Taller Banco de Sangre - Complicaciones infecciosas

26
Infectious Complications
of Blood Transfusion

26

P reventing transmis-
sion of infectious diseases through blood
rus (EBV), and others. Infectious agents
that pose a serious threat to transfusion
transfusion presents one of the greatest recipients are those that persist in the
challenges of transfusion medicine. The circulation of asymptomatic individuals
emergence of acquired immunodefi- who are healthy enough to be blood do-
ciency syndrome (AIDS) in the 1980’s nors.
heightened public awareness of the com- Several viruses, such as HAV, circu-
plications of transfusion, and for the late only transiently during the initial
first time, many patients and clinicians acute phase of infection, when the indi-
became concerned with the specifics of vidual is clinically ill and not a candidate
blood collection and testing. Although for donation, and generally they are not
the risk is lower than ever before, the a serious threat to transfusion recipi-
risk of transmitting viral, bacterial, and ents. However, viremia may be present
parasitic diseases through transfusion for up to 28 days before symptoms de-
persists, along with the potential for velop; blood donated during this viremic
novel infectious agents. Several recent phase could be infective, but only a few
textbooks and reviews address these is- documented transfusion-transmitted
1,2
sues. cases have been reported. 3
Although HDV, formerly called the
delta agent, can cause infection after
transfusion or other parenteral trans-
Hepatitis mission, it causes disease only when
Hepatitis is inflammation of the liver there is concomitant or prior HBV infec-
that can be caused by many different tion.4 HEV causes an epidemic enteric
toxic and infectious agents, including form of hepatitis, but there have been no
hepatitis A, B, C, D, and E viruses (HAV, reports of spread by transfusion. The
HBV, HCV, HDV, HEV), as well as cy- agent of a transfusion-associated and
tomegalovirus (CMV), Epstein-Barr vi- community-acquired non-A,non-B,non-

563
Copyright © 2002 by the AABB. All rights reserved.

564 AABB Technical Manual

C hepatitis has been cloned and shown to Chronic Carriers of HCV
be a novel flavivirus distinct from HCV.5
Most persons infected with HCV become
chronic carriers, with 70-80% having
Clinical Manifestations of Hepatitis persistent infection as demonstrated by
HCV RNA in serum and liver; at least
Most individuals who acquire HBV or 50% of these have biochemical or his-
HCV infection have a subclinical infec- tologic evidence of chronic liver dis-
tion without obvious symptoms or 9
ease. Despite this chronic inflammatory
3,4
physical evidence of disease. Some de- process, most HCV-infected individuals
velop overt hepatitis with jaundice, nau- remain asymptomatic. Whereas the
sea, vomiting, abdominal discomfort, fa- acute infection with HCV is clinically
tigue, dark urine, and elevation of liver benign, approximately 10% of patients
enzymes. Signs and symptoms usually with chronic HCV infection develop cir-
resolve spontaneously. Hepatitis C tends rhosis and/or hepatocellular carcinoma
to be milder than hepatitis B, but in decades after the acute event.
either hepatitis B or C, the clinical
course of infection may be complicated
by fulminant hepatitis, relapsing or Posttransfusion Hepatitis
chronic hepatitis, or long-term progres- The risk of posttransfusion HBV has
sion through cirrhosis to hepatocellular fallen dramatically, from an estimated 1
carcinoma. Hepatitis A tends to be quite in 10 a decade ago to an estimated 1 in
mild, clinically, and virtually never pro- 50,000 transfused recipients or about 1
gresses to chronic hepatitis or a chronic 9,10
per 200,000 transfused units. HCV an-
6,7
carrier state. tibody testing combined with stringent
selection measures for donors have con-
Chronic Carriers of HBV tributed to this remarkable decline (Fig
11
26-1). After implementation of the first
After initial HBV or HCV infection, some generation of anti-HCV tests, the risk
patients fail to clear infectious material was estimated at one case per 3300 units
12
from the bloodstream and become transfused. With presently available,
chronic carriers for years or even for life. more sensitive tests, the risk is probably
HBV carriers produce, in addition to the lower, but is difficult to determine be-
infectious viral particle, large amounts cause posttransfusion hepatitis is often
of noninfectious material detected by asymptomatic.
the assay for hepatitis B surface antigen
(HBsAg). About 5% of those infected
with HBV as adults become HBsAg carri- Hepatitis A Virus
ers; the vast majority recover and de- Because HAV infection does not cause a
velop protective antibody against HBsAg chronic carrier state, transmission by
(anti-HBs). The risk of becoming an blood transfusion requires the collec-
HBsAg carrier is strongly age-depend- tion of blood from a viremic donor, usu-
ent; 90% or more of infants infected per- ally late in the incubation phase just
inatally become carriers, and many pro- before signs or symptoms occur. Several
gress to cirrhosis and cancer. There are of the rare transfusion-transmitted HAV
approximately 300 million HBsAg carri- infections occurred in infants, making
8
ers worldwide with a prevalence of up to secondary transmission by fecal-oral
10% in some Asian countries, 0.1-0.5% spread more frequent than would be ex-
in the United States, and 0.02-0.04% in pected from adults who sustain the usu-
8
US blood donors. ally mild disease. In 1991 and 1992, an


Chapter 26: Infectious Complications of Blood Transfusion 565

Figure 26-1. The decline in posttransfusion HCV infection (reprinted with permission from
Busch MP, et al11).

outbreak of hepatitis A infection oc- Figure 26-2 illustrates the sequence
curred in several European hemophilia of test results typical of individuals with
centers, associated with Factor VIII con- acute HBV infection that completely re-
centrate manufactured in two plants by solves. The period between exposure to
a single manufacturer, but such an out- HBV and emergence of circulating
break has not been reported in the
13
HBsAg is usually about 2-6 weeks. 3
United States. HAV, which lacks a lipid HBsAg is the first serologic marker to
envelope, is not inactivated by sol- appear, but tests on symptomatic pa-
vent/detergent treatment. tients usually show simultaneous pres-
ence of antibody to hepatitis B virus core
protein (anti-HBc) and either of two ad-
ditional HBV markers, HBeAg or its an-
Serologic Markers
tibody (anti-HBe). Blood from individu-
Laboratory tests can identify markers of als with circulating HBsAg can infect
previous exposure and probable current others. An asymptomatic HBsAg-posi-
infectivity for HBV and HCV. Table 26-1 tive individual may either be a chronic
lists the serologic tests commonly used HBV carrier or be in the early phase of
in the diagnosis of hepatitis and includes acute HBV infection. Current tests can
terms and abbreviations in current use. detect as little as 100-200 pg/mL, 3 but


Table 26-1. Serologic Tests in the Diagnosis of Viral Hepatitis
566

Agent Test Reactivity Interpretation
B Virus HBsAg Anti-HBc Anti-HBs HBeAg Anti-HBe
Total IgM
+ +/– +/– – +/– – Early acute HBV or chronic carrier
+ + + – + – Acute HBV
– + + – +/– +/– Convalescent HBV or possible early chronic carrier
+ + – – +/– +/– Chronic carrier*
AABB Technical Manual

– + – + – +/– Recovered HBV
– – – + – – Vaccinated or recovered HBV
– + – – – – Recovered HBV? Window? False positive?

