transfusion-transmitted bacterial infection: risks, sources and interventions

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Vox Sanguinis (2004) 86, 157–163

REVIEW © 2004 Blackwell Publishing

Blackwell Publishing, Ltd.Transfusion-transmitted bacterial infection: risks, sources and interventionsS. J. WagnerBiomedical Research and Development, American Red Cross, Rockville, MD, USA

Records of the transmission of bacterial infections by transfusion date back to thebeginning of organized blood banking. Despite tremendous strides in preventing viralinfection through careful donor screening and viral testing, there has been littleimprovement in reducing the risk of bacterial sepsis since the introduction of closedcollection systems. Based on the French Haemovigilance study, the British SeriousHazards of Transmission (SHOT) study and fatality reports to the United States Foodand Drug Administration, the risk of clinically apparent sepsis exceeds the risk of HIV,HBV, and HCV transmission. Sources of contamination include the skin, blood, dispos-ables, and the environment. Potential interventions to reduce transfusion-associatedbacterial sepsis include improvements to donor arm preparation, diversion of the firstaliquot of whole blood, introduction of bacterial testing and/or implementation ofpathogen reduction methods.

Key words: bacteria, sepsis, transfusion, detection, pathogen reduction.

Received: 9 September 2003, revised 27 January 2004, accepted 28 January 2004

Historical perspective

Bacteria were probably the first recognized infectious diseaserisk from transfusion; some of the first reports of sepsis dateback to the time when blood was stored in glass bottles [1].Comparing the early accounts of pervasive contaminationof blood with data from today strongly suggests that thefrequency of contaminated units was greatly reduced by theadvent of closed, sterile systems for the collection and stor-age of blood [2]. Following the introduction of sterile plasticblood containers, the transmission of bacteria has remainedrelatively constant and contrasts the remarkable declineof human immunodeficiency virus (HIV), hepatitis C virus(HCV) and hepatitis B virus (HBV) transmission over the past18–20 years with the advent of viral screening [3,4]. Cur-rently, clinically apparent bacterial sepsis is a significantlygreater threat than transfusion-transmitted viral infectionsfrom screened agents, based on data from the Serious Hazardsof Transmission (SHOT) study, the French Haemovigilance

study and the Food and Drug Administration (FDA) fatalityreports [5–7]. Transfusion-associated bacterial sepsis is causedmore frequently by contaminated platelets than by red cellcomponents because many species of bacteria can proliferateunder the room temperature conditions utilized for plateletstorage and attain late-stage logarithmic or stationary phaselevels prior to transfusion.

Assessment of the frequency of post-transfusion sepsis

Three measures have traditionally been employed to gaugethe frequency of bacterial contamination in blood. Manualand automated blood cultures produce the highest measuredfrequencies of contamination, yet the difficulties in maintainingan aseptic environment during sample transfer can cause false-positive test results. The most careful studies use repeat culturesto distinguish between true and false positives and have foundone repeat positive unit in ≈ 1500 uncontaminated units ofplatelets from individual donors [8,9]. No studies have beenpublished on the repeat positive culture rate of red cell units,although initial culture positive results can vary from 0 to0·6% [10,11]. Few of these contaminated units contain organ-isms capable of outgrowth at refrigerated temperatures.

Correspondence : Stephen J. Wagner, American Red Cross, 15601 Crabbs Branch Way, Rockville, MD 20855, USAE-mail: [email protected]

158 S. J. Wagner

© 2004 Blackwell Publishing Ltd. Vox Sanguinis (2004) 86, 157–163

Clinical signs of sepsis, such as fever, changes in bloodpressure, and/or rigors, confirmed by culture of the sameorganisms from the blood bag and the recipient, are moreinfrequent than culture-positive units, with prevalencevalues ranging from one in 10 000–100 000 platelet units[12–15]. The majority of these platelet studies averagearound one case of clinical apparent sepsis in 15 000 units.Culture-confirmed cases of clinically apparent sepsis fromred cell units are rarer still, with one study reporting one in5 000 000 units [13]. However, the measured frequency ofclinical sepsis can depend on the patient population. Inseverely immunocompromised patients receiving plateletsafter bone marrow transplantation, clinical sepsis with con-firmatory culture of the same organism in the blood bag andrecipient occurred in one in 358 units [16].

