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Chapter 14
Transfusion-Transmitted Diseases
JoAnn Christensen, MS, MT(ASCP)SBB and Elizabeth F. Williams, MHS,
MT(ASCP)SBB

Introduction Zika Virus Transfusion-Associated Parasites

Donor Testing Profile Babesia microti
Transfusion-Associated Hepatitis Other Viruses Trypanosoma cruzi
Hepatitis A Cytomegalovirus Malaria (Plasmodium Species)
Hepatitis B Epstein-Barr Virus Prion Disease
Hepatitis C Parvovirus B19 Creutzfeldt-Jakob Disease
Hepatitis D Human Herpesvirus 6 and Human Pathogen Inactivation
Hepatitis E Herpesvirus 8 Plasma Derivatives
Hepatitis G Virus Emerging Viruses Cellular Components
HIV Types 1 and 2 Chikungunya Virus Quarantine and Recipient Tracing
Profile Dengue Virus (DENV) (Look-Back)
Human T-Cell Lymphotropic Viruses Ebola Virus Summary Chart
Types I/II (HTLV-I/II) Bacterial Contamination Review Questions
Profile Overview References
West Nile Virus Syphilis
Profile Tick-Borne Bacterial Agents

OBJECTIVES
1. Describe the pathology, epidemiology, laboratory testing, and prophylaxis/treatment of the following diseases: hepatitis A
through G, HIV 1 and 2, human T-cell lymphotropic viruses I and II, and West Nile virus (WNV).
2. Explain the implications of the following diseases for blood transfusions: Epstein-Barr virus, cytomegalovirus (CMV),
parvovirus B19, herpesvirus 6 and 8, dengue virus, chikungunya virus, Zika virus, Ebola virus, general bacterial contamination,
syphilis, Babesia microti, Trypanosoma cruzi, malaria (Plasmodium species), Leishmania donovani, and Creutzfeldt-Jakob
disease and variant Creutzfeldt-Jakob disease.
3. Describe procedures for look-back and recipient follow-up.
4. Describe pathogen inactivation for plasma and cellular components.

Introduction Donor Testing

Blood is a lifesaving resource. In the United States, blood com- Once a donor passes the medical screen and donor question-
ponents are subjected to rigorous testing that makes them naire, required serologic testing is performed for hepatitis B
extremely safe and renders the likelihood of a transfusion- surface antigen (HBsAg), antibody to hepatitis B core antigen
transmitted disease (TTD) very small. However, bacterial, (anti-HBc), antibody to hepatitis C virus (anti-HCV), anti-
viral, parasitic, and prion pathogens constantly evolve, and bodies to human immunodeficiency virus (anti-HIV 1/2),
if not detected in the testing process, can cause harm and antibody to human T-cell lymphotropic virus types I and II
even death. (anti-HTLV-I/II), and syphilis. Each donor must also be

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308 PART III Transfusion Practices

tested at least once for antibodies to Trypanosoma cruzi. Re- hepatitis viruses.2 The hepatitis viruses affect the liver as the
quired nucleic acid testing (NAT) is performed for: HBV primary clinical manifestation. Hepatitis viruses can be
DNA, HIV-I RNA, HCV RNA, WNV RNA, and ZIKV RNA transmitted through the fecal-oral route or parenterally
(Table 14–1).1,2 (through contact with blood and other body fluids).
As current test methods are extremely sensitive, confir- Hepatitis A virus (HAV) and hepatitis E virus (HEV) are
matory tests are used to detect false-positives. These tests, mainly transmitted through the fecal/oral route. Hepatitis B
which vary by the disease, include polymerase chain reaction virus (HBV), hepatitis C virus (HCV), hepatitis D virus
(PCR), Western blot (WB), and radioimmunoprecipitation (HDV), and hepatitis G virus (GBV-C or HGV) are primarily
assay (RIPA). transmitted parenterally.2
Surrogate markers (alanine aminotransferase [ALT] and
anti-HBc) were used in the past to detect non-A, non-B hepa- Hepatitis A
titis. Due to the sensitivity of the current testing for HCV, ALT
is no longer required; however, blood centers are continuing The hepatitis A virus (HAV) belongs to the Picornaviridae
to perform both tests. ALT testing has continued because the family of viruses and is a small, nonenveloped, single-
European Union requires it for recovered plasma. The Food stranded RNA enterovirus.
and Drug Administration (FDA) recommends performance of
Clinical Manifestations and Pathology
anti-HBc as an additional screen for HBV.2
Many other organisms may be transfusion transmitted; Symptoms, if they occur at all, generally appear abruptly
however, tests for them are not required in the blood screen- and last fewer than 2 months, but may persist for as long
ing process. These include other viruses such as Epstein- as 6 months in some individuals.3 They may include nau-
Barr virus (EBV), CMV, parvovirus B19 (B19), Ebola virus, sea, vomiting, anorexia, fatigue, fever, jaundice, dark urine,
dengue virus, chikungunya virus, bacteria (now considered and abdominal discomfort. Less than 10% of children
to be the leading cause of death from transfusion),2 parasites under 6 years will develop jaundice. Jaundice is more com-
such as Babesia microti, malaria, Leishmania donovani, and mon in older children and adults, occurring in 40% to 50%
prion diseases. of children between 6 and 14 years and 70% to 80% of
individuals older than 14 years.4 The disease is rarely fatal.
Transfusion-Associated Hepatitis Fulminant, cholestatic, or relapsing hepatitis may occur.
Symptoms usually resolve within 3 weeks and are generally
Hepatitis is a generic term describing inflammation of self-limiting.5 In rare cases, a patient may develop fulmi-
the liver. Symptoms typically include jaundice, dark urine, nant liver failure.
hepatomegaly, anorexia, malaise, fever, nausea, abdominal
pain, and vomiting. The clinical symptoms of hepatitis range Epidemiology and Transmission
from being asymptomatic to death. Transmission is primarily through the fecal-oral route—
It can be caused by many things, including viruses, bac- spread through water, food, and person-to-person contact.
teria, noninfectious agents such as chemicals (including Poor hygiene and poor sanitation contribute to the spread
drugs and alcohol), ionizing radiation, and autoimmune of HAV. Because young children are generally asymptomatic,
processes.2 EBV, CMV, parvovirus, and herpes simplex virus the disease is predominantly spread from person to person
(HSV) can cause hepatitis as a complication, but because it within the household. Other individuals at risk are those
is not the primary disease, these viruses are not considered who travel to countries where HAV is endemic, are users of
illegal drugs, have clotting factor disorders, work with non-
human primates, and are men who have sex with men.5 A
Table 14–1 Disease Transmission risk factor cannot be identified in 46% of cases.6
Prevention—Required Tests The incubation period for HAV is 28 days on average, and
Diseases Required Tests the peak viremic period occurs 2 weeks before the onset of
the elevation of liver enzymes or the appearance of jaundice.5
Hepatitis B HBsAg, IgM, and IgG antibody to HBc, HBV DNA Transmission of HAV by clotting factor concentrates treated
Hepatitis C IgG antibody to HCV, HCV RNA
with solvent or detergent pathogen process has been re-
ported.7 Rates in the United States have dropped following
HIV IgM and IgG antibody to HIV-1/2, HIV-1 RNA introductions of the Hep A vaccine in 1995 and universal in-
HTLV IgG antibody to HTLV-I/II
fant vaccination in 2006. In 2014 there were a reported 1,239
acute new cases in the United States7 (Table 14–2). Out-
Syphilis IgG or IgM antibody to T. pallidum antigens breaks of acute hepatitis A involving men who have sex with
or nontreponemal serologic test for syphilis men have been reported in European countries.6
West Nile virus WNV RNA
Laboratory Diagnosis
Trypanosoma cruzi IgG antibody to T. cruzi (one-time testing) Most of the virus is shed in the feces during the incubation
Zika virus ZIKV RNA period and declines to low levels by the onset of symptoms
(Fig. 14–1). The presence of IgM anti-HAV antibody is
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Chapter 14 Transfusion-Transmitted Diseases 309

Table 14–2 Disease Burden From Hepatitis A, B, and C in the United States
Hepatitis A Hepatitis B Hepatitis C
2013 2014 2015 2013 2014 2015 2013 2014 2015

Number of acute cases reported 1,781 1,239 1,390 3,050 2,791 3,370 2,138 2,194 2,436

Rate of infection per 100,000 population 0.6 0.4 0.4 1.0 0.9 1.1 0.7 0.7 0.8

Number of persons with chronic infections No chronic disease 850,000–2.2 million 2.7–3.9 million

Data from Centers for Disease Control (www.cdc.gov/hepatitis/Statistics/).

Markers in HAV Infection Clinical Manifestations and Pathology

The clinical picture of HBV infection is highly variable. Most
Icterus people with acute illness will recover with no liver damage,
Enzymes 15% to 25% of chronically infected persons develop liver dis-
ease, and an estimated 3,000 persons in the United States die
HAV from HBV-related illness per year.4 The individual may be
(Stool)
Anti-HAV completely asymptomatic or may present with typical signs
Exposure Anti-HAV
IgG of disease, including jaundice, dark urine, hepatomegaly,
IgM anorexia, malaise, fever, nausea, abdominal pain, and vom-
iting. For children younger than 5 years, fewer than 10%
5 20 30 show signs of jaundice and clinical illness. However, infec-
Days Years tions acquired at birth or between ages 1 to 5 years result in
Figure 14–1. Markers in acute HAV infection. The typical pattern of HAV infection a chronic infection 90% and 30% of the time, respectively.
includes early shedding of virus in the stool, appearance of IgM anti-HAV, and For those older than 5 years, up to 50% will have clinical
immunity on recovery. illness, but only 2% to 10% will develop a chronic infection.
Chronic infections are associated with cirrhosis and liver
cancer. Hepatitis B related mortality rate for 2014 was
required for diagnosis of hepatitis A. IgM antibodies are 0.5 deaths per 100,000 population.4
detectable at or prior to the onset of clinical illness and de-
Epidemiology and Transmission
cline in 3 to 6 months. IgG antibodies to HAV appear soon
after IgM and may persist for years after the infection.4 HBV is transmitted through exposure to bodily fluids con-
taining the virus from an infected individual. Concentrations
Prophylaxis and Treatment of the virus are at high levels in blood, serum, and wound
A vaccine to HAV was licensed in the United States in 1995. exudates; at moderate levels in semen, vaginal fluids, and
Use of the vaccine was initially recommended for at-risk saliva; and at low levels in urine, feces, sweat, tears, and
populations. In 2006 use of the vaccine was recommended breast milk. Transmission may be sexual, parenteral, or peri-
for all children ≥1 years of age as well as at-risk populations. natal.8 Percutaneous transmission may occur through needle
The number of cases has decreased 90.8% from 2000 stick (drug use, occupational hazard, acupuncture, tattooing,
(13,397 cases reported) to 2014 (1,239 cases reported).4 or body piercing), hemodialysis, human bite, transfusion
The vaccine is produced from inactivated HAV. It is believed of unscreened blood or blood products, or sharing razors.
that the risk is low for pregnant women and that no special Permucosal transmission can occur through sexual inter-
precautions should be taken for immunocompromised per- course or vertically from mother to infant (transplacental or
sons.5 Other prevention methods include improvement in through breast milk).8 According to the Surveillance for Viral
water purification, good hygiene, and improved sanitation. Hepatitis Report of 2014, higher rates of hepatitis B continue
Immune globulin can be used preexposure to protect those among adults, especially among males between the ages of
traveling to high HAV-endemic areas or postexposure to pre- 30 to 49 years.4
vent infection in those exposed within a family, after an out-
Laboratory Diagnosis
break at a day-care center, or from a common source of
exposure such as a restaurant. Immune globulin should be HBV consists of several proteins or antigens to which the
used postexposure within 2 weeks for maximum protection.7 body can make antibodies (Fig. 14–2). A surface antigen
protein, HBsAg, is on the outer envelope of the virus. It can
Hepatitis B also be found floating free in the plasma. Antibodies can be
produced to two proteins within the core: hepatitis B core
Hepatitis B virus (HBV) is a partially double-stranded circu- antigen (HBcAg) and hepatitis B envelope antigen (HBeAg).
lar DNA virus of the Hepadnaviridae family.4 Viral replication levels of these markers along with the
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310 PART III Transfusion Practices

