Time-dependent association of glucocorticoids with adverse outcome in community-acquired pneumonia: a 6-year prospective cohort study

Abstract

Background: The hypothalamic-pituitary-adrenal stress axis plays a crucial role in community-acquired pneumonia (CAP), with high cortisol being associated with disease severity and corticosteroid treatment resulting in earlier time to recovery. Our aim in the present study was to compare different glucocorticoid hormones, including cortisol, 11-deoxycortisol, cortisone, and corticosterone, regarding their association with short- and long-term adverse outcomes in a well-defined CAP cohort.

Methods: We prospectively followed 285 patients with CAP from a previous Swiss multicenter trial for a median of 6.1 years and measured different admission glucocorticoid serum levels by liquid chromatography coupled with tandem mass spectrometry. We used adjusted Cox regression models to investigate associations between admission hormone levels and all-cause mortality at different time points.

Results: Mortality was 5.3% after 30 days and increased to 47.3% after 6 years. High admission cortisol was associated with adverse outcome after 30 days (adjusted OR 3.85, 95% CI 1.10-13.49, p = 0.035). In the long term (i.e.,), however, high admission cortisol was associated with better survival (adjusted HR after 3 years 0.53, 95% CI 0.32-0.89, p = 0.017; adjusted HR after 6 years 0.57, 95% CI 0.36-0.90, p = 0.015). Compared with 11-deoxycortisol, cortisone, and corticosterone, cortisol showed the highest association with mortality.

Conclusions: Among different glucocorticoid hormones, cortisol showed the highest association with mortality in CAP. Whereas a more pronounced glucocorticoid stress response on hospital admission was associated with higher short-term adverse outcome, long-term outcome was favorable in these patients. These data should support the correct interpretation of glucocorticoid blood data.

Keywords: 11-Deoxycortisol; Community-acquired pneumonia; Corticosterone; Cortisol; Cortisone; Disease severity; Glucocorticoid hormones; Mortality/outcome prediction; Pneumonia severity index.

Fig. 1

Association of admission glucocorticoid levels with all-cause mortality at different time points in CAP. Data for multivariate Cox regression models are presented as HR (95% CI). HRs >1 reflect a positive association between glucocorticoid levels and all-cause mortality. Multivariate model is adjusted for age, sex, and comorbidities (coronary artery disease, cerebrovascular disease, chronic kidney disease, neoplastic disease). CAP Community-acquired pneumonia

Fig. 2

Kaplan-Meier 6-year survival estimate according to admission glucocorticoid levels in CAP: fourth versus first-to-third quartiles. CAP Community-acquired pneumonia

Fig. 3

Glucocorticoid levels in patients with various severity classes of CAP. Data represent median and IQR, with scatter plots presenting all values. P values are determined by Kruskal-Wallis test and considered statistically significant at p < 0.05. Bold values indicate statistical significance. CAP Community-acquired pneumonia, PSI Pneumonia severity index

Fig. 4

Correlation of admission glucocorticoid levels with inflammatory markers in CAP. Data are presented with scatterplots showing all values (blue), overlaid by linear fit lines (red). Correlation analyses were performed by Spearman’s rank correlation (r; p value). We used multivariate linear regression models to calculate regression coefficients (Coef.). p < 0.05 is considered statistically significant. Bold values indicate statistical significance. We used admission glucocorticoid and PCT levels and high peak CRP levels. CAP Community-acquired pneumonia, CRP C-reactive protein, PCT Procalcitonin. *Multivariate model is adjusted for age, sex, and comorbidities (coronary artery disease, cerebrovascular disease, chronic kidney disease, neoplastic disease)