D Virus HBsAg Anti-HBc Anti-HBs Anti-delta
+ + – + Acute HDV or chronic HDV
– + + + Recovered HDV

A Virus Anti-HAV
Total IgM
+ + Acute HAV
+ – Recovered HAV or vaccinated

C Virus Anti-HCV Recombinant Antigens
(Screen) C-100-3 5-1-1 C22-3 C33-c
+ Not Available Possible acute or chronic HCV
+ + + + +/– Probable chronic HCV
+ + + – – Probable false positive
+ – – + + Probable chronic HCV
+ – – + – False positive or acute or chronic HCV
+ – – – + False positive or acute or chronic HCV
+ – – – – False positive

E Virus Anti-HEV
Total IgM
+ + Acute HEV
+ – Recovered HEV
Abbreviations used include: HBsAg (hepatitis B surface antigen), anti-HBc (antibody to hepatitis B core antigen), anti-HBs (antibody to
HBsAg), HBeAg (hepatitis B e antigen), anti-HBe (antibody to HBeAg), anti-delta (antibody to delta antigen), anti-HAV (antibody to hepatitis A

virus), anti-HCV (antibody to hepatitis C virus) and anti-HEV (antibody to hepatitis E virus).
*Those with HBeAg are more infectious and likely to transmit vertically.
Chapter 26: Infectious Complications of Blood Transfusion
567


Figure 26-2. Serologic markers in hepatitis B virus infection that resolved without complica-
tions. In the acute phase, markers often appear before onset of liver function (LFT) abnormali-
ties and symptoms (SYMP). Numerous markers persist after recovery.

antigen is usually present in great excess and Drug Administration (FDA) for fur-
relative to the concentration of infec- ther differentiation of repeatedly reac-
tious virus. tive EIA results. An individual who is
Anti-HCV has been detected in 80- positive by RIBA is considered to have
90% of samples from patients initially true anti-HCV antibody; in these cases,
diagnosed as having non-A,non-B HCV nucleic acid is almost always de-
(NANB) hepatitis, either transfusion- or tectable by polymerase chain reaction
community-acquired.14 Tests for anti- (PCR) and infectivity rates of 80-90%
bodies to HCV are enzyme immunoas- have been reported.16,17 Regardless of
says (EIA) using recombinant antigens RIBA results, a donation with a repeat-
of HCV coated on a solid phase as the edly reactive EIA result cannot be used
capture reagent. Figure 26-3 shows the for transfusion.
proposed structure of the genome of
HCV and the specific gene products in-
corporated in test kits for anti-HCV. Surrogate Markers
The clinical significance of a positive Before HCV was identified and anti-HCV
screening test for anti-HCV in healthy testing feasible, several tests on donor
blood donors is unclear without supple- blood were introduced to reduce NANB
mental testing. Between 0.4 and 1.0% of hepatitis following transfusion. In the
US blood donors have repeatedly reac- absence of specific tests for the NANB
tive EIA results.3 Some of these individu- agent, the AABB in 1987 mandated test-
als have asymptomatic chronic HCV in- ing for alanine aminotransferase (ALT)
fection, and their blood is potentially and anti-HBc, as surrogates for the di-
18
infective; others may have false-positive rect detection of the agent. Posttrans-
results. A recombinant immunoblot as- fusion hepatitis declined thereafter, but
say (RIBA) has been licensed by the Food the impact of surrogate testing on the



Figure 26-3. Proposed HCV genome and recombinant proteins used in testing for anti-HCV.
The second-generation test for anti-HCV detects antibody to c200 (including c33c and c100-3)
and c22-3. Supplementary tests detect antibody to specific gene products including c22-3,
c33c, c100-3, and 5-1-1.15

safety of transfusion has been difficult to anti-HBc to have a continued role in
evaluate. More stringent criteria for donor preventing HBV transmission. 21,22 AABB
selection had recently been introduced in Standards no longer requires ALT test-
response to reports of AIDS in transfusion ing and allows reentry of otherwise suit-
recipients. Because some of the popula- able donors who had previously been ex-
tions at risk for HIV infection also have cluded solely because of elevated ALT. 22
high risk for NANB and HBV infection, the
changes in donor eligibility criteria may
have affected hepatitis transmission.
One study during this period observed Human Immunodeficiency
a drop in the incidence of hepatitis in the
general population, but there were Virus
much greater drops in posttransfusion Human immunodeficiency virus, type 1
HBV and NANB infection than could be (HIV-1) is the etiologic agent of AIDS.
explained simply by the change in back- This syndrome was recognized in 1981,
ground rates.19 well before the discovery of the causative
Current very sensitive tests for anti- virus. Wider implications of the immune
HCV have deprived surrogate tests of disorder were noted when, in 1982, AIDS
23
their role in preventing NANB hepati- was reported in three hemophiliacs and
tis. 2 0 A National Institutes of Health in a 17-month-old infant whose multiple
(NIH) consensus conference held in transfusions at birth included a unit of
1995 recommended that screening of platelets from a donor who subsequently
24
volunteer blood donors for ALT be dis- developed AIDS. Within a few years,
continued but considered testing for over 50% of hemophiliacs receiving clot-



ting factor concentrates developed HIV- few weeks after infection, viremia is first
25
1 infection. detectable in the plasma. During this
viremia, 20-50% of acutely infected per-
sons have a mononucleosis-like illness,
Properties of the Virus with fever, enlarged lymph nodes, sore
26 27
Montagnier and Gallo identified HIV throat, rash, joint and muscle pain with
as the viral cause of AIDS. HIV is a cy- or without headache, diarrhea, and vom-
topathic retrovirus initially called lym- iting.28
phadenopathy-associated virus (LAV) or As HIV-1 antibodies appear and symp-
human T-cell lymphotropic virus, type toms resolve, viremia diminishes, leav-
III (HTLV-III). It is a 100 nm RNA virus ing some infected peripheral blood T
that preferentially infects CD4-positive lymphocytes. The virus can be transmit-
T lymphocytes (helper cells) in lymph ted by blood or genital secretions during
nodes and other lymphoid tissue, but this phase. 28 Tissue monocytes may serve
also infects other cells that express as a latent infected reservoir in nonlym-
28
CD4. The core of the retrovirus con- phoid tissues.
tains an enzyme, reverse transcriptase, Persistent infection of CD4+ T lym-
that enables the virus to copy its single- phocytes with an asymptomatic clinical
stranded RNA into DNA; the viral DNA is status has been observed to last a median
then integrated into host DNA. Viral rep- of 10 to 12 years.29 (See Fig 26-4.) After
lication and release are complex proc- years of asymptomatic standoff, both
esses requiring the products of several viremia and the percentage of infected T
viral genes. lymphocytes increase. Loss of the im-
HIV virus then replicates and dissemi- mune functions served by helper T cells
nates initially as cell-free virions, and a impairs immune reactivity, and there

Figure 26-4. Natural history of HIV infection and its serologic markers.



32
may be inappropriate immune activation lence had stabilized in most US cities.
and cytokine secretion. Eventually there Heterosexual transmission, especially
is a sharp decline in the number of viable male-to-female, and mother-to-child
CD4+ T lymphocytes and profound im- transmission have attracted increasing
28
munosuppression. concern.

Definition of AIDS Human Immunodeficiency Virus, Type 2
As the number of CD4+ cells decreases, First discovered in 1985, human immu-
the risk and severity of opportunistic ill- nodeficiency virus, type 2 (HIV-2) causes
nesses increase. Enumeration of CD4+ endemic infection in many countries in
cells is used to guide clinical and thera- West Africa but is seldom seen else-
peutic management of HIV-infected per- 33
where. The first case of HIV-2 infection
sons. The AIDS classification system de- in the United States was reported in
vised by the CDC evaluates the number March 1988 in a young West African who
of CD4+ T cells (≥500/µL, 200-499/µL, had recently immigrated to the United
or ≤ 200/µL), the presence or absence of States. The spectrum of disease attribut-
systemic symptoms, and existence of any able to HIV-2 is similar to that caused by
of the 26 clinical conditions considered HIV-1; however, there appears to be a
30
to be AIDS-defining illnesses. Among longer incubation period and lower inci-
these conditions are Kaposi’s sarcoma; 34
dence of progression to AIDS. HIV-2 is
cytomegalovirus retinitis, or infection of spread both sexually and vertically, but
sites other than liver, spleen, or lymph transmission is less efficient than for
nodes; toxoplasmosis of the brain; pri- HIV-1. Tests in the United States on in-
mary lymphoma of the brain; candidiasis jecting drug users, persons with sexually
of the esophagus, bronchi, trachea or transmitted diseases, newborn infants,
lungs; tuberculosis at any site or infec- and homosexual men confirm the very
tion with atypical mycobacteria; and limited prevalence and transmission of
chronic intestinal cryptosporidiosis. the agent.
33,34

Pneumocystis carinii pneumonia (PCP)
is the most common serious opportunis-
tic infection. Transfusion Considerations
Transfusion-Transmitted HIV-1
Risk Factors for HIV Infection All blood components can transmit HIV-
Infected individuals are at risk of infect- 1. By the mid-1990’s over 7500 cases of
ing others through sexual contact, child- AIDS had been reported in which trans-
birth, breast-feeding, and parenteral ex- fusion or a tissue transplant was the only
posure to blood. Those identified early as identifiable risk. In addition, approxi-
being at highest risk were men who had mately 4200 cases occurred in hemo-
sex with other men; needle-sharing drug philiacs who received clotting factor
users; hemophiliacs who received clot- concentrates. Transfusion-associated
ting factor concentrates; and, to a lesser AIDS, including cases in hemophiliacs,
extent, recipients of blood transfusions. constituted about 2.3% of all AIDS
35
By 1989 the rate of infections spread cases. All but about 30 reflected trans-
within each group was no longer in- fusions given before routine anti-HIV
creasing exponentially and appeared to testing began, in 1985. The interval be-
have reached a plateau in the popula- tween transfusion and diagnosis of AIDS
31 35
tions most at risk, and HIV seropreva- was a median of 58 months.



