There is good evidence that blood transfusion practice varies by time and geography, and often departs from evidence‐based guidelines. On the other hand, interventions to change physician practice around the ordering of blood transfusions can be successful. The challenge is therefore to develop reliable evidence to support rational transfusion practice. Both observational studies and randomized clinical trials have strengths and limitations. Observational studies are cheaper and usually larger with concomitant improved statistical power, and may be more representative by including a wide range of patients and hospitals in the routine setting unaffected by a research protocol. Weakness of observational studies include confounding by unmeasured factors; indication bias, namely overestimation of adverse outcomes by the fact that transfused patients tend to be sicker than similar patients who did not receive transfusion; and the fact that available data may not suit the research question. Randomized clinical trials have the advantage of minimizing the effects of confounding and bias by virtue of the randomization process. Limitations of randomized trials include their expense which reserves them for specific research questions and may limit statistical power; and ethical problems in study design such as inability to utilize a placebo by withholding transfusion. Finally, inclusion and exclusion criteria can limit the generalizability of conclusions by restricting enrollment to a set of patients that differ from those seen in general medical practice. In this review, I shall attempt to illustrate the complementary contributions and limitations of observational epidemiological studies and randomized clinical trials in understanding several transfusion‐related adverse outcomes: mortality; TRALI; TACO; and the RBC storage lesion. I conclude that evidence for the efficacy and adverse outcomes of blood transfusion needs to be obtained from a balanced combination of observational studies and clinical trials.

Background

In 1997 the FDA approved the first double-red-blood-cell (2RBC) collection device. Soon after, travel deferral for variant Creutzfeldt-Jakob disease (vCJD) risk was adopted. To show the importance of including 2RBCs in predictive models of the blood supply, an existing whole-blood (WB) model was updated to include 2RBC collection and then run to simulate the effect of vCJD deferral on total RBC availability.

Study design and methods

The model simulates donation of allogeneic WB and 2RBCs, with donors stratified into eight age and sex groups. The model was updated with 2003 donation and economic data from 16 blood centers.

Results

The distribution of donations by demographic group differed both within and between WB and 2RBCs. Overall, 2RBC donation made up 24 percent of transfusable RBC units, at a lower per-unit acquisition cost from both the blood bank and the societal perspectives. Component fees from hospitals would alter this interpretation. The model predicts that vCJD travel deferral led to a 3.3 percent (95% confidence interval [CI], 2.3-4.1) decrease in the total number of RBC units, which was more than offset by 2RBC collection, resulting in a 10.4 percent (95% CI, 9.8%-11.1%) net increase in RBC units. Modeled 2RBC results match operational records, whereas vCJD deferral is overestimated.

Conclusion

Shifting to 2RBC collection led to a substantial gain in available RBCs: even with policies that adversely affect the quantity of RBCs in the supply, 2RBC collection results in a net gain. The economics of 2RBC collection are not as clear, however.

Human T-lymphotropic virus type II (HTLV-II) is a human retrovirus which is endemic in Amerindian and pygmy tribes. Molecular subtypes show geographic segregation consistent with an ancient origin of this virus within humans in Africa or South America. More recently, injection drug users in the United States and Europe have become infected with HTLV-II, and secondary sexual transmission has introduced the virus at low levels into the general population and blood donors. HTLV-II has been linked with a spastic paraparesis called HTLV-associated myelopathy / tropical spastic paraparesis (HAM/TSP), and perhaps with other neurological syndromes. It is also associated with an increased incidence of pneumonia and bronchitis, inflammatory conditions such as arthritis, and perhaps with increased mortality. Except for a few cases of cutaneous lymphoma in patients coinfected with HIV, there is no evidence that HTLV-II causes lymphoproliferative disease. HTLV-II and HIV coinfection has not been proven to alter the course of HIV disease, but such patients may have altered levels of CD4+ and CD8+ lymphocytes, and antiretroviral therapy may paradoxically increase HTLV-II proviral load.

Blood safety remains an important public health concern in Africa where lack of availability or provision of unsafe blood adversely impacts morbidity and mortality in the region. In recognition of this shortfall, the World Health Organization (WHO) established a goal of regional blood safety by 2012 through improved "organization and management, blood donor recruitment and collection, testing of donor blood as well as appropriate clinical use of blood" (Tagny et al: Transfusion. 2008;48:1256-1261; Tapko et al: Status of Blood Safety in the WHO African Region: Report of the 2006 Survey http://www.afro.who.int/en/divisions-a-programmes/dsd/health-technologies-a-laboratories.html. Brazzaville, Republic of Congo: WHO Regional Office for Africa; 2006). Although there has been substantial progress toward meeting these objectives, there are continued obstacles to both development and sustainability. In a setting where transfusion oversight is still being improved, transfusion-transmitted infections are of real concern. The high prevalence of some transfusion-transmissible agents such as hepatitis B virus and HIV in the general population means that some infected blood units escape detection by even well-performed laboratory testing, resulting in potential downstream transmission to patients. The spectrum of transfusion-transmitted infection include conventional as well as exotic pathogens, many of which are endemic to the region, thereby imparting ongoing challenges to recruitment and testing strategies.

