United States General Accounting Office

GAO Reportto the RankingMinorityMember,

Committeeon Commerce,House

Representatives

of

February 1997 BLOODSUPPLY

fimsfusionAssociatedRisks

GAO/PEMD-97-2

I

~GAO United States

General Accounting OffIce

Washington, D.C.20548

Program Evaluation and

MethodologyDivision

I

I

B-274942

I

February 25, 1997

1

The Honorable John D. Dingell

Ranking MinorityMember

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.

Youexpressed 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.

Youalso 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. Weprovide that information in our

report entitled Blood Supply: FDAOversight and Remaining Issues of

Safety.l

Background On June 30, 1992,4,619persons had been reported with suspected

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. Only38 cases of

I

1l_T. S. GeneralAccountingOffice,BloodSupply:FDAOversightand RemainingIxues of SafetY,

GAO/PEMD-97-l(Washington,D.C.: 1997).

1

‘Withinthe human body’sdisease-fightingcapabilities, it can develop antibodiesthat are specific to

each viral infection.The initial HfV-1tesk detected the HIVantibody in blood donated by infected

persons.

I

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

I

t
B-274942

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 Bsurface

antigen (HBsAg),antibody to hepatitis Cvirus (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

benefits.

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 antibodiesthat the human body produces in its immuneresponse 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-cellleukemia and lymphoma.Tests cumentlyavailable are specific for

antibodiesto HTLV-1,althoughthere are varyingdegrees of cross-reactivity with antibodiesto 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.4Health 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 26million 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.

Results in Brief The blood supply is safer today than any time in recent history. Improved

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.

1

Nevertheless, because blood is a biologicalproduct, 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 chemicallyinto 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 bleedingin patients with

clotting factor deficiencies, such as hemophilia;and specific immuneglobulins,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 ofthe final concentrated material cost-effectively.

I

Page 3 GAO/PEMD-97-2Blood Supply:Transfusion-AssociatedRisks
B-274942

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.5Whilethese 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 50percent, 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

yeax.

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

1million.

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 surgeWpatients

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 250times 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 overallrisk for afltypes of blood components. Strictly speaking, different blood

components carry different risks. Thisis 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 survivalrates 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 suggeststhat the mortality rate is between 38and 53percent amongseverely anemic

patients who refuse transfusion (Spence et al., 1990and 1992).Mortalityis higher(75percent) for

those with active bleedingwho require emergency surgery (Carson et al., 1988).

Page 4 GAO/PEMD-97-2Blood Supply:Transfusion-AssociatedRisks
B-274942

Wetook 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.

Objectives, Scope,

and Methodology

Our objective in this report was to quantify the current risks associated

with blood transfmion. To respond to your request, we reviewed data on

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-Iand 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, Leishmaniasistropica, was detected in seven Desert Stormveterans,

leadingto deferral of individualswho had been in the Persian Gulfin or after 1990.Withthe absence of

any data substantiating transmission ofthis parasite, the ban was lifted in January 1993.CMVis a type

of herpes virus. Estimates suggest that between 60and 90percent of the general population have been

infected by the time they are adults. Primary infection is usuallythe result ofrespiratory or sexual

contact, and the acute phase of the virus usuallypasses withoutsymptoms.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 forsevere 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. About50percent of adults

show evidence of past infection and no licensed screening testis available.The neurologicaldisease

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
B-274942

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 derivativesin 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. Wediscuss 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

calculations.

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
~

B-274942

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

weaknesses.

Weused 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.

Principal Findings In the context of other health-related risks, the risks of blood transfusion

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 HCVbased on research suggestingthat the

anti-HCVscreening test misses some infected donors. L1singthis estimate, we predict that 4 in 10,000

patients willdevelop serious chronic disease or die. Someresearchers do not accept this theory,

believingthat the risk is closer to 1in 103,000.Usingthis estimate changesthe prediction onlyslightly

to 2 of every 10,000patients.

I

Page 7 GAO/PEMD-97-2Blood Supply:Transfusion-AssociatedRisks
B-274942

Five FactorsThatHelp The risk of contracting a disease from blood transfusion continues to

ReduceRisk 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 HIVtest 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 HIVtest 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 viralscreening 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-HCVtests were introduced, the rate fell to about 1percent—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).Ofthese 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: 18of every 100,000donations (349) from first-time donors tested

positive for HIV.

Page 8 GAO/PEMD-97-2Blood Supply:Transfusion-AaaociatedRisks
B-274942

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

inactivation.

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

risk.

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 IIIfor a discussion

of plasma

Page 9 GAO/PEMD-97-2Blood Supply:Trans*ion-Associated Risk
B-274942

Table1:IndividualandOverallRisksof

AdverseOutcomesFromAllogeneic

BloodTransfusion~

1. Riskestimateper

unit(12.057million 2. Patientriskper

Agentoractivity unitsdonated) transfusionof5 units

Virusb

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-Iand -11 1:50,000 1:10,000

Non-ABC hepatitis 1:5,900 1:1,180

Bacterium

Platelet contamination

Random donor 1:10,200 1:1,700

Apheresis 1:19,500 1:19,500

Yersiniaf 1:500,000 1:100,000

Parasiteb

T. cruzi 1:42,000 1:8,400

Subtotalriskof infection 5:10,0009 2.7:1,0009

Trensfueionh

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

Subtotalriskoftransfusion 3:10,000 1.5:1,000

reaction

Total

Risk 8:1O,OOOI 4.2:1,0001

Page 10 GAO/PEMD-97-2Blood Supply:Transfusion-AssociatedRisk
B-274942

3. Annualnumberof 5. Numberof

implicatedcomponent recipient whodonot

unitaif23.19million dieof underlying 6. Numberof recipientswhodevelop

componentsavailable 4. Numberofrecipientsaffected di=ase ortmuma chronicdiseaseor dieasa resultof

and19.23million (likelihoodofseroconversion) 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 likelihoodthata unitwillescapedetection

by multipletestsis almostnonexistent.Therefore,the individualriskspresentedhereare

independent,andthetotalriskis calculatedby summingindividualrisks.Numbersmaynotbe

exactbecauseof rounding.An exampleusingHIVacrosscolumns1-6is asfollows:

1:Theriskof HIVis 1in every450,000donatedunits.Thatis,ofthe 12.057millionunitsdonated,

27will be HIVpositive(12.057million/450,000(notshown)).

2:Assumingeachpatientreceivesanaverageof about5 unitsof blood(exceptplateletsnoted

below),thenthe riskto the patientis450,000/5,or 1 in 90,000.

3: Eachallogeneicunitis madeintoanaverageof 1.87transfusedcomponents.Hence,

12.057millionunits= 22,583,000componentsplus607,000apheresisplatelets= 23,190,000

totalcomponents.The27 unitsof HIV-positivebloodbecome52differentcomponents.

Page 11 GAO/PEMD-97-2Blood Supply:Trmsfusion-AssociatedRisks
B-274942

4:Notall recipientswilldevelopthe diseasepresentinthe blood(seroconvert);90 percentof the

52recipientsof HIVbloodwill seroconvert(47patients).Thisconceptappliesonlyto viruses.

5: Mostpatientsreceivingbloodareat greatriskof dyingfromtheirunderlyingconditions;

30 percentdiewithin2 years.ForHIV,33of the47 patientswill survive.

6: Notall agentsandactivitiesleadto chronicdiseaseor death.ThelikelihoodthatHIVwill is

nearly100percent,soall33patientswhosurvivetheirunderlyingconditionswilldie.

bThenumberof virus-andparasite-contaminatedunitsis basedonthenumberof allogeneicunits

donated(12.057million)andthe numberof componentsmade(23.190million).

CAtotalof 6.330millionindividualunitsof plateletsweretransfused.Patientriskandavailable

componentsarebasedon4.688millionrandomdonorplateletstransfused(56percentoftotal

platelettransfusions)and607,000singledonorapheresisplateletstransfused(eachapheresis

unithas6 individualunitscollectedfrom 1 donor,totaling3.642millionplatelets,or 44percentof

totalplatelettransfusions).Forexample,patientriskfor a randomdonorunitis theriskfor each

donorunitdividedby theaveragenumberof 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

sameasthe per-unitrisk(1:19,500)becausethe plateletsarecollectedatthesametimefroma

singledonor.Numberof implicatedapheresisunitsis 607,000/19,500,or 31units.

‘Seroconversionnotrelevant.Numberscarriedoverfromcolumn3.

*Notrelevantfor bacterialcontaminationortransfusion-relatedoutcomesthatarenear-term

events.

‘Riskis basedon 12.057millionred bloodcell unitsbecauseYersiniaoccursonlyintheseunits.

QRiskis basedonsumof viralrisksplusYersiniariskplusa weightedsumof plateletrisksbased

on proportiontransfused((randomplateletriskx 0.56)+ (apheresisplateletriskx 0.44)).

‘The numberof unitsassociatedwithtransfusionproblemsis basedonthenumberof units

actuallytransfused(4.688millionrandomdonorplatelets,607,000apheresisplatelets,

10.741millionwholebloodandred bloodcells,and3.194millionothercomponents),Riskis

basedon 19,230,000totaltransfusions.SeeappendixIIfor supplyandtransfusioncalculations,

‘Riskis basedon 10.741millionred bloodcellsandwholebloodtransfusedbecause

1’ compatibilityis an issueonlyfortheseunits,

IAssumesa 64-percentchancethata randomtransfusionto an unintendedrecipientwouldbe

compatibleand 100-percentreportingof incompatibleerroneoustransfusions.

‘Seroconversionnotrelevant.Assumes36-percentincompatible.

‘Riskis basedon sumof viralrisksplusYersiniariskplusa weightedsumof plateletriskbasedon

proportiontransfused((randomplateletriskx 0,56)+ (apheresisplateletriskx 0,44))plus

transfusion-relatedrisks.