Most but not all recipients of HIV-in- Risk of Posttransfusion HIV
fected blood transfusions become in-
fected. In one large study, HIV infection Since 1985, the cases of HIV transmission
developed in 89.5% of recipients who by transfusion have resulted from dona-
received blood from anti-HIV positive tion by a recently infected individual not
donors. 36 With the exception of coagula- yet reactive on an anti-HIV screening test.
tion factor concentrates, plasma deriva- With screening tests available before 1992,
tives such as albumin and immune the seronegative interval (“window pe-
globulins have not been reported to riod”) averaged 45 days. Presently avail-
transmit HIV infection. able, more sensitive screening tests now
have closed the seronegative window to
39
approximately 22-25 days.
Since implementing donor testing to
Transfusion-Transmitted HIV-2 prevent posttransfusion HIV infection in
1985, the risk of transfusion-transmitted
There have been two brief reports of pos- HIV has declined remarkably40 (Fig 26-5).
sible HIV-2 transmission through blood In the San Francisco area, the peak risk of
component use, both in Europe. Two transmitting HIV between 1978 and 1985,
women were infected by whole blood ob- was almost 1% per unit. Donor screening
tained from a donor who developed AIDS policies in 1983 and 1984 lowered the
at least 16 years after becoming infected transmission risk substantially and the in-
with HIV-2; both women were asympto- troduction of testing for anti-HIV acceler-
37
matic 14 years after transfusion. Two ated the rate of decline. Since 1985, the
hemophiliac patients who received clot- sensitivity of antibody detection has con-
38
ting factors were also infected. tinued to improve.

Figure 26-5. Projected risk of HIV-1 infection per unit of blood transfused between January
1978 and December 1984 (reprinted with permission from Busch MP, et al11).



Risk from seronegative donations will ity, calculated as True Positive/(True
vary in proportion to the incidence of HIV Positive + False Negative) × 100. Speci-
infection in the donor community. Recent ficity, calculated as True Negative/(True
overall estimates of posttransfusion HIV Negative + False Positive) × 100, is much
risk in the United States approximate one less significant. Current tests for anti-
per 420,000 transfusions.2,41 HIV have specificity in excess of 99.5%.
Specificity indicates the accuracy of
findings in tested persons who do not
HIV Testing of Blood Donors have the disease. If the disease has low
AABB Standards and the FDA require prevalence in the test population, the
that all units of blood and components likelihood is high that most positive
be nonreactive for anti-HIV-1 and HIV-2 screening test results will be false posi-
and for HIV-1 antigen (HIV-1-Ag) before tive.
they are issued for transfusion. EIA-detectable antibody develops
days to a week after the onset of symp-
Screening Tests for Antibodies to toms,42 about 6 days after the onset of
HIV p24 antigenemia.42,43 A few days
HIV-1/2
later HIV-1 antibodies become detect-
Figure 26-6 shows the sequence of able by the HIV-1 Western immunoblot.
screening and confirmatory testing for
anti-HIV-1/2. EIA is the test of choice of Confirmatory Testing for Antibodies to
most donor centers for donor screening.
Because the consequence of missing
HIV-1/2
even one true positive is great, screening The most commonly used confirmatory
tests are designed to have high sensitiv- test for antibodies to HIV-1/2 is the

Figure 26-6. Decision tree for anti-HIV-1/HIV-2 testing of blood donors.



Western blot (WB). With this technique, to obtain counseling and medical follow-
protein components (in this instance, up. EIA anti-HIV-1/2 results not con-
antigenic viral material) are separated firmed as a true positive may have tech-
into bands according to molecular nical or biologic causes. Many blood
weight and transferred to a nitrocellu- donors with repeat-reactive EIA anti-
lose membrane. Antibody(ies) in the test HIV-1/2 screening tests are negative on
serum react with individual bands, de- WB confirmatory testing; these donors
pending on the specificity(ies) present. usually have nonreactive EIA results on
Most persons infected with HIV, whether a subsequent donation. Therefore, the
asymptomatic or exhibiting AIDS, show FDA has approved reentry protocols to
multiple bands, representing antibodies qualify donors as suitable for subsequent
to essentially all of the various gene donations (see Table 26-2). Reentry re-
products. A fully reactive test serum quires retesting at least 6 months later,
should react with the p17, p24, p26, and to detect delayed seroconversion; the
p55 gag proteins; the p31, p56, and p66 use of EIA tests based on whole-virus
pol proteins; and the gp41, gp120, and lysate; and use of either a licensed West-
gp160 env glycoproteins. ern blot to ensure appropriate sensitivity
A sample is defined as anti-HIV-posi- of the methods or an FDA-licensed im-
47,48
tive if at least two of the following bands munofluorescence assay. The later
are present: p24, gp41, or gp120/160.44 sample must also be nonreactive in an
Negative WB results have no bands pre- EIA test for anti-HIV-2, if standard test-
sent. WB results classed as indetermi- ing does not include HIV-2, and a test for
nate have some bands present but not HIV-1-Ag.
those in the criterion for HIV positivity.
Individuals infected with HIV may have
indeterminate WB patterns when in- Direct Detection of Virus
itially tested, but develop additional AABB Standards and the FDA require
bands within 6 months. Healthy indi- that all units of blood and blood compo-
viduals with an initial indeterminate WB n e n t s b e n o n r e a c t i ve f o r a n F D A -
continue to have indeterminate results licensed test for HIV-1-Ag. HIV-1-Ag may
on repeat samples, and are negative on appear in blood early in the course of
clinical examination and additional infection, somewhat before antibody is
t ests, including viral cultures and detectable. Transmission of HIV has
PCR.45,46 Healthy donors who continue been reported from transfusion of se-
to show the same indeterminate pattern ronegative blood later shown to contain
for more than 6 months can be reassured p24 antigen; the donors subsequently se-
29
that they are unlikely to have HIV infec- roconverted. Mathematical models,
tion, but they are not eligible to donate constructed with findings from geo-
blood. graphic areas with very high incidence of
new HIV infections, suggest that routine
antigen testing would detect one anti-
Confirmation and Reentry, Anti-HIV-1/2 gen-positive/antibody-negative dona-
41,49
When the EIA screening test for anti- tion in every 1.6 million tested.
HIV-1 is repeatedly reactive, a confirma-
tory test will determine whether the do-
Confirmatory Testing for HIV-1 Antigen
nor is a true positive and will aid in
counseling the individual. Persons who When the EIA screening test for HIV-1-
have true positive test results should be Ag is repeatedly reactive, a confirmatory
notified confidentially and encouraged test will aid in counseling the donor. The


