected                                                13,794,000         100.0
                                          Rejected on testing                                                       625,000            4.5
                                          TotalU.S. bloodsupply                                                  13,169,000
                                          Volunteersupply(totalU.S. minus directed and                           11,616,000
                                          autoloaous donations)        .
                                          Directed donations                                                        436,000
                                          Autologous donations crossed over                                            5,000
                                          TotelallogenelcbloodSUPPIY                                             12,057,000
                                          Whole blood and red blood cell allogeneic transfusions                 10,741,000
                                          Untransfused allogeneic whole blood and red blood cells                  1,316,000         10,9
                                          Other allogeneic transfusions
                                            Random donor platelets (average 6 donors per unit)                    4,688,000            56
                                            ADheresis Dlatelets (1 donor Der unit)                                  607,000a           44
                                            Plasma                                                                2,255,000
                                            Cryoprecipitate                                                         939,000
                                          Untransfused allogeneic nonred blood cell components                    2,644,000
                                            Available                                                            23,190,000
                                            Transfused                                                           19,230,000
                                          Availableallogeneicsupplynottransfused                                  3,960,000          17.0
                                          ‘A totalof 8,330,000individualunitsof plateletsweretransfused.Onetherapeuticunitof
                                          apheresisplateletsis equivalentto 6 individualplateletunits.Therefore,3,642,000individualunits
                                          (or 44 percentof the total plateletstransfused)weretransfusedas 607,000therapeuticunitsof

                                          Source:E. L. Wallaceet al., “CollectionandTransfusionof Bloodand BloodComponentsin the

                                          Page 52                          GAO/PEMD-97-2
                                                                                       Blood Supply:Trnsfuaion-Associated Risks
Appendix II
Our Methods md Analysis

By dividing the number of available products by the number of donations,
we determined that, on the average, allogeneic blood products are divided
into 1.9trmfused components.1 We used the number of components
available wherever possible to determine the available number of
implicated units. We used the number of unik donated to calc~ate
bacterially contaminated red blood ceh with the assumption that all units
donated were made into red blood cells. For complications that are
directly related to transfusion (for example, ABOblood group
incompatibility and circdatory overload), we used the number of units

We could not estimate the total number of platelets available, so we used
the number of platelets transfused to calctiate bacterially contaminated
platelet units. Because unit and patient risks differ for random donor and
apheresis platelets, we considered these separately, noting that 56 percent
of transfused platelets are random donor platelets using art average of 6
donors per therapeutic unit and the remainder are apheresis platelefi
consisting of 1 donor per therapeutic unit. Our analysis is based on
transfusions of a therapeutic unit of platelets that totaled 5,295,000in 1992
(4,688,000pooled concentrates from random donors and 607,000apheresis

Table 11.3illustrates how we conducted the remainder of our analysis. For
example, patient risk depends on the risk per unit and the number of units
transfused. If, as in HAV,
                         the risk per unit is 1 in 1,000,000,then a patient
who has received an average transfusion of 5 units wodd have a risk of 1
in 200,000(1,000,000divided by 5). That is, if 1 of every 1,000,000units is
contaminated, then 1 of every 200,000patients who receive 5 units could
receive an wv-contaminated unit. We must emphasize, however, that we
used the “average”transfusion of 5 units. Martytrauma and surgery
patients require massive transfusions of 100or more units of blood.
Patient risk-and, therefore, each subsequent step of the analysis-is
entirely dependent on the number of units transfused. For example,
among patients who receive 100units of blood, 1 of every 10,000patients
cotid receive a wv-contaminated unit (1,000,000divided by 100).

‘our estimate of 1.9components per donated allogeneicunit is somewhat higher than the 1.8
commonlycited in the literature. This is because we did not include autologous units, which are
usuallytransfused as whole blood or red blood cells, the platelets and plasma being discarded.

Page 53                            GAO/PEMD-97-2Blood Supply:Transfusion-AssociatedRisks
                                      Appendix 11
                                      Oor Methodsnd Analysis

         Celculetionsfor Individual
andOverallRisksof Adverse
Transfusion                                                     1. Riskestimateper
                                                                unit(12.057million       2. Patientriskper
                                      Agentor activity          unitsdonated)            transfusionof 5 units
                                      HAV                       1:1,000,000              Risk from COI.1 divided by
                                      HBV                       1:63,000                 average transfusion of 5
                                      HCV                       1:4,100                  units. For example, for HAV,
                                      HIV                       1:450,000                (1,000,000/5)= 200,000, or
                                      HTLV-I and -2             1:50,000                 1 in 200,000 patients.
                                      Non-ABC                   1:5,900                  Total sum of risks to
                                                                                         patients for viruses is
                                                                                         (1/200,000 +      1/1,180)=
                                                                                         0.0023, or 1 in 435
                                      Yersinia                  1:500,000                For Yersinia, risk from
                                                                                         column 1 divided by
                                                                                         average transfusion of 5
                                                                                         units = 1:100,000.

                                      Platelet contamination    Random donor              For random donor platelets,
                                                                1:10,200                  risk from column 1 divided
                                                                                          by average donors in a
                                                                Apheresis                 pooled unit (6) = 1:1,700
                                                                1:19,500                  For apheresis platelets,
                                                                                          which have one donor per
                                                                                          unit, risk from column 1 =

                                      T. cruzi                  1:42,000                  Risks from COI.1 divided by
                                                                                          average transfusion of 5
                                                                                          Total risk to patient for
                                                                                          parasite = 0,00012, or
                                                                                          1 in 8,400
                                      Subtotal infection risk   Sum of virus risks and    Same method as column 1
                                                                yersinia                  using patient risks =
                                                                (1/1,000,000+...1/        2.7:1,000
                                                                500,000) plus weighted
                                                                sum of platelet risk
                                                                [(1/10,200 x
                                                                0.56) + (1/19,500X
                                                                0.44)] = 0.0005 or
                                                                5: 10,000

                                       Pa$e 54                  GAO/PEMD-97-2
                                                                            Blood Supply:Transfusion-AssociatedRisks
                                              Appen& II
                                              Our Metioda and ~