Transfusion-associated sepsis is the most frequent causeof death from infectious agents, representing 17–22% of allreported fatalities, and only surpassed by fatalities from ABOerrors [7,17]. Fatalities have been reported to occur in onein 50 000–500 000 platelet units [12,13] and in one in8 000 000 red cell units [13]. It is acknowledged that manyepisodes of transfusion-related sepsis are unrecognized andtherefore not reported, so some reports of clinical and fatalprevalence are probably underestimated.

Bacterial contamination of red cells

Yersinia enterocolitica contamination, as a result of asymp-tomatic bacteraemia in the donor, represents ≈ 46% of thedocumented cases of clinical sepsis from contaminated redcells and occasionally is involved in transfusion-associatedsepsis from autologous units [18–22]. Yersinia grows well inred cell concentrates as it uses citrate and requires a sourceof iron. Several in vitro studies have documented the abilityof leucocyte or buffy coat depletion to prevent the outgrowthof Yersinia during storage at 1–6 °C [23–27]. However, it isuncertain whether spiking experiments model the intracellu-lar and extracellular localization of the organism in the bloodof a bacteraemic patient [28]. The efficacy of leucocyte deple-tion to prevent Yersinia outgrowth in stored red cells mustawait future analysis of Yersinia transmission rates in leu-codepleted and non-leucodepleted blood. After Yersinia, themost prevalent organisms implicated in sepsis from red cellsare Pseudomonas spp. (25%), followed by Serratia spp. (11%)and other organisms (18%) [5,13,18]. Approximately 80% ofthe reported cases of red cell-associated sepsis involvedpsychrophiles, or organisms capable of growth at refrigeratedtemperatures. Analysis of documented cases of septic fatal-ities from red cells [7] yields a similar distribution of bacterialspecies as found in clinically apparent sepsis [5,13,18], and,coupled with their similar overall frequencies, suggests thatthe same organisms that cause fever, blood pressure changesand rigors, also often cause recipient death.

Bacterial contamination of platelets

The organisms identified in platelet units implicated inclinical cases of transfusion-associated sepsis includeStaphylococcus spp. (42%), Escherichia coli (9%), Bacillusspp. (9%), Salmonella spp. (9%), Streptococcus spp. (12%),Serratia spp. (8%), Enterobacter spp. (7·0%) and other organ-isms (4%) [5,13,18]. About 56% of the organisms were iden-tified as Gram positive, and most were aerobes.

Unlike red cells, there are differences in the distributionof bacterial species in documented cases of septic fatalitiesfrom transfusion of contaminated platelets compared withcases of clinically apparent sepsis [5,7,13,18]. Staph. epidermidisis less common in septic fatalities and more common in septicreactions. Klebsiella spp. are associated with 17·3% of septicfatalities, but rarely associated with non-fatal cases of sepsis.Finally, Gram-negative organisms are implicated in a greaternumber of fatalities (60%) than Gram-positive organisms(40%).

Sources of contamination

The source of bacterial contamination in blood cannotalways be easily identified. Sources are sometimes inferredby an isolated strain’s typical niche (skin, enteric or soilorganism), or implicated by coincidental isolation of thesame organism on the donor’s arm or blood-bag surfaceas identified in the septic episode. Sources of bacterialcontamination include the skin, blood, disposables, and theenvironment. For donors who have developed scarring at thephlebotomy site, the skin may persistently harbour organ-isms, such as Staphylococcus spp., in a refuge unaffected bydisinfectants. One frequent plateletpheresis donor was impli-cated in two septic episodes involving a coagulase-negativeStaphylococcus that repeatedly contaminated units collectedfrom a scarred and dimpled site of the donor’s right antecu-bital fossa [29]. In contrast, when phlebotomy was on the leftarm, the units were routinely culture negative.