Table 26-2. Reentry of Donors With Repeatedly Reactive Screening Tests
Tests
Anti-HIV-1 or -HIV-1/2 Anti-HIV-2 HIV-1-Ag HBsAg
Initial sample
Not eligible for reentry Licensed Western blot Different HIV-2 EIA RR Confirmed by Confirmed by
positive or indeterminate neutralization neutralization or
or IFA reactive anti-HBc RR
Evaluate for reentry Licensed Western blot or Different HIV-2-EIA NR and Not confirmed by Not confirmed HBsAg
IFA NR licensed Western blot or neutralization specific and anti-HBc
IFA NR NR

Follow-up sample (drawn 6 months later) (drawn 6 months later) (drawn 8 weeks later) (drawn 8 weeks later)
Not eligible for reentry EIA RR or Western blot RR HIV-1 or different HIV-1-Ag RR, HBsAg RR or anti-HBc
positive or indeterminate HIV-2 EIA RR or a neutralization RR
or IFA reactive licensed Western blot or confirmed
IFA reactive or
indeterminate
Eligible for reentry Original EIA method NR Screening test and a HIV-1-Ag and HBsAg NR and
and whole virus lysate different HIV-2 EIA NR anti-HIV-1/2 NR or anti-HBc NR

anti-HIV-1 EIA NR and and licensed Western Hiv-1-Ag RR, not
licensed Western blot or blot or IFA NR confirmed
IFA NR (temporary deferral
for 8 weeks)
NR = nonreactive
RR = repeatedly reactive
Chapter 26: Infectious Complications of Blood Transfusion
575


HIV RNA (RT-PCR) HIV Antibody
in plasma and platelets

HIV DNA (PCR)
in PBMC
Infectious
Exposure
HIV p24 Ag

-10 0 10 20 30 40 50 60 70
Days pre/post-Infectiousness
Figure 26-7. Virologic events during primary HIV infection. After initial infection and propa-
gation of HIV in lymph nodes, a blood donor becomes infectious (defined as day 0) with HIV
RNA being detectable in plasma on days 14-15, HIV DNA detectable in leukocytes at day 17-20,
and HIV antibodies detectable between days 20 and 25 (reproduced with permission from
Busch MP42).

confirmatory test is an EIA neutraliza- ten, signed, and dated request from the
tion test. Donors whose serum shows patient’s physician authorizing this
neutralization with this test are consid- shipment, 2) there is a written statement
ered confirmed positive for HIV-1-Ag from the transfusion service indicating
and should be permanently deferred. Do- willingness to receive this product, and
nors whose serum shows no neutraliza- 3) the transfusion service takes respon-
tion with this test are currently consid- sibility for ensuring that there is docu-
ered not confirmed, and must be mented verification of the accurate iden-
reported as HIV-1-Ag indeterminate; tity of the transfusion recipient. These
they should be temporarily deferred units must be labeled “BIOHAZARD” and
50
from donation for a minimum of 8 “FOR AUTOLOGOUS USE ONLY.”
weeks. See below for the reentry proto- In the absence of a repeatedly reactive
col for HIV-1-Ag. Units from repeatedly anti-HIV-1/2 test, a repeatedly reactive
reactive donations must be quarantined, EIA HIV-1-Ag screening test should be
and destroyed or not used for transfu- further tested with a neutralization test
sion or for further manufacturing into for the purposes of counseling. Persons
injectable products. Units from repeat- with a confirmed HIV-1-Ag test should
edly reactive autologous donations be notified confidentially and encour-
should be withheld from transfusion. aged to obtain counseling and medical
However, these units may be supplied for follow-up. These persons should be in-
autologous use only if: 1) there is a writ- formed that they are probably infected



w ith H IV. They should be notified HIV-1 Seroprevalence in Blood Donors
promptly because they often have high
viral titers and may be at high risk for When donor screening for anti-HIV was
transmitting HIV infection. Counseling first introduced in 1985, from 0.1-0.8%
for persons with repeatedly reactive EIA of sera gave repeatedly reactive EIA re-
and HIV antigen tests should incorpo- sults, depending on the location of the
rate arrangements for follow-up anti- donor center and the reagents used; only
body testing.51 0.04% of donors were confirmed as posi-
Persons testing repeatedly reactive tive by Western blot. During the second
for HIV-1-Ag, but not confirmed by neu- and third years of testing most centers
tralization probably have a low preva- reported repeat-reactive rates around
lence of HIV infection. These people 0.1-0.2% and confirmed positive rates of
should be requested to return for repeat 0.01-0.04%. By 1992 the proportion of
testing. If the donor is retested and confirmed positives among donors had
found negative for the screening test for declined to 0.005-0.01% with an overall
12
HIV-1-Ag, that donor could be consid- rate of 0.006%. More sensitive tests
ered for reentry. Donors can be reen- using PCR technology may detect addi-
tered if they have been retested at least 8 tional potentially infectious donors (Fig
weeks after their repeatedly reactive do- 26-7). Following expected advances in
nation, and are found to be nonreactive automation and reliability, this technol-
for the HIV-1-Ag screening test and for ogy may assume a role in future donor
the HIV antibody test. These donors screening.
could be counseled that their repeatedly
reactive tests were reactive but that their
Recipient and Donor Tracing
supplemental tests were not confirmed,
which likely represents a false-positive (Look-Back)
test. These donors can be reinstated as Identification of persons who have re-
blood or plasma donors. ceived seronegative or untested blood
If a donor with a repeatedly reactive from a donor later found to be infected
EIA and not confirmed HIV antigen test by HIV is referred to as “look-back.” Be-
is retested after 8 weeks, and samples cause the interval between infected
test repeatedly reactive on the EIA transfusion and onset of AIDS can be
screening test and are not confirmed by very long, recipients are usually un-
neutralization, that donor could be tem- aware of their infection and may be in-
porarily deferred for 8 weeks as long as fectious to others. To identify these indi-
the HIV antibody test is negative.52 If a v i d u a l s , b l o o d c e n t e r s m u s t h a ve
reinstated donor tests repeatedly reac- procedures to notify recipients of pre-
tive on any subsequent evaluation sub- vious donations from any donor later
sequent to having been reinstated, that found to have a confirmed positive test
22
donor should be temporarily deferred for anti-HIV or a confirmed positive
again and is eligible for reentry 8 weeks test for HIV-1-Ag. If a patient with AIDS
or later. 52 Such donors should be coun- is known to have donated previously, re-
seled that their repeatedly reactive tests cipients of blood or blood products from
were reactive on at least two donations these donations should be traced and
(or samples) but that their supplemental notified. Recipient tracing and testing is
tests were not confirmed. This may likely usually done through the patient’s phy-
represent a false-positive test, but they sician, not through direct contact with
are permanently deferred from being the patient. Look-back should start with
blood or plasma donors. the recipients of the most recent dona-



tions. If recipients of units (donated at HTLV, Type II
least 6 months before the last known
negative test) are tested and found nega- Human T-cell lymphotropic virus, type
tive, earlier recipients are probably not II (HTLV-II) was described several years
at risk, as infectivity earlier than 6 after HTLV-I. There is at least 60% simi-
54
months before a negative screening test larity of genetic sequences to HTLV-I ;
is extremely unlikely. antibodies to either show strong cross-
The FDA recommends the quarantine reactivity in tests with viral lysates.
of previously collected units of Whole HTLV-II also shows clustering, but in
Blood, blood components, Source Leu- different populations. High prevalence
kocytes, or Source Plasma from any per- has been noted among some Native
son who tests repeatedly reactive by American populations and in intrave-
screening test for HIV-1-Ag in the ab- nous drug users in the US, in whom
sence of repeatedly reactive screening seroprevalence is 1-20%. The only dis-
tests for antibodies to HIV-1 and HIV-2. ease associated with HTLV-II has been
HAM; occurrence seems to be somewhat
less frequent than with HTLV-I.