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

Page 12 GAO/PEMD-97-2Blood Supply:Transfusion-AssociatedRisks
B-274942

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 Cvirus would remain undetected and be released for trartsfusion

is 1in every 4,100units of blood; for HIV,the likelihood is 1in every

450,000units.ll Amore 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: FDAOversight 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 FDAfor 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 rangesfrom 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. Weused 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-97-2Blood Supply:Trmsfusion-AssociatedRiska
B-274942

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 artimplicated unit

is 4.2 in 1,000,or 1 in 238 patients.15

In order to fullyunderstand 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]eof a problem that has been virtusflyeliminated M SClentlStS

discovered how it acts. Donorlymphocytesengraft and multiplyin the recipient, who is usually

immunocompromised.The donor cells react against the “foreign”tissues ofthe 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 bysummingtransfusion-related, noninfectious risks from the second columnof 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 unitsin 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 1of 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 receivingblood and dyingbut, rather,

that those who receive a blood transfusion are typicallyquite ill or traumatized and, consequently,may

die from the underlyingreason for which the transfusion was administered.The mortality rate maybe

even higherfor platelet recipients, who are often extremely ill with cancer or other life-threatening

problems.

Page 14 GAO/PEMD-97-2Blood Supply:Transfusion-AssociatedRisks
B-274942

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 23million 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 1percent 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 1million.

Table2: Riskaof SurgeryendBlood

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

aAssumes23millionsurgeriesin 1993,or9 percentoftheU.S.population,withanestimated13

percentof the surgeriesusingbloodand0.012probabilityof surgeryandbloodtransfusion

occurringtogether.Assumesfurtherthatonly3 millionofthe4 millionpatientswhoreceived

transfusedbloodweresurgerypatients;the remaining1millionreceivedtransfusionsfor cancer

therapy,hemophilia,andotherdisorders.

‘iTherisk for HfVwe present does not include tie expected reduction resulting from the introduction

of the new p24antigen HIVtest. Althoughno confirmatory data have been collected, it is estimated

that the risk of HfVin blood screened by the new test willbe 1in 700,000.Whenwe used this risk

estimate in our analysis, we concluded that it woulddetect an additional 19of the 52conmminated

components in the supply and ultimatelyprevent 12~essthan1percent) ofthe 1,523cases of chronic

disease and death associated with transfusion.

la~ong the estima~d ZGOmillion U.S. population, 9 percent underwent surgery (23milliondividedby

200million).furthermore, 13percent ofthow surgery patients received blood (3 millionestimated

surgery transfusions dividedby 23millionsurgeries). The likelihoodthat an average U.S.citizen with

no plans forsurgery would undergo surgery and receive blood is 1in 100(probability ofsurgery and

blood = 0.09X0.13= 0.01).

Page 15 GAO/PEMD-97-2Blood Supply:Transfusion-AssociatedRisks
B-274942

Blood fiansfusion Risksin In order to determine whether these risks are small or large, we compared

Perspective them to other health-related risks. Data from the MedicalPractice Study

suggest that more than 1million 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).Arecent study at two large

Massachusetts hospitals found that 6.5percent 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 Per100,000

Outcome

patientsor

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 thesefiguresincludetheriskof dyingfrom

transfusion.However,thatriskisa verysmallproportionofthe otherrisks,

bT.A. Brennanet al.,“IncidenceofAdverseEventsandNegligencein HospitalizedPatients:

ResultsoftheHarvardMedicalPracticeStudyl,” NewEnglandJournalof Medicine,324:6(1991),

370-76.

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

1995).

‘D. W.Bateset al,, “IncidenceofAdverseDrugEventsandPotentialAdverseDrugEvents:

implicationsfor Prevention,”JournaloftheAmericanMedicalAssociation,274:1(1995),29-34.

‘B, N.Doebbelinget al.,“ComparativeEfficacyofAlternativeHand-WashingAgentsin

ReducingNosocomialInfectionsin IntensiveCareUnits,”NewEnglandJournalof Medicine,327

(1992),88-93,

Furthermore, the annual risk from trufusion to arI average person in the

United States who foresees no plarIfor surgery is the same as or lower

than the annual risk of dying from tuberculosis or from accidental

Page 16 GAO/PEMD-97-2Blood Supply:Transtiion-Associated Risks
B-274942

electrocution or drowning, and it is as much as nearly 600times 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 Per100,000

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-97-2Blood Supply:Transfusion-AssociatedRisk
B-274942

Conclusions We found that the current risks from blood trmsfusion are small

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.

Medicaltesting and manufacturing technologies continue to improve

blood safety. Medicalpractice is being transformed to accommodate new

knowledge about the risb andbenefits 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

supply.

Agency Commenti The Department of Health and Human Services (HHS) generally agreed

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 15days after the date

of this letter. Wewill 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-97-2Blood Supply:Transfusion-AssociatedRisks
B-274942

Administration, md others who are interested. Wewill 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,

Kwai-CheungChan

Director for Program Evaluation

in Physical Systems Areas

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

Letter 1

Appendix I

TransfusionAssociated

Complications

HIV-I and HTV-2

Hepatitis A

Hepatitis B

Hepatitis C

Other Hepatitis Viruses

24

24

29

30

32

35

HTLV-Itid HTLV-11 36

Parasites 39

Bacteria 41

Noninfectious Complications of Transfusion 44

Appendix II

Our Methods ad The Evaluation of Transfusion-Risk Studies

The United States Blood Supply

Analysis Risk Estimates and Their Cordidence Intervals

48

48

51

58

Appendix III

Plasma Products Plasma Product Uses

Plasma Donors

60

60

61

Plasma Fractionation and Product Manufacture 62

History of Disease Transmission From Plasma Products 63

Rates of Vti Test PositivityAmong Commercial and Volunteer 64

Donors

summary 69

Appendix W 70

Further Reducing Drug Therapies to Reduce the Need for Blood Transfusion 70

Alternatives to Blood

Risk

70

Reducing the Use of Transfusions 71

Controlling the Sources of Donation 72

Extending ViralInactivation to Celldar Components 73

Closing the WindowPeriod 73

summary 74

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

Appendix V 75

Comments From the

Department of Health

and Human Services

Appendix VI

Major Contributors to

This Report

78

Bibliography 79

Tables Table 1:Individual and Ovedl RiBksof AdverseOutcomesFrom

AllogeneicBlood Trmfusion

Table 2: Risks of Surgery and Blood Transfusion

Table 3: Likelihood of Various Health Outcomes

Table 4: Annual Rates of Various Health Outcomes

Table 11.1:Scientific Studies Used as Source of Our Risk

Estimates

Table 11.2:Estimate of Toti AllogeneicBlood Supply and

Transfusions

Table 11.3:Calcdations for Individud and Overall Risks of

Adverse Outcomes Prom AllogeneicBlood Transfusion

Table 11.4:Estimated Risksfor Specific Blood Componen@

Table 11.5:Test Sensitivityad SpecificityRates and Window

Period Estimates

Table 111.1:Uses for Plasma Componenk

Table 111.2:ViralTest AntibodyPositivity Rates: ClinicalTrial

Data

10

15

16

17

49

52

54

58

59

60

68

Figure Figure 111.1:Reported Confirmed HIVPrevalence Rates Among 66

Donations in California, 1989-94

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

Abbreviations

ABRA

Me

ATL

CDC

m

CMV

FDA

WSP

HAv

HBc

HBV

HBsAG

HCV

HDV

HEV

HGV

HHS

HIV

HTLv

IGIV

NIH

TRALI

Page 22

American Blood Resources Association

American Red Cross

Addt T-cellleukemia and lymphoma

Centers for Disease Control and Prevention

Creutzfeldt-Jakob disease

Cytomegalovirus

Food and Drug Administration

HTLV-I-associatedmyelopathy and tropical spastic

paraparesis

Hepatitis Avirus

Hepatitis B core

Hepatitis Bvirus

Hepatitis B surface antigen

Hepatitis Cvirus

Delta hepatitis

Hepatitis E virus

Hepatitis G virus

Department of Health and Human Services

Human immunodeficiency virus

Human T-lymphotropic virus

Immune Globtin Intravenous

National Institutes of Health

Transfusion-related acute lung iqjury

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

1

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

fiansfusion-AssociatedComplications

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-riskand 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, 21.8million 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

3.7percent of all reported cases. HIV-2is endemic only in WestAfrica,

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 17cases, 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’Semergence: 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
AppendixI

Transfusion-AssociatedComplication

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 Angelesis not known, but she is originallyfrom 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. Asecond case of HIV-1group O infection has been identified in

the United States under CDC’Ssurveillance activities for unusual HIV-1

variants.

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 levelsthat 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-97-2Blood Supply:Transfusion-AssociatedRisk
Appendix I

Transfusion-AssoeiatedComplications

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 1per 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)(Vyaset 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 1per 40,000units.1Ward’sgroundbreaking reasoning

was as follows.

from May 1986to May 1987,0.012percent of repeat blood donors md

0.041percent 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 HIVafter 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 HIVantibody 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 18million 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 18million

= 1 per 39,130,or about 1per 40,000.

‘Warddid not report confidence intervals.

‘Personal communication from RogerDoddof the American RedCross.

‘mat is, [number of donors x (the HfVpositivityrate x the proportion of the time between donations

when the donor could be in the windowperiod)] + [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

99percent.

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

Transfusion-AssociatedComplications

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 1per 153,000uni~ ifthe 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 1in 88,000with a 14-weekwindow 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 LosAngeles 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 HIVstatus 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, 34to 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 millionMCdonations 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 ofthe window

period), the true value would fall somewhere between tie two endpoints of the stated interval. These

researchers found preliminary evidence suggestingthat antibodytests used after March 1987had a

smaller windowperiod of 42days, a findingthat was later confirmed.

