Transfusion and risk of infection in Canada: Update 2012

Abstract

Although multiple critical steps are taken to minimize the risk of infection from transfusion of blood or blood products in developed countries, this risk can never be entirely eliminated. In Canada, the risks of noninfectious transfusion reactions, such as transfusion-related acute lung injury and major allergic or anaphylactic reactions, are greater than that of infection. This updated practice point provides an overview of transfusion infection risks in Canada. Infectious agents, systemic conditions, donor and recipient factors, and collection and infusion techniques are considered. Suggestions are offered to improve both system and process, and to help practitioners who are discussing informed consent with patients and parents before administering blood or a blood product.

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In Canada and other developed countries, many steps are taken to minimize the risk of infection from transfusion of blood or blood products (1), but this risk is never reduced to zero because these biological products are taken from living donors who are never ‘germ free’ (2). However, the risk of noninfectious transfusion reactions, such as transfusion-related acute lung injury (TRALI) and major allergic or anaphylactic reactions, are greater than that of infection (3). This updated practice point provides an update on transfusion infection risks in Canada. It replaces a 2006 note (4), and may be helpful to practitioners in discussion with patients and parents toward informed consent before administering blood or blood products.

STEPS TO PREVENT INFECTIONS FROM BLOOD TRANSFUSION

Restrictive transfusion policies and effective blood conservation programs

A crucial step in enhancing safety is to assess carefully whether the patient is likely to benefit from administering blood or a blood product (ie, that potential benefits outweigh the potential risks) (3). This assessment is key in paediatrics because many adverse events in this age group are due to human error, such as overtransfusion or the inappropriate transfusion of neonates (3). Studies of adults in critical care settings have shown that a restrictive transfusion policy is at least as effective as a liberal transfusion strategy in terms of outcome (5). While outcomes of restrictive policies in neonatal and paediatric intensive care settings are not as clear-cut, preventative and/or intervention strategies that minimize the need for transfusion are recommended (6–8).

Evidence-based effective policies for donor selection, screening, product collection, testing and infusion

While any infectious agent that has a blood phase has the potential to be transmitted by transfusing blood or blood products, the probability of infection in the recipient depends upon a number of factors, including (9):

• the prevalence of the agent in the blood of the donor population;

• the tolerance of the agent to blood handling, storage and manufacturing processes;

• the infectivity and pathogenicity of the agent;

• the recipient’s health and immune status;

• the effectiveness of donor screening or donor testing for the agent; and

• the effectiveness of aseptic technique procedures used to collect the blood or blood product from the donor and to infuse the product into the recipient.

In Canada, the infectious disease risks of transfusion are minimized through multiple steps, including: blood collection from volunteer unpaid donors; donor interview and selection protocols; careful aseptic technique procedures for collection and infusion (10,11); the diversion of the first 40 mL of blood collected into a diversion pouch (12) (ie, not used for transfusion); donor screening by serological and other tests, including bacterial detection in platelets (13) (Table 1); viral inactivation procedures used in manufacturing plasma-derived products (Table 2) (9); and leukocyte reduction techniques that reduce the transmission risk of white cell-associated viruses, such as cytomegalovirus (CMV) (9). Unfortunately, the solvent/detergent and inactivation by heat procedures noted in Table 2 cannot be used for red blood cells or platelets, because neither component can withstand these vigorous processes. Pathogen reduction methods for platelets are in development but not licensed in Canada. The solvent/detergent method of pathogen reduction is licensed for plasma, and was introduced in mid-2012.

TABLE 1.

Testing of blood donors in Canada^* by Canadian Blood Services (CBS) and Héma-Québec (HQ)

HIV-type 1/2 and subtype O	Antibody/NAT (HIV-1)
HBV	Hbs Ag, Anti-HBc, NAT
HTLV type I/II	Antibody
Syphilis	Treponemal test/PK-TP
HCV	Antibody/NAT
WNV	NAT all units year round at CBS; all units tested during the summer plus testing donors with travel risk of WNV in the winter at HQ
Other	CMV antibody on selected units only: Trypanosoma cruzi (agent for Chagas’ disease) antibody on at-risk donors
Bacteria	Bacterial culture on platelets

^*Personal communications: Dr Gilles Delage, HQ and Dr Sheila O’Brien, CBS. CMV Cytomegalovirus; Hbs Ag Hepatitis B surface antigen; HBV Hepatitis B virus; HCV Hepatitis C virus; HTLV Human T-lymphotropic viruses; NAT Nucleic acid testing; WNV West Nile Virus

TABLE 2.

