Free and Total Cortisol Levels as Predictors of Severity ... - ATS Journals

Free and Total Cortisol Levels as Predictors of Severity and Outcome in Community-acquired Pneumonia ¨ ller3, Roland Bingisser3, Mirjam Christ-Crain1,4, Daiana Stolz2, Sukhdeep Jutla1, Orestes Couppis1, Christian Mu ¨ ller4, and Ashley B. Grossman1 Philipp Schuetz4, Michael Tamm2, Ray Edwards5, Beat Mu 1

Department of Endocrinology, William Harvey Research Institute, Barts and The London, Queen Mary’s School of Medicine and Dentistry, London, United Kingdom; 2Department of Pneumology, 3Department of Internal Medicine, and 4Department of Endocrinology, University Hospital Basel, Basel, Switzerland; and 5NETRIA, St. Bartholomew’s Hospital, London, United Kingdom

Rationale: High cortisol levels are of prognostic value in sepsis. The predictive value of cortisol in pneumonia is unknown. Routinely available assays measure serum total cortisol (TC) and not free cortisol (FC). Whether FC concentrations better reflect outcome is uncertain. Objectives: To investigate the predictive value of TC and FC in community-acquired pneumonia (CAP). Methods: Preplanned subanalysis of a prospective intervention study in 278 patients presenting to the emergency department with CAP. Measurements and Main Results: TC, FC, procalcitonin, C-reactive protein, leukocytes, clinical variables, and the pneumonia severity index (PSI) were measured. The major outcome measures were PSI and survival. TC and FC, but not C-reactive protein or leukocytes, increased with increasing severity of CAP according to the PSI (P , 0.001). TC and FC levels on presentation in patients who died during follow-up were significantly higher as compared with levels in survivors. In a receiver operating characteristic analysis to predict survival, the area under the receiver operating characteristic curve (AUC) was 0.76 (95% confidence interval, 0.70–0.81) for TC and 0.69 (0.63–0.74) for FC. This was similar to the AUC of the PSI (0.76 [0.70–0.81]), and better as compared with C-reactive protein, procalcitonin, or leukocytes. In univariate analysis, only TC, FC, and the PSI were predictors of death. In multivariate analysis, the predictive potential of TC equaled the prognostic power of PSI points. Conclusions: Cortisol levels are predictors of severity and outcome in CAP to a similar extent to the PSI, and are better than routinely measured laboratory parameters. In CAP, the prognostic accuracy of FC is not superior to TC. Clinical trial registered with www.controlled-trials.com (ISRCTN04176397). Keywords: pneumonia; cortisol; prognosis

High cortisol levels reflect a higher degree of stress (1). The effects of cortisol are directed toward the acute provision of energy, protection against excessive inflammation, and improvement in hemodynamic status (2, 3). Therefore, appropriate activation of the hypothalamic–pituitary–adrenal axis during illness is essential for survival, and parallels the degree of stress. Several studies have shown a positive correlation between serum total cortisol and severity of critical illness as well as risk of death (4–10). The activation of the hypothalamic– pituitary–adrenal axis in critically ill patients is characterized

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject

High cortisol levels are of prognostic value in sepsis. The predictive value of cortisol in pneumonia is not known. Whether the free or total cortisol concentration better reflects outcome is uncertain. What This Study Adds to the Field

Total and free cortisol levels are independent predictors of severity and outcome of pneumonia, in contrast to routinely measured laboratory parameters. The prognostic accuracy of free cortisol is not superior to that of total cortisol.

by an increase in free cortisol levels and a possibly smaller increase in total cortisol levels (11). The free cortisol, rather than the protein-bound fraction, is responsible for the physiologic function (11). Accordingly, serum free cortisol concentrations, as compared with serum total cortisol concentrations, might offer a better reflection of the degree of stress and the subsequent activation of the hypothalamo–pituitary–adrenal axis in critically ill patients (11). However, whether free cortisol concentrations are better correlated with outcome such as death or treatment failure remains an open question. The major cause and precursor of sepsis and critical illness is respiratory tract infections. Community-acquired pneumonia (CAP) is the major infection-related cause of death in developed countries (12, 13). In the assessment and management of CAP, predictors of outcome are crucial to estimate disease severity, and to guide therapeutic options such as the need for hospital or intensive care presentation, the intensity of work-up, the choice and route of antimicrobial agents, and the suitability for discharge (14, 15). The value of cortisol concentrations to predict outcome in CAP is currently unknown. This is the first study to evaluate the prognostic value of cortisol levels, measured on presentation, in the prediction of severity of disease and outcome in a well-defined cohort of patients with CAP (16), and to compare the prognostic value of free and total cortisol concentrations (17).