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

Tranafuaion-AssociatedComplications

percent, which predicted the erroneous release of 1 in every 2.6million

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 HIVtest-positive donations

were positive ofi’other tests. This study concluded that there was a

residual risk of HIVtransmission 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 HIVamong firsttime donors is unavailable,

researchers must rely on 1985data collected when HIVtesting begartthat

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

‘Nopoint estimate is reported.

%chreiber’s calculation ofthe windowperiod is 3 daysless 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
Appendix1

Transfusion-AssociatedComplications

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

average.7

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

future.

Transmission-by- Donegan and colleagues (1990)retrospectively tested 200,000blood

TransfusionStudies component specimens stored in late 1984and 1985for HIVantibody and

contacted recipients of positive donations to de~rmine their status. Ofthe

124recipients with no known risk factors for HIV, 111(89.5percent) 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. Alater 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 willsuccumb to it

eventually.

Hepatitis A

HAVis almost always transmitted by the fecal-oral route. Commonly

reported risk factors among patients with HAVinclude 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

7Forsimilarreasons, we did not use Schreiber’s estimates for HTLV-Irisk (1 in 641,000,confidence

interval from 1in 256,000to 1in 2,000,000)or for HCV(1 in 103,000,confidence intervalfrom 1in

28,000to 1in 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

Transfusion-AssociatedComplications

chronicdiseasemd mortality is 0.2percent or less. Avaccine 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 1million, 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. Antigentests are

99.9-percentsensitive; 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 HIVor 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

levels.

8HAVis a very stable virus capable of withstanding considerable heat in dry conditions.In 1$)92,

hemophiliacpatients receivingfactor 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 ofthis product. Aheat-inactivation process should eliminate this risk,

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

Transfusion-AaaociatedComplications

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 59days,

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 HBvtransfusionrisk 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

0.03percent 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 1percent of infected individualstest 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 virusthat requires the help of HBVto replicate in the human

body. Persons confected with HBVand HDVmay have a more severe acute illness and a higherrisk of

fulminanthepatitis than others infected onlywith HBV.Nodirect measure of the incidence of HDVis

available,but CDC’Smodelssuggest that HDVaccounts for 7,500infections annually.Its prevalence

amongHBVinfected donors is estimated at between 1.4and 8 percent. Hepatitis Bimmunizations

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 Alterrounds this last

figure to 0.00040percent in table 2 of her article. Weuse 0.00043percent, which changesthe estimate

slightly.

1l’rherisk oftransmission among donomwho test positive on the antibody test done is 4 Percent,

because in most cases a positive antibodytest indicates an old,resolved infection.

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

Tranafision-AaaociatedComplicatiooa

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 1in 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

abuse.

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 Bvaccination 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 Wardet d. (1989)that traced back

selected recipients of transf~ions and found that 50percent of a transfusion control groupthat 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 generalsurge~ population as they were

often referred from a subspecialty surgical area and had a poorer prognosisfor survival.[n a more

recent study,Vamvakasand Taswell(1994)enrolled all residenta of a U.S.county whounderwent

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

Tranafaaion-AaaociatcdComplications

180,000(average 120,000)new HCVinfections each year in the United

States. Diagnosisis 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 HCVis 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, 12percent 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 1in every 222units of blood. When surrogate

testing was implemented, the risk decreased to about 1 in every 525unik.

The first-generation ~ti-HCV test further reduced the risk to 1in 3,333

units. When the second generation HCVtest was introduced in 1992,these

researchers found 15cardiac surgery patients infected with HCVamong 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 HCVtesb reduced HCV risks to between 1in 2,000and 1in 6,000

component units.

The current estimate of the window period is 82 days with a range of 54to

192days. Blood containing the virus is infective from 1week 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-97-2Blood 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 1in every 103,000units (95-percent

confidence interval, 28,000to 288,000).

Amuch 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

HCV.

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

13No~mfidemce inteti RPO*.

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

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

Transfusion-AssociatedComplications

Much still needs to be learned about the long-term effects of HCVinfection.

Eighty-fivepercent or more develop persistent HCVinfection, and while

about 70percent of infected individuals develop chronic hepatitis,

long-term follow-up studies suggest that only 10to 20 percent develop

clinicalsymptoms 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 DiBisceglieand 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 10to 51percent of

patien@,and the effect of long-term therapy had not been determined.

.

Other Hepatitis

Viruses

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 10such 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-97-2Blood Supply:Transtiion-Associated Risks
Appendix I

Tranafoaion-AaaociatedComplication

Blood-Supply-RiskStudies The prevalence of HGVin blood donors as measured by HGVRNAdetected

by PCRis higher tha tiat of HCV.The HGVvirus 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

(“NewHepatitis GVirus,”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 is endemic in southern Japan, tie Caribbean basin, and Africa.

Popdations in Japan have rates of HTLV-Iinfection 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-Iseroprevalence 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

Tranafnaion-AaaociatedComplication

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

0.008percent.

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

I

The current estimate of the window period for HTLV-Iand HTLV-11 is 51 days

with a range of 36 to 72 days (Manns et al., 1992).When blood screening

for HTLVwas introduced in 1988,nearly 2,000U.S. donors were found to be

positive. The HTLVinfections among blood donors in the United States are

nearly evenly divided between types I and 11.15Most HTLV-I positive donors

were born in or report sexual contact with a person from the Caribbean or

Japan, while nearly all HTLV-11positive 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-Iantigens to detect

both types, the sensitivity of detection of HTLV-11 is lower than that for

HTLV-1antibodies. 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 1in 641,000(cotildence interval from 1in 256,000to 1in

2,000,000).

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 sopercentof HTLV-IandHTLV-11aeropoait.ivityamongintravenoushg We= *~ from

HTLV-11infection. HTLV-11alao appeara endemicamongNorthAmericanIndiansinFloridaandNew

Mexico.

ltiNCIcofildenceinteti rePo~.

Page 37 GAO/PEIUD-97-2Blood 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 74percent; 6 to 10days, 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-cellleukemia 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 1percent of persons infected with

HTLV-Idevelop ~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-11had 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

Transfusion-AssociatedComplications

resembles that of HTLv-I-infectedpatienti with HAM/1’SP. HTLV-HWasfirSt

isolated in 2 patients with hairy cell leukemia, although no virus has been

isolated from additional cases of this disease.

Parasites

Disease Factors Several bloodbome parasites can be present in donated blood. Few direct

measures of risk exist; therefore, estimates are based on reported cases.

Withthe exception of one parasite, the risk of transfusion-associated

parasite transmission is less than 1in 1million.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 14of 13,309

(10.5percent) 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 UnitedStates. 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 sandflyin endemic areas, such as the Persian Gulf.Viscero&opic

Leishmaniasisaffects the internal organs of the body.Veterans of Desert StQrrnwere deferred from

donatingblood when 7 cases were discovered amongmilitary personnel serving in Desert Stormand

Desert Shield.Whileca..es of cutaneous Leishmaniaaishave been reported in Texas, this variant ofthe

disease in not thought to be a risk for bloodtransfusion. Nocases oftransfusion-transmitted

viscemtropic Leishmaniasis have been reported in the UnitedStates. Babesiosisis caused by the bite

of an infected tick, a problemfoundmostlyin endemic areas ofthe northeastern UnitedStates. To

date, CDCreports 15cases oftransfusion-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 handlingof infected [:ats or cat litter. Other means of transmission include eating raw or

undercooked pork, goat, lamb, beef, or wildgame.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 eligibleblood donors

who have Hispanics urnames and 1 in 300 eligibleblood 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 LosAngele 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

Additionalscreening questions ARCasked 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. Ofthose 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. Ifthe 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 14to 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

10percent.lg

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 RogerY.Dodd,AmericanRedCross,Jerome H.Hollandbbomto~.

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

Transtiion-Associated Complications

Between 20 and 30 percent of infected individuals develop chronic Chagas’

disease, often years to decades followinginfection. 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. Asthe

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 70percent

to 90 percent of infected laboratory mice using the antifungal drug D0870

(Urbina et al., 1996).

Bacteria

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 ifthe 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. Yersiniais 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-97-2Blood Supply:Transfusion-AssociatedRisk
Appenti I

Transfusion-AssociatedComplications

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 10donors. Bacterial sepsis can occur if any of the pooled uni~ are

?. contaminated. Indeed, Morrow and colleagues (1991)found that the rate

,.,, of sepsis was 12times 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

definitivelycaused 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

Transfusion-AaaociatedComplications

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

chillsthat may mask underlying bactiremia. Morrow and colleagues of

Johns Hopkins MedicalInstitutes (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 clinicalsymptoms were evaluated.

More recently in Hong Kong,Chiu and colleagues (1994) conducted a

3-yearprospective 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. Atotal

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: 1in every 2,100

platelet units, 1 in every 350transfusions, and 1in 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 Navyin 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-97-2Blood Supply:Transfusion-AssociatedRisb
Appendix I

Transfoaion-AssociatedComplications

(1994) estimates that 1in every 500)000red blood cell units maybe

contaminated by Yersinia or other bacteria.21

fiansmission-by- Manysurgical 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

initialsigns 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 50minutes to 17days

following transfusion (Morduchowicz et al., 1991;Tipple et al., 1990).

Goldman and Bl~chman (1991)reported that 26percent of identified

transfusion-associated sepsis cases ended in death.

Noninfectious Transfusions can result in serious or fati complications as a result of

Complications of serological or clerical errors in blood typing, mismanagement of the

transfusion, or unanticipated reactions in the recipient to elements of the

fiansfusion donor’s blood. Manyof 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-97-2Blood 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 OfTRALIto be 1 in 10,000units.22

However, Popovsw argues that TaALIis rarely diagnosed and reported.

Therefore, Walker’sfigure is probably an underestimate. Popovsky et al.

(1992)report that, prior to 1985,only 31 cases OfTRALIhad 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.