Human T-Cell Clinical Observations
Lymphotropic Viruses For both HTLV-I and -II, infection per-
Types of Viruses sists lifelong, as does the presence of
antibody. Studies of prevalence and
Human T-cell lymphotropic virus, type I transmission use seroconversion as the
(HTLV-I) was the first human retrovirus endpoint for diagnosis. Infection does
isolated and the first to be causally associ- not cause any recognizable acute events,
ated with a malignant disease of humans, and with the exception of those develop-
adult T-cell lymphoma-leukemia (ATL). ing ATL or HAM, infected individuals ex-
HTLV-I is also associated with the perience no health consequences. Most
neurologic condition originally called carriers are asymptomatic and com-
tropical spastic paraparesis but now often pletely unaware of the infection.
called HTLV-associated myelopathy
(HAM). Both these conditions occur in a
small minority (no more than 2-4%) of Transmission
persons harboring the virus, and they de-
53
velop only after many years of infection. Both viruses are very strongly cell-asso-
Infection during childhood is an impor- ciated. Contact with infected viable lym-
tant aspect of, possibly a requirement for, phocytes can cause infection, but plasma
developing ATL, whereas childhood or does not appear to be infective. Cellular
adult infection can cause HAM. components from infected donors cause
Prevalence of HTLV-I infection shows seroconversion in 40-60% of recipients
striking geographic clustering, with pock- in Japan, but apparently in a much
55
ets of high endemicity in parts of southern smaller proportion of US recipients. Af-
Japan, of sub-Saharan Africa, of the Carib- ter refrigerated storage for 10 days or
bean basin, and of Brazil. Transmission is more, red cells from an infected donor
by sexual contact (predominantly male-to- are far less likely to cause seroconver-
female), by parenteral exposure to blood, sion. Transfusion-transmitted HTLV-I
and by mother-to-child transmission infection has been associated with HAM
through breast milk. of rather rapid onset.



Donor Tests of high prevalence. The screening re-
quirement in place since 1989 has prob-
Donor screening for anti-HTLV-I began ably removed from the active donor pool
in the United States in 1989; at that time most multi-unit donors with lifelong in-
the rate of confirmed positive tests was fection.
53
0.017%, a figure that has since de-
clined as seropositive persons have been
eliminated from the donor pool. The cur-
rently licensed EIA screening test does Cytomegalovirus
not accurately discriminate between
anti-HTLV-I and anti-HTLV-II. Cytomegalovirus (CMV) infection is
Further testing of serum that is re- widespread; transmission can occur
peatedly reactive for anti-HTLV against through infectious body secretions, in-
antigen preparations specific for the two cluding urine, oropharyngeal secre-
agents (HTLV-I or HTLV-II), or by PCR tions, breast milk, blood, semen, and
on material from peripheral blood cervical secretions. About 1% of new-
mononuclear cells, can characterize the borns are infected, transplacentally or
infecting agent. Half or more of blood through exposure to infected cervical se-
donors reactive on EIA screening prove cretions at delivery or by breast milk. In
to have HTLV-II infections. A donation early childhood, CMV is often acquired
that is repeatedly reactive on EIA may through close contact, especially day
not be used for transfusion. Although care settings; in adulthood, through sex-
there is no requirement to perform addi- ual intercourse. Anti-CMV is present in
tional testing, most centers do so, and if 40-70% of healthy blood donors in the
56
supplementary tests are positive (see Ta- United States.
ble 26-3), the donor is notified and per-
manently deferred. Clinical Observations
In persons with an intact immune sys-
tem, CMV infection may be asympto-
Look-Back
matic and remain latent in tissues and
Look-back is required for recipients of leukocytes for many years. Infection,
units drawn before the donor was found either primary or reactivation of latent
22
to be seropositive. Because recipients infection, can be associated with a
of units from seropositive donors do not mononucleosis-like syndrome of sore
consistently seroconvert, and because throat, enlarged lymph nodes, lympho-
many seropositive donors have lifelong cytosis, fever, viremia, viruria, and hepa-
infection, the time frame for look-back titis. Intrauterine infection may cause
is not self-evident. Five years or five pre- jaundice, thrombocytopenia, cerebral
vious donations was adopted as a reason- calcifications, and motor disabilities;
able approach, but if the earliest tested the syndrome of congenital infection
recipient proves to be seropositive, look- causes mental retardation and deafness,
back should be continued backward. A and may be fatal.
definite separation between infective CMV causes serious morbidity and
and noninfective donations is more mortality in premature infants and in
likely to occur with donors who acquired recipients of organ and marrow trans-
infection as adults, usually through in- plants. 57 Pneumonitis, hepatitis, retini-
travenous drug use or through sexual tis, and multi-system organ failure are
contact with intravenous drug users or manifestations of infection, which can
with individuals from geographic areas result from blood transfusions given to


580

Table 26-3. Recommended Actions for HTLV-I Testing

First Donation to Be Tested for HTLV-I Antibodies Subsequent Donation(s)

EIA Donation WB/RIPA Donor EIA Donation WB/RIPA Donor
AABB Technical Manual

Repeatedly Destroy* Positive Defer and Not Applicable/Donor Deferred
reactive all components counsel
Repeatedly Destroy* Negative No action Repeatedly Destroy* Negative Defer and
reactive all components or indeterminate reactive all components or counsel
indeterminate
or positive
Nonreactive† All components Not done No action
acceptable
*Destroyed unless appropriately labeled as positive for HTLV-I antibodies, and labeled for laboratory research use or further manufacture into
in-vitro diagnostic reagents.

†
Assuming that separate prior donations have been repeatedly reactive for HTLV-I antibody no more than once. If separate prior donations had
been repeatedly reactive for HTLV-I antibodies on two or more occasions, the donor should have been either permanently or indefinitely
deferred.


many premature infants and to trans- moval with high-efficiency filters (5 ×
6
plant recipients. Other causes, however, 10 leukocytes per component, or less)
such as organ transplants from CMV- can significantly reduce if not prevent
positive donors or reactivation of latent posttransfusion CMV in high-risk neo-
22,61,62
virus, may be as much or more of a risk nates and transplant recipients.
than transfusion. Other approaches are also important to
consider, especially avoidance of un-
needed transfusions. Prophylactic ther-
Transfusion-Transmitted CMV apy with CMV immune globulin and pro-
Although over half of blood donors are phylactic use of antiviral agents are
CMV-seropositive, it has been esti- under scrutiny for high-risk immuno-
58
mated that less than 2% of these are suppressed organ transplant recipi-
58
able to transmit the virus. Posttransfu- ents.
sion hepatitis may, rarely, be due to CMV.
The postperfusion mononucleosis syn-
drome that first focused attention on
CMV in transfused components is now Other Viral Complications
rarely seen. Posttransfusion CMV infec-
tion is generally of no clinical conse- of Blood Transfusion
quence in immunocompetent recipi- The transmissibility and clinical signifi-
ents. cance of other viruses and virus-like
Several categories of immunocom- agents such as Epstein-Barr virus, hu-
promised patients should be protected man herpes virus 6, parvovirus, the
from risk of CMV transmission.59 These agent of Creutzfeldt-Jakob disease, and
63
include low-birth-weight premature in- others are being studied.
fants born to seronegative mothers; se-
ronegative recipients of bone-marrow
from CMV-negative donors; seronegative Epstein-Barr Virus
pregnant women, because the fetus is at Epstein-Barr virus (EBV) causes most
risk of transplacental infection; and re- cases of infectious mononucleosis and is
cipients of intrauterine transfusions. closely associated with the endemic
Often included in this category are se- form of Burkitt’s lymphoma in the Far
ronegative recipients of any organ trans- East, and with nasopharyngeal carci-
plant from a seronegative donor; serone- noma. Most persons have been infected
gative individuals who are candidates for by the time they reach adulthood; al-
autologous or allogeneic bone marrow though usually asymptomatic, infection
transplants; and those few patients with persists, remaining in B lymphocytes
57
AIDS who are free of CMV infection. and oropharyngeal epithelium. Infec-
tion is spread by contact with infected
saliva. Primary infection in children is
Preventive Measures either asymptomatic or is characterized
Blood from donors who test negative for by a sore throat and enlarged lymph
CMV antibody has virtually no risk of nodes. Primary infection in older, immu-
57,58
transmitting CMV, but the supply of nologically mature persons usually
seronegative blood is limited. Another causes a systemic syndrome, infectious
approach is to remove leukocytes from mononucleosis, with fever; tonsillar in-
donated blood. Although the precise leu- fection, sometimes with necrotic ulcers;
kocyte population that harbors the virus enlarged lymph nodes; hematologic and
60
has not been defined, leukocyte re- immunologic abnormalities; and some-