(Received in original form February 23, 2007; accepted in final form August 9, 2007)

METHODS

Supported by the Swiss Foundation of Medical and Biological Stipends (SSMBS, PASMA-114617/1) (to M.C.-C.).

Setting and Study Population

Correspondence and requests for reprints should be addressed to Mirjam ChristCrain, M.D., University Hospital, Petersgraben 4, CH-4031 Basel, Switzerland. E-mail: m.christ-crain@unibas.ch Am J Respir Crit Care Med Vol 176. pp 913–920, 2007 Originally Published in Press as DOI: 10.1164/rccm.200702-307OC on August 16, 2007 Internet address: www.atsjournals.org

Data from 278 patients of an initial cohort of 302 patients presenting to the emergency department with CAP were analyzed. The primary objective of the study was to evaluate antibiotic duration by procalcitonin guidance as compared with standard recommended guidelines (16). Baseline data were similar in both cohorts (Table 1). A predefined secondary endpoint was the assessment of prognostic factors in CAP.

914

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 176

TABLE 1. BASELINE CHARACTERISTICS OF THE 278 PATIENTS Characteristic Age, yr Male sex, no. (%) Smoking status Current smokers, no. (%) Smoker history, pack-years Antibiotic pretreatment, no. (%) Coexisting illnesses, no. (%) Coronary artery disease Hypertensive heart disease Congestive heart failure Peripheral vascular disease Cerebrovascular disease Renal dysfunction Liver disease Diabetes mellitus Chronic obstructive pulmonary disease Neoplastic disease History, no. (%) Cough Sputum Dyspnea Examination, no. (%) Rales Laboratory findings C-reactive protein (mg/L), median (IQ range) Procalcitonin (mg/L), median (IQ range) Leukocyte count (3 109 cells/L), median (IQ range) Total cortisol (pmol/L), median (IQ range) Free cortisol (pmol/L), median (IQ range) Radiographic findings, no. (%) Pleural effusion Multilobar CAP PSI, points PSI class, no. (%) I, II, and III IV V

Value 69 6 17 174 (63) 71 (26) 41.6 6 25.5 56 (20) 88 72 15 19 16 74 30 57 66 43

(32) (26) (5) (7) (6) (27) (11) (21) (24) (16)

247 (89) 201 (72) 209 (75) 249 (90) 132 0.5 12.7 716 52.8

(67–212) (0.2–2.3) (9.1–16.3) (423–1,209) (34.5–90.5)

36 (13) 48 (17) 99.1 6 35.5 111 (40) 120 (43) 47 (17)

Definition of abbreviations: CAP 5 community-acquired pneumonia; IQ 5 interquartile; PSI 5 pneumonia severity index. Plus–minus values represent means 6 SD. Because of rounding, percentages may not sum to 100.

Briefly, consecutive patients with CAP admitted from November 2003 through February 2005 to the University Hospital Basel (Basel, Switzerland), a 950-bed tertiary care hospital, were included. Patients had to be more than 18 years of age with suspected CAP as the principal diagnosis on presentation. Exclusions included patients with cystic fibrosis or active pulmonary tuberculosis, hospital-acquired pneumonia, or severely immunocompromised patients. Patients were examined on presentation to the emergency department by a resident supervised by a board-certified specialist in internal medicine. Baseline assessment included clinical data and vital signs, comorbid conditions, and routine blood tests. CAP was defined by the presence of one or several of the following recently acquired respiratory signs or symptoms: cough, sputum production, dyspnea, core body temperature exceeding 38.08C, auscultatory findings of abnormal breath sounds and rales, leukocyte count greater than 10 3 109 or less than 4 3 109 cells/L and an infiltrate on chest radiograph (13). The pneumonia severity index (PSI), a validated severity scoring system for patients with pneumonia, was calculated (18). Chest radiographs were screened by the physician in charge and reviewed by a senior radiologist, unaware of clinical or laboratory findings. The study was approved by the local ethics committee for human studies and written informed consent was obtained from all patients.