3. Annualnumberof                                                  5. Numberof recipients
implicatedunitsif 23.19                                            who do not die of                 6. Numberof recipientswho
millioncomponents               4. Numberof recipientsaffected     underlyingdiseaseor            developchronicdiseaseor die as
availableand 19.23million        (likelihoodof seroconversion)     traumafirst (30%die            a resultof transfusion(likelihood)
transfusions                    Number                      0/0    within2 yea;s)                 Number                          %

Total components available      No. of implicated units      9070 No, of seroconverted            No. of surviving patients           0.2%
divided by no. of units in      from COI,3 multiplied by     70 recipients from col. 4            from COI.5 multiplied by             10
sample expected to contain      seroconversion rate in       90 multiplied by likelihood of       the likelihood of chronic           20
one implicated unit from COI.   COI.4. For example, for      90 survival. For example, for        disease or death in COI.           100
1. For example, no. of HAV      H.4V, 23X 0.90 =             27   HAV, 21 X0.70 = 15              6. For example, for HAV,          4.75
units is 23.19                  21 recipients                90   seroconverted recipients        15x 0.002=                          15
million/1,000,000 = 23. Total                                     who survive beyond 2            0 recipients who develop
virally contaminated units =                                      years                           chronic disease or die

Same as above, based on         Seroconversion not                 Not relevant for bacterially   Same as for viruses                 26
total red blood cell units =    applicable to bacteria.            contaminated units that
12.057 million/500,000 =        Totals carried over from           harm in the near term.
24 bacteria-contaminated red    COI.3                              Totals carried over from
blood cells                                                        Col. 4
Same as above, based on         Seroconversion not                 Not relevant for bacterially   Same as for viruses                 26
platelet transfusions =         applicable to bacteria.            contaminated units that
4,688,000 as random donor       Totals carried over from           harm in the near term.
units and 607,000 as            Col. 3                             Totals carried over from
apheresis units =                                                  Col. 4
(4,688,000/10,200 +
(607,000/19,500 = 491

Same as above, based on         Same as for viruses (55)      10   Same as for viruses            Same as for viruses                 30
number of available
components = 23.19
million/42,000 = 552
parasite-contaminated units

11,561                          9,649                              6,911                          1,286


                                               Page 55                     W/PEMD-97-2 Blood Supply:Trnsfusion-hociated             Riaks
Appendix 11
Our Methodsand AIIalyein

                                1. Riskestimateper
                                unit(12.057million          2. Patientriskper
Agentor activity                unitsdonated)               transfusionof 5 units
ABO Incompatible                1:12,000                    Risks from COI.1 divided by
                                                            average transfusion of 5
                                                            units. Total sum of patient
                                                            risks of transfusion
                                                            complication =
                                                            (1/2,400 + .. 1/2,000)=
                                                            0.0015, or
                                                            1 in 666
Acute lung injury               1:10,000
Anaphylaxis                     1:150,000
Circulatory overload            1:10,000

Subtotal transfusion reaction   3:10,000                    1.5:1,000

Risk                            Sum of all risks:           Sum of all risks: 0.0042, or
                                1/450,000 + ,.. 1/10,000    4,2:1,000, or 1:238
                                = 0.0008, or 8:10,000, or

Pqe 56                          WEMD-97-2       Blood suPPly:
                                                           tition-A880cia@d          Eisb
                                               Appendix 11
                                               Our Methodsand Anatysb

3. Annualnumberof                                                  5. Numberof recipients
implicatedunitsif 23.19                                            whodo notdie of                6. Numberof recipientswho
millioncomponents                4. Numberof recipientsaffected    underlyingdiseaseor         developchronicdiseaseor die as
availableand,9023million          (likelihoodOf SerOCOnVerSiOfl)   traumafirst (30%die         a resultof transfusion(likelihood)
transfusions                     Number                       %    within2 yea;s)              Number                          0/0

Same as above, based on          Seroconversion not                Not relevant for           Same as for viruses              6
total red blood cell and whole   applicable to                     transfusion-related
blood transfusions =             transfusion-related               complications that harm in
10.741 million/12,000 = 895      complications. Totals             the near term.
incompatible units               carried over from COI.3           Totals carried over from
                                                                   Col. 4

Same as above, based on          Seroconversion not                Not relevant for           Same as for viruses              5
total transfusions of all        applicable to                     transfusion-related                                        20
components. For example,         transfusion-related               complications that harm in                                  5
for acute lung injury, 19.23     complications. Totals             the near term,
million units/10,000 = 1,923     carried over from COI.3           Totals carried over from
                                                                   Col. 4
4,869                            4,296                             4,296                       237

16,430                           13,945                            11,207                      1,523

                                 % of recipients who               % of recipients who         Y. of recipients who

                                 seroconvert =                     seroconverted and           develop chronic disease
                                 13,945/4,000,000 =                survived more than 2        or die =
                                 0>0035= 1:287                     years = 11,207/4,000,000    1,523/4,000,000 =
                                                                   = 0.0028 or 2,8:1,000, or   0.0004, or
                                                                   1:357                       4:10,000. or 1:2.500

                                               Page 57                     GAO/PEMD-97-2
                                                                                       Blood Supply:Transfusion-AssociatedRisks
                                       Appendix II
                                       Our Methodsand Andysie

                                       It is important to note that although we present a composite risk estimate
                                       for a unit and a patient, these risks actually vary depending on the type of
                                       component transfused. This is most appwent for apheresis platelet
                                       recipien~ who are exposed to only one donor per therapeutic unit rather
                                       than the average of 5 donors for red blood cell or fresh frozen plasma
                                       recipients and 6 donors for random donor platelet recipien~.

