Tixagevimab/cilgavimab pre-exposure prophylaxis and breakthrough infection risk in vaccinated solid organ transplant recipients: concern for immortal time bias effect.

We read with interest the recent Brief Communication from Al Jurdi et al1Al Jurdi A. Morena L. Cote M. Bethea E. Azzi J. Riella L.V. Tixagevimab/cilgavimab pre-exposure prophylaxis is associated with lower breakthrough infection risk in vaccinated solid organ transplant recipients during the omicron wave.Am J Transplant. 2022; 22: 3130-3136https://doi.org/10.1111/ajt.17128Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar describing their experience with COVID-19 breakthrough infection following tixagevimab/cilgavimab (T/C) administration in their vaccinated solid organ transplant recipient population. The main finding was a lower incidence of COVID-19 infection in the group that received T/C, especially among the subgroup of lung transplant and kidney transplant recipients. We would like to add the concept of immortal time bias to the discussion of the limitations in the interpretation of the study results. The immortal time bias can occur when participants in an observational cohort study cannot experience the outcome during some period of follow-up time.2Lévesque L.E. Hanley J.A. Kezouh A. Suissa S. Problem of immortal time bias in cohort studies: example using statins for preventing progression of diabetes.BMJ. 2010; 340: b5087https://doi.org/10.1136/bmj.b5087Crossref PubMed Scopus (768) Google Scholar This usually happens when the assignment into a treatment group and a control occurs by using information that is observed after the participants enter the study. Because participants in the treated group must have been event free for the time between entering the cohort and getting the first dose of the intervention medication, they are considered “immortal” (or “event free”) and contribute “immortal” (or “event free”) time to the treated group by design. Therefore, bias is introduced when this period of “immortality” is not accounted for in the design of a study. This “immortal time bias” can lead to a distortion of observed events in favor of the treatment group. In the study by Al Jurdi et al,1Al Jurdi A. Morena L. Cote M. Bethea E. Azzi J. Riella L.V. Tixagevimab/cilgavimab pre-exposure prophylaxis is associated with lower breakthrough infection risk in vaccinated solid organ transplant recipients during the omicron wave.Am J Transplant. 2022; 22: 3130-3136https://doi.org/10.1111/ajt.17128Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar there could have been a distortion in results due to immortal time bias; there were notable differences in infection rates between the early and late periods of data collection. Between January and March, the infection rates were 1.8% in the T/C group and 6.3% in the no T/C group and from April to May, they were 3.2% in the T/C group and 8.1% in the no T/C group. Of the initial doses of T/C, 98.2% were administered during the early period, and infections occurring during this period would preclude administration of T/C. Consequently, this difference in rates between the early and late periods suggests the presence of an immortal time bias that could distort results in favor of the intervention group and may give the false impression of benefit. Among the subset of lung transplant recipients examined by Al Jurdi et al,1Al Jurdi A. Morena L. Cote M. Bethea E. Azzi J. Riella L.V. Tixagevimab/cilgavimab pre-exposure prophylaxis is associated with lower breakthrough infection risk in vaccinated solid organ transplant recipients during the omicron wave.Am J Transplant. 2022; 22: 3130-3136https://doi.org/10.1111/ajt.17128Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar there were fewer infections in the T/C group. The immortal time bias effect in their patient population throughout the period of T/C administration should be considered when evaluating these conclusions. It is likely that the effectiveness of T/C is overestimated in the Al Jurdi cohort. The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation. Response to letter entitled: Tixagevimab/cilgavimab pre-exposure prophylaxis and breakthrough infection risk in vaccinated solid organ transplant recipients: Concern for immortal time bias effectAmerican Journal of TransplantationVol. 23Issue 3PreviewIn their Letter to the Editor, Riggs et al1 describe the concept of immortal time bias as a possible limitation of our retrospective cohort study evaluating the efficacy of tixagevimab-cilgavimab pre-exposure prophylaxis in solid organ transplant recipients (SOTRs).2 Immortal time bias can occur when study participants cannot experience the outcome during a period of follow-up time (Fig. 1A). A frequently used example is evaluating the efficacy of inhaled glucocorticoids in reducing readmission and death rates after hospitalization for acute exacerbation of chronic obstructive pulmonary disease. Full-Text PDF