TRALIpresents 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, TRALIimproves 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-97-2Blood 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-compatiblewith 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 18cases (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

recipient.

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 1per 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 12,000units.

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 700individuals are IgA-deficient,but anaphylaxis

occurs only in those who have developed antibodies to IgAas a result of

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

Transfusion-AssociatedComplications

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 andthe 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-97-2Blood Supply:Transfusion-AssociatedRisk
Appendm II

OurMethodsandAnalysis

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.

The Evaluation of

Transfusion-Risk

Studies

●

●

●

●

s

In recent years, many estimates of transfusion risks have been published

in the scient~lc literature. As more becomes known about how viruses are

transmitted through blood transfusion, the methods used to evaluate these

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

research:

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),

and

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 yieldsthe 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.

Bywindow 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

tissed.

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

Our Methodamd Analyaia

Appendix I provides detailed findingsfrom 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

strengths.

Table11.1:ScientificStudiesUsedasSourceof OurRiskEstimates

Study Riskof Riskofchronic

Complication Source type” Strengthb Riskperunit aeroconversion diseaseor death

HAV Dodd (1994). c 6 1:1,000.000

GAO estimate go~oc

Institute of Medicine C 0.270

(1995)

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

1:10,200;

apheresis =

1:19,500

T. cruzi

Goldman and R 6 26

Blaichman (1991) >,

Dodd (GAO interview) P 1 1:42,000

Dodd (GAO interview) R 1 10

(continued)

Page 49 OAO/PEMD-97-2Blood Supply:Tr-tiion-Associated Riaks
study Riskof Riskofchronic

Complication Souroe W* Strengthe Riskparunit aaroconversion diseasaordeath

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

(1995)

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 = currenttimeperiod; 2 = State Ofart teStS;3 = representativesample;4 = validmeasures,

includingtestsensitivityandtesterrorswherepossible:5 = mostconservativeestimate;6 = only

estimateavailable.

CExtrapolatedfromHCVseroconversiondata.

Where datawerederivedfromcompendiumsources,we did notevaluatestrengths.

‘Calculatedfromdataprasented.

‘Estimatebasedon clinicalpresentationof symptomsand prognosisasdiscussedin R.Berkow

\~d~jThe MerckManualof DiagnosisandTherapy(WhitehouseStation,N.J.:MerckandCo.,

Page 50 GAO/PEMD-97-2Blood Supply:Transtiion-Associated Rish
Appendix II

Our Methodaand Andyei.Y

The United States Our analysis differs on several dimensions from the mslyses in the

Blood Supply

literature. Other studies have considered ordy volunteer donations

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-97-2Blood Supply:Transfusion-AssociatedRisks
r

~

Appendix 11

Our Methodsand -~

Table11.2:EstimateofTotalAllogeneic

;

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

Totalalloganelcbloodproducts

Available 23,190,000

Transfused 19,230,000

Availableallogeneicsupplynottransfused 3,960,000 17.0

‘A totalof 8,330,000individualunitsof plateletsweretransfused.Onetherapeuticunitof

apheresisplateletsisequivalento 6 individualplateletunits.Therefore,3,642,000individualunits

(or44 percentofthe totalplateletstransfused)weretransfusedas 607,000therapeuticunitsof

apheresisplatelets.

Source:E.L.Wallaceet al.,“CollectionandTransfusionof BloodandBloodComponentsinthe

UnitedStates,1992,”~ansfusion,35:10(1995),802-11.

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

Our Methodsmd 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 Weused 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

transfused.

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 56percent

of transfused platelets are random donor platelets using art average of 6

donors per therapeutic unit and the remainder are apheresis platelefi

consisting of 1donor 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

units).

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 1in 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. Wemust 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 higherthan the 1.8

commonlycited in the literature. Thisis 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
Appendix11

Oor Methodsnd Analysis

Table11.3:Celculetionsfor Individual

andOverallRisksof Adverse

OutcomesFromAllogeneicBlood

Transfusion 1. Riskestimateper

unit(12.057million 2. Patientriskper

Agentoractivity unitsdonated) transfusionof5 units

Virus

HAV 1:1,000,000 Risk from COI.1 divided by

HBV 1:63,000

HCV

average transfusion of 5

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

Bacterium

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 =

1:19,500

Parasite

T. cruzi 1:42,000 Risks from COI.1 divided by

average transfusion of 5

units.

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)] = 0.0005or

5:10,000

Pa$e54 GAO/PEMD-97-2Blood Supply:Transfusion-AssociatedRisks
Appen& II

Our Metioda and~

3. Annualnumberof 5. Numberofrecipients

implicatedunitsif23.19 whodo notdie of 6. Numberof recipientswho

millioncomponents 4. Numberofrecipientsaffected underlyingdiseaseor developchronicdiseaseor dieas

availableand19.23million (likelihoodofseroconversion) traumafirst(30%die a resultoftransfusion(likelihood)

transfusions Number 0/0 within2yea;s) Number %

Total components available

divided by no. of units in

sample expected to contain

one implicated unit from COI.

1. For example, no. of HAV

units is 23.19

million/1,000,000 = 23. Total

virally contaminated units =

10494

No. of implicated units 9070 No, of seroconverted

from COI,3 multiplied by 70 recipients from col. 4

seroconversion rate in 90 multiplied by likelihood of

COI.4. For example, for 90 survival. For example, for

H.4V,23X 0.90 = 27 HAV, 21 X0.70 = 15

21 recipients 90 seroconverted recipients

who survive beyond 2

years

No. of surviving patients 0.2%

from COI.5 multiplied by 10

the likelihood of chronic 20

disease or death in COI. 100

6. For example, for HAV, 4.75

15x 0.002= 15

0 recipients who develop

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

bacteria-contaminated

platelets

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

(continued)

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

Our Methodsand AIIalyein

1. Riskestimateper

unit(12.057million 2. Patientriskper

Agentoractivity unitsdonated) transfusionof5 units

Transfusion

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

Total

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

1:1,250

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

Our Methodsand Anatysb

3. Annualnumberof 5. Numberofrecipients

implicatedunitsif23.19 whodo notdieof 6. Numberofrecipientswho

millioncomponents 4. Numberofrecipientsaffected underlyingdiseaseor developchronicdiseaseor dieas

availableand,9023million (likelihoodOf SerOCOnVerSiOfl) traumafirst(30%die a resultoftransfusion(likelihood)

transfusions Number % within2yea;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

0>0035= 1:287

or die =

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-97-2Blood 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

patienti.

Table11.4:EstimatedRiaksfor Specific

BloodComponents Bloodcomponent Riskparunit 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 allvirusesexceptHTLV-Iand-Il. T. cruzi,ABOincompatibility,acutelung

injury,anaphylaxis,andcirculatoryoverload.

Clncludesrisksfor all viruses,plateletcontamination,T.cruzi,acutelunginjury,anaphylaxis,and

circulatoryoverload.Per-patientriskforrandomdonorplateletsbasedon6 individualdonorunits.

Per-patientriskfor apheresisplateletsbasedon 1individualdonorunit.

‘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

Their Cotidence are point estimates. The nature of our analysis required that we use

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

GAO/PEMD-97-2Blood Snpply:Transfusion-AssociatedRisks
Appendix II

Our Methodsand 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’

blood.

Table11.5:TestSensitivityandSpecificityRatesandWindowPeriodEstimates

Testcharacteristic 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-Itestis consideredto havelowersensitivityfor HTLV-11infections.

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 HCVtests 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).

GAO/PEMD-97-2Blood Supply:Transfusion-AssociatedRisks
AppendixIII

PlasmaProducts

Inthis appendix,we describe some of the waysin which the

mufacturing of plasma differsfromthatof 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.

Plasma Product Uses More than 40 million hospital patients use plasma products each year.

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

deficiency

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

exDosureto 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 Xllldeficient 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

(continued)

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

PlasmaProducta

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

transfusions

Rubella immune globulin For passive immunization subsequent to

exposure to German measles

Serum cholinesterase To treat prolonged apnea subsequent to

the administration of succinylchoiine

chloride

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.”

Pl~ma Donors Plasma is typically collected from paid donors in a commercial setting.

Donors receive between $15and $20for 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

syphilisin 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’fingerwith fluorescentdye. Nearbycenters use different

colors.

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

PlasmaProducts

As with whole blood donated by the volunteer popdation, fusttime donors

are known to carry higher viral test positivity rates tharIrepeat 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 fractionation Plasma collected at plasmapheresis centers is shipped in separate

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 HAVor 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-97-2Blood Supply:Transfusion-AssociatedRish
Appendix 111

PlasmaProducts

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.

History of Disewe In the 1980sbefore the etiology of HIVtransmission was understood, many

fiansmission From

hemophilia patienk used plasma products infected with HIV,with

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

derivatives.

In January 1996,CDCreported the transmission of HAVby 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.

Clinicaltrials 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, they had not been virally inactivated with FDA-aPPrOVed

methods. In the 74 cases in which risk-factor data were available, 68

(92 percent) had receipt of IGIVas 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-negativepregnant women and

Page 63 GAO/PEMD-97-2Blood Supply:Transfusion-AssociatedRiska
Appendix111

PlasmaProducts

specific immune globtins for HBV,tetanus, and varicella-zoster. No new

cases of HCVtrwrnission by IGIVhave been reported to date.

Asimilar 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 virus in that it is readily inactivated. In 1988,CDCreported

on a worldwide survey of 75suspected cases of HIVtr-mission by

heat-treated factor concentrates. Among the 75 recipients, 18met 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.

Rates of ViralTest Despite the evidence that viral inactivation and removal processes make

Positivity Among

today’s plasma produc~ safer than ever, the fact remains that the paid

commercial plasma donor pool has higher rates of viral infectivity than the

Commercial md volunteer whole blood donor pool.