Naturally occurring antibodies against ABO antigens present in human sera have been shown to neutralize ABO-expressing HIV in vitro. We investigated associations between ABO and RhD blood groups and HIV infection among blood donors from all blood collection centers in eight of South Africas nine provinces. Whole blood donations collected from first time donors between January 2012 and September 2016 were tested for HIV RNA by nucleic acid testing and HIV antibody using third generation serology assays. ABO and RhD blood types were determined using automated technology. Odds ratios for the association between HIV positivity and ABO and RhD phenotypes were calculated using multivariable logistic regression analysis. We analyzed 515,945 first time blood donors and the overall HIV prevalence was 1.12% (n = 5790). After multivariable adjustment, HIV infection was weakly associated with RhD positive phenotype (OR = 1.15, 95% CI 1.00-1.33) but not with ABO blood group. The observed association with RhD positive phenotype was marginal and likely due to residual confounding by racial group but could serve to generate hypotheses for further studies.

Background

Blood collected in the United States and Canada is screened for West Nile virus (WNV) using nucleic acid testing (NAT). The role that donor-reported symptoms of infection disclosed at or shortly after donation may play in enhancing blood safety has been debated. Little data are available on subsequent manifestations of WNV-specific disease outcomes in viremic donors.

Study design and methods

Donors with initially reactive NAT results were informed by telephone and asked to complete symptom interviews. The questionnaires are focused on three time periods: the week before, the day of, and the 2 weeks after donation. Symptoms and risk factors were compared between confirmed-positive and false-positive donors (classified based on confirmatory NAT and serology). Additional analyses comparing confirmed-positive symptomatic and asymptomatic donors were conducted.

Results

A total of 423 of 536 initially reactive donors were interviewed between 2003 and 2006: 292 confirmed-positive for WNV and 131 false-positive. Individual symptoms were not significant predictors of WNV infection, except skin rash in the week before donation (odds ratio [OR], 3.0; 95% confidence interval [CI], 1.2-7.9) and body aches in the period after donation (OR, 2.8; 95% CI, 1.1-7.4). Specific combinations of symptoms were not good predictors of infection, but donors with three or more concurrent symptoms before donation were more likely to have WNV infection (OR, 2.5; 95% CI, 1.2-5.1). Demographic characteristics, predonation symptoms, and serology profiles in confirmed-positive donors did not predict postdonation symptom severity. Thirty-five confirmed-positive donors (12%) sought medical care for WNV infection, with two hospitalizations, but no cases of neuroinvasive disease.

Conclusion

The number rather than type of symptoms is associated with confirmed WNV infection, but the overall predictive value is low. Very few infected donors develop clinically significant disease.

Background

Concern about West Nile virus (WNV) transfusion-transmitted infections missed by minipool (MP) nucleic acid testing (NAT) has prompted consideration of the use of individual-donation (ID) NAT. Strategies were investigated for the application of limited ID-NAT capacity in 2004.

Study design and methods

Patterns of WNV MP-NAT-reactive donations tested by the Blood Systems Laboratory each week for 79 blood centers from June 29 to November 23, 2003 (196 MP-NAT repeat-reactive [RR] donations among 801,697 units), were analyzed. ID-NAT initiation strategies were developed consisting of counts of RR donations and/or weekly RR rates, together with three ID-NAT discontinuation strategies, and ID testing burden was assessed based on these combined start and stop strategies.

Results

The effectiveness, reported as the percentage of MP-RR donations that would trigger ID-NAT based on each initiation strategy, ranged from 57 to 100 percent. The addition of a 1- or 2-week no-yield requirement for ID discontinuation substantially increased testing burden. Combined strategies resulted in projected ID-NAT of between 10 and 50 percent of donations for a 10- to 20-week period. For this organization, the most feasible ID-NAT initiation strategy was 2 MP-reactive donations and a weekly rate of 1 in 1000, which had an effectiveness of 81 percent and led to peak weekly ID-NAT of 20 to 25 percent of donations depending on the discontinuation rule.

Conclusion

This new approach of targeted ID-NAT based on ongoing monitoring of MP-NAT yield may prove to be a rational policy for agents like WNV that cause seasonal and regional epidemics.