Outcome All patients were monitored for a mean duration of 6.9 6 1.9 weeks (16). At the follow-up visit, outcome was evaluated on the basis of clinical, laboratory, radiographic, and microbiological criteria. Cure

2007

was defined as resolution of clinical, laboratory, and radiographic signs of CAP. Improvement was defined as reduction in clinical signs and symptoms, improvement in laboratory findings (i.e., C-reactive protein, procalcitonin, and leukocyte count), and reduction in the number or intensity of radiographic signs of CAP. Treatment success represented the sum of the rates for cure and improvement. Treatment failure included death, recurrence, or persistence of clinical, laboratory, and radiologic signs of CAP at follow-up. Patients who survived until follow-up were counted as survivors, whereas patients who died within the follow-up period were counted as nonsurvivors.

Measurement of Total and Free Cortisol Levels Total cortisol levels were measured with an enzyme immunoassay (EIA) kit (provided by NETRIA, St. Bartholomew’s Hospital, London, UK). Serum samples and standards were added to the antibodycoated plate. Enzyme conjugate solution was then added. The mixture was shaken and incubated at room temperature for 1 hour. To remove all the unbound material the plate was washed four times. Bound enzyme conjugate was detected by the addition of substrate, which generated optimal color after 10 minutes. Results were obtained by measuring and comparing the absorbance of wells containing samples with that of wells containing standards, using a microplate reader at 450 nm with blank subtraction at 650 nm. The interassay coefficient of variance at 49, 411, and 729 nmol/L was 10, 5.3, and 9.1%, respectively. The intraassay coefficient of variance at 50, 250, and 750 nmol/L was 6.9, 4.3, and 6.5%, respectively. The calculated sensitivity of the assay was 25 nmol/L. Free cortisol was measured in house by a newly developed assay (19). The fractions of free and bound cortisol from the serum samples were first separated by equilibrium dialysis, followed by measurement of the concentration of the free fraction from the dialysate, using an enzyme immunoassay (NETRIA, St. Bartholomew’s Hospital). Dialysis tubing was cut into sacs 7 mm in length with a knot tied at one end. Cartridges were assembled by inserting the sacs into LP-3 tubes. Eight hundred microliters of buffer solution (1% hydrolyzed gelatin in phosphate-buffered saline [0.05 M phosphate, 0.15 M sodium chloride]) was pipetted into the space between the inner wall of the LP-3 tube and the outer aspect of the dialysis sac. Undiluted sample (200 ml) was then pipetted directly into the dialysis sac. Excess tubing was folded over the mouth of the LP-3 tube and a stopper was inserted to complete the cartridge. All cartridges were placed on an elevated rotator in a 378C heated chamber and left overnight. Dialysate was then collected and the enzyme immunoassay was performed. The calculated sensitivity of the enzyme immunoassay (96-well microtiter plates triple-coated with gammaglobulin, donkey anti-sheep immunoglobulin, and anti-cortisol antiserum in a 1:30,000 dilution) was 0.37 6 0.49 nmol/L (mean 6 SD). The interassay coefficient of variance was 3.5% at 2.1 nmol/L, 6.8% at 24 nmol/L, and 10.0% at 52 nmol/L. The intraassay coefficient of variance was assessed by precision profile as follows: 10% at 1 nmol/L, 6% at 10 nmol/L, 5% at 20 nmol/L, and 7% at 100 nmol/L. Assay time was about 90 minutes.

Measurement of Other Laboratory Parameters Procalcitonin was measured in a time-resolved amplified cryptate emission technology assay (Kryptor PCT; Brahms AG, Hennigsdorf, Germany) with a functional assay sensitivity of 0.06 mg/L. C-reactive protein was measured in an enzyme immunoassay (EMIT; Merck Diagnostica, Zurich, Switzerland).