Coring of skin or the flushing of organisms from skin flapsinto the primary blood container during phlebotomy haslong been recognized as a source of contamination [30,31].Several studies have investigated the potential for diversionof the first 10–40 ml of whole blood to prevent skin plugs orflushing of organisms from skin flaps from entering the pri-mary collection container [32–34]. The diverted whole bloodcan be used for viral testing and may allow collection of unitsthat would otherwise be destroyed because of the inability tocollect blood in tubes from a small percentage of donors afterblood collection. In vitro studies suggest that this manoeuvremay remove 95–98% of surface bacteria [32,33]. A prospec-tive clinical study demonstrated that use of a 10-ml diversionof whole blood to a satellite pouch reduced overall bacterialcontamination from 0·35 to 0·21% (P = 0·05) and, in particular,


Transfusion-transmitted bacterial infection: risks, sources and interventions 159

the skin organism, Staph. epidermidis, from 0·14 to 0·03(P < 0·02) [35].

Skin disinfection reduces bacterial load, but will notcompletely sterilize the phlebotomy site. In addition, someskin-disinfection methods may not be equivalent in efficacy.In two donor-based studies, 70% isopropyl alcohol followedby 2% tincture of iodine performed better than 0·75% povi-done iodine followed by 1% povidone iodine [36,37]. More-over, the motion of disinfectant application (up and downwas superior to spiral) and applicator design (stick was super-ior to swab) had an impact on the extent of disinfection ofsurface organisms in one study [37]. Other comparativedisinfection studies involving hospital patients, rather thanhealthy blood donors, failed to show differences in thefrequency of culture-positive samples between phlebotomycleansing agents [38].

Commercial disinfectants are not always sterile. Onemanufacturer’s 1% povidone iodine solution was shown tobe contaminated with P. cepacia [39]. A subsequent studydemonstrated that the bacterium could survive in the solu-tion for up to 68 weeks. Although all lots contained 1% avail-able iodine, different lots from the manufacturer variedgreatly in the amount of free iodine because the element iscomplexed with povidone and the strength of the complexdepends on the physical and chemical properties of thesolution (e.g. temperature of storage, ionic strength, etc.).Interestingly, the contaminated lots of povidone iodine wereassociated with relatively low levels (0·23–0·46 p.p.m.) offree iodine compared to other samples analysed in the samestudy. This report demonstrates the importance in maintainingsterile conditions and ensuring sterility of the final product,even when preparing and packaging disinfectant solutions,and may illustrate a disadvantage of complexed disinfectants.

Some units become contaminated because donors haveasymptomatic or low-grade bacteraemia. For example, oneplateletpheresis donor was linked to seven cases of Sal.cholera-suis sepsis, three of which were confirmed by positivecultures of the platelet unit. Two of the septic episodes were

fatal. The donor unknowingly had a low-grade bacteraemiafrom Salmonella osteomyelitis of the tibia [40]. Other occur-rences of transfusion-associated sepsis may arise from tran-sient, rather than chronic, bacteraemia. Dental proceduresand even toothbrushing can often be associated with transientbacteraemias [41,42]. In light of the potential for dental pro-cedures to cause transient bacteraemias, some countriesdefer donors if they had visited the dentist earlier in the day.

Other cases of sepsis arise from the contamination ofdisposables. Two well-recognized reports from Denmarkand Sweden involved an outbreak of Ser. marcescens sepsis,which, when investigated, implicated a common lot of bloodcontainers [43,44]. A survey of 1515 blood containers inDenmark demonstrated the presence of the organism in 11bags (0·73%). Subsequent investigation of the manufactur-ing plant identified contamination with an organism of thesame ribotype as identified in the contaminated units. Theauthors speculated that the source of contamination mighthave originated from the exterior of the blood container.

The environment can also be a source of skin contamina-tion. One unusual and fatal case of sepsis involved the anaer-obe, Clostridium perfrigens, which contaminated a plateletpool and was traced back to the skin of a young female donor[45]. The organism is a spore-forming anaerobe, commonlyfound in soil and the human intestinal tract. Apparently themother carried her two infants in the crook of her arm; theauthors speculated on the transference of fecal material fromthe baby’s diaper to the donor’s antecubital fossa.