times hepatitis or other organ involve- no evidence for a carrier state. Transmis-
ment. EBV infection targets B lympho- sion of parvovirus through blood compo-
cytes, which undergo polyclonal prolif- nents other than clotting concentrates
eration and then provide a T-lymphocyte has not been reported. 66
response, seen as “atypical lympho- Parvovirus has been found regularly
cytes.” in clotting factor concentrates and has
Transfusion-transmitted EBV infec- been transmitted to hemophiliacs. Be-
tion is usually asymptomatic, but has cause it lacks a lipid envelope, it is not
been a rare cause of the postperfusion reliably inactivated by solvent/detergent
syndrome that followed massive transfu- treatment, and it also resists heat in-
sion of freshly drawn blood during car- activation utilizing temperatures below
diac surgery and is a rare cause of post- 100 C. 67 The infection is usually without
transfusion hepatitis.64 EBV plays a role serious morbidity but hypoplastic ane-
in the development of nasopharyngeal mia has been reported in HIV-infected
carcinoma and at least one form of hemophiliacs. 68,69
Burkitt’s lymphoma, and has the in-vitro
capacity to immortalize B lymphocytes.
Although it contributes to the develop- Colorado Tick Fever
ment of lymphoproliferative disorders in Colorado tick fever is an acute viral ill-
immunosuppressed recipients of mar- ness acquired from tick bites in the
row and organ transplants, there is no mountainous regions of the western
evidence that transfusion-transmitted United States. The virus can persist in
EBV infection contributes to the devel- peripheral blood up to 90 days after
opment of malignancies in transfusion symptoms disappear, but no chronic
recipients. asymptomatic carrier state has been re-
ported. The virus has been transmitted
70
by blood transfusion. In the only re-
Parvovirus ported case, the blood donor developed
Parvovirus B19 is the cause of erythema the febrile illness 4 days after removing
infectiosum (fifth disease), a contagious an attached tick and 18 hours after do-
febrile illness of early childhood. In nating blood. The virus was isolated
adults, parvovirus can infect and lyse red from a segment of the donated blood
cell precursors in the marrow; sudden after 2 weeks of storage and from periph-
and severe anemia may occur in patients eral blood of the recipient who had colon
with underlying chronic hemolytic dis- carcinoma and developed a prolonged
orders. Infection during pregnancy im- febrile illness.
poses a risk, estimated to be less than
10%, of fetal infection, which causes se-
vere anemia and consequent circulatory
Tick-Borne Encephalitis Virus
failure. Ti c k - b o r n e e n c e p h a l i t i s vi ru s i s a
The red cell P antigen is the cellular flavivirus transmitted by the bite of ticks
receptor for parvovirus B19, and people from various parts of the world. One va-
who do not have the P antigen are natu- riety (Kumlinge disease) is restricted to
rally resistant to infection. 65 About 30- southwestern Finland and nearby is-
60% of normal blood donors have par- lands where 126 patients had serologic
vovirus antibodies, which indicate evidence of infection. Of these, three
immunity rather than chronic persist- were laboratory acquired and two were
71
ent infection.66 Viremia occurs only in acquired by transfusion. The blood do-
the early phases of infection and there is nors became ill with Kumlinge disease



only hours after donating but they ne- (eg, dura mater, pituitary growth hor-
glected to inform the blood bank. mone of human origin) and persons with
a family history of CJD.22 Family history
has been defined as having a blood rela-
Creutzfeldt-Jakob Disease tive who has had this diagnosis. 78
Creutzfeldt-Jakob disease (CJD) is a fatal
infection of the nervous system caused
by a proteinaceous particle smaller than
a virus. This infectious agent, now usu- Nonviral Infectious
ally termed a prion, was once thought to
be a slow virus because symptoms do not
Complications of Blood
develop until many years after the initial Transfusion
infection. In the US, there is about one
case of CJD per million people, nearly all Bacterial Contamination
in older individuals. In the vast majority Bacterial contamination, one of the ear-
of cases, the mode of acquisition is un- liest recognized complications of stored
known. The agent causing CJD is resis- blood, remains an important cause of
tant to commonly used disinfectants and transfusion morbidity and mortality. It
sterilants. Fatal CJD has been transmit- accounted for about 16% of transfusion
ted through administration of growth fatalities reported to the FDA between
79
hormone derived from human pituitary, 1986 and 1991. No matter how care-
transplantation of cornea, allografting of fully blood is drawn, processed, and
dura mater; and insertion of contami- stored, complete elimination of micro-
72
nated intracerebral electrodes. bial agents is impossible. Bacteria are
Early experimental studies in ani- believed to originate with the donor,
mals and humans suggested the possi- either from the venipuncture site or
79
bility that dementing illnesses such as from inapparent bacteremia. Bacterial
Alzheimer’s disease and CJD could be multiplication is more likely in compo-
transmitted by blood transfusion. This nents stored at room temperature than
was based on the demonstration of the in refrigerated components, especially
agent in human leukocytes and the de- when room-temperature storage is in
80
velopment of degenerative changes at gas-permeable containers. Organisms
the intracerebral sites where human that multiply in refrigerated blood and
cells were introduced into hamsters or components are described as psychro-
mice.73 Subsequent studies have failed to philic and are often gram-negative;
confirm transmissibility of Alzheimer’s gram-positive organisms are more often
disease through blood leukocytes,74 and seen at room temperature. Strict adher-
population-based, case-control studies ence to phlebotomy protocols and scru-
have shown no evidence that blood pulous attention to sterile techniques
transfusion is a risk factor for the devel- during component preparation and stor-
opment of CJD or Alzheimer’s dis- age should minimize contamination
ease.75,76 arising from sources outside the donor.
Although transmission of CJD Infusion of bacterially contaminated
through blood transfusion has never components can cause a devastating sep-
been reported, individuals at increased tic reaction, with mortality rates up to
risk for CJD are excluded from donating 26%.79 In red cell components, the reac-
blood77 ; this group includes persons who tions may reflect the effects of endotoxin
have received tissue or tissue derivatives produced by such gram-negative organ-
known to be a source of the CJD agent isms as Pseudomonas species, Citrobac-



ter freundii, Escherichia coli, a n d selection of blood donors is the first and
Yersinia enterocolitica. Bartonella and most important step.
Brucella species have also caused septic The donor’s present appearance and
transfusion reactions. recent history should be of good health;
additional questioning may be needed if
there is present or recent history of an-
Clinical Considerations tibiotic use, of medical or surgical inter-
ventions, or of any constitutional symp-
Severe reactions are characterized by toms. Questions to elicit the possibility
high fever, shock, hemoglobinuria, DIC, of bacteremia are especially important
and renal failure. If bacterial contamina- for autologous donors, who may recently
tion is suspected, the transfusion should have had hospitalization, antibiotic
be stopped immediately and a Gram’s
therapy, or invasive diagnostic or thera-
stain and blood culture should be ob-
peutic procedures; there have been sev-
tained from the unit and recipient as
eral reports of Yersinia sepsis complica-
promptly as possible after the reaction is
t i o ns f o l l o w i n g i n fus i on o f s tored
observed. Color change to dark purple or
autologous blood.82,83 At the time of do-
black, clots in the bag, or hemolysis sug-
nation, the temperature and pulse
gest contamination, but the appearance
should be within normal limits.
of the blood in the bag is often unre-
There must be scrupulous attention
markable. Bacterial multiplication may
to selection and cleansing of the donor
cause the oxygen in a red cell unit to be
phlebotomy site. Skin preparation re-
consumed, causing hemoglobin desatu-
duces but does not prevent the contami-
ration and darkening of the unit when
nation of components by bacteria.
compared with the color of cells in the
81 Scarred or dimpled areas associated with
attached sealed segments. The pres-
previous dermatitis or repeated phlebot-
ence of bacteria in a Gram’s stain of the
omy can harbor bacteria and should be
component is confirmatory, but absence
avoided.
of visible organisms does not exclude the
Care in the preparation of compo-
possibility, especially if blood contained
nents and handling of materials used in
in attached segments was used for the
administration is essential. If a water-
Gram’s stain. The patient’s blood, the
bath is used, components should be pro-
suspect component, and intravenous so-
tected by overwrapping and outlet ports
lutions in all the administration tubing
inspected for absence of trapped fluid,
used should be cultured for aerobic and
and the waterbath should be frequently
anaerobic organisms at various tempera-
tures. emptied and disinfected.
Treatment should not await the re- The color and character of the compo-
sults of these investigations, and should nent should be checked before release
include immediate intravenous admini- for transfusion. Some workers suggest
stration of antibiotics combined with comparing the color of blood in the con-
therapy for shock, renal failure, or DIC tainer with that of the sealed segments.81
if present. The extent of bacterial growth in platelet
components correlates with the dura-
tion of storage. In recognition of im-
Preventive Measures proved platelet function resulting from
improved containers and preservatives,
Prevention of septic reactions depends in 1983 the FDA increased storage limits
upon reducing or preventing bacterial of platelets at room temperature from 3
contamination of components. Careful to 7 days. In 1986, because of reports of



