Lymphopenia and risk of infection and infection-related death in 98,344 individuals from a prospective Danish population-based study

Abstract

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.

Arterial and venous thrombosis by high platelet count and high hematocrit: 108 521 individuals from the Copenhagen General Population Study

“…Information on comorbidity was retrieved from the national Danish Patient Registry . We obtained information on both inpatient hospitalizations, emergency room visits, and outpatient visits, and categorized comorbid disease according to the Charlson comorbidity index, as described previously . For calculation of this index, we identified 16 489 individuals with any malignancy (including lymphoma and leukemia, except malignant neoplasms of the skin), 9392 with chronic pulmonary disease, 5180 with diabetes, 4449 with congestive heart failure, 3258 with rheumatic disease, 2581 with peptic ulcer disease, 2078 with dementia, 1651 with renal disease, 1603 with liver disease, 314 with hemiplegia/paraplegia, and 16 with AIDS/HIV.…”

“…16 We obtained information on both inpatient hospitalizations, emergency room visits, and outpatient visits, and categorized comorbid disease according to the Charlson comorbidity index, [17][18][19] as described previously. 20,21…”

Diagnosis of severe respiratory infections in immunocompromised patients

“…About 10% of critically ill cancer patients with severe pneumonia have neutropenia [22]. Lymphopenia is also associated with an increased risk of pneumonia [23]. Humoral immunosuppression and hypogammaglobulinemia are risk factors for bacterial pneumonia, especially with Streptococcus pneumoniae and Haemophilus influenzae [24].…”

Modelling pharmacokinetics and pharmacodynamics of the selective S1P1 receptor modulator cenerimod in healthy subjects and systemic lupus erythematosus patients

“…Although a direct relationship between total lymphocyte (LY) count reduction and clinical efficacy was not yet established for autoimmune diseases including multiple sclerosis and SLE, it is widely accepted that larger reduction yields better efficacy. By contrast, too low LY counts are generally associated with an increased risk of infections . Consequently, LY counts are frequently measured in studies with S1P (1) receptor modulators as surrogate for the immunomodulatory effect (efficacy) and as safety measure.…”

“…By contrast, too low LY counts are generally associated with an increased risk of infections. 9 Consequently, LY counts are frequently measured in studies with S1P (1) receptor modulators as surrogate for the immunomodulatory effect (efficacy) and as safety measure. Thereby, LY count thresholds for efficacy and safety proved useful to guide dose selection and benefit-risk evaluation of S1P (1) receptor modulators.…”