Dane Core Coat has been diagnosed, family members should be tested. If un-
particle particle protein infected, they should be vaccinated. If infected, they should
(HBcAg) (HBsAg)
(HBeAg)
be treated.
Detergent
Hepatitis C
+
Treatment
28nm Hepatitis C virus (HCV) is a member of the Flaviviridae virus
42nm 200 x 22nm
family and is caused by a virus with an RNA genome.8
SDS Clinical Manifestations and Pathology
The incubation period of HCV is 2 to 26 weeks. The average
+ incubation period is 7 to 8 weeks, followed by seroconver-
sion occurring in 8 to 9 weeks.9 Most HCV cases are asymp-
DNA Polymerase
activity
tomatic. Some cases report nonspecific symptoms such as
anorexia, malaise, fatigue, or abdominal pain. Most sympto-
Figure 14–2. Diagram of the intact Dane particle (HB virion) as seen by electron matic cases are very mild. Of HCV-infected individuals,
microscopy. Detergent treatment disrupts the particle into a core particle and outer 75% to 85% become chronic carriers, 60% to 70% develop
coat protein, releasing DNA (double- and single-stranded) and DNA polymerase
chronic liver disease, 5% to 20% develop cirrhosis over a
activity.
period of 20 to 30 years, and 1% to 5% will die from cirrhosis
or liver cancer. Of the three types of hepatitis (A, B, C),
host’s production of IgM or IgG antibodies are all used to hepatitis C accounted for the highest rate of death due to
make an initial diagnosis and follow the course of infection hepatitis in 2014 (5.0 deaths per 100,000 population).4
(Table 14–3).5
HBV DNA is the first marker to appear and can be Epidemiology and Transmission
detected by polymerase chain reaction (PCR) testing before Because most HCV cases are asymptomatic, the worldwide
HBsAg reaches detectable levels. HBsAg is detectable 2 to incidence is unknown. There was a 2.6-fold increase of
12 weeks postexposure during the acute stage and becomes reported acute hepatitis C cases from 2010 (850 cases) to
undetectable in 12 to 20 weeks after development of anti- 2014 (2,194). It is estimated that there are 2.7 to 3.9 million
HBsAg (Fig. 14–3). If the patient develops chronic HBV, the chronic carriers in the United States.4 In 2014 the rate of
level of HBsAg remains high. HBsAg can be used to monitor reported acute cases was 0.7 per 100,000 population (see
the stages of HBV from the acute, active infection to recov- Table 14–2). The risk of post-transfusion HCV has declined
ery or a chronic infection. It is also used to screen donor dramatically since the introduction of testing.
blood.8 HCV can be transmitted percutaneously through needle
HBeAg appears after the HBsAg and, in recovering stick, hemodialysis, human bite, transplant or transfusion,
patients, disappears before HBsAg. In chronic patients, it or by acupuncture, tattooing, or body piercing. It can also
remains elevated. HBeAg is present during the time of active be transmitted permucosally through sexual intercourse,
replication of the virus and is considered a marker of high contact with an infected toothbrush or razor, or perina-
infectivity.9 tally. Hepatitis C is transmitted mainly by exposure to
HBcAg is present in the serum but is undetectable. How- contaminated blood, with IV drug use being the main
ever, IgM anti-HBc is the first antibody to appear, and it per- source of infection. Recent increased cases have been re-
sists for about 6 months. Appearance of this antibody ported from the HIV-positive men who have sex with men
indicates current or recent acute infection.9 population.4

Prophylaxis and Treatment Laboratory Diagnosis

The donor questionnaire is used to identify individuals at Diagnosis of HCV is difficult. Not only are symptoms so
risk for HBV infection. For those who are not eliminated by mild in acute cases as to make separation of acute HCV
that process, testing for HBsAg, anti-HBc, and HBV DNA is from chronic HCV difficult, but also separating HCV from
required.10 other forms of liver disease is not easy. Diagnosis depends
An HBV vaccine was licensed in 1981 and introduced in on biochemical changes suggestive of HCV, detection of
1982. Hepatitis vaccination programs will eliminate domestic HCV RNA or anti-HCV in serum, or a known exposure to
HBV transmission, and the increased vaccination of adults the virus.
with risk factors will help accelerate the progress toward Today, anti-HCV testing via enzyme immunoassay (EIA)
elimination.4 or chemiluminescent immunoassay (ChLIA) methodology
Hepatitis B immune globulin (HBIG) injections and the and HCV RNA testing are performed on all donor units. For
vaccine given soon after exposure or within 12 hours of supplemental confirmatory testing, the recombinant im-
birth, if the mother is infected, may prevent infection. Three munoblot assay (RIBA) is no longer available; however, blood
other treatments licensed by the FDA are interferon (IFN)- centers may obtain FDA approval to use an alternate testing
α-2b,11 lamivudine, and adefovir dipivoxil.12 Once a patient pathway, including line immunoblot8 (see Table 14–3).
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Chapter 14 Transfusion-Transmitted Diseases 311

Table 14–3 Molecular and Serologic Tests in the Diagnosis of Viral Hepatitis
Virus Test Reactivity Interpretation
Anti-HBc
HBV DNA HBsAg Total IgM Anti-HBs HBeAg* Anti-HBe

+ + +/– +/– – +/– – Early acute HBV infection/chronic carrier

+ + + + – + – Acute infection

+/– – + + – +/– +/– Early convalescent infection/possible

early chronic carrier

+/_ + + – – +/– +/– Chronic carrier

– – + – + – +/– Recovered infection

– – – – + – – Vaccination or recovered infection

– – + – – – – Recovered infection? False-positive?

+ – – – – – – Window period

HDV RNA HBsAG Anti-HBc Anti-HBs Anti-HDV

+ + + _ + Acute or chronic HDV infection

– – + + + Recovered infection

Anti-HCV Recombinant
Antigens

Screening
HCV RNA EIA 5-1-1 c100-3 c33c c22-3

+/– + Not available Possible acute or chronic HCV infection

– + – – – – False-positive

+/– + + + – – Possible false-positive (if RNA is

negative); possible acute infection
(if RNA is positive)†

+/– + – – + + Early acute or chronic infection (if RNA

is positive); false-positive or late recov-
ery (if RNA is negative)†

+ + + + + + Acute or chronic infection

– + +/– +/– + + Recovered HCV†

HAV RNA Anti-HAV

Total IgM

+ + + Acute HAV

– + – Recovered HAV/vaccinated

HEV RNA Anti-HEV

Total IgM Acute HEV

+ + +

+ + – Recovered HEV

Taken from AABB Technical Manual, 15th ed., pp. 670–671. Bethesda, Maryland, 2005, with permission.
HBsAg = hepatitis B surface antigen; anti-HBc = antibody to hepatitis B core antigen; anti-HBs = antibody to HBsAg; HBeAg = hepatitis B envelope antigen; anti-HDV = antibody to
hepatitis D virus; anti-HAV = antibody to hepatitis A virus; anti-HCV = antibody to hepatitis C virus; anti-HEV = antibody to hepatitis E virus
*Those with HBeAg are more infectious and likely to transmit vertically.
†Anti-5-1-1 and anti-c100-3 generally appear later than anti-c22-3 and anti-c33c during seroconversion and may disappear spontaneously during immunosuppression or after

successful antiviral therapy.

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312 PART III Transfusion Practices

HBsAg Anti-HBs Hepatitis E

HBeAg Anti-HBc IgM
Anti-HBc IgG
Anti-HBe
Hepatitis E (HEV) is a member of the Caliciviridae family of
nonenveloped RNA viruses. It is rare in the United States;
however, it is the leading cause of hepatitis in the United
LFT Kingdom.14 Recent studies have reported the rate of 1:9,500
SYMP donors in the United States are HEV RNA positive.14 As in
HAV, HEV is spread through the fecal-oral route, usually
through contaminated drinking water in developing coun-
tries. A carrier state does not develop after the acute, usually
self-limiting illness. Chronic HEV infection has been re-
ported in patients on immunosuppressive therapy following
solid organ transplantation.15

Clinical Manifestations and Pathology

Weeks after exposure Symptoms are the same as for any hepatitis. Generally, these
cases are short-lived but can be prolonged. HEV causes an
Figure 14–3. Markers in HBV infection.
acute, self-limiting hepatitis that may last from 1 to 4 weeks
in most people.15

Prophylaxis and Treatment Epidemiology and Transmission

Currently there is no HCV vaccine. Prevention consists of HEV genotypes (G) 1, 2, and 4 (usually occurring in devel-
worldwide screening of blood and blood products; de- oping countries) and HEV G3 (usually occurring in devel-
struction or sterilization of needles and surgical or dental oped countries) are responsible for acute, sporadic cases
instruments; universal precautions; and education about of infection that can be short-lived or prolonged. The fecal-
the risks. oral route is the most common form of transmission for G1
Optimal therapy for chronic HCV is now considered to and G2. Transmission route for G3 and G4 are foodborne.14
be pegylated IFN and ribavirin combination.13 In a small Most cases in the United States are G3 contracted through
study by Gerlach and colleagues,13 50% of patients with eating undercooked pork or venison.15 HEV G1, G2, and G4
acute HCV spontaneously and permanently cleared the virus do not progress to a chronic state. Cases of chronic HEV G3
within the first 3 to 4 months. Patients who were still viremic infection have been reported.14 HEV is a major cause of
at 3 months and were treated at that point had an 80% clear- hepatitis globally and is becoming a concern for transfusion
ance rate. However, most cases were not symptomatic and transmission as more cases of transfusion-associated infec-
therefore were not noticed and treated until the patient was tions are reported in developed as well as underdeveloped
in the chronic phase. Treatment with INF-α and ribavirin in countries. Some countries have introduced HEV screening
these chronic cases achieved only a 30% to 54% sustained for blood donations.14
viral clearance.13
Laboratory Diagnosis
Hepatitis D Both IgM and IgG antibody to HEV (anti-HEV) may occur
following HEV infection. The titer of IgM anti-HEV de-
Hepatitis D (HDV) is a defective, single-stranded RNA virus clines rapidly during early convalescence; IgG anti-HEV
that is found only in patients with HBV infection. It requires persists and appears to provide at least short-term protec-
HBsAg in order to synthesize an envelope protein and repli- tion against disease (see Table 14–3). Antibodies are usually
cate. It was previously called the delta antigen. If HBV and identified using highly sensitive enzyme immunoassays
HDV are contracted concurrently, this coinfection, as com- that are recombinant and synthetic HEV antigens.9 Nucleic
pared with HBV alone, appears to cause a more severe acute acid testing for HEV RNA is used by research labs but is
disease, with a higher risk of fulminant hepatitis (2% to 20%) not available for commercial use. There are also no FDA-
but a lesser risk of developing chronic hepatitis. approved serologic methods approved for diagnostic use in
Those at highest risk of infection are IV drug users. This the United States.15
infection can also be transmitted sexually. It is believed that
20 million people are infected worldwide, but the number Prophylaxis and Treatment
of new infections appears to be declining, most likely due to Meat such as pork, venison, and shellfish must be thor-
the implementation of the Hep B vaccine.8 oughly cooked and water supplies must be cleaned and
HDV is detected by testing for IgM or IgG anti-HDV or sewage disposal handled properly to prevent HEV infection.
HDAg and HDV RNA in the serum. Tests for HDV are not Currently, no commercially available vaccine exists for the
required for blood donations. If a donor has HBV, the unit will prevention of hepatitis E. Ribavirin has been shown to be
not be used for transfusion. As HDV cannot exist without effective for treatment of chronic HEV, but its effectiveness
HBV, testing for HBV will eliminate any infections with HDV. for treatment of acute infection is not clear.14
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Chapter 14 Transfusion-Transmitted Diseases 313

