Clinical Transfusion Medicine - part 9 pps

Viruses present in both allogeneic leukocytes and as virions in plasma transmitted by all types of blood products.. Viruses present in plasma only as free virions transmitted by all type

Table 34.1 Viruses known to be transmitted by blood transfusion

I Viruses present in allogeneic leukocytes only (transmitted by red cells and platelets,

but not transmitted by frozen plasma, cryoprecipitate or plasma derivatives).

(a) Cytomegalovirus (CMV or HHV-5)

(b) Epstein-Barr Virus (EBV or HHV-4)

(c) Human T-Lymphotrophic Virus (HTLV-1/11)

(d) Human Herpes Virus, type 6 (HHV-6)

(e) Human Herpes Virus, type 8 (HHV-8)

II Viruses present in both allogeneic leukocytes and as virions in plasma (transmitted by

all types of blood products)

(a) Human Immunodeficiency Virus (HIV-1; HIV-2)

III Viruses present in plasma only as free virions (transmitted by all types of blood

products)

(a) Hepatitis A (HAV)

(b) Hepatitis B (HBV)

(c) Hepatitis C (HCV)

(d) Hepatitis D (HDV)

(e) Hepatitis E (HEV)

(f) Hepatitis G (HGV)

(g) B19 parvo virus

Among the viruses in this group, routine tests are performed only for the HTLV viruses The transmission of all viruses in this group by blood transfusion is likely

to be either greatly reduced or eliminated by the use of leukoreduction filtration, but in practice, at this time, this approach is only used to prevent CMV infection (Chapter 38)

Group II viruses are those which are present both in allogeneic leukocytes and

in plasma They are, therefore, transmitted by all types of blood products The most important virus in this group is the human immunodeficiency virus(es) (HIV type 1 and type 2) Since May of 1985, all blood donations have been rou-tinely screened for the antibody to HIV-1 and, since early 1996, rourou-tinely screened for p-24 antigen, an early plasma marker of HIV infection This has been

ful in eliminating the vast majority of potentially infectious units Regrettably, blood donors who are exposed to HIV virus may be infectious for a period prior

to development of plasma markers, (either of p-24 or of anti-HIV-1) This period

is sometimes described as the serosilent window period and constitutes the current

danger for the residual small number of cases of HIV which are transmitted by blood transfusion Further efforts in this area will soon involve the use of nucleic acid analysis of plasma to detect HIV viral RNA, and it is likely that this will fur-ther shorten the duration of the serosilent window period It should be noted, however, that the current risk of transmission of HIV by blood transfusion is ex-tremely low (see Table 34.2) HIV virus appears less likely to be transmitted by either washed blood components or red blood cells which are transfused later in their shelf life, i.e., stored in a refrigerator for greater than 25 days In addition, leukoreduction of red cell products is known to cause a significant reduction in the viral load due to a reduction in allogeneic leukocytes and also platelets which contain HIV virions on their surface These approaches are not applicable in prac-tice, however, in attempting to prevent HIV-1 transmission

Group III viruses are present in free plasma only and viruses in this group, like group II, may be transmitted by any type of allogeneic blood product The most prominent viruses in this group are the hepatitis viruses They will be discussed in alphabetical order rather that in order of clinical significance

Hepatitis A virus (HAV) causes acute infectious hepatitis and does not have a chronic carrier state Hepatitis A transmission by blood transfusion has only been shown to occur in association with the transfusion of plasma derivatives, such as factor VIII concentrates in patients with hemophilia This has been related to in-adequate viral attenuation steps (Chapter 31) The commonly transfused blood components such as red cells and platelets are rarely associated, if ever, with hepa-titis A transmission

Hepatitis B (HBV) is a very important virus in blood transfusion because hepa-titis B has a chronic asymptomatic carrier state In 1972, testing for hepahepa-titis B (serum hepatitis) was the first viral test to be performed to detect hepatitis in

Table 34.2 Approximate estimates of likelihood of clinical significant viral disease transmission by blood transfusion (1999)

(Herpes Viruses Not Included) Risk is per unit

blood donors The hepatitis B test detects hepatitis B antigen Further develop-ments in tests for hepatitis B since that time have improved test sensitivity for detecting donors who are carriers Hepatitis B transmission by blood transfusion results commonly in the development of clinical features of hepatitis, usually be-tween 2-6 months after the transfusion episode Most cases of hepatitis B will resolve spontaneously, but acute fulminant forms of hepatitis with liver failure can occasionally occur Even when resolution occurs, approximately 10% of such patients will develop a chronic carrier state These carriers may later develop other complications, such as cirrhosis or hepatocellular carcinoma after a period of

