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

Activation of the hypothalamic-pituitary-adrenal (HPA) axis and stimulation of the central noradrenergic stress system by cytokines and other mediators are major pathophysiological adaptations in response to infection and inflammation [1‐4]. Appropriate activation of the HPA axis during illness is crucial for survival and mirrors the stress level. The effects of cortisol include protection against excessive inflammatory reaction, acute supply of energy, and improvement in hemodynamic status [5, 6].

Endogenous adrenocortical function is of prognostic value in critical illness and sepsis [7‐14], of which community-acquired pneumonia (CAP) is a major source [15‐17]. Morbidity in CAP is still high also, owing to higher risk for cardiovascular events [18, 19]. Researchers in multiple studies have investigated the adrenal steroid metabolism in relation to CAP-associated outcomes [14, 20‐25]. In observational trials, researchers have reported increased admission cortisol levels to be independent predictors of disease severity and short-term mortality in patients across the spectrum of mild to severe CAP [20‐24]. Interestingly, the predictive accuracy of free cortisol was not superior to that of total cortisol, independent of serum albumin levels [20]. The prognostic accuracy of cortisol levels in short-term mortality prediction was equal to that of the pneumonia severity index (PSI), but better than the CURB-65 score (confusion of new onset, blood urea nitrogen >7 mmol/L, respiratory rate ≥30 breaths per minute, systolic blood pressure <90 mmHg or diastolic blood pressure ≤60, and age ≥65 years) and routinely measured laboratory parameters such as C-reactive protein (CRP), procalcitonin (PCT), or white blood cell count [20, 21, 23]. In addition, in severe CAP, baseline serum cortisol levels were shown to be independent predictors of mortality with superior predictive ability compared with stimulated cortisol with corticotropin or Δ-cortisol [24]. Despite evidence regarding short-term outcomes, less is known about the predictive potential of glucocorticoid levels in regard to long-term mortality. Aside from that, most studies have been focused on cortisol only, and data regarding other human glucocorticoids, such as 11-deoxycortisol, cortisone, and corticosterone, are largely lacking. Identification of patients at risk for adverse outcome after an index hospitalization for CAP may optimize in-hospital and post-acute care strategies to improve survival. A better description of metabolite signatures in CAP may improve pathophysiological understanding and provide new targets for a more personalized therapy. In the present study, our aim was to study different compounds of the glucocorticoid pathway, including cortisol, 11-deoxycortisol, cortisone, and corticosterone, regarding their association with short- and long-term adverse outcomes in a well-defined CAP cohort.

The key findings of our present study of the prognostic value of different glucocorticoid hormones over a follow-up period of 6 years in patients with CAP are threefold. First, among different glucocorticoid hormones, cortisol showed the highest association with outcome in the short and long term. Second, the association of different glucocorticoid metabolites with adverse outcome inversely changed over time; whereas high levels of cortisol on initial hospital presentation were independently associated with short-term adverse outcome, a more pronounced initial glucocorticoid stress response was associated with favorable long-term outcome. Third, admission levels of 11-deoxycortisol showed the best correlation with disease severity.

The HPA stress axis plays an important role in patients with CAP, with cortisol being associated with short-term outcome [20‐24] and corticosteroid treatment that might result in earlier time to recovery [35]. The release of cortisol in acute illness is essential for improvement in hemodynamic status, acute supply of energy, and protection against excessive inflammatory reaction [5, 6]. Importantly, the acute stress response involves activation of the glucocorticoid pathway and the adrenergic system, resulting in tachycardia, increased myocardial oxygen consumption, and probably enhanced platelet aggregation, which might translate into acute myocardial infarction, thus potentially raising short-term mortality [18]. Owing to its positive correlation with the degree of illness-induced stress [36], cortisol has been presumed to be a prognostic marker mirroring characteristics of acute critical disease and disease progression. Considering cortisol as the strongest inhibitor of inflammation, a higher level of proinflammatory cytokines in acute illness could lead to a more pronounced increase in cortisol [1‐3, 37]. On the basis of several clinical observational studies [20‐24], cortisol levels have lately emerged as a useful prognostic tool regarding short-term mortality. The present analysis of a large, well-characterized cohort provides novel insights into the role of the glucocorticoid pathway in regard to adverse outcome in hospitalized patients with mild to severe CAP.

Regarding short-term outcome, our findings are in line with previous data derived from clinical observational studies suggesting that high levels of cortisol ae associated with mortality in CAP [20‐24]. In our study, high admission cortisol levels were independently associated with short-term adverse outcome, including the combined endpoint mortality/ICU admission. Association of cortisol levels with 30-day all-cause mortality alone showed a similar trend; likely due to the small event number, the results did not reach statistical significance.