Hepatitis G Virus HIV is a retrovirus that is spherical in shape, with an ap-

proximate diameter of 100 nm. It consists of an envelope of
GB virus C (GBV-C) and hepatitis G virus (HGV) are two glycoproteins, core proteins, and an inner core of viral RNA
genotypes of the same enveloped RNA virus that belongs to and reverse transcriptase. Infection with the virus causes a
the Flaviviridae family. Approximately 1% to 2% of U.S. slowly progressing immune disorder. The causative viruses,
donors have tested positive for HGV, making this virus more HIV-1 and HIV-2, are similar in structure, varying primarily
common than HCV.16 However, recent reports do not impli- in the envelope proteins (Fig. 14–4 and Table 14–4). Almost
cate GBV-C/HGV as a cause of hepatitis. all cases in the United States result from infection with the
HIV-1 virus. HIV-2 is prevalent in West Africa but is very
Clinical Manifestations and Pathology
rarely diagnosed in the United States; when it is diagnosed
Although acute, chronic, and fulminant hepatic failure cases in the United States, it is usually linked to an association
have been associated with GBV-C/HGV, there are other studies with West Africa.23
that do not implicate GBV-C/HGV. One article showing a
strong association with fulminant hepatitis dealt with a certain Profile
mutated strain of GBV-C/HGV.17 In another article by Halasz,18
33 GBV-C/HGV individuals were identified who had no coin-
fection with other known hepatitis viruses. No evidence of liver Clinical Manifestations and Pathology
disease, clinical or biochemical, was found. In fact, there is Primary infection with HIV may be asymptomatic or may re-
some evidence that patients with HIV who have a coinfection sult in a mild, chronic lymphadenopathy with symptoms
with HGV have a slower progression to AIDS.16 Overall data similar to those seen in infectious mononucleosis. Symptoms
do not support GBV-C/HGV as a major cause of liver failure. may occur within 6 to 12 weeks of infection and persist for
a few days to 2 weeks. HIV enters the cell by the binding of
Epidemiology and Transmission the virus glycoprotein 120 with cell surface receptors. Cells
HGV is transmitted by the bloodborne route. Parental trans- possessing these receptors include CD4+ lymphocytes,
mission through contaminated blood and the presence of the macrophages, and other antigen-presenting cells. The disease
virus in bile, stool, and saliva suggest transmission through may have a long, clinical latency period with the absence of
the fecal-oral and respiratory routes.9 It has been found in clinical symptoms. During this period, antibody concentra-
20% to 24% of intravenous drug users and in higher rates tion and viral load reach equilibrium. As the viral load in-
among people with HIV.19 Vertical or perinatal transmission creases and the CD4 count decreases, the patient progresses
from mother to child has been documented.20 toward clinical AIDS. When the CD4 count is less than
Most adult infections appear to be transient, with viral 200/µL, the patient is classified as having clinical AIDS. The
clearance followed by antibody to the viral envelope (E2)
production. Vertical or perinatal infections and other infec-
tions established early in life can last for years but do not HIV-2
HIV-1
cause liver disease.18,20

Laboratory Diagnosis gp120 gp41 gp125 gp36

Reverse transcription polymerase chain reaction (RT-PCR) RNA p26 RNA
p24
for GBV-C/HGV-RNA is used to diagnose a current, ongoing
infection. Anti-E2 along with a negative PCR for GBV-C/
RT RT
HGV-RNA indicates a past infection and recovery. Individu-
als who never develop the GBV-C/HGV E2 antibody are still Figure 14–4. Schematic representation of human immunodeficiency virus
infected.21 These assays are first generation, and the evalua- genomes, HIV-1 and HIV-2. RT = reverse transcriptase.
tion has not been completed on the sensitivity and specificity
of these assays.18
Table 14–4 Components of the HIV Virus
Prophylaxis and Treatment
Bands Observed
Interferon-α treatment has been used with conflicting
results. In most cases, the level of the GBV-C/HGV-RNA Gene HIV-1 HIV-2 Protein
returned to normal levels once therapy was discontinued. Gag p18, p24, p15 p16, p26, p55 Core
Only a small percentage of cases with low pretreatment viral
loads had a predictable sustained response.22 Pol p31 Endonuclease

p51, p65 p68 Reverse transcriptase

HIV Types 1 and 2
Env gp41 gp36 Transmembrane protein
HIV-1 and HIV-2 are well recognized as the etiologic agents gp120, gp160 gp140, gp125 Envelope unit
of AIDS. AIDS was first diagnosed in 1981, but the causative
agent was not identified until 1984. gp = glycoprotein (number indicates molecular weight); p = protein
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314 PART III Transfusion Practices

resultant immunodeficiency allows the onset of opportunis-

tic infections such as Pneumocystis carinii pneumonia, p24
Anti-p24
Kaposi’s sarcoma (KS), fungal infections, and a host of oth- Anti-gp41,
ers. About 50% of patients do not progress to clinical AIDS 120, 160
for 10 years or more.

Epidemiology and Transmission

The number of cases of HIV infection rose rapidly in the
1980s after identification of the disease. After the incorpo-
ration of combination retroviral drug therapy in treatment
protocols in the late 1990s, there was a significant reduction
in the reported numbers of new AIDS cases and deaths.
Reduction of death rates has resulted in an increased number
of persons living with AIDS. The Centers for Disease Control
and Prevention (CDC) estimates that 1.1 million adults and
adolescents were living with diagnosed and undiagnosed Infection Acute Asymptomatic ARC AIDS
6 wks- months
HIV infection at the end of 2011 in the United States.23 2 mo to years
HIV is transmitted through sexual contact with an in-
fected person, use of contaminated needles during drug use, Figure 14–5. Pattern of serologic markers detected in HIV infection. ARC =
and very rarely through transfusion of blood or blood com- AIDS-related complex.
ponents. Congenital transmission may also occur. High-risk
populations include men who have sex with men and HIV-2 enzyme-linked immunoassay, and a rapid diagnostic test
IV drug users. The blood supply is most at risk from those used for HIV-1 and HIV-2 differentiation.24 HIV-1 RNA detec-
individuals who have been recently infected with the virus tion by NAT was introduced in 1999 as an investigational new
but have not yet produced antibodies. drug (IND). In 2002 the first NAT test for HIV-1 RNA was ap-
It was recognized over a decade ago that transfusion of proved (licensed) for use in the United States. HIV-1 RNA test-
blood and components from HIV-infected individuals may ing closed the window period between time of infection and
result in HIV infection in the recipient and development of the detection of antibody to 7 to 10 days.24 False-positive test
transfusion-associated AIDS. HIV infection may occur after results for either antibody and/or NAT may allow for donor
receiving a single contaminated unit of whole blood or its reentry.25 The risk of HIV-1 infection through transfusion is
components. Albumin and immune globulins have not been 1:1,000,000 per unit transfused.24
reported to transmit HIV. Blood donor screening practices
have dramatically reduced the incidence of transfusion- Prophylaxis and Treatment
related transmission, but the possibility of transmitting In 2005, the CDC revised recommendations for routine test-
HIV remains when the donor has not yet seroconverted and ing and has implemented an initiative aimed at reducing
the level of virus in the blood is low. This subpopulation of barriers to early diagnosis of HIV infection entitled Advanc-
HIV-infected persons who are unaware of their positive ing HIV Prevention: New Strategies for a Changing Epi-
serostatus may pose the greatest risk to the blood supply. demic. This initiative also aims to increase access to medical
care, treatment, and prevention for those persons living with
Laboratory Diagnosis HIV.26 To reduce perinatal transmission, the CDC recom-
The use of very sensitive serologic testing in screening the mends routine HIV testing of all pregnant women and
blood supply has resulted in an extremely low risk of HIV screening of all neonates whose mothers have not been
transmission. The pattern of serologic markers detected in tested.
HIV infection is shown in Figure 14–5. The window period Treatment with highly active antiretroviral therapy has
is that time after infection but before antibody or antigen is lengthened life and improved quality of life for those infected
detectable by currently available testing procedures. It is pos- with HIV. Use of this therapy has resulted in the most stable
sible for a donation to be infectious but to test negative for HIV morbidity and mortality rates since 1998.27
HIV-1/2 antibodies when the donor is in the window period.
Antibodies are detectable at about 22 days after infection. Human T-Cell Lymphotropic Viruses
In 1985, using an EIA to screen all blood donations for Types I/II (HTLV-I/II)
antibodies to HIV-1 was instituted. Testing for HIV-2 was
initiated in 1992. EIA is used for the qualitative detection of HTLV-I and HTLV-II are RNA retroviruses. HTLV-I causes a
HIV-1/2 in a ChLIA test. Positive screening tests are repeated T-cell proliferation with persistent infection.28 Once the RNA
in duplicate, and if at least one of the duplicates also tests pos- has been transcribed into DNA, it is integrated randomly into
itive, a confirmatory test is performed. The confirmation of the host cell’s genome.29 Once integrated into the DNA, the
HIV-1/2 is performed using one or a combination of tests. provirus can either complete its replication cycle or remain
These include HIV-1 indirect immunofluorescence assay (IFA), latent for many years.
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Chapter 14 Transfusion-Transmitted Diseases 315

Profile whereas HTLV-II is seen in some Native American popula-

tions.28,31 Indications from the high numbers of carriers and
Clinical Manifestations and Pathology low numbers of individuals diagnosed with actual disease are
HTLV-I was the first retrovirus to be associated with a human that most carriers are asymptomatic their entire lives.28,29
disease. That association was with adult T-cell lymphoma/ The risk of HTLV-I/II transmission through transfusion is
leukemia (ATL), a highly aggressive, mature T-cell non- less than 1:2,000,000 units transfused.24
Hodgkin’s lymphoma with a leukemic phase.30 ATL does not
respond well to chemotherapy, and mean survival time with Laboratory Diagnosis
acute ATL is less than 1 year. Immunodeficiency similar to Because the majority of carriers are asymptomatic, diagnosis
that of patients with AIDS develops, making the ATL patient is based on seroconversion after exposure. In the United
susceptible to other hematologic malignancies.29 HTLV-I is States, FDA-licensed EIA using whole virus lysates from both
also associated with the progressive neurological disorder viruses is used to detect both anti-HTLV-I and anti-HTLV-II.
known as HTLV-I-associated myelopathy or tropical spastic With 60% homology between HTLV-I and HTLV-II, antibody
paraparesis (HAM/TSP). A few case reports in the literature cross-reactivity makes it difficult to distinguish between the
suggest that HTLV-II may impact the development of neuro- two viruses. Results are reported as reactive or negative for
logical diseases, including HAM, but subsequent studies have HTLV-I/II. For first-time reactive donors testing is repeated
failed to support this with convincing evidence.31 using a second licensed HTLV-I/II screening test and with a
Epidemiological data suggest blood donors infected with licensed Western blot test. There are no NAT tests available
HTLV-I or HTLV-II have an excess of infectious syndromes, for HTLV-I/II and no FDA guidance for donor reentry.24
such as pneumonia, bronchitis, and urinary infections.32 The AABB33 and FDA have published guidelines on the
HTLV-I is associated with uveitis and infective dermatitis of use of the unit for transfusion and donor notification as
children, Sjögren’s syndrome, polymyositis, and facial nerve shown in Figure 14–6. The guidelines state that if the donor
palsy.9 is repeatedly reactive by the test of record (original EIA)
but negative by the second licensed EIA of a different type
Epidemiology and Transmission (different manufacturer), the donor is still eligible for dona-
HTLV-I is transmitted vertically (breastfeeding), sexually tion. The donor can continue to donate as long as the test-
(transmission from male to female more common), and of-record EIA is negative on the next donation. If the donor
parenterally (blood transfusion or IV drug abuse).9 Because is repeatedly reactive by test of record on two separate occa-
recipients of RBCs, platelets, and whole blood, but not fresh- sions or on the same donation by the test-of-record assay and
frozen plasma, have seroconverted, it is believed that trans- the different manufacturer’s EIA, the donor is indefinitely
mission requires introduction of infected living white blood deferred.
cells (WBCs).28,29 This theory is supported by the fact that
units stored for at least 7 days before transfusion are less Prophylaxis and Treatment
likely to transmit the virus. ATL does not respond well to treatment. However, early
There appears to be a strong correlation between disease treatment with corticosteroids appears to have some effect
development and host factors such as cytotoxic T lympho- on HAM/TSP. There is no treatment for chronic or advanced
cytes and HLA types. Susceptibility to ATL seems to correlate disease.28 The best prophylaxis is to prevent exposure. How-
with polymorphisms of the tumor necrosis factor α (TNF-α) ever, as the majority of infected individuals are asympto-
that result in an increased production of TNF-α.29 In indi- matic, it is difficult to prevent spread to an uninfected
viduals with HAM/TSP, both cellular and humoral immune individual vertically or sexually. Infected mothers should not
responses are increased as compared with those of asympto- breastfeed.
matic carriers and seronegative controls.31 However, ATL
seems to occur in persons who were infected as infants, with West Nile Virus
a latent period of approximately 67 years, whereas HAM/TSP
is generally seen in individuals who are infected in childhood West Nile virus (WNV) is a member of the Flavivirus family
or as an adult, with a variable latency as short as weeks to and is a human, avian, and equine neuropathogen. It is a
months. There is a 40% to 60% probability of seroconversion single-stranded RNA lipid-enveloped virion that is common in
within 51 days following an infected blood transfusion.28 For Africa, West Asia, and the Middle East. WNV is a member of
both diseases, the host’s ability to keep the proviral load low the Japanese encephalitis virus antigenic complex that includes
correlates with asymptomatic carriers.29,31 St. Louis encephalitis virus prevalent in the Americas, Japanese
Worldwide, it is estimated that 10 to 20 million people are encephalitis virus prevalent in East Asia, and Murray Valley
infected with HTLV-I and HTLV-II.29,31 It is endemic in parts encephalitis virus and Kunjin virus prevalent in Australia.34
of southern Japan, central and West Africa, the Caribbean, WNV was first documented in the Western Hemisphere
the Middle East, Melanesia, Papua New Guinea, the Solomon when 149 cases were reported in New York in 1999. In the
Islands, and in Australian aborigines. In the United States, United States, reported cases of WNV reached 9,862 cases
HTLV-I and HTLV-II are seen primarily in IV drug users. with 264 reported deaths in 2003. By 2015, WNV cases num-
HTLV-I is also seen in immigrants from endemic areas, bered 2,175, and 146 deaths were reported.35
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316 PART III Transfusion Practices

First Donation or
Previous Donation Previous Donation
Negative Repeat Reactive

Current EIA Current EIA

repeat Negative or repeat Negative or

reactive non-repeat reactive non-repeat
reactive reactive
2nd licensed 2nd licensed
EIA Unit ok to EIA unit ok to use
use donor not
notified, but
negative reactive negative reactive remains in
surveillance
category
unit destroyed unit unit destroyed unit
donor not destroyed destroyed
notified, but donor notified;
entered into indefinite
surveillance confirmatory deferral confirmatory
category tests* tests*

Not performed performed performed performed

donor notified
indefinite deferral neg, or Ind pos

Donor Donor donor donor

notified notified counseling notified
indefinite permanent indefinite
Ind - indeterminant; pos - positive; neg - negative deferral deferral deferral
EIA - enzyme immunosorbent assay
*confirmatory tests - western blot; immunoblot;
recombinant immunoprecipitation assay

Figure 14–6. Flowchart for HTLV-I/II testing.