10-30 years The current risk for transmission of hepatitis B is, however, quite low and estimated at 1:60,000 Although HBV remains a rare cause of transfusion transmitted hepatitis in North America and Europe, it is a far greater problem in Eastern and Southern Europe, North Africa and Asia where many first time do-nors are HBV positive As in the case of HIV, plasma testing for HBV using nucleic acid amplification technology (such as PCR) will likely further reduce HBV trans-mission by blood transfusion

Hepatitis C remains an important form of hepatitis transmitted by blood trans-fusion In the older literature, this virus was often referred to as non-A, non-B hepatitis The presence of hepatitis C virus is detected using an antibody test to hepatitis C virus (Anti-HCV) Since its introduction in 1990, this test has been very successful in eliminating many blood donations with the potential to trans-mit hepatitis C virus A greatly improved anti-HCV test was implemented in 1992

In the late 1980s, surrogate markers for hepatitis C infection, i.e., measurements

of alanine aminotransferase (ALT) and antibody to the core protein of hepatitis B (anti-HBc) were initiated in an attempt to reduce hepatitis transmission by blood transfusion and were successful in reducing some cases of hepatitis C transmis-sion The introduction of anti-HCV testing, however, rendered these surrogate tests less useful, although they are still used in some blood centers Hepatitis C associated hepatitis has an incubation period of 2-6 weeks Most cases of hepatitis

C are asymptomatic (approximately 75% of cases), but a chronic carrier state de-velops in 50-70% of exposed patients Chronic carriers of hepatitis C may develop

a chronic hepatitis, or cirrhosis and have an increased incidence of hepatocellular carcinoma Thus, the end result of hepatitis C infection in many cases may lead to

a need for liver transplantation, 10-30 years after exposure The current risk of hepatitis C infection per unit has decreased from a peak of perhaps 1-5% in the 1960s, to a current risk of approximately 1:100,000 Nucleic acid testing, expected

to be introduced in 1999, will further reduce this risk to 1:500,000

Hepatitis D virus (HDV or delta virus) differs from the other viruses in that it can only cause infection in recipients who are hepatitis B surface antigen positive, i.e., carriers of HBV It is therefore only commonly seen in patients, such as hemo-philiacs who have been exposed to plasma derivatives

Hepatitis E virus (HEV) is common in Eastern Europe, Asia and in Africa HEV has been implicated in transfusion transmitted hepatitis in underdeveloped countries, but no cases have been described in the United States HEV is very

similar to hepatitis A virus in clinical features and is not known to have a chronic carrier state

Hepatitis G virus (HGV) is a more recently described virus with some similar-ity to HCV It has a high seroprevalence rate in many blood donor populations studied (up to 4%) Infection with HGV can be associated with transient transaminasemia, but it is not known clinically to have any short or long term effects At this time, a co-infection with hepatitis G and hepatitis C does not ap-pear to increase the severity of hepatitis C infection Testing for anti-HGV virus is not routine, and early information indicates that routine testing is not warranted This situation will presumably undergo more close scrutiny as further informa-tion develops regarding this virus Whether the liver cell is the target cell for this virus is also unsettled at this time

The B-19 parvovirus is another virus known to be transmitted by blood trans-fusion The parvoviruses are infections only for animals with the exception of B-19, which causes an acute infection, “fifth disease,” in children and arthritis in adults Nevertheless, B-19 virus transmission by transfusion ordinarily appears to rarely cause significant clinical symptoms However, B-19 virus infection may cause

a transient bone marrow suppression This is of clinical significance in certain patients, such as patients with hemolytic states or in bone marrow transplant pa-tients where a transient marrow failure is significant Routine viral attenuation methods which are successful in destroying the hepatitis or HIV viruses, such as physical or chemical methods, have shown little success in inactivating the B-19 parvovirus (Chapter 31)

More recently, other viruses have been described such as TT virus (transfusion transmitted virus) but little is known regarding the significance or prevalence

Blood Transfusion Transmitted

Infections II: Bacteria, Protozoa,

Helminths and Prions

Although viral disease transmission by blood transfusion is the dominant con-cern regarding the transmission of infectious diseases by blood transfusion, bac-teria, protozoa, helminths and possibly other agents may also be transmitted by blood transfusion

The most important bacteria transmitted by blood transfusion are shown in Table 35.1 Bacterial sepsis associated with red blood cells is a potentially life threat-ening situation (Chapter 32.1) The risk of bacteria contaminating red cell prod-ucts causing a septic reaction is related to the duration of in vitro storage More than 50% of all cases of red cell-associated bacterial sepsis are due to a single

bacterial species, Yersinia enterocolitica This is because Y enterocolitica survives

well during long periods of refrigerated storage; in addition, as red cell hemolyze

during storage, the iron released is used by Y enterocolitica to facilitate growth.