                                       Table 11.4presen~ our calcdations for specific blood components,
                                       contrasting them with the overall per-unit and per-patient risk estimates
                                       we present elsewhere in the report. Note that only the per-patient risk for
                                       apheresis platelet recipients is substiti~y different from the combined
                                       risk estimates. Indeed, on a per-patient basis, the risk for apheresis platelet
                                       recipients is an order of magnitude lower than the risks for the other

Table11.4:EstimatedRiaksfor Specific
BloodComponents                        Bloodcomponent                                               Riskpar unit         Riskperpatient
                                       Redbloodcells”                                                  7,7:10,000              3.8:1,000
                                       Fresh frozen plasmab                                            7.5:10,000              3.7:1,000
                                       Random donor platelets                                          7,8:10,000              4.7:1,000
                                       Apheresis platelets                                             7,3:10,000             7,3:10,000
                                       Red blood cells and platelets combinedd                         8.0:10,000              4.2:1,000
                                       alncludesrisksfor all viruses,Yersinia,T, cruzi,andall transfusionrelatedrisks.
                                       ‘Includesrisksfor all virusesexceptHTLV-Iand-Il. T. cruzi,ABOincompatibility,acutelung
                                       Clncludesrisksfor all viruses,plateletcontamination,T. cruzi,acutelunginjury,anaphylaxis,and
                                       circulatoryoverload.Per-patientriskfor randomdonorplateletsbasedon 6 individualdonorunits.
                                       Per-patientriskfor apheresisplateletsbasedon 1 individualdonorunit.

                                       ‘Includesrisksfor all viruses,Yarsinia,plateletcontamination,T. cruzi,ABOincompatibility,acute
                                       lunginjury,anaphylaxis,and circulatoryoverload.

Risk Estimates and                     Aswe discussed earlier, estimates that are commonly quoted in the media
                                       are point estimates. The nature of our analysis required that we use
Their Cotidence                        precise fik estimates, but confidence intervals give a better sense of
Intervals                              possible risk. Precise numbers such as the ones we use in our analysis are
                                       known as point estimates. Their precision is necess~ for calcdating
                                       purposes but should not be construed as definitive. Scientists know that
                                       statistical measurement is not perfectly precise. Thus, they calcdate a
                                       range, or cotildence interval, of estimates that is wide enough that they
                                       are confident in believing that the real number is somewhere between the

                                                                                     Blood Snpply:Transfusion-AssociatedRisks
                                     Appendix II
                                     Our Methods and Analysis

                                     two endpoin~ of the range. Appendix I includes the cofildence interv~
                                     for the different estimates of risk where we could find them in the
                                     scientific literature.

                                     Point estimates are artficidly precise in the sense that they do not take
                                     into account factors hat introduce error. Factors that can affect the
                                     measurement of transfusion risks include the sensitivity md spectilcity of
                                     the tests used to detect viruses and the window period of undetectability.
                                     Table 11.5provides the sertsitivity (likelihood of detecting truly infected
                                     persons) and specificity (likelihood of testing positive o~y if persons have
                                     the disease in question) md estimates of the window period of
                                     undetectability for a sample of tesk used to detect viruses in donors’

Table 11.5:
Test characteristic                    HTLV-I     HIV-I and-2        HBsAG                                    HCV                 HBcore
Sensitivity                     98.17-99.87Yoa        99,15-loo%                         99Y0                65-91Y.b                     100YO
Soecificitv                     99.58-99.85Y0       99,83-99,94%                      99.970’                99.847.                 99.73VOC
Days in window period (range)     51 (36-72)             22 (6-38)          59 (37-87)           82 (54-192)                  Not relevant
                                      aTheHTLV-Itest is consideredto havelowersensitivityfor HTLV-11

                                     bSensitivitydatabasedon reactivityin patients with acute (65 percent) and chronic (91 percent)
                                     nontransfusion associated non-A, non-B, hepatitis, The only available data for
                                     transfusion-associated non-A, non-B, hepatitis suggest that second-generation HCV tests detect
                                     seroconversion to anli-HCV earlier than do first-generation HCV tests in 73.3 percent of patients.

                                     calculated from manufacturer’s test kit insert. (Total donations screened - no. repeat
                                     reactive/total donations screen - no. confirmed) x 100 = specificity,

                                     Source: HTLV-I data from Summary Basis of Approval for Abbott HTLV-I 2,0 EIA (92-0318). HIV-1
                                     and -2 data from package insert for Abbott HIVAB HIV1/HlV2 (rDNA) EIA (83-9848/R8), HBsAg
                                     sensitivity data from FDA summary basis of approval for Ortho Antibody to HBsAg ELlSA Test
                                     System (85-372). HBsAg specificity data from package insert for ORTHO Antibody to HBsAg
                                     ELlSA test system 2 (631-20-086-6). HCV data from package insert for ORTHO HCV 2.0 ELlSA
                                     Test System (631-20-226-7). Specificity data based on reactivity in patients with
                                     nontransfusion-associated non-A, non-B, hepatitis. Sensitivity was 65 percent in acute cases and
                                     91 percent in chronic cases. HBcore sensitivity data from Hepatitis B Virus Core Antigen
                                     (Recombinant) ORTHO ELlSA Test System (631-20-132-3). HBcore specificity data from FDA
                                     summary basis of approval for the same test (90-0731 and 91-0109).

                                                                                    Blood Supply:Transfusion-AssociatedRisks


                      Inthis appendix,we describe some of the ways in which the
                      mufacturing of plasma differs fromthat of blood. We give particdar
                      attention to differences that stem from volunteer versus ptid, or
                      commercial, donors. We note viral inactivation processes. Fintiy, we
                      discuss what little information we codd find on the differences in viral
                      seropositivity rates of paid and volunteer donors.

                      More than 40 million hospital patients use plasma products each year.
Plasma Product Uses   Plasma is the liquid portion of blood, containing nutrients, electrolytes
                      (dissolved salts), gases, albumin, clotting factors, hormones, and wastes.
                      Many different componenb of plasma are used, from treating the trauma
                      of burns and surgery to replacing blood elements that are lacking as a
                      resdt of disease such as hemophilia. Table 111.1describes plasma
                      components and their uses.                            ;,j ‘