Profile and then bite humans. Although at least 65 species of

mosquitoes have been found to carry WNV, the genus Culex
Clinical Manifestations and Pathology is the chief vector.39 The infection in humans has an incuba-
WNV is usually subclinical but may cause a mild flulike dis- tion period of approximately 3 to 14 days following the
ease. However, the strain in the United States is often associated mosquito bite, with symptoms lasting 3 to 6 days. Other
with more severe disease. In 2002, outbreaks determined animals can become infected, including horses, cats, dogs,
by antibody screening found that 20% to 30% of infected bats, chipmunks, skunks, squirrels, and domestic birds and
individuals exhibited symptoms ranging from mild fever and rabbits. Although mosquito bites are the most common route
headache to extensive rash, eye pain, vomiting, inflamed of infection, there is a slight risk of contracting WNV from
lymph nodes, prolonged lymphocytopenia, muscle weakness, blood components, organ transplants, pregnancy, and breast
disorientation, and even acute flaccid paralysis and po- milk. Following the introduction of blood donor NAT screen-
liomyelitis.36 The association of paralysis and poliomyelitis ing for WNV RNA in 2003, there have been 14 cases of
with WNV is recent. It is a peripheral demyelinating process transfusion-associated WNV infection reported in the Amer-
similar to Guillain-Barré syndrome.37 WNV is capable of cross- ican Red Cross system; translating to a risk of transmission
ing the blood-brain barrier and can cause what is known as of WNV through transfusion at 1 per 84,000,000 units
West Nile encephalitis, West Nile meningitis, or West Nile donated.24
meningoencephalitis.38 Approximately 1 in 150 infections re-
sults in severe neurological disease that may cause permanent Laboratory Diagnosis
neurological impairment, with encephalitis reported more Viremia usually lasts approximately 6 days and peaks around
often than meningitis. The risk of severe neurological disease the onset of symptoms. Once clinical symptoms occur, the
increases markedly for anyone over the age of 50 years.38 IgM WNV-specific antibody titer increases and the virus con-
centration in the bloodstream decreases. Until July 2003,
Epidemiology and Transmission diagnosis depended on the clinical findings and specific
Birds are the primary amplifying hosts in a mosquito-bird- laboratory tests. IgM antibody-capture enzyme-linked im-
mosquito cycle. Incidentally, mosquitoes feed off infected birds munosorbent assay (ELISA) was the method used to detect
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Chapter 14 Transfusion-Transmitted Diseases 317

IgM antibody to the WNV in serum and cerebrospinal fluid infected individuals experience symptoms. ZIKV has been
(CSF). In the 1999 and 2000 outbreak in New York, 95% of associated with severe neurological complications including
all infected patients for whom CSF was tested had a demon- increased rates of microcephaly and fetal brain anomalies
strable IgM antibody. However, because all Flaviviruses are during pregnancy and Guillain-Barre syndrome.43
antigenically similar, cross-reactivity has been observed in
testing persons who have been vaccinated for a Flavivirus, Epidemiology and Transmission
such as yellow fever or Japanese encephalitis, or who have ZIKV was first described in a rhesus monkey in 1947. Human
been recently infected with another Flavivirus, such as illness due to ZIKV was confirmed in cases in Nigeria in
St. Louis encephalitis or dengue fever. The plaque reduction 1953. Outbreaks of ZIKV infections occurred in Micronesia
neutralization test is the most specific test for arthropod- and in French Polynesia in 2007 and 2013, respectively. By
borne Flaviviruses and helps to distinguish false-positive IgM 2015, ZIKV cases were reported in the Americas with cases
antibody-capture ELISA from cross-reactivity.40 reported in the United States from Puerto Rico. In July of
Clinically, the serologic tests for IgM antibodies to WNV 2016, the first cases of ZIKV infection were reported on the
using ELISA can be used for testing symptomatic patients. continental United States in Florida.44 In 2016, ZIKV infec-
Because the virus is in the bloodstream before either symp- tions became a nationally notifiable condition and subject to
toms or antibodies develop, blood screening tests for WNV surveillance by the Centers for Disease Control and Preven-
that identify the virus itself were needed. In June 2003, two tion (CDC). Provisional 2016 data indicate that there were
commercial WNV-screening NATs were distributed, and im- 5,102 symptomatic (excluding congenital disease cases)
plementation of donor blood testing began “under phase III ZIKV cases. Approximately 95% of the reported cases
investigational new drug (IND) FDA approval.”41 As of involved travelers returning from affected areas.45 The CDC
July 14, 2003, all civilian blood donations were being established a U.S. Zika pregnancy registry for surveillance
screened by NAT. Units are initially screened individually or data on congenital disease cases. Data gathered in 2016
in pools of 6 or 16, depending on the kit manufacturer. through June of 2017 include a reported 1,687 completed
Individual samples are tested if the pool is positive with pregnancies and eight pregnancy losses (with birth defects).
NAT.41 Testing facilities must establish policies and proce- Eighty-eight of the 1,687 completed pregnancies resulted in
dures to define when pools versus individual NAT testing a live-born infant with birth defects.46
will be performed based on threshold levels during seasonal
activity.41 From 2003 through 2016 the Red Cross has de- Laboratory Diagnosis
tected approximately 3,500 WNV-infected donors.24 Approximately 80% of ZIKV infections are asymptomatic.
WNV has become a major area of focus for transfusion When symptoms do occur, the period of viremia without
safety, especially since there have been large outbreaks in the symptoms ranges from 3 to 12 days.44 ZIKV RNA has been
United States when comparing WNV with other transmissi- found in asymptomatic blood donors, and there have been
ble diseases tested by NAT testing. There is a similar interval reported cases of probable transmission of ZIKV through
in which it is detected, but when comparing testing by the transfusion.44 The FDA has established ZIKV as a transfusion-
minipool method, WNV has a much shorter duration of transmitted infection. In February of 2016, the FDA and
viremia.42 CDC issued guidance documents making recommenda-
Prophylaxis and Treatment tions for reducing the risk of ZIKV transmission through
transfusion. The February guidance included recommen-
Individuals should avoid mosquitoes and wear mosquito re-
dations to defer donors for 28 days following travel to
pellant and appropriate clothing if they are going to be in a
countries with active ZIKV transmission as well as donors
mosquito-infested area. Once infected, there is no licensed
who had sexual contact with men who traveled to those
treatment, only supportive therapy. Research is ongoing for
countries. The FDA guidance also included recommenda-
the use of ribavirin, interferon-α,36 and West Nile immune
tions for areas of active ZIKV transmission to import blood
globulin to treat WNV. Having survived the illness, a person
from nonactive areas or to test donor blood for ZIKV RNA
is immune for life.
using NAT or to use blood components that were pathogen
Zika Virus reduced using an FDA-approved technology. In August of
2016, the FDA released an updated guidance for the in-
Zika virus (ZIKV) is an arbovirus in the Flavividae family, dustry requiring testing of all donations with an individual
genus Flavivirus. ZIKV is transmitted by the Aedes aegypti and donor nucleic acid test for ZIKV under an investigational
Aedes albopictus mosquitoes. Cases of transmission through new drug application.44 By the end of 2016, all donor
intrauterine, perinatal, laboratory-acquired, sexual- and blood collected in the United States is tested for ZIKV RNA
transfusion-associated transmission have been reported.43 using NAT. NAT-reactive donor blood is further tested
using a polymerase chain reaction (PCR) diagnostic test
Profile and antibody testing.45 Antibody test platforms include
enzyme-linked immunoabsorbant (ELISA) and immuno-
Clinical Manifestations and Pathology fluorescence assays. These tests have a low specificity with
ZIKV disease symptoms include fever, headache, rash, and noted cross-reactivity with antibodies directed against
muscle and joint pain. It is estimated that less than 20% of other flaviviruses.43
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318 PART III Transfusion Practices

Prophylaxis and Treatment Epidemiology and Transmission

Similar to WNV infections there is no medicine available Transmission occurs from person to person through contact
for treatment of ZIKV infection. Avoidance of mosquito with infected body fluids, which may include urine, semen,
bites through use of insect repellent is recommended saliva, blood, cervical secretions, and breast milk. CMV is
to reduce the risk of infection in areas of active ZIKV the most frequently transmitted virus from mother to fetus.50
transmission.47
Laboratory Diagnosis
Other Viruses Antibodies formed to CMV last a lifetime and can be de-
tected by ELISA. Other laboratory tests include PCR, fluo-
Cytomegalovirus rescence assays, indirect hemagglutination, and latex
agglutination. If the patient is symptomatic, active infection
Cytomegalovirus (CMV) is a member of the herpesvirus can be detected by viral culture of urine, throat swabs, and
group and is found in all geographic locations and socio- tissue samples.48
economic groups, with a higher prevalence in developing
countries. In areas with lower socioeconomic conditions, Prophylaxis and Treatment
the prevalence approaches 100%. Of adults in the United Currently, there is no treatment for CMV for a healthy indi-
States, 50% to 85% have been exposed to CMV by the age vidual. Infants are being evaluated using antiviral drug ther-
of 40 years.48 apy, and ganciclovir is being used for patients with depressed
immunity.
Clinical Manifestations and Pathology
Blood and blood components are not universally screened
When exposure occurs after birth to an individual with a for CMV because of the generally benign course of this dis-
competent immune system, there are generally few symp- ease and the high percentage of virus carriers. To prevent
toms. Rarely, mononucleosis-like symptoms with fever and CMV transmission, leukocyte-reduced blood or blood from
mild hepatitis occur. Once an individual is exposed, CMV seronegative donors may be used. Leukoreduction using
can remain latent in the tissues and leukocytes for years, high-efficiency filters such that the final level of leukocytes
with reactivation occurring from a severe immune system is less than or equal to 5 × 106 leukocytes per component
impairment.48 appears to work well with high-risk neonates (weighing less
Those at the highest risk of a CMV infection are fetuses and than 1,200 grams) and transplant recipients.2 In an AABB
immunocompromised individuals receiving allogeneic mar- bulletin, prestorage leukoreduction was encouraged rather
row transplants or solid organ transplants. CMV-seronegative than bedside leukoreduction.
recipients transplanted with CMV-seronegative allogeneic
marrow are at risk if they receive untested or non–WBC- Epstein-Barr Virus
reduced blood components. CMV-seronegative women who
become infected in the first two trimesters have up to a Epstein-Barr virus EBV is a ubiquitous member of the her-
40% chance of delivering an affected infant, many of whom pesvirus family. As many as 95% of the adult population in
will have clinically apparent disease. Intrauterine transfusions the United States have been exposed to the virus by the age
with CMV-positive components is also a high risk to the of 40 years and maintain an asymptomatic latent infection
fetus.49 in B lymphocytes for life. Infections occurring in infants or
Individuals at moderate risk are recipients of solid organ young children are usually asymptomatic. In adolescence
transplants, persons with HIV, and individuals who may re- and young adulthood, EBV causes infectious mononucleosis
quire an allogeneic marrow transplant in the future. When in 30% to 50% of patients.51
the individual becomes immunosuppressed, a reactivation Although transfusion transmission is rarely an individual’s
of a latent infection is possible, resulting in a clinically ap- first exposure to the virus and reactivation usually occurs
parent infection.49 only in immunocompromised individuals, there are a few
Low-birth-weight neonates and autologous marrow recip- cases in the literature of transfusion-associated EBV. EBV is
ients are considered to be at low risk. Preterm, multitrans- not detected by current practices and could cause severe con-
fused neonates weighing less than 1,200 grams are currently sequences in immunocompromised patients, particularly
considered to be at a lower risk than once considered as a organ transplant patients.52
result of better transfusion techniques and management EBV has been called the “kissing disease” because the
of their condition. However, leukocyte-reduced or CMV- virus usually replicates in the cells of the oropharynx, pos-
negative units reduce the risk of CMV infection in these low- sibly in infected B cells. The virus is shed in the saliva and is
birth-weight neonates.49 The neonate may be exposed at the most frequently associated with infectious mononucleosis.
time of delivery, through breastfeeding, or through contact EBV was first discovered in 1964 in Burkitt’s lymphoma
with seropositive individuals. Approximately 1% of all new- cells.53 Since then it has been associated with many illnesses
borns are infected with CMV, but most are asymptomatic at besides infectious mononucleosis and cancers such as na-
birth.50 The fetus that is exposed to the mother’s reactivation sopharyngeal carcinoma, non-Hodgkin’s lymphoma, oral
of the virus during pregnancy rather than a primary expo- hairy leukoplakia in AIDS patients, T-cell lymphomas, and
sure rarely has any damage.50 Hodgkin’s disease.9
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Chapter 14 Transfusion-Transmitted Diseases 319