Volunteer Donors In 1978,FDArequired that each blood unit be labeled as either volunteer or

paid. In the regdations, FDAconcluded 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

derivatives.

Wewere unable to obtain national data on the viral test positivity rates

among paid plasma donors compared to volunteer blood donors. Wedid,

however, fmd several sources of information pertaining to this issue. First,

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

PlasmaProducta

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

donations.

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

PlasmaProducti

Figure111.1:ReportedConfirmedHIVPrevalenceRatesAmongDonationsin California,1989-94°

70

60

so

40

30

20

10

0

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

I

1.93 2.93 3.93 4.93 1.e4

Mn

2.W 3.94 4.e4

Ouaftef.Yesr

■ Woodbanka❑ Plasmacenters

aReportedWesternBlotConfirmedHIVprevalenceratesper 100,000 commercial plasma

donations and volunteer whole blood donations in California (1989-94).

Source:CaliforniaDepartmentof HealthServices,OfficeofAIDS,HIV/AiDSEpidemiologyBranch,

Sacramento,California,August1995.

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

Plasmaproducts

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 urdikelythat 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&. Astable 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-97-2Blood Supply:Transfusion-AssociatedRisks
Appendix III

PlaamaProducta

Table111.2:ViralTestAntibody

PositivityRetes:ClinicalTrielDetes HCV

Donortriel HIV-1end-2 1stgeneration(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-97-2Blood Supply:Transfusion-AssociatedRish
Appendix III

PlasmaProduc@

HTLV-lb

2ndgeneration(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,

Summ~ Clearly,most commercial plasma donors are healthy and free of disease.

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 80percent

of HTLV-Iand HTLV-11 infections among intravenous drug users stem from

HTLV-11, but the HTLV-I antibody testis somewhat less sensitive for HTLV-11

infections.

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-11is 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-97-2Blood Supply:Transfusion-AssociatedRiska
AppendixIV

FurtherReducingRisk

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.

Drug Therapies to Physicians are increasingly considering alternatives to blood transfusion.

Reduce the Need for Recombinant human e!ythropoietin-a growth factor that stimdates the

body’smanufacture 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 levelsthat 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

transtiions.

Alternatives to Blood Researched are also working to develop substitutes for blood. One

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.

IStromaisthestructural portion of erythrocytes. The hematocrit is the percentage ofthe volumeof 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 cellsubstitute, 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 willsubstitute 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 10units, 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.

Reducing the Use of AvoidingunnecessaW transfusions is a primary goal of transfusion

Transfusions

medicine specialists. “Transfusion trigger” refers to the clinical evenfi and

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 10percent 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-97-2Blood Supply:Transfusion-AssociatedRisks
Appendix N

FurtherReducingRisk

committees(now requiredfor accreditationby the JointCommission 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

trauma.

Controlling the Nonemergency patients can theoretically reduce the risks of receiving

Sources of Donation viraUycontaminated or incompatible blood by donating their own blood

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. Ofthe 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-97-2Blood 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

status.

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.

Extending Viral

Inactivatfin to

Cellular Components

Promising advances in the inactivation of viruses for plasma have been

discussed in appendix III. Resemch on the viral inactivation of celldar

components of blood has been more difficdt. Extending storage time,

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

buckwheat.

Closing the Window The majority of virally continated units are donated by persons who

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 21.6million transfusions conducted

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

~er ReducingIUsk

each year. This translatesinto a cost of $2.3milliondollarsper life-year

saved comparedto the mediancost of $19,000per life-yearsaved for other

medical life-savinginterventions (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.Wewere 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 HIVin the blood supply.

Summary The risks of transfusion will continue to decrease as a direct result of

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

thatrisk 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-97-2Blood Supply:Transfusion-AssociatedRisks
Appendix V

CommentsFromtheDepartmentof Health

andHumanServices

Note: GAO comments

supplementing those in the

report text appear at the

end of this appendix, .........

●☛ ☎

.“‘4 DEPARTMENTOFHEALTH&HUMANSERVICES Offk. OfInspwtorQ.mml

;%

~%ati” W~shington, O.c.20201“

~ 27190

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 reevaluationwhen the final version of this report is

received.

The Department also provided extensive technical comments

directly to your staff.

‘l’heDepartment appreciates the opportunity to comnent on this

draft report before its publication.

Sincerely,

htih~

P

June Gibbs Brown

InspectorGeneral

Enclosure

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-97-2Blood Snpply:Tranafaeion-AssociatedRisk
APpessduV

bmments Promthe Departmentof Health

and Hu.sssanServices

cOMMENTSOFTHEDEPARTMENT OFHEALTH

AND HUMAN SERVICES ON THE GENERAL ACCOUNTING

OFFICE fGAOJ DRAFT REPORT. “BLOOD SUPPLY:

Transfusion-associatedRisks(GAO/PEMD-97-2~

GENERAL COMMENTS

The Department of HealthandHumanServiceaisingeneral agreement with the principal

findings and conclusions of the GAO drafi report (GAO/PEMD-97-2)on “Blood Supply:

Transfusion-associatedRisks.” Specifically,the Departmentconcurs that the U.S. blood

supplyis currentlysaferthanit has ever been. This level of safety largely reflects

improvementsin 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 andhepatitisAtransmission

from clotting factor concentrates illustrate the need for ontinued vigilance.

In this report, the GAO estimates the risk ofadverse events, includingtransmission of viral

and bacterial pathogens, associated with the transfusion of screened blood. Such estimates

can assist public health officials, industry, clinicians, and consumersin making informed

therapeutic and programmaticdecisions to reduce the risks associated with transfusion.

Because many of these risks are already low, new interventionswill likely beof decreasing

benefit. Wemncur with GAO that new interventionswill “...require careful consideration

in order to identify areas of improvementthat would maximize safety with reasonable

costs.”

The Depanment has reviewed the report and providedGAO 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
AppendixV

CommentsFromthe DepartmentofHealth

and HumanServices

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

GAOComments We agree with the department’s belief that our estimates shotid be

referenced. Wepoint 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-97-2Blood Supply:Transfusion-AssociatedRisks
m

AppendixVI

MajorContributorsto ThisReport

Program Evaluation Marcia G.Crosse, Assistant Director

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-97-2Blood Supply:Tran8tiion-Assock@d Eisb
Bibliography

Aach, R.D., et al. “Hepatitis CVirusInfection in Post-Transfusion Hepatitis:

An AnalysisWith First- and Second-Generation Assays.” New England

Journal of Medicine,325:19(1991), 1325-29.

“AbbottAnnounces Discovery of New Hepatitis Viruses.”CCBC

Newsletter, April 14, 1995,pp. 1-3.

Ali,A. “Evaluation of the Current Use of Red CellTransfusion in the

Perioperative Period.” Perioperative Red CellTrmfusion: Program and

Abstracts, NIHConsensus Development Conference, June 27-29,1988,pp.

25-27.

Allm~, W.F. “StayingAlivein the 20th Century.”Science 85, 6:8(1985),

31-37.

Allman,W.F. “WeHave Nothing to Fear.” Science 85, 6:8 (1985),38-41.

Alter, H.J. “ToC or Not to C:These Are the Questions.” Blood, 85:7(1995),

1681-95.

Alter, H.J. “Transfusion Tramitted Hepatitis C and Non-A,Non-B,

Non-C.”National Institutes of Health, Department of Transfusion

Medicine,Betiesda, Md., 1994.

Alter, H.J. “Hepatitis G.”Presentation at the International Conference on

the VirologicalSafety of Plasma Derivatives. National Institutes of Health,

Betiesda, Maryland,November 20-22,1996.

Alter, M.J. “The Detection, Transmission, md Outcome of Hepatitis C

VirusInfection.” Infectious Agents and Disease, 2:3 (1993), 155-66.

Alter, M.J. “Hepatitis B and D.”In J.L. Fridey and R.A.S.Sacher.

Hepatotropic Viruses. Bethesda, Md.:American Association of Blood

Banks, 1995.

Alter, M.J. “ResidualRisk of Trmfusion-Associated Hepatitis.” In NIH

Consensus Development Conference on Infectious Disease Testing for

BloodTransfusions. NIH Consensus Development Conference, sponsored

by the National Heart, Lung, and Blood Institute and the NIH OffIce of

Medical Applications of Research, Bethesda, Md.,January 9-11,1995.

Page 79 GAO/PEMD-97-2Blood Supply: Transfusion-Associated Risks
Biblio@aphy

Alkr, M.J., et al. “TheNatural History of Cornmunity-Acqtied Hepatitis C

in the United States.” New Englad Journal of Medicine, 327 (1992),

1899-1905.

Alter, M.J.,et al. “RiskFactors for Acute Non-A, Non-B Hepatitis in the

United States and Association With Hepatitis C VirusInfection.”Journal of

the American MedicalAssociation, 264:17(1990),2231-35.

Altman, L.K.“HepatitisVirus Passed to HemopWacs in Clotting

Compound, Health OfficialsSay.”New York Times,January 19, 1996,p.

A14.

American Association of Blood Bmks. “ReceivingBlood.” 1995.

http:llwww.aabb.org/docs/receive.html. Pp. 1-5.

American Association of Blood Banks. “Questions and Answers About

Blood and Blood Banking.”(1994), 1-8.

America Hospital ksociation. Hospital Statistics: The AHAProfile of

United States Hospitals, 1994-95ed. Chicago, Ill.: 1994.

Axehod, F.B., and C. Kasprisin.‘Blood Center and Transfusion Service

Donor/Recipient NotWlcationDilemmas.”AABBTechnical/Scientific

Workshop, New Orleans, Louisiana, November 11-12,1995.

Bates, D.W.,et al. “Incidence of Adverse Drug Even@and Potential

Adverse Drug Events: Implications for Prevention.” Journal of the

American Medicd Association, 274:1(1995),29-34.

