Persistent Lymphocytopenia Does Not Increase Nosocomial Infection Risk in the ICU

To the Editor: Critical illness is associated with a myriad of proinflammatory and antiinflammatory immunologic responses that can lead to impaired immunity. Hallmarks of such critical illness–induced immunosuppression are anergy and apoptosis of lymphocytes. Lymphocytopenia has been implicated in the development of infections through a combination of diminished T-cell and B-cell responses (1), and several studies have reported associations between deficits in lymphocyte subpopulations and an increased risk of ICU-acquired infections (ICU-AIs) and/or death (2–5). Immunotherapies to promote recovery of lymphocyte counts have therefore been proposed (1, 6–8). However, most prior studies focused on specific patient subgroups, lacked repeated measurement of lymphocyte counts, and failed to appropriately adjust for confounders and competing events (such as death or discharge), which may prevent observation of ICU-AI onset. Therefore, it remains unclear whether persistent lymphocytopenia truly constitutes a risk factor for infection or merely is a marker of disease severity. To study the prevalence, temporal evolution, and clinical correlates of lymphocytopenia in ICU patients and to estimate the attributable risk of lymphocytopenia in causing ICU-AI, we analyzed 2,302 critically ill adults (>18 yr) who had been admitted to the University Medical Center Utrecht (the Netherlands) between January 2011 and December 2018 with an ICU admission related to trauma, major surgery, or sepsis and a length of stay greater than 4 days. Exclusion criteria were known prior immunodeficiency, pregnancy, and recent heart surgery or burn injuries. Data were obtained as part of the Molecular Diagnosis and Risk Stratification of Sepsis project (ClinicalTrials.gov identifier NCT01905033), during which all possible infectious events in the ICU had been prospectively adjudicated by a dedicated research team (9). Comprehensive results of our study have been previously reported on medRxiv (10.1101/2020.07.14.20153601).