Bacterial detection methods

Several methods have been investigated for detecting bac-teria in platelet products prior to transfusion. A partial listing,along with their approximate detection limits, is given inFig. 1. Because bacteria grow in components during storage,the most sensitive methods are recommended if samplingis performed within 1 or 2 days of blood collection, whileless sensitive methods may be acceptable if sampling is

Fig. 1 Approximate detection limits and times to

obtain results for various methods of bacterial

detection in blood.

160 S. J. Wagner


performed within a few hours prior to transfusion. In general,a method’s sensitivity seems to be related to its time to detec-tion. Rapid methods, such as pH and/or glucose dipsticks,can detect > 107 colony-forming units (CFU)/ml bacteria andrequire seconds to perform [46,47].

A swirling test can also be performed in seconds and hasbeen used to detect bacterial levels of > 107 CFU/ml in plateletcomponents [46]. Swirling is the ‘pearly’ appearance of plate-lets that occurs when a unit is inverted and is caused by localincreases in turbidity when asymmetric platelets align withfluid flow. Platelets cease to swirl when contaminated withhigh levels of bacteria because the declining pH in the unitcauses asymmetric platelets to become spherical. One advant-age of swirling is that the platelet unit does not need to besampled in order to perform the test.

Investigative techniques, using semiautomated fluores-cent microscopy or cytometry, can detect 102−104 CFU/mlof bacteria in platelet components within minutes [48–50].These methods are based on the preferential lysis of whiteblood cells (WBCs) and most platelets by detergents, stainingof intact bacteria with a dye that fluoresces only when boundto nucleic acid, capture of stained bacteria on a filter, andautomated analysis of bacterial counts by fluorescent micro-scopy or scanning non-flow cytometry. In contrast to thesemiautomated methods, manual methods for microscopycan detect > 105 CFU/ml (acridine orange) or > 106 CFU/ml(Gram stain) bacteria and require similar times for analysisas semiautomated methods.

Two immunological methods are in development for ageneralized detection of bacteria in platelet components nearthe time of transfusion. In one method (Verax Biomedical,Worcester, MA), gold-conjugated antibodies against lipotei-choic acid, for detection of Gram-positive bacteria, or againstlipopolysaccharide for detection of Gram-negative bacteria,bind to organisms in a contaminated platelet sample that isintroduced to an antibody-impregnated centre spot of a teststrip and subjected to bidirectional lateral flow [51]. Theantibody–antigen complex is then captured by a line ofantibodies immobilized to each distal portion of the nitro-cellulose strip. The assay can distinguish Gram-positive fromGram-negative organisms and detect 103−104 CFU/ml bacteriain ≈ 20 min. In another method (Immunetics Inc., Cambridge,MA), antibodies against peptidoglycan of Gram-positive andGram-negative organisms are utilized in a single-incubationimmunoassay conducted in a 96-well format [52]. The assaycan detect 103 CFU/ml of a variety of Gram-positive andGram-negative species within 1 h.

A molecular biology method based on ribosomal RNA candetect > 104 CFU/ml bacteria in platelet components within60–90 min [53]. In this technique, unamplified bacterial 16SrRNA, which is present at ≈ 5000 copies per cell, has beenused as a target for a DNA probe directed against ubiqui-tiously conserved bacterial rRNA sequences (GeneProbe, San

Diego, CA). The chemiluminescent assay can detect a widevariety of bacteria and has been recently improved by semi-automation. Amplification of bacterial rRNA sequences hasalso been evaluated and can detect organisms, at 1–10 CFU/ml levels, in platelet components [54,55]. The amplified assayrequires several more hours to perform than the unamplifiedmethod developed by GeneProbe. One of the difficulties inobtaining optimal sensitivity from amplified systems is thatrecombinant polymerases are often contaminated with lowlevels of rRNA.

Two automated culture methods, the BioMerieux BacT/Alert system (Durham, NC) and the Pall bacterial detectionsystem (Pall BDS; Pall Medical, East Hills, NY), have beenstudied for bacterial detection in platelet components [9,56–63]. Because of their sensitivity to detect at least 1–10 CFU/ml in vitro, culture methods have become popular and havebeen implemented in several countries over the last fewyears. However, clinical studies on the use of culture methodsfor detection of bacteria in platelet components and theprevention of sepsis in transfusion recipients are somewhatlimited; widespread use of the techniques, coupled with well-designed studies, will be necessary to accurately gauge theirimpact on transfusion safety.

