BackgroundNeutropenia increases the risk of infection, but it is unknown if this also applies to lymphopenia. We therefore tested the hypotheses that lymphopenia is associated with increased risk of infection and infection-related death in the general population.Methods and findingsOf the invited 220,424 individuals, 99,191 attended examination. We analyzed 98,344 individuals from the Copenhagen General Population Study (Denmark), examined from November 25, 2003, to July 9, 2013, and with available blood lymphocyte count at date of examination. During a median of 6 years of follow-up, they developed 8,401 infections and experienced 1,045 infection-related deaths. Due to the completeness of the Danish civil and health registries, none of the 98,344 individuals were lost to follow-up, and those emigrating (n = 385) or dying (n = 5,636) had their follow-up truncated at the day of emigration or death. At date of examination, mean age was 58 years, and 44,181 (44.9%) were men. Individuals with lymphopenia (lymphocyte count < 1.1 × 109/l, n = 2,352) compared to those with lymphocytes in the reference range (1.1–3.7 × 109/l, n = 93,538) had multivariable-adjusted hazard ratios of 1.41 (95% CI 1.28–1.56) for any infection, 1.31 (1.14–1.52) for pneumonia, 1.44 (1.15–1.79) for skin infection, 1.26 (1.02–1.56) for urinary tract infection, 1.51 (1.21–1.89) for sepsis, 1.38 (1.01–1.88) for diarrheal disease, 2.15 (1.16–3.98) for endocarditis, and 2.26 (1.21–4.24) for other infections. The corresponding hazard ratio for infection-related death was 1.70 (95% CI 1.37–2.10). Analyses were adjusted for age, sex, smoking status, cumulative smoking, alcohol intake, body mass index, plasma C-reactive protein, blood neutrophil count, recent infection, Charlson comorbidity index, autoimmune diseases, medication use, and immunodeficiency/hematologic disease. The findings were robust in all stratified analyses and also when including only events later than 2 years after first examination. However, due to the observational design, the study cannot address questions of causality, and our analyses might theoretically have been affected by residual confounding and reverse causation. In principle, fluctuating lymphocyte counts over time might also have influenced analyses, but lymphocyte counts in 5,181 individuals measured 10 years after first examination showed a regression dilution ratio of 0.68.ConclusionsLymphopenia was associated with increased risk of hospitalization with infection and increased risk of infection-related death in the general population. Notably, causality cannot be deduced from our data.

In the general population, older age is associated with short leukocyte telomere length and with high risk of infections. In a recent study of allogeneic hematopoietic cell transplantation for severe aplastic anemia, long donor leukocyte telomere length was associated with improved survival in the recipients. These findings suggest that leukocyte telomere length could possibly be a marker of immune competence. Therefore, we tested the hypothesis that shorter leukocyte telomere length is associated with higher risk of infectious disease hospitalization and infection-related death. Relative peripheral blood leukocyte telomere length was measured using quantitative polymerase chain reaction in 75,309 individuals from the general population and the individuals were followed for up to 23 years. During follow up, 9228 individuals were hospitalized with infections and infection-related death occurred in 1508 individuals. Shorter telomere length was associated with higher risk of any infection (hazard ratio 1.05 per standard deviation shorter leukocyte telomere length; 95% confidence interval 1.03–1.07) and pneumonia (1.07; 1.03–1.10) after adjustment for conventional infectious disease risk factors. Corresponding hazard ratios for infection-related death were 1.10 (1.04–1.16) for any infection and 1.11 (1.04–1.19) for pneumonia. Telomere length was not associated with risk of skin infection, urinary tract infection, sepsis, diarrheal disease, endocarditis, meningitis or other infections. In conclusion, our findings indicate that leukocyte telomere length may be a marker of immune competence. Further studies are needed to determine whether risk of infections in allogeneic hematopoietic cell transplantation recipients can be reduced by considering donor leukocyte telomere length when selecting donors.

Background It is unclear whether high platelet count or high hematocrit predict risk of thrombosis in individuals from the general population. Objectives We tested the hypothesis that individuals from the general population with high platelet count or high hematocrit have high risk of arterial and venous thrombosis. Methods We prospectively followed 108 521 individuals from The Copenhagen General Population Study for a median of 8 years. Platelet count and blood hematocrit were measured at study entry. Results and Conclusion Multivariable adjusted hazard ratios for individuals with platelet counts in the top 5 percentiles (>398 × 109/L) vs in the 25th‐75th percentiles (231‐316 × 109/L) were 1.77 (95% confidence interval [CI], 1.38‐2.24) for arterial thrombosis in the brain (38 and 26 events/10 000 person‐years) and 0.82 (95%, 0.61‐1.11) for arterial thrombosis in the heart (23 and 28 events/10 000 person‐years). For individuals with hematocrit values in the top 5 percentiles (women/men: >45/>48%) vs the 25th‐75th percentiles (women/men: 38.1‐42/41.1‐45%), hazard ratios were 1.27 (95% CI, 0.91‐1.75) for arterial thrombosis in the brain (40 and 26 events/10 000 person‐years) and 1.46 (95% CI, 1.06‐2.00) for arterial thrombosis in the heart (43 and 25 events/10 000 person‐years). Neither high platelet count nor high hematocrit was associated with risk of venous thromboembolism. When excluding individuals with myeloproliferative neoplasia from the main analyses, results on risk of thrombosis were similar. In this prospective study, high platelet counts were associated with 1.8‐fold risk of arterial thrombosis in the brain, whereas high hematocrit was associated with 1.5‐fold risk of arterial thrombosis in the heart.