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

Abstract

Background

Neutropenia 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 findings

Of 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 × 10 ⁹/l, n = 2,352) compared to those with lymphocytes in the reference range (1.1–3.7 × 10 ⁹/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.

Conclusions

Lymphopenia 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.

Abstract

Stig Bojesen and colleagues highlight the increased risk of future infection or death for those with lymphopenia using data from a large Danish cohort.

Author summary

Why was this study done?

• Neutropenia and lymphopenia are low concentrations in the blood of the white blood cells—neutrophil granulocytes and lymphocytes, respectively; both are important for protecting against infections.

• Individuals with neutropenia have a well-documented increased risk of infection.

• It is currently unknown whether lymphopenia is associated with risk of infection in individuals from the general population.

What did the researchers do and find?

• We investigated whether a low lymphocyte count could predict risk of later hospitalization due to an infection or risk of death due to an infection.

• The study population consisted of 98,344 individuals from the general population in Copenhagen, Denmark. All included individuals answered a questionnaire on lifestyle and health, had a physical examination, and had blood samples drawn at the date of examination.

• We found that lymphopenia in the general population was associated with a 1.4-fold increased risk of infection and a 1.7-fold increased risk of infection-related death.

What do these findings mean?

• The study design cannot address questions of causality; however, risk of infection was increased in individuals with lymphopenia even 2 years after blood sampling, indicating that undiagnosed infection or comorbidity is not likely to be the only explanation for the results.

• Physicians are generally not recommended to intervene in patients with lymphopenia without an associated diagnosed disease. This might deserve reconsideration, since individuals with lymphopenia have increased risk of infection and infection-related death.