Parvovirus B19 Disease transmission of parvovirus B19 is rare. Very high

levels of parvovirus B19 (up to 1012 IU/mL) in plasma of
Human B19 parvovirus (B19) is a small, nonenveloped acutely infected asymptomatic donors may pose a greater
virus.2 It causes a common childhood illness called “fifth dis- risk for plasma derivatives. This is due to the pooling of
ease” and is usually transmitted through respiratory secre- larger plasma units by manufacturers when processing these
tions. Fifth disease presents with a mild rash described as products.57 There have been no confirmed reports that
“slapped cheek” when occurring on the face and a lacy red immunoglobulin and albumin products have transmitted
rash when occurring on the trunk and limbs. Approximately parvovirus B19 infection.57
50% of adults have been exposed as children or adolescents
and have protective antibodies. Primary infection in an adult Human Herpesvirus 6 and Human Herpesvirus 8
is usually asymptomatic, but a rash or joint pain and swelling
may occur transiently.54 Human herpesvirus 6 (HHV-6) is a very common virus that
As in all viral infections, the virus must enter the cell causes a lifelong infection. Seroprevalence approaches 100%
through a specific cell receptor. B19 parvovirus enters the in some populations. The virus replicates in the salivary
red blood cell (RBC) via the P antigen and replicates in the gland and then remains latent in lymphocytes, monocytes,
erythroid progenitor cells.54 The cytotoxicity of erythroid and perhaps other tissues.
precursors can lead to serious illness in individuals In childhood, HHV-6 causes roseola infantum, also
with chronic hemolytic anemia, such as sickle cell disease known as “exanthem subitum” or “sixth disease.” Symptoms
and thalassemia, who may have a transient aplastic crisis. are those of a mild, acute febrile disease. In immunocompe-
Severe RBC aplasia or chronic anemia may manifest in tent adults, it is very rare to find infection or reaction from
patients with chronic or acquired immunodeficiency or sites other than the salivary gland where secretions from
malignancies or in organ transplant recipients. Hydrops saliva are a known source of transmission. Side effects are
fetalis and fetal death can occur when the virus is transmit- not common but can include lymphadenopathy and fulmi-
ted during pregnancy.54 nant hepatitis.
The viremic stage occurs shortly after infection. A donor HHV-6 has been associated with a number of diseases
would be asymptomatic but capable of transmitting the virus other than roseola infantum, such as multiple sclerosis and
during this period. This is a concern for donor centers lymphoproliferative and neoplastic disorders. There is no
because the rate of seroconversion is high after exposure. evidence to support a TTD association; with the high level
In one study, B19 DNA was found in approximately 1 out of of seropositivity in the population, blood components are
800 donations. B19 is very resistant to heat and detergent not being tested for HHV-6.30
and has been found through PCR to be present in plasma HHV-8 is another human herpesvirus. Unlike HHV-6, it
components. Because of the lack of inactivation in the is not common in the population but has been seen in
manufacturing process, B19 has been implicated in several Africa.58 Only 3% of donors are seropositive in the United
studies, with transmission through factor concentrates and, States.59 It is associated with several diseases that generally
in one study, through an antithrombin III concentrate.55 affect the immunosuppressed patient. These include Kaposi’s
There has been ongoing regulatory concern about the sarcoma (KS), primary effusion lymphoma, and multicentric
safety of plasma derivatives that has led some manufacturers Castleman’s disease. Spread is generally through sexual con-
and regulatory authorities to require B19 DNA qualification tact. However, in KS patients, 30% to 50% have circulating
testing of plasma and release testing of manufactured lots.56 lymphocytes harboring HHV-8, which lends support to the
The FDA recommends manufacturers of plasma-derived premise that exposure to HHV-8 could be transfusion-
products to engage in practices that will reduce the time associated. There has been no evidence to support this to
between product collection and process testing in order for date.59 In post-transplant patients who develop KS, it ap-
the collection establishments to be notified of positive test pears to be due to reactivation. The transmission of HHV-8
results within the in-date period of any blood components has been associated with organ transplants and injection
that are intended for transfusion.57 drug use.58
In a study by Weimer and colleagues,55 plasmas were
tested for B19 DNA levels by PCR, and those with high titers Emerging Viruses
were eliminated from the pool used in the manufacture of
antithrombin III (ATIII). After the manufacturing process, Chikungunya Virus (CHIKV)
PCR was used to compare ATIII concentrates made from a
pool in which high titers were excluded and ATIII concen- CHIKV is a small enveloped single-stranded RNA virus of
trates that were made from a pool that had not been tested the family Togaviridae. The virus is vector borne, transmitted
for B19 DNA. None of the concentrates manufactured through mosquitoes mainly from the Aedes family.60 Primary
with high-titer plasma eliminated from the pool were PCR- disease symptoms include high fever, severe joint pain,
positive, whereas 66% of the concentrates that were not headache, muscle pain, rash, and leukopenia. Joint pain may
tested prior to manufacturing were PCR-positive. This indi- persist for months in 10% to 15% of those infected.60 Menin-
cates the effectiveness of eliminating high-titer plasmas in goencephalitis has been described during an outbreak on Re-
reducing the B19 DNA to undetectable levels. union Island in 2005 to 2007.60 During the Reunion Island
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320 PART III Transfusion Practices

outbreak the estimated risk of viremic donations was 132 to There are no FDA-approved therapeutics or vaccines for
1,500 per 100,000 donations.60 Despite the relative high risk, EVD. Due to the severity of EVD and the possibility of asymp-
there were no reported transfusion-associated cases. In 2016 tomatic viremia, the FDA has determined that Ebola virus
there were 175 CHIKV cases in the United States and 171 in meets the criteria of a transfusion-transmitted infection.64
U.S. territories reported to the CDC.61 Of the cases reported FDA guidelines published in January of 2017 include recom-
in the United States, all were reported from travelers from mendations that donor history questionnaires include assess-
affected areas. The U.S. territory of Puerto Rico reported 170 ment of donors for a history of Ebola virus infection or
locally acquired CHIKV infections.61 There is no medication disease, assessment of donors with a history of travel in the
for treatment of the disease and no vaccine for prevention. past 8 weeks to a country with widespread transmission of
Similar to WNV and ZIKV, avoidance of mosquito bites is EVD or cases in urban areas with uncertain control measures,
the recommendation to reduce risk of infection. Theoreti- a history of contact in the past 8 weeks with a person known
cally, CHIKV could be spread through transfusion, but there to have Ebola virus infection, a history of sexual contact with
have been no reported cases of CHIKV transmission through persons known to have recovered from EVD, and a history
transfusion even during outbreaks.60 of notification by a public health authority that he or she may
have been exposed in the past 8 weeks.64 Donors must be in-
Dengue Virus (DENV) definitely deferred if they have a history of Ebola virus infec-
tion or disease. Eight-week deferral periods are required from
DENV is a small enveloped single-strand RNA virus in the the date of the donor’s departure from a country with wide-
genus Flavivirus.62 The virus is vector borne by the mos- spread transmission of Ebola virus, after the last date of donor
quitoes Aedes aegypti and Aedes albopictus. Transmission contact with a person infected with Ebola virus, after the last
of DENV through transfusion and organ transplantation date of donor sexual contact with a person known to have re-
has been reported.62,63 Symptoms of disease usually occur covered from EVD, or after notification of exposure from a
4 to 7 days following the bite of an infected mosquito. public health authority.64
Illness usually presents with onset of fever, rash, a severe
headache, lumbosacral aching pain followed by muscle Bacterial Contamination
pain, bone pain, anorexia, nausea, vomiting, and weak-
ness. Severe dengue is rare and includes capillary leakage Overview
sequelae leading to shock with a subset demonstrating
hemorrhagic manifestations.62 It is estimated that 40% of As the infection risk for other diseases has decreased due to
the world’s population live in endemic areas, and the better donor testing, bacterial contamination has come to the
World Health Organization (WHO) estimates that 50 to forefront and has become a great concern as a transfusion-
100 million infections occur each year, with 22,000 deaths. transmitted disease.66 Although the incidence of transfusion-
Nearly all reported DENV infection cases in the continen- associated bacterial sepsis is low, the morbidity and mortality
tal United States are associated with travelers from rates are high. Common sources of bacterial contamination
endemic areas. There have been outbreaks reported in the are from donor skin or from asymptomatic donor blood.2
U.S. territory of Puerto Rico, and DENV is considered Platelets have been the most frequent source of septic trans-
endemic in that area as well as in the Virgin Islands and fusion reactions because room temperature storage promotes
most United States–affiliated Pacific Islands.63 There is cur- bacterial growth. In 2004, bacterial contamination screening
rently no FDA or AABB guidance for donor deferral and no methods were implemented, resulting in lower numbers of
tests licensed for donor testing. Risk of DENV infection can reported cases of transfusion-related fatalities due to bacterial
be reduced by mosquito control and avoidance. Vaccines are contamination. Although the percentage of fatalities due to
in clinical trials, and there are no medicines for treatment bacterial contamination has decreased since 2004, reported
of DENV illness other than those used in supportive care.62 cases to the FDA have essentially leveled off between fiscal
year 2005 and fiscal year 2015. Bacterial contamination
Ebola Virus accounted for 13% of confirmed or possible transfusion-
related fatalities in fiscal year 2005 and approximately 13.5%
Ebola virus is a member of the family Filoviridae and can in fiscal year 2015.67
cause severe hemorrhagic fever. Ebola virus disease (EVD)
has historically been associated with high mortality rates. Clinical Manifestations and Pathology
Symptoms of EVD include fever, severe headache, muscle The most common signs and symptoms of transfusion-
pain, weakness, followed by diarrhea, vomiting, and abdom- associated sepsis are rigors, fever, and tachycardia.68 Other
inal pain. Diffuse hemorrhage has been reported. Symptoms symptoms may include shock, low back pain, disseminated
occur most often within 4 to 10 days following infection and intravascular coagulation (DIC), and an increase or decrease
generally within 21 days. In the 2014 outbreak in West Africa, in systolic blood pressure.2 Of all the blood components,
5% reported symptom onset at >21 days.64 Ebola virus RNA platelets are associated with the highest risk of sepsis and
has been detected in semen of EVD survivors for up to 199 fatality.69 Sepsis due to platelets can occur hours after
days following symptom onset.65 There have also been the transfusion, and the connection may be unrecognized.
isolated reports of asymptomatic Ebola virus infection.64 This may be because many patients who receive platelets
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Chapter 14 Transfusion-Transmitted Diseases 321