Statistical Analysis Discrete variables are expressed as counts (percentage) and continuous variables as means 6 SD or median (interquartile range) unless stated otherwise. Frequency comparisons were made with the chi-square test. Two-group comparison of normally distributed data was performed by Student t test. For multigroup comparisons, one-way analysis of variance with least-squares difference for post hoc comparisons was applied. For data not normally distributed, the Mann-Whitney U test was used if only two groups were compared and Kruskal-Wallis oneway analysis of variance was used if more than two groups were being compared. Receiver operating characteristics were calculated by STATA (version 9; StataCorp, College Station, TX). The principal

Christ-Crain, Stolz, Jutla, et al.: Cortisol as Predictor in Pneumonia

outcome measure was survival until follow-up. Correlation analyses were performed by Spearman rank correlation. Univariate and multivariate analysis to predict the binary end point, death, was performed by including the PSI score, C-reactive protein, leukocyte count, procalcitonin, and total and free cortisol levels. To assess the influence of these variables on death or clinical failure, we produced Kaplan-Meier survival curves: comparison between the groups was done by log-rank test. Levels that were nondetectable were assigned a value equal to the lower limit of detection for the assay. All testing was two-tailed and P values less than 0.05 were considered to indicate statistical significance.

RESULTS Patients

Detailed baseline characteristics of the study population are summarized in Table 1. The mean age of the 278 patients was 69 6 17 years; 71 (25.5%) were smokers and 56 (20.1%) had been pretreated with antibiotics. Overall, 87% of patients had relevant comorbidities. No patient was taking etomidate, barbiturates, or muscle relaxants: 21 patients (7.6%) were taking sedative drugs, which may interact centrally with the pituitary– adrenal axis (20). Total and free cortisol levels in patients with and without these drugs were not significantly different. The mean PSI of all patients was 99.1 6 35.5 points: 22 patients (7.9%) were in PSI class I, 37 (13.3%) were in PSI class II, 52 (18.7%) were in PSI class III, 120 (43%) were in PSI class IV, and 47 (17%) were in PSI class V. No patient on presentation was undergoing intravenous steroid treatment; 27 patients were receiving oral corticosteroid treatment on presentation (corresponding to a median dose of 5 mg of prednisone daily; range, 2.5–50 mg daily). Therefore, all analyses were performed by including and excluding these patients, respectively. Total and Free Cortisol Levels and Severity of CAP

Both total and free cortisol levels increased with increasing severity of CAP, classified according to the PSI score (P , 0.001) (Figure 1). Mortality among patients in PSI classes I–III was 1.8%, 16% among patients in PSI class IV, and 21% among patients in PSI class V (Figure 1). Post hoc analysis revealed

915

a significant difference in free cortisol levels (P 5 0.04) but not in total cortisol levels (P 5 0.23) between PSI groups IV and V. The gradual increase with PSI class was also significant for procalcitonin (P , 0.001), but not for C-reactive protein (P 5 0.24) or for total leukocyte count (P 5 0.13). Serum albumin levels showed a trend toward lower levels with higher PSI class (P 5 0.06). The results remained similar when excluding patients with corticosteroid therapy on presentation. Four patients (1.4%) were hypotensive, with a systolic blood pressure less than 90 mm Hg at presentation to the emergency department. Total and free cortisol levels in these patients were 1,304.5 (834–1,805) and 160.1 (85.3–279.8) nmol/L, respectively. Because we report data on presentation to the emergency department, the consensus criteria to define septic shock, which include adequate fluid resuscitation over several hours (21, 22), do not apply and no patient was formally classified as having septic shock. There was a significant correlation between total and free cortisol levels (r 5 10.71; P , 0.001). The correlation was still significant when taking into account only patients with hypoalbuminemia (i.e., albumin < 2.5 g/L [11]) (r 5 10.68; P , 0.001). Total and free cortisol levels correlated with other markers of infection, that is, procalcitonin (r 5 10.30 and 10.37; P , 0.001 for both), C-reactive protein (r 5 10.20 and 10.27; P , 0.001 for both), and total leukocyte count (r 5 10.14 and r 5 10.17; P , 0.05 and P , 0.01, respectively). Total and Free Cortisol Levels as Prognostic Marker for Outcome

At follow-up, 245 patients had survived and 31 patients had died. Two patients were lost to follow-up. Thus, the overall mortality rate was 11.2%. The mortality among patients taking corticosteroids was 11.1% (3 of 27 patients). For the subsequent analyses, only steroid-naive patients were considered. On presentation, total and free cortisol levels in patients who died during follow-up were significantly higher as compared with levels in survivors (1,141 [941–3,355] and 88.4 [51.9–124.1] vs. 697 [429–1,081] and 52.4 [35.0–88.9] nmol/L; P , 0.001 and 0.001, respectively) (Figure 2). Albumin levels tended to be lower in nonsurvivors (27.7 6 6.8 g/L) compared

Figure 1. Total and free cortisol levels in patients with various severities of community-acquired pneumonia. Data represent means 6 SEM, with scatter plots presenting all values. PSI 5 pneumonia severity index. The top row of mortality rates indicates the mortality rate given by the original publication (18). The bottom row indicates the mortality rates as assessed in our study cohort.