Specific manufacturing procedures for virus inactivation or removal

Procedure	Agents inactivated	Agents not inactivated
Inactivation by heat	CMV, HAV, HBV, HCV, HIV, WNV, Parvovirus B19
Inactivation by solvent/detergent	CMV, HBV, HCV, HIV, WNV	HAV, Parvovirus B19, enteroviruses
Ultrafiltration using 35 nm and 15 nm filters	Removes even small viruses but also macromolecules (eg, Factor VIII is decreased)
Leukocyte depletion	Decreases CMV, HTLV type I/II	Non-WBC associated viruses

CMV Cytomegalovirus; HAV Hepatitis A virus; HBV Hepatitis B virus; HCV Hepatitis C virus; HTLV Human T-lymphotropic viruses; WBC White blood cell; WNV West Nile virus

Table 3 identifies specific inactivation steps in the manufacture of different plasma-derived products that decrease viral infection risks. Of note, the majority of Factor VIII and Factor IX used in Canada are recombinant products, not plasma-derived, and, hence, do not have the infectious risks of a blood product.

TABLE 3.

Manufacturing steps to decrease infectious risks of plasma preparations and plasma-derived components

Plasma preparation	Virus risk pre-inactivation process(es)	Pools screened for HIV, HCV, HBV, and HTLV type I/II*	Further virus inactivation steps
Cryoprecipitate (a blood component – not a fractionation product)	++	Yes	None†
Factor VII	+	Yes	Al(OH)3 ± nanofiltration ± vapour heat treatment
Factor VIII‡	+	Yes	pasteurization process, solvent/detergent ± dry heat treatment
Factor IX‡	+	Yes	Vapour heating
Antithrombin concentrates	+	Yes	Sephadex A-50, solvent/detergent ± DEAE sepharose FF chromatography ± nanofiltration
Albumin	+	Yes	Isolation of filtrate ± isolation of filtrate IV ± isolation of filtrate d ± pasteurization ± cold ethanol fractionation ± heated treated
IVIG products	+	Yes	Cold ethanol fractionation, solvent/detergent ± caprylate ± column chromatography ± low pH treatment ± nanofiltration ± heat treatment ± octanoic acid fractionation ± depth filtration ± virus filtration
IMIG	+	Yes	Cold ethanol fractionation, solvent/detergent ± heat inactivation ± precipitation filtration ± ultra filtration ± diafiltration
Specific antibody products§	+	Yes	Cold ethanol fractionation or ion exchange column chromatography, solvent/detergent, virus filtration ± heat inactivation
			Anion-exchange column chromatography ± Planova 20N Virus Filter ± solvent/detergent ± cold ethanol fractionation ± heat inactivation ± precipitation filtration ± ultra filtration ± diafiltration

^*Human T-lymphotropic viruses (HTLV) type I/II are cell-associated viruses, so they are not found in manufactured plasma-derived products and serological screening of source plasma is not required. Similarly, cytomegalovirus (CMV) is primarily cell-associated, and the manufacturing processes remove risk;

^†Hence the risk of transmission of infection from cryoprecipitate is similar to the risk from blood and blood products, and greater than from plasma-derived manufactured products;

^‡Very few patients in Canada are treated with plasma-derived Factor VIII or Factor IX. Please note: As there may be more than one product per plasma preparation, the above summarizes the inactivation steps of products in each preparation.

^§eg, Hepatitis B (HBV) immune globulin, Tetanus immune globulin, Rabies immune globulin, Rh (D) immune globulin, etc. DEAE Diethylaminoethanol; HCV Hepatitis C virus; IMIG Intramuscular immunoglobulin; IVIG Intravenous immunoglobulin. Adapted from manufacturers’ package information

The risk of bacterial contamination of platelets is greater than for red cells because platelets are stored at room temperature (22°C ± 2°C), which supports bacterial pathogen multiplication (14,15). Initial aliquot diversion and bacterial detection have decreased the risk significantly (13), as has the automated culture of platelet components, but bacterial contamination of platelet concentrates remains a concern (16). The risk of bacterial contamination of frozen components, such as fresh frozen plasma and cryoprecipitates, is much lower because the usual microbes (Table 4) are killed by freezing and other storage conditions. While plasma contamination from the water bath used to thaw the product was a problem in the past, the use of microwave techniques or appropriate plastic covering designed specifically for this purpose have minimized the risk (17).

TABLE 4.