“Baxter to Begin Phase III Trial of Hemoglobin Therapeutic.” CCBC

Newsletter. September 27, 1996,p. 3.

Berkow, R. (cd.). The Merck Mmual of Diagnosis and Therapy.

Whitehouse Station, N.J.:Merck and Co., 1996.

Bl@chmm, M.A.,md Canadian Red Cross Society.

“Transfusion-Associated Bacterial Sepsis: The Phoenix Rises YetAgain.”

Transfusion, 34:11(1994),940-41.

“Bloodand Plasma Products From Donors WithCJDShould be Recalled.”

CCBCNewsletter, August 11, 1995,pp. 46.

Page 80 GAO/PEMD-97-2Blood Supply:Transfusion-AssociatedBiEb
“Bloodand Plasma Should Be Screened with Hrv-1AntigenTest.” CCBC

Newsletter, August 11, 1995,pp. 1-3.

“BloodProducts Advisory Committee Addresses Risks of Non-Envelope

Virusesin Plasma Products.” CCBCNewsletter, March 29, 1996,pp. 5-6.

“BloodSupply Safety.”Hearing Before the Subcommittee on Oversight and

Investigations of the Committee on Energy and Commerce, House of

Representatives, 103rdCong., 1stsess. (Jtiy 28, 1993).Serial No. 103-42.

Washington,D.C.:U.S. Government Printing Office, 1993.

Blumberg,N., et al. “ACritical Survey of Fresh Frozen Plasma Use.”

Transfusion, 26 (1986), 511-13.

Boyle,L.,and S. Moore. “Grantiocyte-Associated Transfusion Reactions.”

In S.M.Wilson,S. Capon, and S.V.Rudmann. Transfusion Reactions:

Refresher and Update. Bethesda, Md.,American Association of Blood

Banks, 1995.

Brashear, R.J., et al. “Detection of Antibodies to Trypanosoma cruzi

AmongBlood Donors in the Southwestern and Western United States. I.

Evaluation of the Sensitivi~ and Specificity of an Enzyme Immunoassay

for Detecting Antibodies to T. cruzi.”Transfusion, 35 (1995),213-18.

Brennan, T.A.,et al. “Incidence of Adverse Events and Negligencein

Hospitalized Patients: Res~ts of the HarvardMedical Practice Study I.”

New England Journal of Medicine, 324:6 (1991), 370-76.

Busch, M.P., et al. “Accuracy of Supplementary SerologicTesting for

Huma T-LymphotropicVirus Types I md II in U.S.Blood Donors.”Blood,

83:4(1994), 114348.

Busch, M.P., et al. “Evaluation of Screened Blood Donations for Humm

Immunodeficiency VirusType 1 Infection by Ctiture and DNA

Amplificationof Pooled Cells.”New England Journal of Medicine,325:1

(1991), 1-5.

Busch, M.P., et al. “Factors Influencing Human Immunodeficiency Virus

Type 1Transmission by Blood Transfusion.” Journal of Infectious

Diseases, 174(1996),26-33.

Page 81 GAO/PEMD-97-2Blood Supply:Transfusion-AssociatedRisks
Biblio@aphy

Busch, M.P.,et d. “TimeCourse of Detection of Viraland Serologic

Markers Preceding Human Imrnunodeficiency VirusType 1

Seroconversion: Implications for Screening of Blood and Tissue Donors.”

Transtiion, 35:2(1995),91-97.

Busch, M.P.,and H.A.Perkins. “Questionable Efficacy of Cotildential Unit

Exclusion.”Letter. Transfusion, 30:7(1990),668.

Carson, J.L., et al. “Severityof Anemia and Operative Motiity and

Morbidi~.” Lsncet, 2 (1988),727-29.

Centers for Disease ControlandPrevention. Hepatitk Surveillance.Report

55.Atlanm June 1994.

Centers for Disease Control and Prevention. “PublicHealth Service

Inter-AgencyGuidelinesfor Screening Donors of Blood, Plasma, Organs,

Tissues, and Semen for Evidence of Hepatitis B and Hepatitis C.”

Morbidity and MortalityWeeklyReport, 40:RR-4(1991), 1-17.

Centers for Disease Control and Prevention. “Safetyof Therapeutic

Produti Used for Hemophilia Patienti.” Morbidity and MortalityWeekly

Report, 37 (1988),441-50.

Centers for Disease Control and Prevention, National Center for Health

Statistics. Vitaland Health Statistics: Advance Data From Vitaland Health

Statistics, Numbers 261-270.Hyattsville,Md.:U.S. Department of Health

and Human Services, April 1996.Tables 3 and 5.

Centers for Disease Control and Prevention and U.S.P.H.S.Working

Group. “Guidelinesfor Counseling Persons Infected with Human

T-LymphotropicVirusType I (HTLV-1) and Type II (HTLV-11).”Annals of

Internal Medicine, 118:6 (1993), 448-54.

Chiu, E.K.W.,et d. ‘A Prospective Study of Symptomatic Bacteretia

Following Platelet Trafusion and Its Management.”Transfusion, 34

(1994),950-54.

Choo, Q.-L.,et al. “Isolation of a DNAClone Derived From a Blood-Borne

Non-A,Non-BViralHepatitis Genome.” Science, 244 (April21, 1989),

359-62.

Page 82 GAO/PEMD-97-2Blood Supply:Transfusion-AssociatedRish
Bibliography

Colombo, M.,et al. “Transmission of Non-A,Non-BHepatitis by

Heat-treated Factor VIIIConcentrate.” Lancet, 2 (1985), 1-4.

cumming, P.D., et al. “Exposure of Patien& to Human Imrnunodeficiency

VirusThrough the Transfusion of Blood Componenk That Test

Antibody-Negative.”New England Journal of Medicine,321:14(1989),

941-46.

Davis, G.L., et al. “Treatment of Chronic Hepatitis C WithRecombinant

Interferon Alfa:A Mtiticenter Randomized, Controlled Trial.”New

England Journal of Medicine, 321:22(1989), 1501-6.

DiBisceglie,A.M.,et al. “Recombinant Interferon AlfaTherapy for Chronic

Hepatitis C:A Randomized, Double-Blind,Placebo-Controlled Trial.”New

England Journal of Medicine,321:22(1989), 1506-10.

Dodd, R.Y.‘Adverse Consequences of Blood Transfusion: Quantitative

Risk Estimates.” In S.T.Nance (cd.). Blood Supply:Risks, Perceptions, and

Prospects for the Future. Bethesda, Md.:American Association of Blood

Banks, 1994.

Dodd, R.Y.“TheRisk of Transfusion-Transmitted Infection.” New England

Journa,lof Medicine,327 (1992),419-21.

Doebbeling, B.N., et al. “Comparative Efficacy of Alternative

Hand-WashingAgentsin Reducing Nosocomial Infections in Intensive

Care Units.” New England Journal of Medicine, 327 (1992),88-93.

Donahue, J.G..,et al. “The DecliningRisk of Post-Transfusion Hepatitis C

VirusInfection.” New England Journal of Medicine,327 (1992),369-73.

Donegan, E., et d. “Infection With Human Immunodeficiency Virusme 1

(HIV-1)Among Recipients of Antibody-Positive Blood Donations.” Annals

of Internal Medicine, 113:10 (1990), 733-39.

Donegan, E., et al. “Trmsmission of HIV-1by Component me and

Duration of Shelf Storage Before Transfusion.” Transfusion, 30 (1990),

851-52.

Donegan, E., et al. “Transfusion Transmission of Retroviruses: Human

T-lymphotropic VirusTypes I and II Compared WithHuman

Immunodeficiency VirusType l.” Transfusion, 34:6(1994),478-83.

Page 83 GAO/PEMD-97-2Blood Supply:fianstiion-Aaaociated Riaka
Biblio@aphy

Epstein, J.S., and W.A.Fricke. ‘Current Safety of Clotting Factor

Concentrates.” Archives of Patiology ad Laboratory Medicine, 114

(1990),335-40.

Farci, P., et al. “ALong-TermStudy of Hepatitis C Virus Replicationsin

Non-& Non-BHepatitis.” New England Journal of Medicine, 325 (1991),

98-104.

“FDA BeginsTesting Immunoglobdin Products for HCVRNA.”CCBC

Newsletter, January 13, 1995.

“FDA Issues Additional Recommendation on Anti-HCV Testing.” CCBC

Newsletter, May 17, 1996,pp. 4-5.

“First Known U.S.Case of Rare AIDSStrain Found in Los Angeles.”Wall

Street Journal, Jdy 8, 1996.

“First HIVGroup O Patient Identfiled in the U.S.”CCBCNewsletter,

Jdy 5-12,1996,pp. 1-3.

Friday,J.L., and R.A.Sacher. “Hepatotropic Viruses.”AABBTechnical

Scientilc Workshop, New Orleans, Louisiana, November 11-12,1995.

“Genelabs Scientisk Publish First ReDorton HeDatitisG Virus.”CCBC

Newsletter, February 2, 1996. ‘

.

Goldman, M.,and M.A.Bl@chman.“BloodProduct-Associated Bacterial

Sepsis.”Transfusion MedicineReview, 5 (1991), 73-83.

Gould, S.A.,et d. “TheDevelopment of Polymerized Pyridoxylated

Hemoglobin Solution as a Red CellSubstitute.” Annals of Emergency

Medicine, 15(1986), 1416-19.

Gould, S.A.,et al. “TheEfficacy of Polymerized pyrido~lated Hemoglobin

Solution as an OzCarrier.” Annals of Surgery, 211 (1990),394-98.

Greene, J.N., et d. “Bacterial Infection Following Blood Product

Transfusion: Some Bad Blood BuggingYou?”Infectious Medicine, 12:4

(1995), 165-70.

Griffiths, E. “Haemoglobin-BasedBlood Substitutes and Sepsis.nLancet,

345 (1995), 158-60.