916


2007

Figure 2. Total and free cortisol levels in survivors and nonsurvivors. Data represent means 6 SEM.

with survivors (30.8 6 6.2 g/L; P 5 0.07). The respective values were not significant for procalcitonin (0.6 [0.4–2.2] vs. 0.5 [0.2– 2.4] mg/L; P 5 0.08), for C-reactive protein (145 [101–204] vs. 132 [66–212] mg/L; P 5 0.64), or for total leukocyte count (13.5 [11.4–16.5] 3 109 vs. 12.1 [9.0–15.6] 3 109 cells/L; P 5 0.18). To evaluate the potential to predict death from CAP, a receiver operating characteristic (ROC) analysis was performed in which sensitivity was calculated with those patients who died before follow-up (n 5 28) and specificity was assessed with those patients who survived until follow-up (n 5 223). The area under the ROC curve (AUC) and likelihood ratios for various cut-off points are summarized in Tables 2 and 3. The prognostic accuracy of total, more than free, cortisol to predict death was superior to that of C-reactive protein, leukocyte count, and procalcitonin, and was comparable to that of the PSI score (Figure 3). With an optimal calculated total cortisol threshold of 960 nmol/L, sensitivity and specificity were 75.0 and 71.7% with positive and negative likelihood ratios of 2.65 and 0.35, respectively. For free cortisol with an optimal threshold of 80.3 nmol/L, sensitivity was 64.3% and specificity was 71.6%, with positive and negative likelihood ratios of 2.27 and 0.50, respectively. Results for the various parameters in predicting treatment failure were similar (data not shown). To estimate the additive value of total cortisol in combination with the PSI score we calculated a logistic regression model combining the PSI score and the total cortisol concentration. With an AUC of 0.79 (95% confidence interval, 0.71–0.87) the combined model tended to improve the prognostic accuracy compared with the PSI alone (P 5 0.22). When we performed a comparison of survival among patients with total and free cortisol levels below and above these calculated optimal cutoff values by Kaplan-Meier survival curves, patients with total or free cortisol levels above this cutoff had significantly lower survival rates compared with

TABLE 2. PREDICTION OF MORTALITY FOR 251 PATIENTS WITH COMMUNITY-ACQUIRED PNEUMONIA: AREA UNDER THE RECEIVER OPERATING CHARACTERISTIC CURVE PLOT ANALYSIS Parameter

AUC

95% CI

TC FC C-reactive protein Leukocytes Procalcitonin Pneumonia severity index

0.76 0.69 0.53 0.58 0.60 0.76

0.70–0.81 0.63–0.74 0.47–0.59 0.51–0.63 0.54–0.66 0.70–0.81

P Value (vs. TC) P Value (vs. FC) — 0.12 0.001 0.01 0.02 0.96

0.12 — 0.01 0.16 0.17 0.25

Definition of abbreviations: AUC 5 area under the curve; CI 5 confidence interval; FC 5 free cortisol; TC 5 total cortisol.

patients with levels below the cutoff (P , 0.0001 and P , 0.001, respectively; Figure 4). When entering total and free cortisol, procalcitonin, Creactive protein, leukocytes, and PSI in a univariate regression analysis, only increasing total cortisol (P , 0.001) and free cortisol levels (P 5 0.004) and a rise in PSI (P , 0.001) were predictors of death (Table 4). In a multivariate analysis, the predictive power of total cortisol equaled the prognostic power of the PSI (Table 4). The results for the different parameters to predict treatment failure were similar (data not shown). In addition, we also calculated whether particularly low (as well as high) cortisol levels, as defined by Cooper and coworkers (23) and Annane and coworkers (24), were associated with poor outcome. Overall, 54 patients (19%) had total cortisol levels below 414 nmol/L, whereas 30 patients (11%) had total cortisol levels below 275 nmol/L. Of the 30 patients with total cortisol levels below 275 nmol/L, 2 died (6.7%), whereas of the 54 patients with a total cortisol level below 414 nmol/L, 3 patients died (5.6%); overall mortality was 11.2%. This difference in mortality between patients with low cortisol levels and patients overall was not statistically significant.