Bacterial detection in the BacT/Alert is based on theevolution of carbon dioxide by proliferating bacteria. Culturebottles containing aerobic or anaerobic growth media areaseptically inoculated by a manufacturer-recommended vol-ume of platelets. As bacteria grow in the culture bottle duringincubation at 34–37 °C, carbon dioxide is released, causinga reduction in the culture medium’s pH. A pH-sensitive diskat the bottom of the culture bottle changes colour, which isdetected by alteration of reflected light on the disk. Becauseinitial bacterial loads in freshly collected blood are thoughtbe very low (< 10 CFU/ml, with some fractions < 1 CFU/ml),the manufacturer recommends that samples be inoculatedinto bottles after ≥ 1 day of platelet storage to allow for somebacterial growth in the platelet component. This ≥ 24 h delayin bottle inoculation ensures that the collected sample vol-ume is more likely to contain organisms from a contaminatedunit. Following inoculation, bottles are incubated in theBacT/Alert for at least 24 h; however, incubation can extendup to the time limit for platelet storage. Bottles are monitoredcontinuously during incubation for colour changes in thesensor disk, indicating the presence of proliferating bacteria.

Bacterial detection in the Pall BDS system is based on themeasurement of reduced oxygen levels in contaminatedplatelet components caused by microbial oxygen consump-tion during proliferation. In a closed system, a small volumeof the unit is filtered to remove leucocytes and platelets,without removing large numbers of bacteria, and transferredinto a pouch. The pouch contains a dissolvable tablet ofsodium polyanethol sulphonate (SPS) to minimize thenatural inhibitors of bacterial growth usually present in blood.



Similarly to the BacT/Alert, sampling is performed at least1 day after blood collection to ensure that the sample volumefrom a contaminated unit is more likely to contain organ-isms. After more than 24 h of incubation at 35 °C, air overthe culture fluid is sampled for a one-time analysis of oxygenlevel. Oxygen levels less than a manufacturer-specifiedcut-off value indicate the presence of proliferating bacteria.Several improvements to the Pall BDS system have beenmade (BDS+) to promote more rapid bacterial growth; theseimprovements include agitation of the pouch during theincubation period and the addition of solid bacterial growthmedia to the SPS tablet.

Pathogen reduction

Another approach for preventing transfusion-associatedbacterial sepsis is the introduction of pathogen-reductionmethods, which are currently under clinical investigation[64]. These methods endeavour to reduce the transfusion-transmission of bacteria, enveloped viruses, some non-enveloped viruses and a number of parasites. However,implementation of a sensitive bacterial detection techniquemight go a long way to improve transfusion safety becausebacterial sepsis is currently the most prevalent serioustransfusion-transmitted disease in the United States andEurope. In addition, pathogen-reduction methods may reduceblood cell yields, function, circulatory survival and/or presenta toxicity risk to recipients, blood bank personnel, or theenvironment. In contrast to the potential risks of implement-ing pathogen-reduction methods, there is little risk in theintroduction of a laboratory test. Implementation of pathogen-reduction methods is also expected to cost many times morethan bacterial detection methods. One way to visualize therelationship between benefit, risk and cost is presented inFig. 2, where each measure is plotted in a three-dimensionalgraph. It is worthwhile to compare the pathogen-reduction

and bacterial-detection coordinates on this graph with thecoordinates of an ‘ideal’ method to prevent infectious diseasetransmission that would inactivate or detect all organismswithout risk or cost. Each country has different infectiousdisease risks, and some countries already have bacterialscreening measures in place. Therefore, each country needsto analyse their current infectious disease risks, estimatewhat fraction of these risks may be caused by bacterial con-tamination, and balance the benefit of reducing these riskswith the costs and risks associated with introducing eitherbacterial screening, if not in place, or pathogen-reductiontechnology.

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