Bacterial agents associated with acute infection during blood product transfusion

Blood component	Storage	Bacterial agent
Packed red cells	1°C to 6°C for 35 to 42 days	Yersinia enterocolitica Gram-negative, including Pseudomonas species
Whole blood	1°C to 6°C for 35 to 42 days	Gram-negative organisms, including Pseudomonas species
Platelets	20°C to 24°C for 5 days	Skin flora (eg, Staphylococcus epidermidis, Streptococcus species, diphtheroids)
		Salmonella species
		Escherichia coli
		Enterococci species
		Clostridium species
		Serratia marcescens
Plasma	Frozen, once thawed can be held at 1°C to 6°C for 24 h	Staphylococcus aureus
		Pseudomonas aeruginosa

Adapted from references 14 and 15

Adverse transfusion events in Canada

The Transfusion Transmitted Injuries Surveillance System (TTISS) (www.phac-aspc.gc.ca/hcai-iamss/tti-it/index-eng.php) now captures more than 80% of all transfusions in Canada, providing national data on transfusion transmitted injuries (ie, infectious diseases and noninfectious adverse events). The TTISS report for the year 2006 noted nine deaths for a rate of 1:130,122 units transfused; the reported rate of adverse events per product infused increased to 1:2950, up from 1:4091 in 2005 (18). The increase in the rate of reported adverse events was primarily due to increased recognition and reporting of transfusion-associated circulatory overload cases, regardless of their severity. Table 5 summarizes the types of reactions with blood product transfused for the 420 events reported in 2006, showing that the most common events were: transfusion-associated circulatory overload (46.2% of serious adverse events); severe/anaphylactic/anaphylactoid reactions (15.9%); hypotensive reaction (11.9%); and TRALI (8.1% + possible 1.9%) (18). Only five cases of bacterial contamination were reported for a rate of 1:292,775 units transfused. The TTISS program continues to verify a high degree of safety in the Canadian blood system and a very small risk of bacterial contamination, although both allergic/anaphylactic reactions and transfusion overload remain concerns.

TABLE 5.

Incidence in Canada of adverse transfusion events according to blood component implicated, 2006

	Red blood cells	Apheresis platelets	Whole blood platelets	Plasma	Cryoprecipitate	Multiple components	Rate per units transfused	Total
Severe allergic/anaphylactic reaction	22 (7.5)	15 (57.7)	13 (32.5)	15 (27.8)	2 (66.7)	–	1:18,017	67 (15.9)
Acute hemolytic transfusion reaction	20 (6.8)	2 (7.7)	2 (5)	–	–	–	1:50,917	24 (5.7)
Delayed hemolytic transfusion reaction	14 (4.8)	–	2 (5)	–	–	–	1:78,073	16 (3.8)
Transfusion-associated circulatory overload	154 (52.4)	5 (19.2)	7 (17.5)	2.7 (50)	–	1 (33.3)	1:6131	194 (46.2)
Transfusion-related acute lung injury	18 (6.1)	–	6 (15)	8 (14.8)	1 (33.3)	1 (33.3)	1:41,825	34 (8.1)
Possible transfusion-related acute lung injury	6 (2)	–	1 (2.5)	–	–	1 (33.3)	1:41,825	8 (1.9)
Transfusion-associated dyspnea	11 (3.7)	3 (11.5)	2 (5)	3 (5.6)	–	–	1:61,637	19 (4.5)
Bacterial contamination	3 (1)	–	2 (5)	–	–	–	1:292,775	5 (1.2)
Hypotensive transfusion reaction	44 (15)	1 (3.8)	4 (10)	1 (1.9)	–	–	1:23,900	50 (11.9)
Post-transfusion purpura	–	–	1 (2.5)	–	–	–	1:1,171,101	1 (0.2)
Others*	2 (0.7)	–	–	–	–	–	–	2 (0.5)
Total	294 (100)	26 (100)	40 (100)	54 (100)	3 (100)	3 (100)	1:2,950	420 (100)

Data presented as n (%) unless otherwise indicated.

^*eg, Hypertensive transfusion reaction (1) and post-transfusion thrombocytopenia (1). Adapted from reference 18

Estimated per unit risks of bacterial, parasitic and viral contamination of blood and blood products

The estimated per unit risks of contamination in blood, blood products and manufactured plasma-derived products in Canada for a number of viral, bacterial, parasitic, prion and tick-borne agents are presented in Tables 6 and 7. As the data in these Tables show, the risks of transmitting infectious agents by blood, and especially by manufactured plasma-derived products, are extremely low in Canada. For context, a 1:3,000,000 risk is similar to that of being hit by lightning.

TABLE 6.