Components            Component                                   Use
                      Albumin                                     Torestoreplasmavolumeintreatmentof
                                                                  shock, trauma, surgery, and burns
                      Alpha 1 proteinase inhibitor                To treatemphysema caused by genetic
                      Antihemophilic factor concentrate           For prophylaxis and treatment of
                                                                  hemophilia A bleeding episodes
                      Anti-inhibitor coagulant complex            To treat bleeding episodes in presence of
                                                                  factor Vlll inhibitor
                      Anti-thrombin Ill                           To prevent clotting and thromboembolism
                                                                  associated with liver disease, anti-thrombin
                                                                  Ill deficiency, and thromboembolism
                      Cytomegalovirus immune globulin             For passive immunization subsequent to
                                                                  exDosure to cvtomeaalovirus
                      Factor IX complex                           For prophylaxis and treatment of
                                                                  hemophilia B bleeding episodes and other
                                                                  bleeding disorders
                      Factor Xlll                                 To prevent and treat bleeding in factor Xlll-
                                                                  deficient persons
                      Fibrinolvsin                                TOdissolve intravascular clots
                      Hepatitis B immune globulin                 For passive immunization subsequent to
                                                                  exposure to hepatitis B
                      lgM-enriched immune globulin                To treat and prevent septicemia and septic
                                                                  shock stemming from toxin liberation in the
                                                                  course of antibiotic treatment
                      Immune globulin: intravenous and            To treat agamma- and
                      intramuscular                               hypogamma-globulinemia; for passive
                                                                  immunization for hepatitis A and measles

                      Page 60                        GAO/PEMD-97-2
                                                                 Blood Supply:Transfusion-&sociated Risks
               Appendix 111

               Component                                           Use
               Plasma protein fraction                             To restore plasma volume subsequent to
                                                                   shock, trauma, surgery, and burns
               Rabies immune globulin                              For passive immunization subsequent to
                                                                   exposure to rabies
               Rho(D) immune globulin                              To treat and prevent hemolytic disease of
                                                                   fetus and newborn infant stemming from
                                                                   Rh incompatibility and incompatible blood
               Rubella immune globulin                             For passive immunization subsequent to
                                                                   exposure to German measles
               Serum cholinesterase                                To treat prolonged apnea subsequent to
                                                                   the administration of succinylchoiine
               Tetanus immune globulin                             For passive immunization subsequent to
                                                                   exposure to tetanus
               Vaccinia immune globulin                            For passive immunization subsequent to
                                                                   exposure to smallpox
               Varicella-zoster immune globulin                    For passive immunization subsequent to
                                                                   exposure to chicken pox

               Source: Adapted from American Blood Resources Association, “Basic Facts About the
               Commercial Plasma Industry.”

               Plasma is typically collected from paid donors in a commercial setting.
Pl~ma Donors   Donors receive between $15 and $20 for the 2 hours required to remove
               whole blood, separate the plasma from the cells and serum, and reinfuse
               the latter back into the donor. People may donate once in 48 hours but no
               more than twice a week. Prospective paid donors, like volunteer donors,
               are screened for medical history and risk behaviors, and each one must
               pass an annual physical examination and tests for total protein and
               syphilis in the blood every 4 months.

               me America Blood Resources Association (MRA)—atrade association
               for plasmapheresis collection centers and plasma derivative
               manufacturers-maintains a national donor deferral regist~. Only
               first-time donors are checked against the registry of known donors
               deferred for positive test results, disease history, or risky behavior. Repeat
               donors’ records are checked at the plasmapheresis center where the
               plasma is removed. Most centers ensure that donors are not migrating
               from one center to artother over the 48-hour minimum donation interval.1

               IFor example, centers may mark the donors’ finger with fluorescentdye. Nearbycenters use different

               Page 61                           GAO/PEMD-97-2
                                                             Blood Supply:Transtiion-Associated Risks
                       Appendix III

                       As with whole blood donated by the volunteer popdation, fusttime donors
                       are known to carry higher viral test positivity rates tharI repeat donors.
                       One manufacturer reported success with its program to detect and remove
                       firsttime donor blood that was found to have positive viral markers
                       (Philip, 1995).

                       Plasma collected at plasmapheresis centers is shipped in separate
Plasma fractionation   collection containers to pharmaceutical manufacturing plants. There the
and Product            plasma is pooled into processing lots of as mmy as 60,000uni~. A
Manufacture            chemical fractionation process separates the various active componen@ of
                       plasma, which are further manufactured into clotting factor products for
                       hemophiliacs, albumin for burn victims, and immunoglobdin preparations
                       for immune-deficient persons.

                       Most plasma derivatives undergo viral inactivation or removal. The two
                       main methods are heat treatment and solventdetergent washing. Heat
                       treatment is accomplished either by exposing the Iyophilized
                       (freeze-dried) product to dry heat or suspending it in a solution.
                       Alternatively,the completely soluble liquid product is heated with the
                       addition of various stabilizers such as sucrose md glycine. Extensive
                       research h= carefily calcdated specified temperatures and times for
                       different heat treatment processes.

                       Another method in use today exposes the product to an organic solvent
                       such as N-Butylphosphate md a detergent such as Triton X-1OOor
                       polysorbate 80 to dissolve the tipid coat of viruses, rendering them
                       inactive. Solvent detergent inactivation cannot eliminate non-lipid-coated
                       viruses such as HAV or paIvovirus B-19.

                       A delicate balance maintains between disabling viruses and retaining
                       adequate concentrations of the unstable components in the plasma. Heat
                       and chemicals ae particdarly damaging to the plasma. Gentle but
                       potentially safe methods still under investigation include nanofdtration to
                       remove virus particles on the basis of molecdar size; monoclond antibody
                       affini~ chromatography to capture the protein of interest while the viruses
                       and unwanted components are washed away; irradiation to inactivate
                       viruses; virucidal agents that, having killed viruses, can then be removed
                       during tier     manufactting; and exposure to dtraviolet hght.

                       Genetic engineering techniques are now used to produce recombinant
                       factors VIIIand IX, meaning that the genes to produce the proteins have

                       Page 62                   GAO/PEMD-97-2
                                                             Blood Supply:Transfusion-AssociatedRish
                    Appendix 111
                    Plasma Products

                    been cloned and can be harvested from genetically engineered Chinese
                    hamster ovary cells in the laboratory. These products have, so far, been
                    found free of human viruses.

                    In the 1980sbefore the etiology of HIV transmission was understood, many
History of Disewe   hemophilia patienk used plasma products infected with HIV,with
fiansmission From   63 percent of all hemophilia patients in the United States becoming
Plasma Products     infected as a result. Mmy more contracted HBV~d HCV.