are already immunosuppressed because of their condition within 24 hours after collection and has drafted new guid-
or treatment, and the sepsis may be attributed to the ance for the field.69
immunosuppression.
Prophylaxis and Treatment
Epidemiology and Transmission The 31st edition of the AABB Standards states that “the blood
Bacterial contamination usually originates with the donor, bank or transfusion service shall have methods to detect bac-
either through skin contamination at the phlebotomy site or teria or use pathogen reduction technology in all platelet
an asymptomatic bacteremia. It may also occur through con- components.”1
tamination during processing.2 Bacterial contamination is Use of apheresis platelets rather than pooled whole
the most common risk of infection due to transfusion of blood–derived platelets from multiple donors reduces the in-
blood. Bacterial contamination of platelets occurs in approx- cidence of contamination occurring during phlebotomy.
imately 1 of 2,000 to 3,000 platelet transfusions.70 Staphylo- However, apheresis platelets cannot meet all platelet trans-
coccus epidermidis or Staphylococcus aureus are the most fusion needs, and whole blood–derived platelets are still
common bacterial contaminants of blood.70 needed. Therefore, proper arm preparation for phlebotomy
According to the CDC,71 Yersinia enterocolitica is the most is of paramount importance. Standard 5.6.2 in the 31st edi-
common isolate found in RBC units, followed by the tion of Standards states that the use of green soap will no
Pseudomonas species. Taken together, these two account for longer be allowed.1 Improved bacterial disinfection has been
more than 80% of all bacterial infections transmitted by correlated with the use of an iodine-based scrub. In donors
RBCs. In a study by Kunishima and colleagues,72 Propioni- allergic to iodine, chlorhexidine or double isopropyl alcohol
bacterium acnes, a common isolate of human skin, was the skin disinfectant may be used.74
most common bacterial contaminant in RBCs. It is a slow- Phlebotomy diversion consists of collecting the first 20 to
growing anaerobic bacteria that can go unrecognized if tested 30 mL of blood in a separate container to be used for testing.
in aerobic conditions or by using short-term bacterial cul- This reduces the quantity of skin contaminants entering the
tural methods. Although P. acnes has been implicated in only unit during phlebotomy and appears to be very effective in
a few cases of transfusion-related sepsis, studies are needed reducing Staphylococcus species contamination. Several
to confirm long-term safety as it has been associated with blood bag manufacturers have developed systems with a di-
sarcoidosis. version pouch.
Leukoreduction of units can be helpful in removing
Laboratory Diagnosis phagocytized bacteria along with the leukocytes. Some ad-
Before the unit of RBCs or platelets is issued, the unit should vocate this for RBCs to reduce Yersinia contamination. Other
be inspected for discoloration (dark purple or black), which methods under consideration listed in the AABB Technical
strongly indicates contamination. The unit may have no vis- Manual include endotoxin assays, detection of by-products
ible evidence of contamination at the time of issue. However, of bacterial metabolism, NAT, and pathogen inactivation
clots in the unit and hemolysis may also indicate contami- methods.30
nation. Because the bacteria in the unit consume the oxygen, Water baths used in a blood bank can have high bacterial
the cells may lyse, resulting in discoloration in the unit as counts unless disinfected frequently. An overwrap is recom-
compared with the segments that remain normal in color.30 mended for any components placed in the water bath, with
To detect bacterial contamination, both the donor blood inspection of the outlet ports before use.
component and the recipient’s blood should be tested. It is If transfusion-associated sepsis is suspected, treatment
better to test the component itself and not the segments, as should begin immediately without waiting for laboratory
they may be negative.2 The FDA has cleared two culture confirmation. Treatment should include IV antibiotics and
methods for quality-control monitoring of bacterial contam- necessary therapy for whatever symptoms are present, such
ination in platelets. Both methods can be used for leukocyte- as shock, renal failure, and DIC.
reduced apheresis platelets, whereas only one can be used
for leukocyte-reduced whole blood–derived platelets. Syphilis
Bacterial screening of platelets was implemented in the
United States from 2003 to 2004. This has reduced the risk Treponema pallidum, the causative agent of syphilis, is a spiro-
of transfusing contaminated platelets to patients. Between chete. It is usually spread through sexual contact but can be
2004 and 2006, the American Red Cross documented a transmitted through blood transfusions. In 2015 in the
residual risk of clinically relevant septic shock reactions United States, 23,872 primary and secondary cases of
of 1 in 74,807 and a fatality rate of at least 1 in 498,711 syphilis were reported.75 The rates reported between 2000
with platelets that were distributed (to outside facilities) and 2015 showed increasing numbers primarily due to in-
after routine bacteria detection by culture techniques.73 creases of reported cases in men who have sex with men.75
This shows a 50% reduction in reported reactions and The standard serologic tests for syphilis (STS) usually do
fatalities in a 10-month period after bacteria screening was not detect a donor in the spirochetemia phase who has not
implemented. yet seroconverted. Spirochetemia is short, and seroconver-
The FDA has approved a psoralen/UV irradiation–based sion usually occurs after this phase. The last reported case
pathogen reduction method for use on apheresis platelets of transfusion-transmitted syphilis was 1996.76 Despite the
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322 PART III Transfusion Practices

low sensitivity and positive predictive value of STS testing, such as the MO1-type Babesia.79 Babesia infection may also
the 30th edition of the AABB Standards continues to require be acquired by blood transfusion and solid organ transplant.
the STS.1 FDA guidelines issued in September of 2014 also Estimates are that between 70 and 100 cases of transfusion-
still recommend STS testing of donor blood largely due to transmitted Babesia (TTB) have occurred over the last
the reported higher rates of HIV-, HCV-, HBV-, HBsAg-, and 30 years in the United States, with at least 12 fatalities in
HTLV-positive donations of donors with positive syphilis test transfusion recipients diagnosed with babesiosis.80,81 In a
results.76 5-year period including fiscal year 2011 through fiscal year
Polymerase chain reaction followed by Southern blotting 2015, there were 18 transfusion-related fatalities related to
and a labeled probe have been used to confirm the presence contaminated blood products reported to the CDC. Three of
of treponemal antigen. The test is capable of detecting as few the reported fatalities were due to contamination of trans-
as one treponeme in CSF. Nontreponemal EIAs, fluorescent fused red blood cells with B. microti.82
treponemal antibody absorption (FTA-ABS), T. pallidum im-
Clinical Manifestations and Pathology
mobilization (TPI), and T. pallidum hemagglutination (TPHA)
are the methodologies utilized. Blood donations that are reac- Most cases of babesiosis are asymptomatic. Symptomatic
tive may not be used unless a confirmatory test such as FTA patients usually develop a malaria-type illness characterized
is determined to be nonreactive.30 Donors that have confirmed by fever, chills, lethargy, and hemolytic anemia. The risk for
positive results can be reinstated for donation after 12 months developing severe complications, which include renal failure,
with documentation of treatment.76 DIC, and respiratory distress syndrome, increases for elderly,
asplenic, or immunocompromised patients. Reported incu-
Tick-Borne Bacterial Agents bation periods for symptomatic patients range from 1 to
8 weeks after transfusion; therefore, it is important that
Lyme disease, Rocky Mountain spotted fever (RMSF), and physicians consider babesiosis when diagnosing a febrile
ehrlichiosis are all bacterial diseases spread by a tick bite. illness following a transfusion.83
Lyme disease is caused by the spirochete Borrelia burgdorferi,
and RMSF (Rickettsia rickettsii) and ehrlichiosis (Ehrlichia Epidemiology and Transmission
species) are caused by bacteria that are obligate intracellular Areas of the United States, such as the northeast, mid-
pathogens. Atlantic, and upper midwestern states are said to have
endemic transmission.79 The incidence is higher during
Transfusion-Associated Parasites the spring and summer months, which corresponds to the
increase in tick activity and outdoor recreation of humans.
At least three parasites have been associated with transfusion- Persons infected with Babesia may not have clinical signs
associated infections: Babesia microti, Trypanosoma cruzi, of illness for an extended time. Infected persons who
and malaria (Plasmodium species). Several additional para- donate blood during the asymptomatic period pose the
sites have been identified in association with transfusion- greatest risk to the blood supply, as they probably have
associated disease. These include Leishmania species, other infectious organisms circulating in their bloodstreams.
Trypanosoma species, Toxoplasma gondii, and the microfilarial Units of packed RBCs (liquid stored and frozen deglyc-
parasites. Most of these infections occur on rare occasions erolized) and platelet units, which contain RBCs, have been
and typically involve patients who are severely immunocom- associated with transmission.80 B. microti can survive in
promised. The risk for acquiring a blood transfusion contain- refrigerated, uncoagulated blood for 21 to 35 days. There
ing these parasites may be underreported in endemic areas were 63 transfusion-transmitted babesiosis cases in the
but has always been very low in the United States. However, United States between 2004 and 2008.79
in October 2003, the AABB put forth a recommendation to
blood collection facilities that all individuals who had been Laboratory Diagnosis
in Iraq should be deferred for 1 year from the last date of Prompt diagnosis is essential, as Babesia responds well to
departure. This was done after cases of leishmaniasis were antibiotic therapy but can be fatal in certain risk groups if
reported in personnel stationed in Iraq. not properly treated. There is no specific test to diagnose an
infection with B. microti. Thick and thin blood smears
Babesia microti stained with Giemsa or Wright stain can be examined for in-
traerythrocytic organisms. A single negative smear does not
Babesiosis, a zoonotic disease, is usually transmitted by the rule out an infection. Serologic studies such as immunoflu-
bite of an infected deer tick. Infection is caused by the proto- orescence assays can be used to detect circulating antibody.79
zoan parasite, Babesia, which infects the RBCs. Most human Currently there is no licensed screening test for blood
cases of Babesia infection that occur in the United States are donors. IND protocols for antibody and DNA testing are
caused by the B. microti parasite.77 There have been reported being used by several blood centers.84
cases of simultaneous transmission of B. microti and Borrelia
burgdorferi, the causative agent of Lyme disease, because the Prophylaxis and Treatment
tick vectors are the same for the two organisms.78 Other re- Babesiosis can be effectively treated with antibiotic therapy.
ported species are Babesia duncani, formally called WA1-type There is no specific drug of choice, but quinine and
Babesia, CA1-type Babesia, and Babesia divergens–like agents clindamycin are very effective. In addition, the combination
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Chapter 14 Transfusion-Transmitted Diseases 323

of atovaquone and azithromycin can be as effective in pa- disease can be transmitted congenitally, transplacentally, or
tients without a life-threatening illness.84 Apheresis has through solid organ transplantation.89
also been successful in patients who fail to respond to an- Screening for Chagas disease was implemented in January
tibiotic therapy.85,86 2007 using an FDA-approved ELISA test.89
There is no test currently available to screen for asymp-
tomatic carriers of Babesia. Many blood banks have added Laboratory Diagnosis
questions to their donor questionnaire that address topics Acute Chagas disease is diagnosed by detecting the organ-
such as living in an endemic area and previous Babesia in- ism in the patient’s blood. Blood smears stained with
fection. Some blood banks have chosen to defer individuals Giemsa or Wright stain may be examined for the charac-
who reside in areas that are heavily tick-infested in the sum- teristic C- or U-shaped trypomastigote (Fig. 14–7). Antico-
mer months.84 This practice may have little value, as donors agulated blood or the buffy coat may also be evaluated for
may remain asymptomatic for months after exposure to the motile organisms.
organism, and there have been transfusion-transmitted cases Chronic Chagas disease is diagnosed serologically. Such
reported in nonendemic areas. Donors with a history of testing includes complement fixation, immunofluorescence,
babesiosis should be deferred from donating blood for an in- and ELISA. False-positive reactions are common; therefore,
definite period of time.1 Because B. microti can be transmit- it is recommended that patient specimens be analyzed using
ted by blood donated from asymptomatic donors, effective more than one assay. Trypomastigotes are rare or absent in
measures for preventing transmission are needed. The AABB the peripheral blood during the chronic phase, so examina-
Transfusion Transmitted Disease (TTD) Committee has pri- tion of blood smears is not useful.
oritized babesiosis as an agent for which there is a critical
need for the development and implementation of an inter- Prophylaxis and Treatment
vention to reduce transfusion-associated infection.84 National screening of the blood supply was initiated in 2007.
Since that time, more than 10,000 donors with T. cruzi in-
Trypanosoma cruzi fection have been identified.89 The FDA approved a second
test to screen blood, tissue, and organ donors in April 2010.
T. cruzi is a flagellate protozoan that is the etiologic agent of
The test, called the Abbott Prism Chagas, is highly sensitive
Chagas disease (American trypanosomiasis). It is estimated
and specific for the detection of antibodies to T. cruzi.90
that 300,000 people are infected within the United States.87
The AABB TTD Committee has given T. cruzi an orange
The disease is naturally acquired by the bite of a reduviid bug,
category rating.56 An orange category agent is considered a
thus making it a zoonotic infection. Insect transmission is the
low scientific or epidemiological risk regarding blood
most common mode of infection, but the organism has also
saftey.56 T. cruzi was assigned a moderate rating by the TTD
been transmitted by blood transfusion and organ transplants.
Committee based on public and regulatory attention to in-
Clinical Manifestations and Pathology troducing blood donor screening.56
In the United States, medication for Chagas disease may
The acute phase of Chagas disease is initiated when the
organism enters the host. The reduviid bug bite produces a be obtained only by contacting the CDC.
localized nodule, referred to as a “chagoma.” The chagoma
is usually painful and may take up to 3 months to heal. Clin- Malaria (Plasmodium Species)
ical symptoms may be mild or absent; therefore, many cases Malaria, another intraerythrocytic protozoan infection,
are not diagnosed until the chronic phase of the disease. may be caused by several species of the genus Plasmodium
Symptoms include anemia, weakness, chills, intermittent
fever, edema, lymphadenopathy, myocarditis, and gastroin-
testinal symptoms. Death may occur within a few weeks or
months after initial infection.
Following the acute phase, the disease may enter a latent
phase, which can last up to 40 years.88 During this phase,
the patient is usually asymptomatic but has parasites circu-
lating in the bloodstream. Transfusion-associated Chagas
disease is most likely to occur during this phase.
Chagas disease usually progresses to the chronic phase
years or decades after the acute phase.88 In the chronic
phase, the organism begins to cause damage to cardiac tissue,
thus causing cardiomyopathy.