bacterial contamination in platelets Asymptomatic carriers are the source
stored longer than 5 days, the FDA re- of transfusion-transmitted malaria, al-
duced the room temperature storage though the parasite density is very low.
limits for platelets to a maximum of 5 Asymptomatic infections rarely persist
days. 84 more than 3 years, but asymptomatic P.
Eventually, the use of detection sys- falciparum and P. vivax infections may
tems may allow units to be monitored for persist for 5 years, P. ovale for 7 years,
contamination at the time of issue. Ap- and P. malariae can remain transmissi-
proaches under consideration include ble for the lifetime of the asymptomatic
Gram’s stain, chemiluminescent probe individual. There are no practical sero-
systems, automated cultures, and dem- logic tests to detect transmissible ma-
onstration of glucose consumption. 85,86 laria in asymptomatic donors. Malaria
Other strategies, such as prestorage leu- transmission is prevented by deferral of
kocyte reduction, use of antibiotics in prospective donors with increased risk
the storage media, and blood gas analysis of infectivity, based on medical and
of stored components, are also under in- travel history. AABB Standards22 defers,
vestigation. from donation of red cells, persons who
have had malaria in the preceding 3
years. Casual travelers to areas in which
malaria is endemic are deferred for a
Malaria year, but because early or prolonged ex-
Malaria is caused by several species of posure may reduce the incidence or se-
the intraerythrocytic protozoan genus verity of symptoms, immigrants, refu-
Plasmodium. Transmission usually re- gees, or citizens of areas in which the
sults from the bite of an anopheles mos- disease is endemic are deferred for 3
quito, but infection can follow transfu- years after leaving the area.
sion of parasitemic blood. In the United
States, malaria is probably the most
commonly recognized parasitic compli- Babesia
cation of transfusion; the risk in the
United States is estimated at 0.25 case Clinical Events
87
per million transfusions. The species Human babesiosis, caused by the in-
involved in transfusion-transmitted ma- traerythrocytic parasite Babesia mi-
laria in the United States are P. malariae croti, is the second most commonly re-
(40%), P. falciparum (25%), P. vivax ported transfusion-transmitted parasitic
87 88
(20%), and P. ovale (15%). Fever, chills, infection. Babesiosis is usually trans-
headache, and hemolysis occur a week to mitted by the bite of an infected deer
several months after the infected trans- tick, from the coastal lands and islands
fusion; morbidity varies but can be se- of northeastern United States including
vere, and deaths have occurred, espe- Martha’s Vineyard, Cape Cod, and Long
cially from P. falciparum. Island. Geographic areas of the hosts and
Malaria parasites survive for at least a the vectors appear to be expanding,
week in components stored at room tem- along with expansion of the deer popula-
perature or at 4 C. The parasites can also tion.
survive cryopreservation with glycerol The parasite can survive for up to 35
and subsequent thawing. Any compo- days at 4 C liquid storage, and has been
nent that contains red cells can transmit transmitted by platelet components and
infection, via the asexual form of the cryopreserved red cells. In an area en-
intraerythrocytic parasite. demic for babesiosis, the risk of post-



transfusion babesiosis was found to be flect either immunologic abnormalities
0.17% for red cells; no cases were asso- unrelated to syphilis (biologic false-posi-
ciated with platelets.89 Symptoms of tives) or inadequately treated syphilis
transfusion-transmitted babesiosis are that is more of a threat to the individual
often so mild that the true nature of the being tested than to a potential recipi-
22
infection may go undiagnosed; this may ent. The STS is required as an indicator
explain the small number of cases docu- of potentially high-risk behavior that
mented in the United States. In sympto- makes transmission of other organisms
matic cases, fever develops 1-4 weeks more likely.
after infection, sometimes associated
with chills, headaches, hemolysis, and Chagas’ Disease
hemoglobinuria. Rarely, the infection is
life-threatening, due to rapidly progres- American trypanosomiasis, or Chagas’
sive hemolytic anemia, renal failure, and disease, is endemic in South and Central
disseminated intravascular coagulation. America and is caused by the protozoan
Asplenic or immunocompromised trans- parasite Trypanosoma cruzi. The human
fusion recipients are at greatest risk.53 host sustains infection after the bite of
reduviid bugs (called cone-nosed or
“kissing” bugs), which usually exist in
Preventive Measures h o l l o w t r e e s , p a l m t r e es , a n d i n
As with malaria, the Babesia carrier thatched-roofed mud or wooden dwell-
state may be asymptomatic. Persons ings.
with a history of babesiosis are indefi-
n i t e l y d e f er r e d , b e c au s e l i f e l o n g Clinical Events
parasitemia can follow recovery from T. cruzi infects humans whose skin or
symptomatic illness. More restrictive mucosa comes in contact with feces of
policies, such as not collecting blood in infected reduviid bugs, usually as the
endemic areas in spring and summer result of a bite. Recent infections are
months, when tick bites are more com- usually either asymptomatic, or the very
mon, would probably have only limited mild signs and symptoms go undetected.
value. No test is currently under consid- Rarely, the site of entry evolves into an
eration for mass screening to detect
erythematous nodule called a chagoma,
asymptomatic carriers of B. microti. which may be accompanied by lym-
phadenopathy. Fever and enlargement of
Syphilis the spleen and liver may follow. Recently
infected young children may experience
Syphilis is caused by the spirochete Tre- acute myocarditis or meningoencephali-
ponema pallidum a n d i s c h a r a c- tis. Acute infection usually resolves
teristically spread by sexual contact. The without treatment, but persisting low-
phase of spirochetemia is brief and the level parasitemia is usual and up to 20-
organisms survive only a few days at 4 C, 40% of chronically infected people
so although transmission by transfusion develop cardiac or gastrointestinal
is possible, it occurs very rarely. Syphilis symptoms years or decades later.
90

transmission by transfusion is not pre-
vented by subjecting the donor blood to
standard serologic tests for syphilis Transfusion Considerations
(STS) because seroconversion occurs In urban areas in which the disease is
well after the phase of spirochetemia. endemic, the second most common
Most positive STS results on donors re- means of infection is transmission of T.