                    Disease has been transmitted in many fewer cases since the introduction
                    of atibody tests and viral inactivation ad removal processes for plasma

                    In January 1996,CDC reported the transmission of HAV    by plasma
                    derivatives factor VIIIand factor IX, which are used to treat hemophilia
                    patients. Both products had been virally inactivated by solvent detergent,
                    but this technique is not completely effective in inactivating HAVor other
                    nonlipid viruses such as parvovirus.

                    Clinical trials have demonstrated that current heat treatment and solvent
                    detergent viral inactivation techniques are effective against HBV, HCV, and
                    HIV. (Colombo         et al., 1985; Horowitz   et al., 1988; Kemoff   et al., 1987;
                    Manucci      et al., 1988; Schimpf     et al., 1987.)

                    In February 1994,Baxter Healthcare announced a voluntary withdrawal of
                    its Immune Globulin Intravenous (IGIV) following reports that the product
                    may have transmitted HCVto 14patients in Spain, Sweden, and the United
                    States. In Jtiy 1994,CDCconfirmed 112reports of possible cases of acute
                    HCV infection     from Baxter’s     IGIV (111 cases)    and that of the American       Red
                    Cross     (1 case).    Because   these produc~     had maintained     a longstanding
                    safety record,         not been virally inactivated with FDA-aPPrOVed
                                          they had
                    methods.                 in which risk-factor data were available, 68
                                  In the 74 cases
                    (92 percent) had receipt of IGIV as the only risk factor for infection.

                    In December 1994,FDAnotified manufacturers      of immunoglobtiin
                    products that it would begin testing for HCVin dl products that had not
                    undergone a validated virus inactivation or removal step. FDAfurther
                    required manufacturers  to submit their plans to incorporate the steps into
                    their manufacturing plan. The immune globulins affected by this policy
                    include Rho(D) immune globuhn for Rh-negative pregnant women and

                    Page 63                           GAO/PEMD-97-2
                                                                  Blood Supply:Transfusion-AssociatedRiska
                      Appendix 111

                      specific immune globtins for HBV,
                                                      tetanus, and varicella-zoster. No new
                      cases of HCVtrwrnission by IGIVhave been reported to date.

                      A similar product, immune globtin for intramuscdar administration
                      (IGIM),is not virally inactivated. Although no cases of HCVtr-mission by
                      this means have ever been reported, concerns have been raised about this
                      product, and FDA allows only the manufacturing lok that have been tested
                      for HCVto be distributed.

                      HIVis a delicate       in that it is readily inactivated. In 1988,CDC reported
                      on a worldwide survey of 75 suspected cases of HIVtr-mission by
                      heat-treated factor concentrates. Among the 75 recipients, 18 met the strict
                      criteria for a probable association, including 8 who had received
                      U.S.-manufactured concentrates. Subsequently, the manufacturer
                      withdrew the product and modfled i& viral inactivation technique
                      (Centers for Disease Control and Prevention, 1988).No cases of HN
                      transmission by plasma products inactivated according to current
                      shdards have been reported.

                      Despite the evidence that viral inactivation and removal processes make
Rates of Viral Test   today’s plasma produc~ safer than ever, the fact remains that the paid
Positivity Among      commercial plasma donor pool has higher rates of viral infectivity than the
Commercial md         volunteer whole blood donor pool.
Volunteer Donors      In 1978,FDA required that each blood unit be labeled as either volunteer or
                      paid. In the regdations, FDA concluded that paid blood donors were more
                      likely to tr~mit hepatitis to recipients than were volunteer donors. Ik
                      conclusions were based on the following research evidence: higher rates
                      of HBSAGpositivity in commercial donors; higher rates of HBVand non-A,
                      non-B, hepatitis  in recipients  of paid donor blood; md a highly researched
                      cohort of tra~ion        recipients in which the elimination of commercial
                      blood resdted in substanti~y fewer cases of posttransfusion hepatitis.

                      Whilethe commercial donor pool for whole blood is all but nonexistent in
                      the United States today, the plasma industry continues to rely on paid
                      donors to supply the raw plasma for further manufacturing into plasma

                      We were unable to obtain national data on the viral test positivity rates
                      among paid plasma donors compared to volunteer blood donors. We did,
                      however, fmd several sources of information pertaining to this issue. First,

                      Page 64                    GAO/PEMD-97-2
                                                             Blood Supply:Transfusion-AssociatedRisks
Appendix III

we found that California requires the reporting of initial md confiied HIV
prevalence rates for both blood bank and plasma collection centers.
Figure 111.1shows that the cotilrmed HIVprevalence rates per 100,000
commercial plasma donations has decreased in recent years but remains
substantially higher than those same rates in volunteer whole blood

Page 65                  GAO/PEMD-97-2
                                     Blood Supply:Transfusion-AssociatedRisk
                                             Appendix III

          ReportedConfirmedHIV PrevalenceRatesAmongDonationsin California,1989-94°









                                              ■   Wood
                                                    banka❑ Plasma
                                                                                 I                        Mn
     l,e9 2.W 3.W 4.W 1.90 2e0 3.W 4.W 1.91 2.91 3.91 4.91 1.W 2.e2 3.W 4.e2 1.93 2.93 3.93 4.93 1.e4 2.W 3.94 4.e4

                                              aReportedWesternBlotConfirmedHIVprevalenceratesper 100,000 commercial plasma
                                              donations and volunteer whole blood donations in California (1989-94).

                                              Source:CaliforniaDepartmentof HealthServices,Officeof AIDS,HIV/AiDSEpidemiologyBranch,

                                              Page 66                                       BloodSupply:
                                                                                GAO/PEMD-97-2          Transfusion-Associated
 Appendix III

 Plasma donors cm donate much more frequently than blood donors, so
 fewer plasma donors are needed to collect 100,000unik. Moreover,
 several plasma units codd be donated during the window period, whereas
 it is urdikely that more than one whole blood unit cotid be donated in the
 window period. Comparing donors to donors wodd probably show an
 even greater discrepmcy.