Epidemiology and Transmission

Chagas disease is endemic in Central and South America
and some areas of Mexico. Cases have also been reported in
the southern United States.89 Infected individuals pose a risk
of infecting the recipients of their donated blood. Chagas Figure 14–7. T. cruzi trypomastigote.
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324 PART III Transfusion Practices

(Plasmodium malaria, Plasmodium falciparum, Plasmodium appropriate therapy and decrease the chance of resistance
vivax, and Plasmodium ovale). Natural transmission occurs by the organism.
through the bite of a female Anopheles mosquito, but in- Some individuals have a natural immunity to certain
fection may also occur following transfusion of infected species of malaria caused by a genetic alteration in their
blood. Malaria is very rare in the United States. One hun- RBCs. These include persons who have sickle cell anemia or
dred and one cases of transfusion-transmitted malaria have trait, G6PD deficiency, or RBCs that lack the Duffy blood
been reported from 1990 to 2005, making the incidence group antigen.
rate of 0.1 cases per 1 million units transfused.91
Prion Disease
Clinical Manifestations and Pathology
Symptoms include fever, chills, headache, anemia, hemoly- Creutzfeldt-Jakob Disease
sis, and splenomegaly. There may be variations in symptoms
among the different species of Plasmodium. Malaria often Creutzfeldt-Jakob disease (CJD) is one of the transmissible
mimics other diseases, and its diagnosis is often delayed due spongiform encephalopathies (TSEs). These are rare diseases
to lack of suspicion in nonendemic areas. characterized by fatal neurodegeneration that results in
sponge-like lesions in the brain. Although a definitive diag-
Epidemiology and Transmission nosis can be made only at autopsy, neurological signs and
Malaria is endemic in tropical and subtropical areas and in symptoms and disease progression are used to make a pre-
West Africa. The World Health Organization (WHO) esti- liminary diagnosis. Animals, such as sheep, goats, cattle,
mated that in 2008 malaria caused 190 to 311 million clini- cats, minks, deer, and elk, and humans can be affected by
cal episodes and 708,000 to 1,003,000 deaths.92 Many people TSE. In humans, sporadic CJD is the most common form,
associate malaria with a history of traveling to an endemic representing 85% to 90% of all cases, generally occurring in
area. However, other transmission modes are possible, late middle age (average age 60 years). An inherited form
including blood transfusions and congenital infection. due to a gene mutation accounts for another 5% to 10% of
Transfusion-associated malaria is acquired by receiving cases, and iatrogenic CJD acquired through contaminated
blood products from an asymptomatic carrier. Plasmodium can neurosurgical equipment, cornea or dura mater transplants,
survive in blood components stored at room temperature or or human-derived pituitary growth hormones accounts for
4°C for at least a week, and deglycerolized RBCs can transmit less than 5% of cases. The sporadic, inherited, and iatrogenic
disease. CJD are considered the classic CJD.94 In 1996, a variant form
of CJD (vCJD) affecting younger individuals was noted, and
Laboratory Diagnosis epidemiological evidence linked vCJD to bovine spongiform
Examination of thick and thin blood smears is performed to encephalopathy, possibly from eating contaminated beef. Of
diagnose infection with malaria. Although each species of the 129 cases reported from 1996 to 2002, most were in the
Plasmodium varies morphologically, diagnosis can be quite United Kingdom.94
difficult. Depending on the species of Plasmodium and the The causative agent of all TSEs is believed to be a prion,
stage of the parasite’s life cycle, timing is crucial when eval- which is described as a self-replicating protein. It does not
uating the blood smear. A single negative smear does not rule contain nucleic acid but is formed when the confirmation of
out a diagnosis of malaria. the normal cell surface glycoprotein, the prion protein, is
changed to an abnormal form. This abnormal form accumu-
Prophylaxis and Treatment lates in the brain and makes the brain tissue highly infectious.
A practical or cost-effective serologic test to screen asymp- It is resistant to inactivation by heat, radiation, and formalin.94
tomatic donors does not exist. According to FDA guidance The median duration of illness for vCJD is 13 to
documents, persons who have traveled to an endemic area 14 months.94 However, the incubation period in humans
are deferred for 1 year, and those who have had malaria or varies from 4 to 20 years and may eventually prove to be
who have immigrated from or lived in an endemic area are longer in some cases.
deferred for 3 years.93 There is no epidemiological evidence linking classic CJD
Chloroquine is generally effective for chemoprophylaxis to TTD. However, in vCJD cases, prion particles have been
and treatment of all four species of Plasmodium, except found in lymphoreticular tissues, including the tonsils,
P. vivax acquired in Indonesia or Papua New Guinea, which spleen, and lymph nodes. As blood is intimately involved
is best treated with atovaquone-proguanil, with mefloquine with the lymphoreticular system, concerns arose regarding
or quinine plus tetracycline or doxycycline as alterna- the ability of vCJD individuals to transmit the prion to re-
tives.92 Therapy has become more complicated due to the cipients of blood or blood products.94
increase in resistance of P. falciparum and, more recently, Currently, there is no reliable diagnostic test that can de-
P. vivax to chloroquine. It is important for the physician tect asymptomatic individuals. Therefore, deferral of donors
to carefully evaluate the species of Plasmodium causing with connection to the United Kingdom and parts of Europe
the illness, the estimated parasitemia, and the patient’s as well as other associated risk factors is used to prevent
travel history. This information is necessary to prescribe transmission.94
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Chapter 14 Transfusion-Transmitted Diseases 325

Pathogen Inactivation Cellular Components

The safety of the blood supply in the United States has im- Pathogen inactivation using psoralen activated by ultraviolet
proved greatly over the years, with improved screening of light has been tested with platelet concentrates. It has been
donors and testing of the blood product. However, pathogen shown to inactivate cell-associated viruses, cell-free viruses,
inactivation methods have been developed to account for and selected prokaryotic organisms. Whether this process
residual risks associated with serologic window periods, will work against intracellular bacterial organisms has not
virus variants, and laboratory errors and for organisms for been established. There are three licensed platelet pathogen
which testing is not performed routinely.73 The possibility reduction systems that are currently in use in the United
of newly emerging pathogens also exists, as evidenced States and Canada: the Cerus Corporation’s INTERCEPT
by WNV, DENV, ZIKV, and DENV, that can be transmitted Blood System, CaridianBCT Biotechnologies’ Mirasol PRT,
by blood. and the MacoPharma’s Theraflex UV.62 These companies also
have processes for pathogen reduction in plasma.56
Plasma Derivatives CaridianBCT Biotechnologies is currently using a photo-
chemical process for red blood cell pathogen reduction. This
Heat inactivation, the first pathogen inactivation interven- system incorporates riboflavin and UV light.56 A process for
tion, has been used since 1948 to treat albumin.3 Even RBCs that uses a chemical cross-linker specific for nucleic
before the introduction of third-generation testing for acid is being designed by Cerus Corporation.56
HBsAg, heat inactivation prevented the transmission of Limitations of pathogen reduction systems include agents
HBV. The transmission of viruses or bacteria has been pre- with intrinsic resistance, such as prions, some bacterial spores,
vented due to albumin’s pasteurization method (60°C for and nonenveloped viruses.56 Some viruses may not be inacti-
10 hours).30 vated if they are of high titer, including B19V and HBV.56
In 1973, third-generation assays for HBsAg were li-
censed. Only one case of HBV transmission by immune Quarantine and Recipient Tracing
globulin was ever documented before then. Intramuscular (Look-Back)
immune globulin has never transmitted HIV or HCV. All
immunoglobulin plasma pools were screened for HBsAg, All blood banks and transfusion services are required to have
and only those that were negative were used. Viral inacti- a process to detect, report, and evaluate any complication of
vation included cold-ethanol (Cohn-Oncley) fractionation transfusion, including recipient development of HBV, HCV,
and anion-exchange chromatography (for one IV im- HIV, or HTLV. There must be an established method to notify
munoglobulin). However, in 1994, the FDA required viral donors of any abnormality with the predonation evaluation,
clearance processing or proof of absence of HCV by NAT laboratory testing, or recipient follow-up. A report should
testing because of outbreaks of HCV from anion-exchange be submitted to the collecting agency when the recipient of
chromatography in Ireland and Germany, countries that did a blood component develops a TTD.1
not use a viral clearance procedure. NAT is now used in the Current donations that test positive for HBV, HCV, HIV, or
processing of all source plasmas.30 HTLV cannot be used for transfusion.1 All prior donations
Coagulation factors had a high rate of viral transmission from these donors become suspect. The timeline and stan-
until the early 1980s. Chronic hepatitis was the biggest prob- dards using the look-back procedure to identify recipients of
lem until HIV emerged. More than 50% of all hemophiliacs a component from the implicated donation or other donations
receiving concentrates became infected with HIV. Since by the same donor differ depending on the disease. Any prior
1987, these clotting factors have become very safe due to im- components still in-date must be quarantined, and the dispo-
plementation of a variety of virus inactivation steps, and sition depends on results of licensed supplemental tests.2
there have been no cases of HIV transmission. Today, all If on recipient follow-up it is noted that a patient devel-
manufacturers use methods that either remove the virus or oped HBV, HCV, HIV, or HTLV after receiving a single unit
inactivate it. The lipid-enveloped viruses—HIV, HBV, HCV, from one donor, that donor is permanently deferred. If the
HTLV, EBV, CMV, HHV-6, and HHV-8—are all inactivated by recipient received donations from several donors, all donors
use of organic solvents and detergents. This process is not do not have to be excluded. These implicated donors may
effective with non–lipid-enveloped viruses such as HAV and be called in for retesting. If a donor has been implicated in
parvovirus B-19.30,95 more than one case of TTD, this donor should be retested
The current risk of enveloped virus transmission is very and possibly permanently deferred.2 Once a donor has been
low because of the combination of procedures such as heat implicated in a TTD, other recipients of a component from
treatment, solvent and detergent treatment, and nanofiltra- the suspected donor should be contacted. The donor must
tion.3 These methods are often used in combination during be placed on the appropriate donor deferral list if subsequent
the manufacturing process. With the exception of one case tests are positive.2 Donors who have been permanently de-
of HCV transmission in IV immune globulin in 1994, there ferred due to positive test results must be notified of the fact.
have been no cases of HBV, HCV, or HIV since 1985 by any Notification and a thorough explanation of the positive test
U.S. licensed plasma derivative.95 results and their implications must be given to the donor.2
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326 PART III Transfusion Practices

Follow-up testing should be performed by the donor’s own abnormalities must be transmitted to the patient and the
physician.2 patient’s physician.1
Autologous donations positive for HBV, HCV, HIV, HTLV, Any fatalities due to a TTD must be reported to the direc-
or syphilis can be used. If they are not transfused at the col- tor of the Center for Biologics Evaluation and Research
lecting facility, the collecting facility must notify the trans- within 1 working day, followed by a written report within
fusion service. Testing must be repeated every 30 days 7 days.96 Table 14–5 summarizes the laboratory tests for
on at least the first unit to be shipped. Information about transfusion-transmitted diseases.