Page S4 GAOiPEMD-97-2Blood Supply:Transfusion-AsnochtedRieka
Bibliography

“Hemoglobin-basedBlood Substitutes MayIncrease Risk for Sepsis,

Scottish Study Suggests.”CCBCNewsletter, Jmuary 27, 1995,pp. 8-9.

“HepatitisVirusPassed to Hemophiliacsin ClottingCompound,Health

OfficialsSay.”New YorkTimes,January19, 1996,p. A-14.

HIV-1AntigenTest U@ustifiedfor Blood Donor Screening, FDAPmel

Finds.”CCBCNewsletter, June 23, 1995.

Hjelle,B., et al. “HighFrequency of Human T-CellLeukemia-Lymphoma

VirusType II Infection in New Mexico Blood Donors: Determination by

Sequence-SpecificOligonucleotide Hybridizations.”Blood, 76 (1990),

450-54.

fielle, B., et al. “HumanT-CellLeukemia VirusType ~ Infection

Frequently Goes Undetected in Contemporary U.S.Blood Donors.”Blood,

81:6(1993), 1641-44.

~elle, B., et al. “Transmission of HTLV-11 via Blood Transfusion.”Vox

Sanguinis, 59 (1990), 119-22.

Horowitz, M.S., et al. “VirusSafety of Solven~etergent-treated

Antihaemophilic Factor Concentrate.” Lancet, 2 (1988), 186-88.

Irdander, C.B.The Consumer’s Medical Desk Reference. New York:

Stonesong Press and The People’s Medical Society, 1995.

Institute of Medicine.HIVand the Blood Supply:An Analysis of Crisis

Decisionmaking. Washington,D.C.:National Academy Press, 1995.

Iwarson, S., et al. “Hepatitis C:Natural History of a Unique Infection.”

ClinicalInfectious Diseases, 29 (1995), 1361-70.

Jackson, J.B., et d. “Absence of HIVInfection in Blood Donors With

Indeterminate Western BlotTests for Antibody to HIV-l.”New England

Journal of Medicine, 322:4 (1990), 217-22.

Johnson, E.S., et al. “The Impact of Direct Ord Questions on Blood Donor

Screening for Humm

769-74.

Page S5

.-. -.. .. - - . - . ---- ..

Lrnmunodellclency Virus.” ‘1’ransmlon, 34 (1YY4),

GAO/PEMD-97-2Blood Supply:Transfusion-bciated Riaka
Bibiio@aphy

Kerndt, P., et al. “Prevalence of Antibody to Trypanosoma CruziAmong

Blood Donors in Los Angeles, Ctiornia.” Transfusion, 31 (1991),814-18.

Kernoff,P.B.A.,et al. “Reduced Risk of Non-A, Non-B Hepatitis After a

%t Exposure to ‘Wet heated’ Factor VIII Concentrate.” BritishJournal of

Hematology, 67 (1987), 207-11.

Kirchhoff,L.V.,et al. “AmericanTrypanosomiasis (Chagas’Disease) in

Central American Immigrants.” American Journal of Medicine,82 (1987),

91$20.

Kleinman,S., and K.Secord. “Riskof Human Immunodeficiency Virus (HIV)

Transmission by ArIti-Hrv Negative:Blood Estimates Using the Lookback

Methodology.”Transfusion, 28 (1988),499-501.

Kleinrnan, S., et al. “Increased Detection of Hepatitis C Virus(Hcv)-Infected

Blood Donors by a Mdtiple-Antigen HCVEnzyme Immunoassay.”

Transfusion, 32 (1992),805-13.

Koretz,R.L.,et ai. “Non-A,Non-BPost-Transfusion Hepatitis: Looking

Back in the Second Decade.” Annals of Internal Medicine, 119(1993),

110-15.

Lackritz,E.M.,et al. “Estimated Risk of Transmission of the Huron

ImrnunodeficiencyVirus by Screened Blood in the United States.” New

England Journal of Medicine, 333:26(1995), 1721-25.

Langrish, P. “Restits of Humw Immunodeficiency Virus Type-1

(HIV-1)/HumanImmunodeficiency Virus Type-2 (HIV-2)Antibody Testing in

Ctifornia Blood Bmks and Plasma Centers, Fourth Qutier of 1994.”

California Department of Health Services, Office of AIDS, Hrv/AIDS

Epidemiology Branch, Sacramento, August 1995.

Leape, L.L., et al. ‘The Nature of Adverse Events in Hospitalized Patients:

Results of the Harvard MedicalPractice Study II.”New England Journal of

Medicine,324:6(1991),377-84.

Lederberg,J., R.E. Shope, and S.C.Oakes Jr. (eds.). Emerging Infections:

MicrobialThreats to Health in the United States. Washington, D.C.:

National Academy Press, 1992.Pp. 26-28.

Page 86 GAOflEMD-97-2Blood Supply:Transfusion-AssociatedRisks
Bibliography

Lee, H.H., et aL ‘Relative Prevalence ad Risk Factors of HTLV-I and HTLV-U

Infection in U.S.Blood Donors.” Lancet, 337 (1991), 1435-39.

Lehky,T.J., et al. “HumanT-CellLymphotropic Virus be II-Associated

Myelopathy:Clinical and Immunological Profdes.” Ann~ of Neurology,

40:5 (1996),714-23.

Levine, P.H., et al. “HTLV-11 Infection in Florida Indians.” AIDSResearch in

Human Retroviruses, 9 (1993),123-27.

Linden,J.V.,B. Pad, and K.P.Dressier. “AReport of 104Transfusion

Errors in New York State.”Transtiion, 32:7 (1992),601-6.

McCdlough, J. “The Nation’sChangingBlood Supply System.”Journal of

the American Medicd Association, 269:17(1993),2239-45.

Mackey,J., and K.S.Lipton. “AABBPosition on Testing of Autologous

Units.” Memorandum. American Association of Blood Bmks, Bethesda,

Md.,May9, 1995.

McPherson, J.L. (cd.). The Nation’sBlood Supply:Is Absolute Safety

Achievable? Washington, D.C.:Council of Community Blood Centers,

1993.

M-, A., et al. “AProspective Study of Tramission by Transfusion of

HTLV-Iartd Risk Factors Associated with Seroconversion.” International

Journ~ of Cmcer, 51 (1992), 88691.

Mannucci, P.M.,et al. ‘Prospective Study of Hepatitis After Factor VIII

Concentrate Exposed to Hot Vapor.”British Journal of Hematology, 68

(1988),427-30.

Menitove,J.E. “HowSafe is Blood Transfusion?” In D.M.Smith Jr. and R.Y.

Dodd (eds.). Transfusion-Trmsmitted Infections. Chicago:ASCPPress, ,

1991.

Morduchowicz, G., et al. “Transfusion Reactions Due to Bacterial

Contamination of Blood and Blood Produc~.” Review of Infectious

Diseases, 13 (1991),307-14.

Morgan, K.O.Health Care State Rankings 1993.Lawrence, has: Morgm

Quitno, 1993.

Page S7 GAO/PEMD-97-2Blood Supply:Transtiion-Associated Risk
Biblio@aphy

Morrow,J.F., et al. “Septic Reactions to Platelet Trsnstiions: A Persistent

Problem.” Journal of tie American MedicalAssociation, 266:4(1991),

555-58.

Nance, S.T.(cd.). Blood Safety:Current Challenges. Bethesda, Md.:

American Association of Blood Banks, 1992.

Nance, S.T.(cd.). Blood Supply:Risks, Perceptions, and Prospeck for the

Future. Bethesda, Md.:American &ociation of Blood Bank, 1994.

National Center for Health Statistics. Healthy People 2000Review.

Hyattsville, Md. 1995.Table III, p. 148.

Nelson, K.E., et al. “Incident Hepatitis C Virus(HCV)and Hepatitis B Virus

(HBV)Infections in Transfused Cmdiac Surgery Patienti: Infection Rates

During Different Methods of Donor Screening.”In NIH Consensus

Development Conference on Infectious Disease Testing for Blood

Transfusions. NIH Consensus Development Conference, sponsored by the

National Heart, Lung,and Blood Institute and the NIH OffIce of Medical

Applications of Research, Bethesda, Md.,January 9-11,1995.

Nelson, K.E., et al. “Transmission of Retroviruses Rom Seronegative

Donors by Transfusion During Cardiac Surgery: A Mdticenter Study of

HIV-1and HTLv-I/11Infections.” Annals of Internal Medicine, 117:7 (1992),

55459.

“NewHepatitis G Virus Discussed at International Hepatitis C Meeting.”

CCBCNewsletter, September 8, 1995,pp. 5-7.

NIH Consensus Development Conference on Infectious Disease Testing for

Blood Transfusions. NIH Consensus Development Conference, sponsored

by the National Heart, Lung,and Blood Institute and the NIHOffice of

MedicalApplications of Research, Bethesda, Md.,January 9-11,1995.

O’Brien,T.R.,J.R. George, and S.D.Holmberg. “Human Irnmunodeficiency ”

Virus Type 2 Infection in the United States: Epidemiology,Diagnosis, md

Public Health Implications.” Journal of the American MedicalAssociation,

267:20(1992),2775-79.

Office of Technology ~sessment. Blood Policy and Technology,

OTA-H-260.Washington, D.C.:January 1985.

Page 88 GAO/PEMD-97-2Blood Supply:Transtiion-Associated Risks
Bibliography

Pan, A.A.,et al. “Chagas’Disease AmongBlood Donors in North and South

America: The Prevalence of Seroreactive Antibodies to Trypanosoma

Cruzi in the United States and Argentina.”Abstract. Transfusion, 32 Supp.

(1992),65S.

Pehta, J.C., “ViralInactivation of Blood Components.” Laboratory

Medicine. 25:2(1994), 102-5.