Second, we malyzed the clinical data that manufacturers submitted to FDA
during the approval process for a sample of viral tes&. As table 111.2
shows, the test-positive rates for commercial plasma donors are
subs~tially higher than those of volunteer whole blood donors.

Page 67                   GAO/PEMD-97-2
                                      Blood Supply:Transfusion-AssociatedRisks
                                      Appendix III

PositivityRetes:ClinicalTriel Detes                                                           HCV
                                      Donortriel            HIV-1end-2                1st generation(1990)
                                      sample           Semplesize     % positive     Samplesize       0/0positive
                                      Bloodvolunteer       13,059          0.09%           9,998           0.6Y0
                                      Plasma paid           3,995           0.15          10,523             6.7

                                      Page 68                GAO/PEMD-97-2
                                                                         Blood Supply:Transfusion-AssociatedRish
                                   Appendix III

 2nd generation(1994)          Ist generation(1990)                  2ndgeneration(1994)                           HBcore
 Samplesize     % positive    Samplesize      Yepositive            Samplesize    Y. positive               Samplesize   ‘Apositive
      14,068          o.s~o        13,690               0.1270              6,510                 0.29~o            2,969       1.1%
       6,005          10.6          3,850               0.55                        c                  c                lod    20.0
                                   aRatesare for repeatedly reactive results. That is, initial test positives are retested.

                                   bHTLV-l is not present in plasma

                                   cNot evaluated

                                   ‘Note the small sample size. Also, subjects were designated “paid donors” butwme may have
                                   donated whole blood rather than plasma,

                                   Clearly, most commercial plasma donors are healthy and free of disease.
Summ~                              However, monetary incentives such as those offered by commercial
                                   plasma-collection centers may be tantalizing to those who are known to be
                                   at risk for infectious diseases, such as intravenous drug users and
                                   prostitutes. Screening questions address these risk behaviors, but there is
                                   no definitive way to screen out all risky donors, md current tests may not
                                   be sufficient to catch all infected units. For example, more than 80 percent
                                   of HTLV-I and HTLV-11 infections among intravenous drug users stem from
                                   HTLV-11, but the HTLV-Iantibody testis somewhat less sensitive for HTLV-11

                                   Newly emerging and yet unknown viruses often enter the population
                                   through high-risk individuals. Viral antibody tests may not yet exist, and
                                   current viral inactivation and removal techniques may be ineffective for
                                   new viruses. It is not known for sure whether HTLV-11 is present in plasma.
                                   Moreover, one infectious donation can contaminate art entire pool of as
                                   many as 60,000units.

                                   Without national data on the differences in prevalence and incidence rates
                                   between paid and volunteer donors, it is not possible to draw fm
                                   conclusions about potential risks posed by plasma derivatives. Such data
                                   would be valuable because they could be used to monitor the blood
                                   industry in its entirety.

                                   Page 69                              GAO/PEMD-97-2
                                                                                    Blood Supply:Transfusion-AssociatedRiska


                        This appendix covem a number of different approaches used to further
                        reduce the risk of blood transtiion. These include drug therapies to
                        reduce the need for -fusion,      dtemative produc=, reducing the use of
                        transtiions, and reducing the risks directly by controlling the sources of
                        donation, e~nding viral inactivation techniques, genetic engineering, or
                        improving M testing.

                        Physicians are increasingly considering alternatives to blood transfusion.
Drug Therapies to       Recombinant human e!ythropoietin-a growth factor that stimdates the
Reduce the Need for     body’s manufacture of red blood cells-has been shown to decrease the
Blood fianstiion        need for blood as well as increase the yield from patients donating
                        preoperatively for themselves. Clinicfdstudies of anemic patients
                        undergoing long-term hemodialysis who use erythropoietin show
                        hematocrik and hemoglobin levels that are high enough to preclude
                        further transfusions (Stack and Snyder, IW1). U.S. patients with anemia
                        now use 200,000to 400,000unik of red blood cells a year (Menitove,
                        1991).Similarly, the arttidiuretic hormone, DDVAP,when given
                        preoperatively b been shown to be effective in decreasing blood loss in
                        cardiac and orthopedic surgery as well as reducing the need for
                        postoperative platelet transfusions. For white blood cells, physicians are
                        prescribing grantiocyte, granulocytemacrophage colony-stimulating
                        factirs, and multilineage colony-stimdating factor (interleukin-3) to
                        prevent chemotherapy-induced neutropenia (abnomally low numbers of
                        circdating neutrophils) and to accelerate recovery from this condition.
                        The recently discovered thrombopoietin is rapidly advancing through
                        clinical triti and will undoubtedly reduce the need for platelet

                        Researched are also working to develop substitutes for blood. One
Alternatives to Blood   synthetic red blood cell substitu~ is made from outdated blood. The
                        product, known as stroma-free hemoglobin solution, has been successful
                        at supporting life for baboons with dangerously low hematocrits with no
                        significant changes in heart rate, cardiac output, oxygen consumption, or
                        mean arterial blood pressure (Gould et al., 1986,1990).1However, recent
                        experiment in Scotland using mice suggest that it may increase
                        susceptibility to bacterial infections (Grifflths, 1995).It appears that
                        bacterial sepsis resti~ when hemoglobin provides bacteria with a source
                        of iron that enhances the bacteria’s ability to replicate.

                        IStroma isthestructuralportion of erythrocytes. The hematocrit is the percentage of the volume of a
                        blood sample occupied by cells.

                        P-e 70                             GAO/PEMD-97-2
                                                                    Blood Supply:Transfusion-AssociatedRish
                      Appendix N
                      Further ReducingRisk

                      If clinical trials can establish that stroma-free hemoglobin can be a safe
                      and effective treatment for anemia, it will have the advantage over red
                      blood cells of being universally compatible, having a long shelf life, and
                      being free of infectious agents.