DISCUSSION Our study has three main findings. First, cortisol concentrations measured on presentation predict the severity and outcome of CAP. Second, the prognostic accuracy of cortisol levels is as

TABLE 3. TOTAL AND FREE CORTISOL AND PNEUMONIA SEVERITY INDEX THRESHOLDS TO PREDICT MORTALITY: SENSITIVITY, SPECIFICITY, POSITIVE LIKELIHOOD RATIO, AND NEGATIVE LIKELIHOOD RATIO AT VARIOUS CUTOFF LEVELS Cutoff TC 594 960 1,650 FC 48.8 80.3 106.8 PSI 90 101 134

Sensitivity

Specificity

LR1

LR–

89.3 75.0 42.9

42.6 71.7 88.8

1.56 2.65 3.82

0.25 0.35 0.64

85.7 64.3 42.9

47.7 71.6 85.1

1.64 2.27 2.88

0.30 0.50 0.67

96.4 89.3 32.1

46.2 59.2 87.4

1.79 2.19 2.56

0.08 0.18 0.78

Definition of abbreviations: FC 5 free cortisol; LR1 5 positive likelihood ratio; LR– 5 negative likelihood ratio; PSI 5 pneumonia severity index; TC 5 total cortisol.

Christ-Crain, Stolz, Jutla, et al.: Cortisol as Predictor in Pneumonia

917

Figure 3. Receiver operator curve analysis of various laboratory parameters predicting survival from community-acquired pneumonia. Data on presentation are shown. Red line, TC; dark-blue line, FC; light-blue line, CRP; pink line; Lc; green line, PCT; black line, PSI. CRP 5 C-reactive protein; FC 5 free cortisol; Lc 5 leukocyte count; PCT 5 procalcitonin; PSI 5 pneumonia severity index; TC 5 total calcitonin.

high as the PSI and higher as compared with commonly measured laboratory parameters. Third, the prognostic accuracy of free cortisol levels is not superior to that of total cortisol in this paradigm. The release of cortisol in acute illness is essential for cardiovascular, metabolic, and immunologic homeostasis. The rationale for a presumed prognostic value of cortisol is due mainly to its positive correlation with the stress level associated with illness. A higher level of proinflammatory cytokines in patients with worse outcome, that is, nonsurvivors, could additionally lead to a more pronounced increase in cortisol as the strongest known natural inhibitor of inflammation (25). However, levels of C-reactive protein, as one example of an inflammatory mediator, were similar in survivors and nonsurvivors. Indeed, in critically ill patients a strong association of cortisol with outcome has previously been reported (4–10). Conversely, low unstimulated cortisol levels in septic patients can also predict absolute or relative adrenal insufficiency (24, 26). On the basis of our study, serum cortisol concentrations are also a prognostic parameter in mild to severe CAP. Interestingly, in this study low cortisol levels were not associated with poor outcome in our study cohort. Indeed, the mortality among patients with relatively low levels was about half of that in the cohort as a whole, although possibly due to the small numbers involved this did not attain statistical significance. It is possible that in our series the absence of patients taking any form of adrenolytic drug excluded the possibility that there was any form of iatrogenic, and hence deleterious, hypoadrenalism. Alternatively, there may be two factors in operation, one directly associating serum cortisol with mortality, and one operating at low cortisol levels to increase mortality, such that at low cortisol levels these cancel each other out. Whatever the explanation, the overriding factor associated with poor outcome was increased cortisol, however measured. Indeed, there is a debate concerning the definition of relative adrenal insufficiency, its treatment, and the identification of patients at risk (1). In a small study, low-dose hydrocortisone infusion appeared to be beneficial (27); however, these preliminary data need to confirmed in a larger study before it can be recommended. Our findings of an

Figure 4. Kaplan-Meier curves showing survival rates stratified by calculated optimal total cortisol (at least 960 nmol/L) (top panel) and free cortisol (at least 80 nmol/L) (bottom panel) levels, respectively. P values determined by log rank test.

association of high cortisol levels with worse outcome question the rationale of hydrocortisone treatment in patients with CAP. However, our study population was different from the population included in the study by Confalonieri and coworkers (27). Whereas they included mainly mechanically ventilated patients in an intensive care unit, we investigated patients presenting to an emergency department with all classes of PSI. Alternatively, it may also be speculated that despite the marked increase in circulating cortisol in severe CAP, this concentration is not high enough to counterbalance the inflammatory response.