Table 14–5 Summary of Laboratory Tests for Transfusion-Transmitted Diseases

Date Test Confirmatory Risk of
Disease Testing Implemented Method Test Method Transmission
Hepatitis B Virus (HBV) B surface antigen 1971 ChLIA Antigen neutralization
(HBsAq)

Hepatitis B core 1986 ChLIA Ultrasensitive HBV

antibody (HBc) DNA detection by
PCR

HBV DNA 2009 NAT All TMA-reactive do- 1 in 800,000 and 1 in

nations confirmed 1,000,00029
by PCR

Human T-Lymphotropic Qualitative 1998 ChLIA Second licensed HTLV-I less than 1 in
Virus (HTLV-I/II) antibody screening test 2 million29
detection for and WB
HTLV-II not yet
both HTLV-I and
proven unequivo-
HTLV-II in a
cally to be of signifi-
combined test
cant clinical concern

Hepatitis C Virus (HCV) Antibody testing 1990 ELISA, ChLIA Second licensed
screening test

HCV RNA 1999 NAT (using NAT 1 in 1,000,00029

TMA in
minipools
of 16…)

Human Immunodeficiency Antibody testing 1985 EIA, ChLIA One or a combination

Viruses, Types 1 and 2 of HIV-1 IFA and
(HIV 1, 2) HIV-2 EIA (a rapid
diagnostic test used
for HIV-1 and HIV-2
differentiation)

NAT 1999 NAT (using 1 in 1,000,00029

TMA in
minipools
of 16…)

Chagas Disease (T. cruzi) Antibody testing— 2007 ELISA, ChLIA ESA 20 reported cases in
qualitative the literature,
detection of worldwide
antibodies to
T. cruzi

Syphilis (T. pallidum) Antibody testing— 1950s Agglutination EIA, as well as a 0 (no cases of
qualitative assay test for reagin (a transfusion-
screening test protein-like sub- transmitted
detects pres- stance that is pres- syphilis recorded
ence of ent during acute in last 50 years)
antibodies to infection and for
T. pallidum several months
following resolution
of infection)
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Chapter 14 Transfusion-Transmitted Diseases 327

Table 14–5 Summary of Laboratory Tests for Transfusion-Transmitted Diseases—cont’d

Date Test Confirmatory Risk of
Disease Testing Implemented Method Test Method Transmission
West Nile Virus (WNV) WNV RNA 2003 NAT (same 1 in 84 million
detection type of assay
as used for
HBV, HIV-1,
and HCV)

Babesiosis (Babesia Antibody testing– 2012 IFA PCR and WB

microti) IND protocols

NAT–IND 2012 NAT PCR and WB 1 in 100,000

protocols

Zika Virus Zika virus RNA– 2016 NAT PCR and antibody Not yet determined
IND protocols testing

ChLIA = chemiluminescent immunoassay; NAT = nucleic acid testing; PCR = polymerase chain reaction; TMA = transcription-mediated amplification; ELISA = Enzyme-Linked,
Immunosorbent Assay Test System; WB = Western Blot Assay; EIA = Enzyme Immunoassay; IFA = Indirect Immunofluorescence Assay; ESA = Enzyme Strip Assay. (American Red
Cross, Infectious Disease Testing. Available from: http://www.redcrossblood.org/learn-about-blood/what-happens-donated-blood/blood-testing.)

SUMMARY CHART
 The first and most important step in ensuring that  Transfusion-associated CMV infection is a concern
transfused blood will not transmit a pathogenic virus for seronegative allogeneic organ transplant recipi-
is careful selection of the donor. ents and fetuses. Reactivation of a latent infection
 HAV is usually spread by the fecal-oral route in com- can occur when an individual becomes severely
munities where hygiene is compromised. immunocompromised.
 On infection with HBV, the first positive test is HBV  The risk of CMV infection for low-birth-weight
NAT and the first serologic marker to appear is HBsAg, neonates is not as great as it was in the past due to bet-
followed by HBeAg and IgM anti-HBc within the first ter transfusion techniques and management of their
few weeks of exposure. conditions.
 HBIG is an immune globulin prepared from persons  The WB confirmation test detects the presence of anti-
with a high titer of anti-HBs and is used to provide pas- HIV and determines with which viral proteins the an-
sive immunity to health-care workers and others who tibodies react.
are exposed to patients with HBV infection.  The window period for HIV can be shortened by using
 A combined vaccine for HAV and HBV is available to the polymerase chain reaction, which detects HIV in-
provide immunity. fection before tests for antigen or antibody are positive.
 HDV infection is common among drug addicts and can  Bacterial contamination is the most frequent cause of
occur simultaneously with HBV infection; diagnosis transfusion-transmitted infection.
depends on finding anti-HDV or HDV RNA in the  Because routine screening for parasitic infections is not
serum. currently available, many blood banks have added
 Of all HCV infections, 60% to 70% are asymptomatic. questions to their donor questionnaire that address
With the implementation of NAT testing for HCV, the topics associated with risk for parasitic infection.
window period has been reduced to 10 to 30 days.  Pathogen inactivation methods are in use for plasma
 HCV is the leading cause of liver transplants in the and platelet products and under development for red
United States. cell products. These methods remove or reduce the
 HEV is an emerging agent associated with transmission residual risk of transfusion-associated disease due to
through transfusion and is the leading cause of hepa- the window period, virus variants, laboratory mistakes,
titis in the United Kingdom. and new, emerging diseases.
 Diagnosis of HIV-1 and HIV-2 infection is dependent  Look-back is a process mandated by the FDA that di-
on the presence of antibodies to both envelope and rects collection facilities to notify donors who test pos-
core proteins; HIV-positive persons with fewer than itive for viral markers, to notify prior recipients of the
200 CD4+ T cells per microliter are considered to have possibility of infection, and to quarantine or discard
AIDS in the absence of symptoms. implicated components currently in inventory.
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328 PART III Transfusion Practices

9. HBV is transmitted most frequently:

Review Questions
a. By needle sharing among IV drug users
1. The fecal-oral route is common in transmitting which of b. Through blood transfusions
these hepatitis viruses? c. By unknown methods
d. By sexual activity
a. HAV and HEV
b. HBV and HCV 10. Which of the following is the most common cause of
c. HDV chronic hepatitis, cirrhosis, and hepatocellular carci-
d. HGV noma in the United States?
2. Which of the following is the component of choice for a a. HAV
low-birth-weight infant with a hemoglobin of 8 g/dL if b. HBV
the mother is anti-CMV negative? c. HCV
d. HDV
a. Whole blood from a donor with anti-CMV
b. RBCs from a donor who is anti-CMV negative 11. The first retrovirus to be associated with human dis-
c. Leukoreduced platelets ease was:
d. Solvent detergent–treated plasma a. HCV
3. Which of the following is an FDA-licensed screening test b. HIV
for HCV? c. HTLV-I
d. WNV
a. NAT + anti-HBc
b. RIBA 12. All of the following statements are true concerning
c. Lymph node biopsy WNV except:
d. HCV RNA a. 1 in 150 infections results in severe neurological
4. Currently, which of the following does the AABB con- disease
sider to be the most significant infectious threat from b. Severe disease occurs most frequently in the over-
transfusion? 50 age group
c. Deaths occur more often in those over 65 years who
a. Bacterial contamination
present with encephalitis
b. CMV
d. Fatalities occur in approximately 38% of infected
c. Hepatitis
individuals
d. HIV
13. The primary host for WNV is:
5. Which of the following is the most frequently transmitted
virus from mother to fetus? a. Birds
b. Horses
a. HIV
c. Humans
b. Hepatitis
d. Bats
c. CMV
d. EBV 14. Tests for WNV include all of the following except:
6. Jaundice due to HAV is seen most often in the: a. ELISA
b. NAT
a. Adolescent
c. Plaque reduction neutralization test
b. Adult
d. Immunofluorescent antibody assay
c. Child younger than 6 years old
d. Newborn 15. Individuals exposed to EBV maintain an asymptomatic
latent infection in:
7. Currently, steps taken to reduce transfusion-transmitted
CMV include: a. B cells
b. T cells
a.Plaque reduction neutralization test
c. All lymphocytes
b.NAT testing
d. Monocytes
c.Leukoreduction
d.Minipool screening 16. Fifth disease is caused by:
8. HBV remains infectious on environmental surfaces for 1: a. CMV
b. EBV
a. Day
c. Parvovirus B19
b. Week
d. HTLV-II
c. Month
d. Year
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Chapter 14 Transfusion-Transmitted Diseases 329

17. Transient aplastic crisis can occur with: 25. Which disease is naturally caused by the bite of a deer
a. Parvovirus B19 tick?
b. WNV a. Chagas disease
c. CMV b. Babesiosis
d. EBV c. Malaria
d. Leishmaniasis
18. Reasons why syphilis is so rare in the U.S. blood supply
include all of the following except:
a. 4°C storage conditions References
b. Donor questionnaire 1. American Association of Blood Banks. Standards for blood
c. Short spirochetemia banks and transfusion services. 31st ed. Bethesda (MD): AABB;
d. NAT testing 2018.
2. Fung MK, Eder AF, Spitalnik SL, Westhoff CM (eds). Technical
19. Nucleic acid amplification testing for HIV was instituted manual. 19th ed. Bethesda (MD): American Association of
in donor testing protocols to: Blood Banks; 2017.
3. Cuthbert JA. Hepatitis A: old and new. Clin Microbiol Rev.
a. Identify donors with late-stage HIV who lack 2001;14(1):38-58.
antibodies 4. Centers for Disease Control and Prevention [Internet]: Atlanta
b. Confirm the presence of anti-HIV in asymptomatic (GA): The CDC [cited 2017 Jul 13]. Surveillance for viral
HIV-infected donors hepatitis—United States, 2014. Available from: www.cdc.gov/
hepatitis/statistics/2014survaillance/index.htm.
c. Reduce the window period by detecting the virus 5. Centers for Disease Control and Prevention [Internet]: Atlanta
earlier than other available tests (GA): The CDC [cited 2017 May 15]. Hepatitis A – questions
d. Detect antibodies to specific HIV viral proteins, and answers for health professionals. Available from: www
including anti-p24, anti-gp41, and anti-gp120 .cdc.gov/hepatitis/hav/havfaq.htm#general.
6. Freidl GS, Sonder GJ, Bovee LP, Friesema IH, van Rljckevorsel RL,
20. Screening for HIV is performed using the following Ruijs WL, et al. Hepatitis A outbreak among men who have sex
technique: with men (MSM) predominantly linked with the EuroPride in
the Netherlands. July 2016 to February 2017. Euro Surveil.
a. Radio immunoassay 2017;22(8):30468.
b. WB 7. Centers for Disease Control and Prevention [Internet]: Atlanta
c. Immunofluorescent antibody assay (GA): The CDC [cited 2017 May 11]. Statistics and surveillance.
d. NAT Available from: www.cdc.gov/hepatitis/statistics/indexhtm.
8. Bishop ML, Fody EP, Schoeff LE. Clinical chemistry tech-
21. The first form of pathogen inactivation was: niques, principles and correlations. 6th ed. Baltimore (MD):
a. Chemical Lippincott Williams & Wilkins; 2010.
9. Miller LE. Serology of viral infections. In: Stevens CD, editor.
b. Heat Clinical immunology and serology: a laboratory perspective.
c. Cold-ethanol fractionation 2nd ed. Philadelphia: FA Davis Company; 2003. p. 324.
d. Anion-exchange chromatography 10. Food and Drug Administration [Internet]: Rockville (MD):
FDA [cited 2017 May 13]. Guidance for industry: use of
22. What is the most common parasitic complication of nucleic acid tests on pooled and individual samples from donors
transfusion? of whole blood and blood components, including source
a. Babesia microti plasma, to reduce the risk of transmission of hepatitis B virus.
Available from: www.fda.gov/BiologicsBlood Vaccines/Guidance
b. Trypanosoma cruzi ComplianceRegulatoryInformation/Guidances/Blood/ucm32750
c. Plasmodium species .htm.
d. Toxoplasma gondii 11. Lox ASF, McMahon BF. AASLD practice guidelines: chronic
hepatitis B. Hepatology. 2001;34:1225.
23. Which organism has a characteristic C- or U-shape on 12. Marcellin P, Chang T, Lim SG, Tong MJ, Sievert W, Shiffman ML,
stained blood smears? et al. Adefovir dipivoxil for treatment of hepatitis B antigen-
a. Trypanosoma cruzi positive chronic hepatitis B. N Engl J Med. 2003;348:808.
13. Gerlach JT, Diepolder HM, Zachoval R, Gruener NH, Jung MC,
b. Plasmodium vivax Ulsenheimer A, et al. Acute hepatitis C: high rate of both spon-
c. Plasmodium falciparum taneous and treatment-induced viral clearance. Gastroenterol-
d. Babesia microti ogy. 2003;125:80-8.
14. Ankcorn MJ, Tedder RS. Hepatitis E the current state of play.
24. Which transfusion-associated parasite may have asymp- Transfus Med. 2017;27(2):84-95.
tomatic carriers? 15. Centers for Disease Control and Prevention [Internet]: Atlanta
a. Babesia microti (GA): The CDC [cited 2010 Aug 9] Viral hepatitis–Hepatitis E
virus. Available from: www.cdc.gov//hepatitis/HEV?HEVfaq
b. Trypanosoma cruzi .htm#section1.
c. Plasmodium species 16. Alter HJ, Nakatsuji Y, Melpolder J, Wages J, Wesley R, Shih JW,
d. All of the above et al. The incidence of transfusion associated hepatitis G virus