                      Perhaps more promising are recombinant red blood cell substitutes that
                      are artificial in the sense that they me not derived from blood. These
                      products are limited by their short shelf life and as yet undetermined
                      toxicity. A double-blind, controlled Phase III clinical trial of a recombinmt
                      red blood cell substitute, Hetisist, is under way for patients suffering
                      from blood loss and shock caused by trauma. The clinical trial will
                      compare the outcomes of accident and trauma victims resuscitated under
                      the current standard of care with those treated with HemAssist plus the
                      current standard of care. It is not clear that HemAssist will substitute for
                      blood at all. The anticipated outcome is survival. At this time, this product
                      is not planned to be used as a substitute for blood in patients with anemia
                      caused by other than acute blood loss. Another blood substitute,
                      PolyHeme(R), is expanding its Phase II clinical trials from infusing the
                      equivalent of 6 units of blood to 10 units, or the equivalent of replacing tie
                      total adult blood volume. At the same time, the manufacturer is pursuing
                      FDAapproval for Phase 111trials of the blood substitute.

                      Avoiding unnecessaW transfusions is a primary goal of transfusion
Reducing the Use of   medicine specialists. “Transfusion trigger” refers to the clinical evenfi and
Transfusions          laboratory data that lead physicians to transfuse blood to patienfi. In a
                      1985study, Ali concluded that 11percent of red blood cell transfusions
                      were probably of doubtful benefit to the patients (Ali, 1988).The most
                      overprescribed blood component, however, is probably fresh-frozen
                      plasma. In 1986,Blumberg and colleagues indicated that as many as 73
                      percent of fresh-frozen plasma transfusions were unjusttiled (Blumberg et
                      al., 1986).Yet, transfusions of plasma numbered 2.056million in 1987and
                      increased by nearly 10 percent in 1992to 2.255million units (Wallace et
                      al., 1993,1995).

                      It is the responsibility of the prescribing physician to evaluate the patient’s
                      specific needs and to transfuse only appropriate blood components. This
                      requires a scientific approach based on clinical laboratory results and
                      careful consultation with the resident transfusion medicine specialist.
                      Because mmy physicians lack knowledge about the specific indications
                      for the use of blood products, many blood banks are tightening their
                      control over the prescription of blood products. Hospital transfusion

                      Page 71                    GAO/PEMD-97-2
                                                             Blood Supply:Transfusion-AssociatedRisks
                      Appendix N
                      Further ReducingRisk

                      committees (now requiredfor accreditationby the Joint Commission on
                      Accreditation of Healthcare Organizations) routinely review and control
                      tr-fusion practices.

                      Intraoperative blood salvage-a procedure in which patients’ own blood is
                      collected during surgery and later reinfused-is becoming a more frequent
                      practice. In 1992,an estimated 427,000patients had their blood collected
                      and reinfused during surgery. However, little is known about the potential
                      risks associated with this procedure.

                      Other ways to reduce transfusions include preoperative md intraoperative
                      hemodilution; improving the scrutiny of laboratory tests among premature
                      ad newborn infmts; improving supportive care (for example, close
                      monitoring of the use of fluids); ad expanding the use of crystalloid and
                      colloids for the treatment of acute blood loss in surgery, obstetrics, md

                      Nonemergency patients can theoretically reduce the risks of receiving
Controlling the       viraUycontaminated or incompatible blood by donating their own blood
Sources of Donation   prior to surgery. However, a recent industry survey of 1,829institutions
                      indicated that autologous transfusion errors occur in nearly 20 percent of
                      W blood bartks. In most of these cases, the hospital transfused a regular or
                      directed donor unit before using the patient’s own blood. The most serious
                      error-giving an autologous unit to an unintended recipient—occurred in
                      1.2percent of responding hospitis.

                      Only about 60 percent of the surveyed facilities test autologous donations
                      for viruses, and about 40 percent permit the transfusion of autologous
                      units that test positive for viruses. The risk of patients’ receiving
                      bacterially contaminated blood that they have donated for their own use is
                      equivalent to that risk within the general blood supply. Moreover,
                      breakage or damage during handling of autologous units was reportedly
                      high. Among 599 question respondents, 201 (34 percent) reported
                      breakage of 308 units during laboratory processing or shipping and 195of
                      605 (32 percent) respondents reported the unavailability of 368 autologous
                      units from breakage or damage outside the laboratory. Of the 368 units,
                      182were damaged by fadty refrigeration.

                      Consequently, the overall risk of receiving potentially virally infected,
                      bacterially contaminated blood or blood not tested at all may actually be
                      increased by a procedure designed to decrease risk.

                       Page 72                   GAO/F’EMD-97-2
                                                             Blood Supply:Trnsfusion-Associated Risks
                      Appendix IV
                      Further ReducingRisk

                      Similarly, some patien~ request that the blood they receive come from
                      directed donations, believing that this will reduce their risk. However,
                      studies indicate that blood donated by the volunteer population can be
                      safer than blood donated by relatives and friends, who may feel social
                      pressure to donate md therefore do not ditige risk behaviors or disease

                      Also of major importance for reducing risk is the increased use of
                      single-donor apheresis platelets, which is slowly replacing the practice of
                      pooling units from 6 to 8 donors. Exposing patients to fewer donors is
                      clearly a way to minimize risk.

                      Promising advances in the inactivation of viruses for plasma have been
Extending Viral       discussed in appendix III. Resemch on the viral inactivation of celldar
Inactivatfin to       components of blood has been more difficdt. Extending storage time,
Cellular Components   washing, platelet removal, or leukocyte reduction—the elimination of
                      white blood cells— for red blood cells reduces but does not eliminate
                      some circtiating viruses. Mildtemperature elevation irreversibly destroys
                      red blood cells. Chemical approaches, such as using ozone, has shown
                      variable results.