TABLE 4. PREDICTION OF MORTALITY: UNIVARIATE AND MULTIVARIATE REGRESSION ANALYSES Predictor Total cortisol Free cortisol C-reactive protein Leukocytes Procalcitonin Pneumonia severity index

Odds Ratio (95% CI)

P Value

Univariate Analysis 1.001 (1.000–1.001) 1.011 (1.004–1.018) 0.999 (0.995–1.003) 1.033 (0.981–1.088) 0.998 (0.969–1.027) 1.024 (1.012–1.036)

,0.001 0.004 0.92 0.21 0.87 ,0.001

Multivariant Total cortisol Free cortisol Pneumonia severity index

Biomarker Analysis 1.001 (1.000–1.001) 0.997 (0.987–1.007) 1.017 (1.004–1.001)

Definition of abbreviation: CI 5 confidence interval. n 5 251 patients.

0.002 0.56 0.01

918


In general, it is assumed that the biologically active fraction of cortisol to which tissues are exposed is free cortisol. Specifically, in critically ill patients there is a fall in binding proteins such that total cortisol levels no longer accurately reflect the free fraction (11, 28). Our newly developed assay for free cortisol used in this study has been validated (19), and has certain advantages over other, commercially available assays. In a standardized model of acute major surgical stress, circulating free cortisol levels showed a more pronounced increase with major stress as compared with total cortisol levels, followed by a more pronounced decrease after resolution of major stress. Although total cortisol levels show a similar increase with major stress as compared with adrenocorticotropic hormone stimulation, the increase in free cortisol was more pronounced than with the surgical stress (19). Nevertheless, although such an assay might have been predicted to better correlate with clinical outcomes compared with total cortisol, free cortisol in our study was no better predictor than total cortisol. However, although albumin levels were slightly lower in nonsurvivors compared with survivors of CAP, the binding protein levels did not correlate strongly with pneumonia severity as assessed with the PSI. This was in contrast to our previous study including patients with major surgical stress. Therefore, in less critically ill patients such as our patients with CAP, fluctuations of cortisol-binding proteins (such as albumin and cortisol-binding globulin) may become less relevant, diminishing any potential advantages of an assay measuring the free hormone. Only 5% of the patients in our study had serum albumin levels below 2 g/L and in only 19% was it below 2.5 g/L. Taken together, these findings suggest that the prediction of outcome is not primarily related to the free fraction of cortisol in CAP. A key decision for a clinician is whether to admit a patient with CAP (29). This decision is complex and depends on many variables, including estimates of the severity of illness. It often relies on the clinician’s judgment; however, the interpretation of clinical signs and symptoms lacks standardization and validation and is prone to interobserver variability (30, 31). In addition, physicians continue to be conservative and commonly overestimate the risk of death for patients with CAP (32). Clinical signs such as body temperature or routinely used laboratory parameters (i.e., C-reactive protein or leukocyte count) are of only limited value to predict disease severity in CAP (33). Thus, clinical judgment alone can be misleading in estimating disease severity, thereby leading to under- as well as overestimation of the severity of CAP. For this reason, prognostic scoring rules have been developed to predict severity of CAP and outcome, with the PSI being a well-validated prognostic classification score (18, 34–37). Limitations of the PSI include a potential overemphasis on age and the fact that, for clinical ease, the PSI dichotomizes continuous values such as heart rate or oxygen saturation into normal and abnormal values. The intraobserver variation of the PSI is reported to be about 10%, with most patients misclassified into the high-risk classes IV and V (38). In addition, the PSI is best validated for assessing patients with a low mortality risk who may be suitable for home management rather than for those with severe CAP at the time of hospital presentation (37). The major limitation for the routine use of the PSI, however, is its laborious calculation. In a study validating the predictive potential of various indices in 731 patients with CAP the PSI score could be calculated in only 70% of all patients (39) restricting its widespread adoption. The American Thoracic Society guidelines do not offer any algorithm for the clinical assessment of disease severity (13, 40). In this context, there is a need for readily measurable parameters predicting the severity level and outcome of CAP. According to our data, the simple measurement of total cortisol provides equivalent prog-