This bacteria produces a toxin which accumulates during storage and gives rise to the clinical symptoms (fever, hypotension) Less often, species such as Pseudomo-nas and Salmonella have been implicated in red cell associated sepsis

Clinical symptoms of red cell sepsis usually, but not always, occur very quickly after the transfusion is initiated Primarily, a high fever is characteristic (>2°C;

>3.5°F) and hypotension may occur; however, lesser degrees of fever or chills with

or without hypotension may be the only manifestation Unless the diagnosis is made promptly and antibiotics started immediately, a fatal outcome may occur

As the organisms are primarily gram negative, an appropriate antibiotic to ad-minister is erythromycin, given immediately intravenously The occurrence of fe-ver (Chapter 32) is not uncommon in patients receiving blood transfusion, and distinguishing bacterial sepsis from other causes of fever is not possible clinically, although the extent of the fever and the presence of hypotension should always suggest bacterial sepsis

Red cell sepsis is a rare event, occurring in approximately 1:500,000 units trans-fused It should be noted that autologous blood collected preoperatively (Chap-ter 3), is considered to be at increased risk for this complication Therefore, au-tologous blood, while safer than allogeneic blood is not entirely safe It is also primarily because of the possibility of red cell sepsis that patients who develop fever in association with blood transfusion and are found not to be hemolyzing (Chapter 32) should not have the red cell transfusion recommenced, since sepsis cannot be excluded

Clinical Transfusion Medicine, by Joseph D Sweeney and Yvonne Rizk © 1999 Landes Bioscience

Measures to prevent this unusual, but potentially fatal complication of blood transfusion are lacking, as questioning blood donors with regard to a history of recent diarrhea, for example, is largely ineffective in identifying implicated do-nors Shortening the storage time of red cells from 42-25 days would be useful, but would cause difficulties with inventory management The bacteria which con-taminates red cell products are generally present in the blood at the time of collec-tion, i.e., the donor is bacteremic but asymptomatic As noted below, this source

of bacteria is very different from the bacteria which contaminate platelet products Bacterial sepsis associated with platelet transfusion is considered a far more common occurrence Unlike red cell products, the bacteria which contaminate platelet products likely originate from the skin of the donor at the time of veni-puncture for blood collection Therefore, organisms such as skin commensals are the prominent bacteria in platelet associated bacterial sepsis (Table 35.1) Plate-lets are also stored at higher temperatures (between 20-24°) and this facilitates the growth of many bacteria Platelet transfusion associated sepsis occurs with plate-lets that have been stored for at least 3 days and, more commonly, 4 or 5 days The clinical features of platelet associated sepsis are similar to those of red cell associ-ated sepsis However, many patients receiving platelet transfusions, such as leuke-mic patients or bone marrow transplant recipients, are concurrently receiving broad spectrum antibiotics because of neutropenic infection Therefore, to an extent, there is protection from the transfusion of a bacterial contaminated platelet product

The frequency of occurrence of bacterial associated sepsis with platelets is un-known since in many instances this may go undiagnosed, but it may be as high as approximately 1:4,000 transfusions Bacterial sepsis is more commonly associated with the use of pooled random donor platelets, as discussed in Chapter 28 How-ever, it is important to emphasize that random donor pools tend to be transfused later in storage than apheresis platelets, and this factor alone may account for this difference in product type associated sepsis

Treponema palladium (the organism which causes syphilis) is known to be

transmitted by blood transfusion and testing for syphilis using an antibody test has been performed since 1948 Transmission by blood transfusion occurs rarely

at this present time Moreover, testing for syphilis using an antibody test is inef-fective in identifying infectious donors since many donors who are bacteremic at the time of donation are in the early phases of infection and seroconversion may not have occurred Routine testing of blood serologically for syphilis, therefore, identifies individuals who have had previous infections, which are now resolved The interest in testing blood donors for syphilis at the present time is the use of this test as a surrogate marker for HIV-1 infection and, for this reason, the test has largely continued to be used It is interesting to note that the only bacterium for which blood donations are routinely tested does not account for any significant fraction of bacterial associated infections transmitted by blood transfusion!!