Interestingly, a more pronounced initial glucocorticoid host response was beneficial for long-term survival. For cortisol, this effect remained robust after adjustment for potential confounders. Because most previous studies have demonstrated a strong HPA stress axis response to be positively associated with adverse short-term outcomes [20‐24], the present findings are somewhat counterintuitive. Hypothesizing that high levels of proinflammatory cytokines lead to an increase in cortisol [1‐3, 37] to avoid excessive inflammation, a more pronounced initial glucocorticoid response might reflect not only the degree of stress but also the ability to generate an adequate immune response. Within this study, we demonstrated an independent correlation between admission cortisol levels and markers of inflammation (PCT and high peak CRP). From this point of view, our findings are in line with those of a previous study demonstrating a more pronounced inflammatory host response reflected by a history of chills, high body temperature, and high peak levels of CRP being associated with lower long-term mortality in patients surviving a CAP episode [38]. These results were similar to those of the Pneumonia Patient Outcomes Research Team cohort study, another large follow-up study of patients with CAP, in which researchers reported an association between the absence of fever and higher long-term mortality than among age-matched control subjects [39]. Contrarily, several studies have shown an association between worse short-term outcomes and strong inflammatory response in CAP [40‐42]. On the basis of these data, it is tempting to hypothesize that survival of a clinically and biochemically pronounced CAP episode—reflected by high admission glucocorticoid levels—might mirror a more robust stress response, and, concordantly, also host defense, and thus a better general condition with lower mortality in the long term. However, a pronounced glucocorticoid response on admission might reflect, as a presumable consequence of inflammation, the ability to generate an appropriate immune response, thereby predisposing these “fitter” patients, with regard to the stress-response, to better long-term survival owing to decreased subsequent infections [43]. Further investigations are still warranted to validate these findings and determine underlying pathophysiology. Given the evidence of pronounced inflammation being associated with favorable long-term outcome in hospitalized patients with CAP, the rationale of steroid treatment in this population should be questioned.

The main strengths of this study include the well-characterized cohort of patients hospitalized for CAP, the long follow-up period of approximately 6 years, and the thorough and highly accurate biomarker measurement by liquid chromatography coupled with tandem mass spectrometry. This technique allows a proper separation and sensitive characterization of even small molecules [44]. Importantly, mass spectrometry is increasingly becoming accepted as a routine diagnostic instrument in clinical laboratories [45]. Furthermore, the large sample size and the high event number of the primary endpoint (47.3%) lead to high statistical power, which allows detecting even small differences in glucocorticoid levels.

The following limitations require consideration. First, the present study is a secondary analysis and therefore not designed primarily to perform observational biomarker outcome studies. Importantly, there was no controlling for the time point of blood sampling, because initial blood samples were taken at the time of first patient contact in the ED. However, although cortisol exhibits diurnal concentration changes, during acute illness, the circadian pattern is usually lost [5, 46, 47]. Also, the long storage of blood may have affected blood hormone levels. In addition, there was no assessment of adrenal insufficiency based on the response to injection of synthetic adrenocorticotropin. Nevertheless, previous data demonstrated a very low rate of adrenal insufficiency in patients with CAP in the absence of septic shock [23]. However, deviation of the present results by different blood sampling time points or adrenal insufficiency cannot be definitively ruled out, although this lack of standardization reflects daily clinical practice. A more standardized hormone level determination at the same time of the day in all patients would most probably have demonstrated an even higher association between glucocorticoid levels and CAP outcomes. Moreover, serial hormone measurements over the course of the disease may add valuable information.

Second, the initial trial was conducted in different secondary and tertiary care hospitals in Switzerland, and thus results may not unconditionally be applied to other geographical or institutional settings. In addition, our analysis was focused specifically on patients with CAP; further studies are required to validate these findings for other medical and surgical patient populations. Finally, because this was an observational study, it is only hypothesis-generating, and correlation does not imply a causal relationship.

Cortisol showed the highest association with outcome in patients with mild to severe CAP. The association of the glucocorticoid levels with adverse outcome in patients with CAP changed over time; whereas high admission levels of cortisol were independently associated with short-term adverse outcome, a more pronounced initial glucocorticoid stress response was highly associated with favorable long-term outcome. Initial 11-deoxycortisol levels showed the highest correlation with disease severity. Underlying pathophysiological aspects are still poorly examined, and future studies are needed to better understand the importance of adrenal hormones in the resolution of patients with CAP.