cruzi by blood transfusion. This may be- ble, and in two reported cases where the
come a problem in the United States, as donor became ill shortly after donation,
96
asymptomatic immigrants from these the recipient did not develop infection.
areas become blood donors. Three cases Potential donors who give a history of
of transfusion-transmitted Chagas’ dis- Lyme disease should be completely
ease have been reported in the United asymptomatic and should have completed
91
States, in New York, Los Angeles, and a full course of antibiotic therapy before
97
Texas, all in immunocompromised re- they may be permitted to donate.
cipients.
An EIA test for antibodies to T. cruzi Parasitic Worms
as well as possibly confirmatory EIA and
RIA tests are in development and should There have been occasional reports of
be submitted for licensure in the near parasitic worm infections transmitted
future.92,93 Blood centers in areas with by transfusion in countries other than
88
many immigrants from Central or South the United States. Microfilariasis is a
America have used questionnaires to potential transfusion risk in tropical
identify potentially infectious donors; zones, acquired by donors through bites
yields have been reassuringly low when by insects carrying Wuchereria ban-
donors whose replies indicated risk fac- crofti or Leishmania species.
tors were screened by serologic test-
ing.91,94,95 At present, it does not appear
indicated to defer donors solely on the
basis of questionnaires. Reducing the Risk of
Infectious Disease
Toxoplasmosis Transmission
Toxoplasmosis is caused by the ubiqui-
tous parasite Toxoplasma gondii and in- Inactivation/Destruction of Agents in
fection has been reported as an unusual Components
transfusion complication in immuno- The first intervention specifically added
88
compromised patients. The disease has to reduce the risk of hepatitis transmis-
not been considered a problem in rou- sion was pasteurization (ie, heating to
tine transfusion practice. 60 C for 10 hours), used for albumin
98
products since 1948. In those rare in-
stances when infections have occurred
Lyme Disease with albumin or plasma protein frac-
Lyme disease is the most common tick- tions prepared with this step, the proc-
borne disease in the United States. Bor- essing had been compromised. The
relia burgdorferi, the causative spiro- plasma fractionation process used for
chete, is transmitted by bites of the deer immunoglobulin products employs cold
tick. No transfusion-related cases have ethanol precipitation, which concen-
been reported, but chronic subclinical trates HCV in the Factor VIII-rich cryo-
infections do occur and experimentally precipitate and other fractions, and
inoculated organisms can survive condi- leaves little in the immunoglobulin frac-
tions of frozen, refrigerated, or room tion. The immunoglobulin fraction also
96
temperature storage. O n t h e o t h er has a high concentration of virus-neu-
hand, the phase of spirochetemia seems tralizing antibodies, and the resulting
to be associated with symptoms that product has a remarkably low risk of
99
would render a potential donor ineligi- virus transmission.



Immunoglobulins tive against nonenveloped agents such
as HAV, parvovirus B19, and the Colo-
Preparations of immunoglobulin in- rado tick fever virus. Virus inactivation
tended for intravenous administration steps have the potential drawback of re-
(IVIG) are expected to be similarly free ducing the potency and biologic effec-
of disease transmission. However, NANB tiveness of the product. Another concern
hepatitis transmission did occur in the is whether virus inactivation steps affect
1980’s during initial clinical trials of immunogenicity, especially the induc-
IVIG products in the United States and tion of Factor VIII inhibitors in hemo-
with routinely manufactured IVIG prod- philiac patients.
100
ucts in Europe. In late 1993 and early U n a v o i d ab l e R i s k s o f H u m a n
1994, there were numerous reports of Plasma. Many methods are highly effec-
HCV infection in US recipients of an tive against enveloped virus, but spo-
IVIG preparation from a single manufac- radic reports of viral transmission con-
turer, who did not use any virus inacti- tinue to occur, possibly due to accident
vation procedures. During this period, or error during the manufacturing proc-
HCV transmission did not occur from ess. The current combination of heat
IVIG of other manufacturers or with in- treatment, solvent/detergent treatment,
101
tramuscular immunoglobulin. and purification steps with monoclonal
antibodies provides clotting factor con-
centrates with a risk of transmitting
Coagulation Factors hepatitis and HIV that is lower than the
Until recently, clotting factor concen- risk associated with use of cryoprecipi-
trates frequently transmitted viral infec- tated Factor VIII derived from individual
tions. As the significance of HIV trans- voluntary whole blood donations. Abso-
mission became recognized, virus lute safety of products derived from hu-
inactivation steps were applied more rig- man plasma may be unattainable; start-
orously to concentrates of Factor VIII ing with the safest possible donated
103
and other clotting factors. Unfortu- plasma is of primary importance.
nately, a large proportion of the hemo- Avoiding Human Plasma. Factor VIII
philiac population receiving concen- concentrates have been produced by re-
trates before processing was improved combinant DNA technology and are li-
104
sustained HIV infection. Chronic hepati- censed for use. Batches are produced
tis was an additional complication in al- by culture of mammalian cells engi-
most all hemophiliacs receiving older neered to secrete Factor VIII into the
clotting factor products.
102 supernatant medium, which is purified
The thermal instability of Factor by ion-exchange chromatography and
VIII made it difficult to develop an ef- immunoaffinity chromatography using
fective heat treatment, until a practical a mouse monoclonal antibody against
approach was adopted in 1985. Since human Factor VIII. Except for addition
then, many disinfection steps have of human albumin to stabilize Factor
been introduced and factor concen- VIII, the product is free of human pro-
trates are now, in general, very safe teins, HIV, hepatitis viruses, and other
products. Each process has its own set unwanted agents.
of advantages and disadvantages. Appli-
cation of organic solvents and deter- Frozen Plasma
gents inactivates viruses with a lipid-
containing envelope (eg, HIV, HBV, HCV, Virus inactivation steps, originally de-
HTLV, EBV, CMV, HHV-6), but is ineffec- veloped for plasma fractionation, are be-



ing considered for transfusions of frozen a mechanism to encourage recognition
plasma. The options under study include and reporting of possible transfusion-as-
organic solvents and detergents, pas- sociated infections. HIV infection
teurization, and use of photochemi- thought to be a result of transfusion
105
cals. Solvent/detergent treatment, ef- should also be reported to the supplier,
fective against lipid-enveloped viruses, although the interval between transfu-
involves addition of 1% Triton X-100 and sion and the recognition of infection or
1% tri-n-butyl phosphate (TNBP) to symptoms may be years.
pooled plasma, followed by oil extraction Infection in a recipient should be re-
of the TNBP and chromatographic ad- ported to the collecting agency so that
sorption of the Triton X-100. To protect donors shown or suspected to be infec-
Factor VIII during pasteurization, stabi- tive can be evaluated and recipients of
lizers are added and subsequently re- other components from the implicated
moved by ultrafiltration. Photochemi- or other donations can be contacted and,
cals such as methylene blue can be added if necessary, tested. A donor who proves
to individual plasma units, which are to have positive results on tests during
then exposed to visible light. Of these the investigation must be placed on a
three approaches, solvent/detergent suitable deferral list.
treatment of plasma has been the best The Code of Federal Regulations [21
studied and validated. CFR 606.170(b)] requires that fatalities
attributed to transfusion complications
(eg, hepatitis, AIDS, and hemolytic reac-
Processing Cellular Components
tions) be reported to the Director, Cen-
The use of chemicals to inactivate vi- ter for Biologics Evaluation and Re-
ruses in red cell and platelet components search (CBER), Office of Compliance,
is actively being studied but is not yet Division of Inspections and Surveil-
106
close to clinical application. Most in- lance, 1401 Rockville Pike, Suite 200N,
activation protocols evaluated to date HFM-650, Rockville, MD 20852-1448. A
have employed photochemicals, pho- report should be made by telephone
toreactive compounds added to the (301-594-1191) within one working day
blood component, which is then exposed and a written report should be submitted
to light of a specific wavelength. These within 7 days.
may act by generating reactive oxygen
species that inactivate virus or by direct
effects on nucleic acid. Management of Posttransfusion
Infections
Reporting Transfusion-Associated Implicated Donors
Infections If documented transfusion-associated
Unexplained infectious disease reported hepatitis, HIV, or HTLV-I occurs in a pa-
in a transfusion recipient must be inves- tient who received only a single unit,
tigated for the possibility of transfusion- that donor must be permanently ex-
22
transmitted illness. Hepatitis is excluded from future donations, and the
pected to become apparent within 2 name be placed in a file of permanently
weeks to 6 months if it resulted from deferred individuals. If posttransfusion
transfusion, but even within this inter- viral infection occurs after exposure to
val the cause need not necessarily have blood from several donors, it is not nec-
been blood-borne infection. Blood cen- essary to exclude all of the potentially
ters and transfusion services must have implicated donors. If only a few donors


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