Lyme disease is due to another spirochete, known as Borrelia borgdorfii

Al-though this organism grows well in both red cells and, particularly platelets, no cases of Lyme disease transmitted by blood transfusion have ever been reported

On rare occasions, contamination of water-baths in which plasma has been thawed may cause sepsis, since a break or leak in a plasma bag can allow bacteria

to enter the bag This is an unusual complication and is generally avoided in blood banks by double wrapping of the plasma bag during thawing Faulty manufactur-ing of platelet bags has also been associated with contamination by bacteria inside the humidified environment of the blood pack, but this is rare

Table 35.2 shows the protozoa and helminths known to be transmitted by blood transfusion With regard to protozoa the most important parasite is that of ma-laria, particularly plasmodium malaria The transmission of malaria by blood trans-fusion is a very uncommon event in the United States, but transmission is more common in malaria endemic zones outside of the U.S It is a practice to question all donors with regard to recent presence in malaria endemic zones, whether they received chemoprophylaxis for malaria, or if they have had an active malarial in-fection Donors are routinely deferred for one year if they have been in an en-demic zone and have had chemoprophylaxis, and for a period of three years if they have had an active, recent infection Malaria transmitted by blood transfu-sion tends to produce clinical symptoms 3-6 weeks after exposure, and classic features of malaria are present The diagnosis is normally made by examination of the peripheral blood smear Another important protozoa disease is Chagas dis-ease, which in endemic in many parts of Central and South America This disease

is caused by Trypanosomiasis cruzi (T cruzi) T cruzi is a concern for blood

trans-fusion authorities in South American countries Some blood centers in these areas

Table 35.1 Bacteria transmitted by blood transfusion

a) Red cells:

Yersinia enterocolitica

Pseudomonas fluoresces

Salmonella sp

(b) Platelets:

Staphylococci (epidermis and aureus)

Salmonella and Serratia spp

B cereus

(c) Miscellaneous:

T pallidum (Syphilis)

Borrelia burgdorfii (Lyme disease)

Water-bath or platelet pack contamination

routinely add methylene blue dye to blood products in order to kill this protozoa

In the United States, several cases of transfusion transmitted Chagas disease have been reported from blood donors who have emigrated to the United States from endemic zones, especially central America In the Southwest United States it is not

an uncommon practice to question blood donors with regard to their previous residence in endemic areas Testing of blood using an ELISA assay for antibodies

to T cruzi is possible but, as yet, has not become routine Babesiosis is a tick-borne

protozoa, prominent in the Northeastern United States, particularly in the islands off Massachusetts, Rhode Island, Connecticut, and New York This red cell intra-cellular parasite can be transmitted by blood transfusion but may not result in significant clinical symptoms in many recipients and, therefore, may go unrecog-nized For patients who have been splenectomized, however, transfusion associ-ated babesiosis may be a life threatening complication In endemic zones, donors are routinely questioned with regard to a history of babesiosis; questioning with regard to recent tick bites has not been shown to be effective in preventing the transmission of this disease African leishmaniasis, or kala-alar, is caused by a

pro-tozoa, Leishmania donovani Leishmania donovani is known to be transmitted by

blood transfusion in Africa In the early 1990s there was concern with regard to

exposure of US war personnel to a related species of leishmaniasis, known as

Leish-mania tropica, and donors who had served in this area were deferred for 18 months Leishmania tropica, however, unlike Leishmania donovani, has never been shown

to be transmitted by blood transfusion Other protozoans such as

Trypanosomia-sis gambiensi, or African sleeping disease, have rarely been transmitted by blood

transfusion Toxoplasmosis gondii has been transmitted by transfusion but largely

in the context of leukocyte transfusions Studies of patients who have received multiple red cell transfusions, such as thalassemia or sickle cell disease patients,

using serological testing for Toxoplasmosis gondii have not shown increased

Table 35.2 Protozoa and helminths transmitted by blood transfusion

1 Protozoa:

a) Plasmodia spp—Malaria

b) T cruzi—Chagas Disease

c) M Bancroti—Babesiosis

d) L Donovani—African Leishmaniasis (Kala-Alar)

e) T Gambiense—Trypanosomiasis

f) T Gondii—Toxoplasmosis

2 Helminths:

a) W Bancroti—Filariasis

seropositivity in multitransfused recipients compared to age and sex matched

con-trols, indicating that the transmission of T gondii by blood products is not likely

to be common

The only helminth infection well implicated to be transmitted by blood

trans-fusion is filariasis (by the organism Wucheria bancroti) The microfilaria of

