Researchers in Lancet Digital Health published their findings of a retrospective cohort study that aimed to explore if data searches could detect unknown transfusion-transmitted diseases. Specifically, the authors of the study used both health-data registries and blood center databases to assess whether data searches could uncover previously unknown transfusion-transmitted diseases that put the blood supply at risk. They described the development of a, “systematic algorithm for performing a phenome-wide search for transfusion-transmitted disease without consideration of any a-priori suspicion of blood-borne transmissibility.” The authors used the algorithm in combination with the Swedish transfusion database (SCANDAT-3S), “to test for possible transmission of 1,155 disease entities based on all relevant diagnostic coding systems in use during the period.” Their analysis included, “1,720,000 patients who were recipients of 18,970,000 blood products from 1,040,000 donors from January 1968 to December 2017.” The researchers noted that study population included, “all patients, irrespective of age, who were recorded to have received at least one red blood cell, plasma, platelet, or whole blood transfusion [and the study’s analyses] were based on the premise that transfusion-transmission of a disease-causing agent would result in an increased disease risk among recipients of blood units from any donor who was a carrier of that agent. Transfusion-transmission could be identified using two independent analytical approaches: (a) by studying disease diagnosis concordance between donors and recipients or (b) by finding a shared increased disease risk among all recipients of a given donor, irrespective of whether that donor was diagnosed. “
According the authors of this study that used healthcare data searches to attempt to detect unknown transfusion-transmitted diseases , “[t]he median follow-up was 4.5 (interquartile range (IQR) 0.9–11.4) years for recipients and 18.5 (8.3–26.2) years for donors. [They] found evidence of transfusion-transmission for 15 diseases, of which 13 were validated using a second conceptually different approach.” The researchers further explained that, “[w]e compared the risk of each disease for patients who received at least one blood unit from a donor who was later affected by the same disease during follow-up with those who did not receive any blood unit from a donor affected by that disease. Patients were followed up from the date of the first transfusion until the date of first diagnosis of each disease, death, emigration, or until the last day of follow-up (Dec 2017). We excluded patients who had been diagnosed with the disease of interest before their first transfusion from the analysis for that disease…Of the 1,155 disease categories investigated, we identified statistically significant associations between the occurrence of disease in donors and an increased risk in recipients for 65 disease categories. After false discovery rate (FDR) adjustment, 15 of these associations remained statistically significant.”
Specifically, this study that used healthcare data searches to attempt to detect unknown transfusion-transmitted diseases found that, “[t]he strongest associations were observed for HIV (hazard ratio (HR) 6.83 [95 percent CI 2.50–18.62]; FDR-adjusted p value 0.018) and viral hepatitis (e.g., hepatitis B and C viruses), captured both as a diagnosis of chronic viral hepatitis (HR 6.31 [5.76–6.91]; FDR-adjusted p value 1.0 × 10−241) and other acute viral hepatitis (HR 3.26 [2.31–4.61]; FDR-adjusted p value 1·9 × 10−9), as well as through downstream complications such as oesophageal varices (HR 1.37 [1.14–1.65]; FDR-adjusted p value 0.047).” Thus, the researchers stated that, “we failed to detect any strong evidence of unknown, widespread transfusion transmission beyond the expected findings of transmission of HIV and viral hepatitis. This reassuring finding indicates that it is unlikely that unknown transmissible agents exist in the Swedish blood donor pool that have a sufficiently high prevalence and clinical penetrance to result in widespread transfusion-transmission.”
However, they also explained that the study, “observed some signals of transfusion-transmission for diseases that might warrant additional investigation. These diseases include unspecific outcome categories such as pneumonia (organism unspecified), other sepsis, and other gastroenteritis and colitis of unspecified origin, which all contain multiple different disease entities. Associations for these outcome categories were statistically significant, but with hazard ratios very close to one. Although speculative, it is possible that these associations are driven either by residual confounding factors or that the small excess risks are reflective of there being only a small fraction of events in these categories that were of a transmissible origin.”
Additionally, the authors noted that another association in their findings worth further exploration was, “tular[e]mia, caused by the bacteria Francisella tularensis, for which there have been sporadic reports of transmission in solid-organ transplants and evidence that the bacteria can invade erythrocytes, making transfusion-transmission plausible. This finding might warrant replication, especially due to the low number of events in the exposed group.”
They concluded in this study which used healthcare data searches to attempt to detect unknown transfusion-transmitted diseases that, “[i]n this large-scale agnostic phenome-wide study of transfusion-transmitted disease during five decades, we did not find evidence for any novel transfusion-transmitted illnesses. Our study constitutes a proof-of-concept of an agnostic, data-driven, exploratory surveillance tool for transfusion-transmitted diseases. This approach might incite additional future efforts to improve input data quality, determine appropriate downstream confirmatory look-back and trace-back activities, and evaluate its effectiveness to improve safety of blood transfusions.”
Citation: Dahlén, T., Jingcheng Zhao, J., Busch, M.P., Edgren, G. “Using routine health-care data to search for unknown transfusion-transmitted disease: a nationwide, agnostic retrospective cohort study.” Lancet Digital Health. 2024.