Pooled prevalence of lymphopenia in all-cause hospitalisations and association with infection: a systematic review and meta-analysis.

Background: Lymphopenia is defined as a decrease below normal value (often 1.0 x 10 cells/L) of blood circulating lymphocyte count. In the general population, lymphopenia is associated with an increased risk of hospitalisation secondary to infection, independent of traditional clinical risk factors. In hospital, lymphopenia is associated with increased risk of healthcare-associated infection and mortality. By summarising lymphopenia's prevalence and impact on clinical outcomes, we can identify an at-risk population and inform future studies of immune dysfunction following severe illness.

Methods: Peer-reviewed search strategy was performed on three databases. Primary objective was to summarise the pooled prevalence of lymphopenia. Primary outcome was infection including pre-existing lymphopenia as a risk factor for admission with infection and as an in-hospital risk factor for healthcare-associated infection. Secondary outcomes were length of stay and mortality. Mortality data extracted included in-hospital, 28/30-day ('early'), and 90-day/1-year ('late') mortality. Meta-analysis was carried out using random-effects models for each outcome measure. Heterogeneity was assessed using I statistic. Joanna Briggs Institute checklist for cohort studies was used to assess risk of bias. The protocol was published on PROSPERO.

Results: Fifteen observational studies were included. The pooled prevalence of lymphopenia in all-cause hospitalisations was 38% (CI 0.34-0.42, I= 97%, p< 0.01). Lymphopenia was not associated with an infection diagnosis at hospital admission and healthcare associated infection (RR 1.03; 95% CI 0.26-3.99, p=0.97, I = 55% and RR 1.31; 95% CI 0.78-2.20, p=0.31, I=97%, respectively), but was associated with septic shock (RR 2.72; 95% CI 1.02-7.21, p=0.04, I =98%). Lymphopenia was associated with higher in-hospital mortality and higher 'early' mortality rates (RR 2.44; 95% CI 1.71-3.47, p < 0.00001, I = 89% and RR 2.05; 95% CI 1.64-2.56, p < 0.00001, I = 29%, respectively). Lymphopenia was associated with higher 'late' mortality (RR 1.59; 1.33-1.90, p < 0.00001, I = 0%).

Conclusions: This meta-analysis demonstrates the high prevalence of lymphopenia across all-cause hospitalisations and associated increased risk of septic shock, early and late mortality. Lymphopenia is a readily available marker that may identify immune dysfunctional patients. Greater understanding of immune trajectories following survival may provide insights into longer-term poor clinical outcomes.