Estimated risk of infectious agents in blood or blood products

Agents	Transfusion-transmitted	Pathogenic	Canadian estimated risk of contamination*
Agents for which all blood donors are tested
HIV†	Yes	Yes	1 in 8 to 12 million
HCV†	Yes	Yes	1 in 5 to 7 million
HBV†	Yes	Yes	1 in 1.1 to 1.7 million
HTLV† types I and II	Yes	Yes	1 in 1 to 1.3 million
WNV	Yes	Yes	No reported cases in Canada since screening was introduced in 2003‡
Bacteria	Yes	Yes	Apheresis platelets: 1 in 105,000 Platelet pools: 1 in 47,000
Syphilis	Yes	Yes	<1 in 100 million
Other agents tested on occasion
CMV	Yes	Yes	Risks vary with donor/recipient but rare§
Chagas
(Trypanosoma cruzi)‡ Tested in high-risk donors	Yes	Yes	No new cases in the last five years; selective testing of at-risk donors implemented in 2009 (HQ) and 2010 (CBS)
Other agents not tested
Parvovirus B19	Yes	Yes	1 in 5000 to 1 in 20,000
GBV-C†	Yes	Unknown	1 to 2 in 100; not known to be pathogenic
TTV†	Yes	Unknown	1 in 100; rarely pathogenic
SEN-V†	Yes	Unknown	1 in 100; not known to be pathogenic
HHV-8†	Unknown	Yes	Unknown
Malaria	Yes	Yes	No new cases in over 10 years
Babesiosis (Babesia microti)	Yes	Yes	1 case reported in 2001
Prion
vCJD	Unknown	Yes	Risk unknown, extremely rare (<1 in 10 million)

^*Risk of contamination refers to the potential residual risk of infection from the listed organisms in blood or blood products after proper screening and manufacturing processes have occurred;

^†Based on residual risk calculations published by Canadian Blood Services (CBS) and Héma-Québec (HQ);

^‡West Nile virus (WNV) not tested in Quebec in winter except in donors with travel risk;

^§Cytomegalovirus (CMV) infection risk is decreased by leukoreduction procedures (see text). HBV Hepatitis B virus; HCV Hepatitis C virus; GBV-C formerly named Hepatitis G virus; HHV-8 Human herpes virus 8; HTLV Human T-lymphotropic viruses; SEN-V SEN virus; TTV Transfusion transmitted virus; vCJD Variant Creutzfeldt-Jakob disease. Adapted from reference 19

TABLE 7.

Estimated risks of infectious agents in manufactured plasma-derived products

Agents	Historical evidence of transmission from plasma product	Pathogenic	Canadian estimated risk of contamination*
Viruses for which all blood donors are tested
HIV	Yes	Yes	<1 in 10 million
HCV	Yes	Yes	<1 in 10 million
HBV	Yes	Yes	<1 in 10 million
HTLV types I and II	Yes	Yes	Only a theoretical risk
Other viruses
CMV	No	Yes	Only a theoretical risk
Parvovirus B19	Yes	Yes	Only a theoretical risk if heat inactivation; otherwise 1 in 100,000 to 1 in 1 million
WNV	No	Yes	Only a theoretical risk
Parasites
Malaria	No	Yes	Only a theoretical risk
Chagas	No	Yes	Only a theoretical risk
Babesiosis	No	Yes	Only a theoretical risk
Prion
vCJD	Unknown	Yes	Theoretical risk of <1 in100 million

^*Risk of contamination refers to the potential residual risk of infection from the listed organisms in plasma-derived products after proper screening and correct manufacturing processes have taken place. CMV Cytomegalovirus; HBV Hepatitis B virus; HCV Hepatitis C virus; HTLV Human T-lymphotropic viruses; vCJD Variant Creutzfeldt-Jakob disease; WNV West Nile virus. Adapted from reference 20

The importance of documenting transfusions

No national electronic record of transfusions yet exists to facilitate potential future trace-back programs for a new transmissible agent. Therefore, it is important to ensure that:

• transfused patients are aware they have received blood, blood products or manufactured plasma-derived products;

• the discharge or outpatient note adequately documents these transfusions, recording label code numbers for specific products; and

• hospital blood banks have such records.

Resources

Expanded discussion on the infectious diseases risks of transfusing blood and blood products can be found at the following websites:

• Canadian Blood Services: www.transfusionmedicine.ca/resources/clinical-guide-transfusion

• Héma Québec. Circular of information for the use of labile blood products, October 2010: www.hema-quebec.qc.ca/userfiles/file/notice_accompagnement_eng_web.pdf

• Public Health Agency of Canada, Transfusion Transmitted Injuries Section. About risks of blood transfusion: www.phac-aspc.gc.ca/hcai-iamss/tti-it/risks_e.html

• Santé et Services sociaux Québec, 2009. Consentement à la transfusion de produits sanguins : Guide destiné aux médecins: http://publications.msss.gouv.qc.ca/acrobat/f/documentation/2009/09-933-01.pdf