                      Photochemical approaches to reduce viruses in red blood cells and
                      platelets have shown more promise. Hypericin, a naturally occurring
                      antiviral agent found in the St. John’s wort plant, has shown preliminary
                      success at destroying HIVnd other viruses in donated blood (“VIMRX
                      Pharmaceuticals Expects,” 1995).More importantly, both viral inactivation
                      ad improved cell recovery and survival have been demonstrated using
                      psoralen derivatives and ultraviolet light, particularly when used with the
                      “quencher” rutin, a naturally occurring flavonoid obtained from

                      The majority of virally continated    units are donated by persons who
Closing the Window    have recently contracted a virus and whose immune systems have yet to
Period                produce the blood antibodies that allow screening testi to detect infection.
                      New screening tests are constantly narrowing this period of
                      undetectability; however, the costs of implementing them throughout the
                      blood supply are considerable while their predicted effect appears to be
                      quite small. For example, current estimates suggest that the full
                      implementation of a new HIVscreening test wotid eliminate 24 cases of
                      transfusion-transmitted HIVamong the 21.6 million transfusions conducted

                      Page 73                   GAO/PEMD-97-2
                                                            Blood Supply:Transfusion-AssociatedRisks
          Appendix IV
          ~er    ReducingIUsk

          each year. This translatesinto a cost of $2.3 milliondollarsper life-year
          saved comparedto the mediancost of $19,000per life-year saved for other
          medical life-saving interventions (Tengs et al., 1995).In comparison,
          traditional antibody tests prevent 16,000cases of transfusion-transmitted
          HIVper year at a cost of about $3,600per life year saved (“HIv-1Antigen
          Test,” 1995).

          FDA recommendedthe use    of this test when it became commercially
          available in early 1996.We were unable to find any studies that
          systematically compared the likely outcomes of targeting similar funding
          levels toward other avenues of reducing risk, such as improving donor
          education and screening or viral inactivation techniques.

          In September 1%, Strainer reported the one and, to date, ordy
          documented case of HIVthat has been detected by the p24 antigen test that
          was not also positive on the traditional antibody test among nearly
          8 million donors tested since March 1996(“Red Cross Reports,” 1996).
          Researched have specdated that the models predicting the detection of
          more donors may have overlooked the possibility that acute illness during
          the early window period may keep donors from givingblood temporarily.

          Remaining unanswered is the possibility that the new antigen test has
          atiacted recently infected “test-seekers” for a more sensitive HIVtest that
          is not available at HIVtesting and counseling sites and who actually
          increase the risks of HIV in the blood supply.

          The risks of transfusion will continue to decrease as a direct result of
Summary   pharmaceutical advances, changes in medical practice, improved selection
          of donors, viral inactivation techniques, and improved viral tests. Because
          the risks of transfusion are already so low, any incremental reductions in
          that risk will come at some cost either to the blood supply or to the health
          care system. A rapidly progressing medical field such as that of blood
          transfusion warrants careful consideration of the costs and benefits of
          different approaches to reducing risk.

          Page 74                    GAO/PEMD-97-2
                                                 Blood Supply:Transfusion-AssociatedRisks
Appendix V

CommentsFromthe Departmentof Health

Note: GAO comments
supplementing those in the
report text appear at the
end of this appendix,


                                                                                    ~   27190
                                                                                                            Offk. OfInspwtorQ.mml


                                               Mr. Kwai-cheung Chan
                                               Director   of Program Evaluation
                                                  in Physical  Systems Areas
                                               United States   General
                                                 Accounting   Office
                                               Washington, D.C. 20548
                                               Dear Mr.   Chan:
                                               The Department has carefully reviewed your draft report entitled,
                                               “Blood supply:  Transfusion-associatedRisks.w The comments
                                               represent the tentative position of the Department and are
                                               subject to reevaluation when the final version of this report is
                                               The Department also provided extensive technical comments
                                               directly to your staff.
                                                   Department appreciates the opportunity to comnent on this
                                               draft report before its publication.

                                                                                   June Gibbs Brown
                                                                            P      Inspector General

                                               The Office of Inspector General (OIG) is transmitting the
                                               Department’s response to this draft report in our capacity as
                                               the Department’s designated focal point and coordinator for
                                               General Accounting Office reports. The OIG has not conducted
                                               an independent assessment of these comments and therefore
                                               expresses no opinion on them.

                                                 Page75                         GAO/PEMD-97-2
                                                                                            Blood Snpply:Tranafaeion-AssociatedRisk
     bmments Prom the Departmentof Health
     and Hu.sssan

                                       Risks(GAO /PEMD-97-2~

The Department of Health    andHuman     Servicea  isingeneral agreement with the principal
findings and conclusions of the GAO drafi report (GAO/PEMD-97-2)on “Blood Supply:
Transfusion-associatedRisks.” Specifically, the Department concurs that the U.S. blood
supplyis currentlysaferthanit has ever been. This level of safety largely reflects
improvements in the aras of donor screening and education; serologic screening tests for
viral pathogens; and viral inactivation techniques. However, recent experiences with
hepatitis C transmission fromintraverroua    immunoglobulin   andhepatitisA transmission
from clotting factor concentrates illustrate the need for ontinued vigilance.

In this report, the GAO estimates the risk of adverse events, includingtransmission of viral
and bacterial pathogens, associated with the transfusion of screened blood. Such estimates
can assist public health officials, industry, clinicians, and consumers in making informed
therapeutic and programmatic decisions to reduce the risks associated with transfusion.
Because many of these risks are already low, new interventions will likely be of decreasing
benefit. We mncur with GAO that new interventionswill “...require careful consideration
in order to identify areas of improvement that would maximize safety with reasonable

The Depanment has reviewed the report and provided GAO with extensive technical
wmmems. In addition, the Department believea that information derived from estimates in
this report should be substantiated by scientific references whenever possible.

     Page 76                             GAO/PEMD-97-2Blood Supply:Transtiion-Associated Risks
              CommentsFrom the Departmentof Health
              and HumanServices

              The following are   GAO’S comments     on   the HHSNovember 27, 1996,letter.

              We agree with the department’s belief that our estimates shotid be
GAOComments   referenced. We point to table 11.1as well as to the scientific citations
              throughout the draft. We regret that the bibliography included in the final
              report was not available at the time of the department’s review.

              Page 77                   GAO/PEMD-97-2
                                                    Blood Supply:Transfusion-AssociatedRisks

MajorContributorsto ThisReport

                     Marcia G. Crosse, Assistant Director
Program Evaluation   Jacqueline D’Alessio,Project Manager
and Methodology      Kurt Kroemer,SeniorAnalyst
Division     ‘-      John E. Oppenheim, Adviser
                     Penny Pickett, Communications Analyst
                     Venkareddy Chennareddy, Reference

                     Page 78                 GAO/PEMD-97-2
                                                         Blood Supply:Tran8tiion-Assock@d Eisb

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