Lymphocyte-to-high-density lipoprotein ratio and mortality in asthma patients: a novel immunoinflammatory biomarker with nonlinear association

Abstract

Background: The lymphocyte-to-high-density lipoprotein ratio (LHR), a novel biomarker reflecting systemic inflammation and immune status, has been widely studied in various diseases. However, its association with mortality risk among asthma patients remains unexplored.

Methods: This study utilized data from the National Health and Nutrition Examination Survey (NHANES) spanning 1999-2018, including 5,323 adult asthma patients. Mortality outcomes were ascertained through linkage with the National Death Index (NDI) up to December 31, 2019. Cox proportional hazards models and Fine-Gray competing risk models were employed to examine the association between LHR and mortality risks. Dose-response relationships were assessed using restricted cubic spline analyses.

Results: Over a mean follow-up period of 106.95 months, 724 all-cause deaths (13.6%) were recorded. After multivariable adjustment, a one-unit increase in log-transformed LHR was associated with reduced risks of mortality: 18% for all-cause (HR = 0.82, 95% CI: 0.74-0.91), 21% for cardiovascular disease (CVD) (HR = 0.79, 95% CI: 0.65-0.96), and 41% for chronic lower respiratory disease (CLRD) (HR = 0.59, 95% CI: 0.45-0.77). Restricted cubic spline analyses showed an L-shaped association of LHR with all-cause and CLRD mortality, with inflection points at 1.78 and 1.52, respectively. For CVD mortality, a linear association was observed. Competing risk models further confirmed the association of LHR with reduced CLRD mortality (SHR = 0.64, 95% CI: 0.46-0.88), while the association with CVD mortality was no longer significant (SHR = 0.85, 95% CI: 0.70-1.03).

Conclusion: LHR is nonlinearly associated with all-cause and CLRD mortality and shows a significant inverse association with CLRD mortality risk. These findings were further validated using competing risk models, highlighting the robustness of the results.

Keywords: NHANES; asthma; competing risk analysis; lymphocyte-to-high-density lipoprotein ratio (LHR); mortality.

Figure 1

Flow chart of study participants.

Figure 2

The association of LHR with all-cause (A), CVD (B), and CLRD mortality (C) among asthma patients visualized by restricted cubic spline. Hazard ratios were adjusted for gender, age, race, education level, marital status, PIR, BMI, Eosinophils, alcohol use, smoking status, ASCVD, hypertension, diabetes, Prescribed medications, PA-MET.

Figure 3

Cumulative incidence of CVD mortality (A) and CLRD mortality (B) across LHR categories (T1, T2, T3) using a competing risk model. Cumulative incidence functions were estimated using Fine-Gray subdistribution hazard models. p-values for Fine-Gray tests: p < 0.001 for both CVD mortality (A) and CLRD mortality (B).

Figure 4

Forest plot for subgroup analysis of association between LHR and all-cause mortality. Except for the stratification factor itself, the stratified analysis was adjusted for all variables. Multivariate Cox regression models were used to calculate hazard ratios (HRs), and interaction p-values were provided for each subgroup.

Figure 5

Forest plot for subgroup analysis of the association between LHR and CVD and CLRD mortality using competing risk models. Subdistribution hazard ratios (HRs) were calculated using Fine-Gray competing risk models. Except for the stratification factor itself, the stratified analysis was adjusted for all variables. Interaction p-values were provided for each subgroup.