Risk of acquiring Creutzfeldt-Jakob disease from blood transfusions: systematic review of case-control studies

Study selection and characteristics

The Medline and Embase searches yielded 302 citations, including 14 case-control studies. Of these studies, four met the inclusion criteria.3^–6 A fifth study released after the searches were conducted was later identified and included in this analysis.7 Thus five studies, involving 2479 patients, were included in the final analysis. Two studies were conducted in the United Kingdom, 4 5 one in Japan,3 one in Europe,6 and one in Australia.7

Only one of the studies had a primary goal to determine the odds of receiving a blood transfusion.5 The other four studies were looking more broadly for risk factors for Creutzfeldt-Jakob disease. All studies used the Masters criteria to define cases of Creutzfeldt-Jakob disease and included definite and probable cases.8 All studies described a clear strategy for identifying cases. Two studies selected population controls 3 7; the rest identified medical or neurological patients as controls. All studies used age and sex matched controls, and all relied on surrogate reporting of transfusion history, most frequently from a close relative (table 1).

Risk of Creutzfeldt-Jakob disease from blood transfusion

All studies showed a trend towards a lower risk of Creutzfeldt-Jakob disease in patients who had received a blood transfusion, with one study showing this association to be significant.6 Odds ratios ranged from 0.54 to 0.89 (table 2). A combined odds ratio using a DerSimonion-Laird random effects model reached significance (odds ratio 0.70 (95% confidence interval 0.54 to 0.89)). A statistical test for heterogeneity was negative (P=0.62).9 The combined odds ratio should be interpreted with caution owing to theoretical concerns relating to combining data from observational studies.10

Two studies provided information on the interval between transfusion and development of Creutzfeldt-Jakob disease. One study only identified cases in which transfusions had been received in the five years up to the development of Creutzfeldt-Jakob disease.3 One study reported a mean interval of 174 months between transfusion and development of the disease.5 Only one study examined for a possible dose-response relation, and it found a progressively lower odds ratio with increasing number of transfusions, although significance was never reached.7

Limitations

Although case-control studies are well suited for determining associations in conditions that have low frequency and long latency periods, they are susceptible to bias. The major source of bias contributing towards the apparent beneficial effect of blood transfusion involves selection of controls in the primary studies. Three of the five studies used medical patients or neurological patients as controls.4^–6 Presumably, these individuals would be at higher risk than the average population of having received a blood transfusion.

Bias may also occur as a result of inaccurate ascertainment of transfusion status. Studies have found that 25-40% of transfusion recipients do not recall having received transfusions.12 The necessary reliance on reporting from surrogates, usually relatives, also contributes to inaccurate ascertainment. However, for recall bias to produce a decreased association between Creutzfeldt-Jakob disease and blood transfusions, family members of patients with Creutzfeldt-Jakob disease would have to be less likely to recall transfusion history than family members of controls.

Three of the five primary studies did not provide the results of matched analyses.3^–5 This is an important methodological limitation and illustrates the need for caution if using data from case-control studies. The failure to use matched analyses generally produces a bias towards the null effect.13

Other studies

Despite the limitations of the primary studies it seems unlikely, from the results presented in this systematic review, that blood transfusions contribute towards development of sporadic Creutzfeldt-Jakob disease. Evidence from other sources also seems to support the lack of an association. Results from animal studies have been equivocal, although a study from the US National Institute of Health concluded that the human blood could not transmit Creutzfeldt-Jakob disease to animals.14 This may, however, be more a function of the species barrier than of infectivity. A study of preserved brain samples of 25 haemophilic patients—who have high exposure to blood transfusions and potentially higher exposure to blood infected with the agent responsible for Creutzfeldt-Jakob disease—found no evidence of the disease.15 “Look back” studies have not identified any cases of Creutzfeldt-Jakob disease developing in recipients who received blood from a donor in whom the disease was later diagnosed. 16 17 No extended controlled cohort studies have been conducted to determine if blood transfusion recipients are at increased risk of Creutzfeldt-Jakob disease.

Generalisability

The results of this systematic review pertain to the transmissibility of sporadic Creutzfeldt-Jakob disease and should not be generalised to variant Creutzfeldt-Jakob disease. Variant Creutzfeldt-Jakob disease differs from the sporadic form in several respects: a shorter latency period, presentation with behavioural symptoms, and longer duration of disease before death. In particular, the lymphoreticular system seems to be a site for collection of the prion protein in variant Creutzfeldt-Jakob disease, with large amounts found in the appendices and tonsils of affected individuals. This affinity for the lymphoreticular system may increase the likelihood of variant Creutzfeldt-Jakob disease being transmitted via blood.18 One case-control study examining the risk of transmission of variant Creutzfeldt-Jakob disease from blood transfusions did not find any association (UK Creutzfeldt-Jakob Disease Surveillance Unit, www.cjd.ed.ac.uk/rep98.html (accessed 1 September 1999)).

Conclusion

This study illustrates some of the difficulties in attempting to determine causal relations in the area of infectivity of blood products. Despite the methodological advantages of case-control studies in studying rare diseases with long latency periods, potential exists for significant levels of bias that can produce apparently spurious results. It is important to recognise these limitations when attempting to address the question of infectivity of variant Creutzfeldt-Jakob disease via blood transfusion.