W bancroti can be seen in the peripheral blood of asymptomatic donors are

ca-pable of transmitting this infection This is only relevant in areas where this infec-tion is endemic; however, such as in the upper Nile areas of Egypt and Sudan There is considerable interest recently in the possible transmission of prion diseases by blood transfusion Prion diseases are caused by an abnormal form of a protein termed PrPsen or PrPc, which is a normal constituent of the neurons in the central nervous system and is also expressed on the surface membrane of B lym-phocytes The abnormal form of this protein, designated PrPSC or PrPRes, is resis-tant to protease digestion The PrPSC form resembles the normal protein PrPc, except that the PrPSC protein is more unfolded Exposure of the normal PrPc pro-tein to the abnormal PrPSC protein causes the normal PrPc protein to become unfolded, like the PrPSC protein, and excessive accumulation of the PrPSC protein then occurs with resulting cell death Much of the attention has focused on Creutzfeld-Jakob disease (CJD) with the recent demonstration that a new variant

of CJD (nvCJD) is caused by the same prion which causes a disease in cattle called bovine spongiform encephalopathy (BSE or Mad Cow Disease) The concern is that asymptomatic donors who are incubating nvCJD, could have the prion par-ticle in blood and could transmit this disease by blood donation A recent obser-vation that B lymphocytes may be important in transporting this disease to the central nervous system in inoculated animals has increased interest in providing leukoreduced blood for all transfusion recipients and has contributed to the re-cent decision by some European countries and Canada to universally leukoreduce all cellular blood products (Chapters 36; 41)

Special Blood Products I:

Leukoreduced and Washed Blood

Products

This chapter will discuss approaches to reducing or attenuating the effects of allogeneic leukocytes or soluble substances present in cellular blood products All transfused blood is filtered, as each blood administration set contains an in-line filter (Chapter 7) This filter is commonly made of nylon mesh and serves the purpose of removing any large clumps of cellular debris, or clots, which formed

in the blood product during storage This nylon mesh has a pore size of 170-260µ

(µ or micron is 10-6 meter) and therefore, will not retain single cells, small clumps

of cells or particulate matter, which may arise from the degeneration of cells dur-ing in vitro storage

Microaggregate filters (2nd generation) represented an improvement in blood filtration Microaggregate filters were introduced in the 1970s and were either classified as depth or screen filters, depending on their mode of action Depth filters removed particles of an average size; screen filters had a threshold (cutoff) discriminating size These microaggregate filters were successful in removing small aggregated cell clumps, particularly the clumps of leukocytes and platelets which develop during red cell storage The discriminating size is between 20-40µ Mi-croaggregate filters will successfully remove approximately 85% of allogeneic leu-kocytes (present as aggregates) in stored red cells When coupled with modifica-tions such as the spin, cool and filter technique (whereby a unit of blood is centri-fuged, then stored after centrifugation for 24 hours and subsequently transfused through a microaggregate filter), up to 95% of the leukocytes are removed Mi-croaggregate filters were very successful in preventing nonhemolytic febrile trans-fusion reactions to red blood cells

In the late 1980s, further developments in filtration technology produced the third generation filters, and these are the most common filters in current use In addition to a screen function, some of these filters are coated with a chemical substance resulting in the selective absorption of different cell types They are therefore, capable of removing large numbers of single cells, in addition to small cell clumps These filters consist of polyester or polyurethane layers contained in a polycarbonate housing The polyester fibers are coated with proprietary chemical material, which confer the selectivety in cell absorption The red cell leukoreduction filters will remove both leukocytes and platelets Platelets may actually facilitate the removal of certain types of leukocytes, particularly granulocytes The platelet leukoreduction filters selectively remove only white cells (and not platelets!) Third generation filters are successful in removing between 99.5-99.9% of allogeneic leukocytes and therefore, the residual leukocyte load transfused is often extremely

Clinical Transfusion Medicine, by Joseph D Sweeney and Yvonne Rizk © 1999 Landes Bioscience