Petersen, L.R., et al. “Duration of Time From Onset of HurnarI

Irnmunodeficiency VirusType 1 Infectiousness to Development of

Detectable Antibody.”Transfusion, 34:4(1994),283-89.

Philip, M.A.Statement of Immuno-U.S.before the Subcommittee on

Human Resources and Intergovernmental Relations, Committee on

Government Reform and Oversight, House of Representatives, U.S.

Congress, Washington, D.C., November 2, 1995.

Popovsky, M.A.,H.C.Chaplin Jr., and S.B.Moore. “Trmfusion-Related

Acute Lung Iqjury:A Neglected, Serious Complication of Hemotherapy.”

Transfusion, 32:6 (1992),589-92.

Popovksy, M.A., and S.B.Moore. “Diagnosticand Pathogenetic

Considerations in Transfusion-Related ?,uute Lung Injury.”Transfusion, 25

(1985),573-77.

Rasenack, J.W.F., et al. “HepatitisB VirusInfection Without

Immunological Markers After Open-Heart Surgery.”Lancet, 345

(February 11, 1995),355-57.

Rawal, B.D. “Dual Reduction in the Immunologic and Infectious

Complications of Transfusion by Filtratio~emoval of Leukocytes from

Donor Blood After Collection.”Transfusion Medicine Review,4:Supp. 1

(1990),36-41.

Rawal, B.D., et al. “Reduction of Human Imrnunodeficiency Virus-Infected

Cellsfrom Donor Blood bv Leukocvte Filtration.” Transfusion, 26 (1984), . “

460-62.

“RedCross Reports First HIVAntigen Positive,

CCBCNewsletter, September 27, 1996,p. 1.

Antibody Negative Donor.”

Page 89 GAO/PEMD-97-2Blood Supply:Transtiion-Associated Rish
Bibliography

Redhead, C.S.“CRSReport for Congress: The Safety of the Blood Supply.”

Congressional Reearch Service. Washington, D.C.:April20, 1992.

Sandier, S.G.,C. Fang, and A. Williams.“RetroviralInfections Transmitted

by BloodTransfusion.” YaleJournal of Biologyand Medicine,63 (1990),

353-60.

Schimpf, K.,et aL“Absence of HepatitisAfter Treatment With a

Pasteurized Factor VIIIConcentrate in Patien@with Hemophilia and No

Previous Transfusion.” New England Journal of Medicine,316 (1987),

91%22.

Schrnunis, G.A.“Trypanosoma Cruzi,the Etiologic Agent of Chagas’

Disease: Status in the Blood Supply in Endemic and Nonendemic

Countries.” Transfusion, 31 (1991),547-57.

Schreiber, G.B., et al. “TheRisk of Transfusion-Transmitted Viral

Infections.” New England Journal of Medicine, 334:26(1996), 1685-90.

“Second HIV-1Group O Case Identtiled in U.S.: FDAChanges Paradigm for

Infectious Threats to the Blood Supply.” CCBC Newsletter, September 27,

1996, pp. 2-3.

Seeff, L.B., et al. “Long-TermMotiity After Trafusion-Associated

Non-A,Non-BHepatitis.” New England Journal of Medicine,327 (1992),

1906-11.

Selik, R.M.,J.W.Ward, and J.W. Buehler. “Trendsin

Transfusion-Associated Acquired Immune DeficiencySyndrome in the

United States, 1982Through 1991.”Tr-fusion, 33:11(1993),890-93.

Sherwood, W.C.“Donor Deferral Registries.”Transfusion Medicine

Reviews, 7:2(1993), 121-28.

Shodell, M. “RiskyBusiness.” Science 85, 6:8 (1985),43-47.

Shulman, I.A. “Parasitic Infections and Their Impact on Blood Donor

Selection and Testing.”Archives of Pathology and Laboratory Medicine,

118(1994),366-70.

Smith Jr., D.M.,and R.Y.Dodd (eds.). Transfusion-Transmitted Infections.

Chicago:ASCPPress, 1991.

P-e 90 GAO/PEMD-97-2Blood Supply:Trmst’usion-AssociatedRish
Bibliography

Spence, R.K.,et aL “Fluosol DA-20in the Treatment of Severe Anemia:

Mdornized, Controlled Study of 46 Patien@.”Critical Care Medicine,

18:11(1990), 1227-30.

Spence, R.K, et al. “IsHemoglobin LevelAlone a Reliable Predictor of

Outcome in the Severely Anemic Surgical Patient?” American Surgeon,

58:2(1992),92-95.

Stack, G., and E.L.Snyder. “Decreasing the Incidence of

Trmfusion-Transmitted Infection: AvoidingUnnecessary Transfusions.”

In D.M.Smith Jr. and R.Y.Dodd (eds.). Transfusion-Transmitted

Infections. Chicago:ASCPPress, 1991.

Tengs, T.O., et al. “Five-HundredLife-SavingInterventions ad Their

Cost-Effectiveness.” Risk Analysis, 15:3(1995),369-90.

Tipple,M.A.,et al. “SepsisAssociatedwithTransfusionof RedCells

Contaminatedwith YersiniaEnterocolitica.”Trmfusion, 30 (1990),

207-13.

Tutwiler,G.F. Statement of AlphaTherapeutic Corporation. Subcommittee

on Human Resources and Intergovernmenti Relations, Committee on

Government Reform md Oversight, House of Representatives, U.S.

Congress, Washington, D.C., November 2, 1995.

U.S. Department of Health and Human Services. Health United States 1993

Chartbook. Hyattsville,Md.: 1994.

U.S. Department of Health and Huma Services, Inspector General.

“Reporting Process for Blood Establishments to Notify the Food ~d Drug

Administration of Errors ad Accidents AffectingBlood.”Memorandum.

Washington, D.C., May31, 1995.

Urbina, J.A., et al. “Cure of Short- md Long-Tern Experimental Chagas’

Disease Using D0870.”Science, 273 (1996),969-71.

Varnvakas,E.C., and H.F. Taswell. “kng-Term SurvivalAfter Blood

Transfusion.” Transfusion, 34:6(1994),471-77.

“VIMRXPharmaceuticals Expects to File.”CCBCNewsletter, September 8,

1995,p. 8.

P*e 91 GAO/PEMD-97-2Blood Supply:Transfusion-AssociatedRisks
Bibliography

Vyas,G.N., et al. “TheRisk of HIVTrmmission by Screened Blood.”New

England Journal of Medicine,334:15(1996),992.

Wagner, S.J., L.I.Friedman, md R.Y.Dodd. “Transfusion-Associated

Bacterial Sepsis.” ClinicalMicrobiologyReviews, 7:3(1994),299-301.

Walker, R.H. “SpecialReport: Transfusion Risks.”American Journal of

ClinicalPathology, 88:3(1987),374-78.

Wallace,E.L.,et al. “CollectionandTransfusionof Blood andBlood

Componentsin the United States, 1989.”Transfusion, 33:2(1993),139-44.

Wallace, E.L., et al. “Collectionand Trafusion of Blood and Blood

Componen@in the United States, 1992.”Transfusion, 35:10(1995),802-11.

Ward,J.W., et al. “TheNatural History of Transfusion-Associated Infection

With Humm Imrnunodeficiency Virus:Factors Influencing the Rate of

Progression to Disease.” New Englad Journal of Medicine,321:14(1989),

947-52.

Ward,J.W.,et al. “Transmissionof Huron IrnmunodeficiencyVirus(HIV)

by Blood Transfusions Screened as Negative for HIVAntibody.”New

England Journal of Medicine,318:8(1988),473-78.

Williams,A.E., et al. “Seroprevalence md EpidemiologicalCorrelates of

HTLV-1Infection in U.S.Blood Donors.” Science, 240 (1988),643-46.

Wilson,R., and E.A.C.Crouch. “RiskAssessment and Comparisons: An

Introduction.” Science, 236 (April 17, 1987),267-79.

Winslow,R. “Health Plans to Cover New AIDSDrugs but Issues of Cost,

Treatment Remain.”WallStreet Journal, July 12, 1996.

Yomtovi~, R. “Bacterial Contamination of Blood Components.” In S.M.

Wilson, S. Capon, and S.V.Rudmann. Transfusion Reactions: Refresher

and Update. Bethesda, Md.:American Association of Blood Banks, 1995.

(97s4.s9) Page 92 GAO/PEMD-97-2Blood Supply:Transfusion-AssociatedRisks
Ordering Information

The first copyof eachGAO report and testimony is free.

Additional copies are $2 each. Orders should be sent to the

following address, accompanied by a check or moneyorder

madeout to the Superintendentof Documents,when

necessary.VISA and MmterCard credit cards are accepted,also,

Orders for 100or morecopiesto be mailedto a singleaddress

are discounted25percent.

Orders by mail:

U.S. General AccountingOffIce

P.O. Box 37050

W~hington, DC 20013

or visit:

Room1100

7004thSt. NW (corner of 4thand G Sts. NW)

U.S. General AccountingOffIce

W~hington, DC

Orders mayalso be placedby calling(202) 512-6000

or by usingfax number(202) 512-6061,or TDD (202) 512-2537.

Each day,GAO issues a list of newly available reports and

testimony. To receivefacsimilecopiesof the dailylist or any

list from thep~t 30days,please call (202) 512-6000usinga

touchtonephone. A recordedmenuwill provide informationon

how to obtainthese lists.

For informationon how to accessGAO reports on the INTERNET,

sendan e-mailmessagewith“info”in the body to:

info@www.gao.gov

or visit GAO’s World Wide Web HomePage at:

httpY/www.gao.gov

@

PRINTEDON ~~ RECYCLEDPAPER
United States

General Accounting Office

Wwhington, D.C. 20548-0001

Bulk Rate

Postage& Fees Paid

GAO

Permit No. G1OO

Official Business

Penalty for Private Use $300

Address Correction Reauested