2007

nostic information as the complex 20-variable severity index. This is remarkable. It therefore represents an additional and easy-to-determine prognostic tool. As a new indicator for those patients with a worse prognosis, it allows such patients to be targeted for more intensive therapy. As the combination of cortisol measurement and the PSI score tended to have an even higher prognostic accuracy, it is advisable to use several clinical and laboratory parameters, which may mirror different physiologic aspects, in the complex task of prognostic assessment and treatment decisions. C-reactive protein has been reported to be a useful marker for predicting disease severity in patients with pneumonia (41). In contrast, in our study C-reactive protein could not differentiate between different severities of CAP, as defined by the PSI, and was not a significant independent predictor of outcome. It should be recognized that C-reactive protein is a rather nonspecific marker of acute-phase inflammation, and is thus subject to the influence of many other factors. IL-6, a key stimulator of hepatic C-reactive protein release, has also been suggested as a useful marker in the determination of the severity of CAP (42). Measurement of plasma cytokines such as IL-6 is, however, a difficult and cumbersome process, partly because of the short plasma half-life and the presence of blocking factors (43). Most recently, D-dimers have also been proposed as prognostic parameter in CAP (44), but these were not measured in our study. Finally, we and others have proposed that procalcitonin is a novel and useful marker of disease severity in communityacquired pneumonia (16, 45). However, the present data suggest, rather, that procalcitonin is useful as a diagnostic and not primarily as a prognostic tool able to guide decisions on antibiotic therapy (16, 46). The following limitations of our study should be mentioned. First, this study had not been prospectively designed to use cortisol concentrations as a primary endpoint, and only single presentation cortisol levels were measured (16). Second, serial cortisol levels show large variations during the day (47), although during infective illness the circadian pattern of cortisol is usually lost (2). In our study, serum cortisol levels were measured at the time of presentation, that is, at different times during the day, which could limit the predictive accuracy of a single cortisol value on presentation to the hospital. A standardized cortisol value determined at the same time of day in all patients would most probably have had an even higher prognostic accuracy. It is also possible that serial measurements over the course of the disease may add prognostic information, and show differences in the values of free and total cortisol (48). Third, we did not assess adrenal function based on the response to injection of synthetic adrenocorticotropin, as used in other studies. However, because these patients did not have septic shock, it seems unlikely that they experienced relative adrenal insufficiency. Indeed, as noted above, there was actually a trend for decreased mortality among patients with relatively low serum cortisol levels. In conclusion, our findings indicate that cortisol levels are significant independent predictors of outcome in mild to severe CAP; the prognostic accuracy of total and free cortisol is as high as that of the PSI and better as compared with routinely measured laboratory parameters. Free cortisol levels are not superior to total cortisol levels. Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript. Acknowledgment: The authors thank the staff of the clinics of emergency medicine, internal medicine, and endocrinology and the department of clinical chemistry, notably Fausta Chiaverio, Martina-Barbara Bingisser, Maya Kunz, Ursula Schild, Vreni Wyss, David Miedinger, Jo¨rg Leuppi, and Charly Nusbaumer, for support during this study.

Christ-Crain, Stolz, Jutla, et al.: Cortisol as Predictor in Pneumonia References 1. Schuetz P, Mueller B. The hypothalamus–pituitary–adrenal axis in critical illness. In: van den Berghe G, editor. Endocrinology and Metabolism Clinics of North America, Vol. 35: Acute endocrinology. Oxford: Elsevier; 2006. 2. Van den Berghe G, de Zegher F, Bouillon R. Clinical review 95: acute and prolonged critical illness as different neuroendocrine paradigms. J Clin Endocrinol Metab 1998;83:1827–1834. 3. Marik PE, Kiminyo K, Zaloga GP. Adrenal insufficiency in critically ill patients with human immunodeficiency virus. Crit Care Med 2002; 30:1267–1273. 4. Sibbald WJ, Short A, Cohen MP, Wilson RF. Variations in adrenocortical responsiveness during severe bacterial infections: unrecognized adrenocortical insufficiency in severe bacterial infections. Ann Surg 1977;186:29–33. 5. Jurney TH, Cockrell JL Jr, Lindberg JS, Lamiell JM, Wade CE. Spectrum of serum cortisol response to ACTH in ICU patients: correlation with degree of illness and mortality. Chest 1987;92:292–295. 6. Span LF, Hermus AR, Bartelink AK, Hoitsma AJ, Gimbrere JS, Smals AG, Kloppenborg PW. Adrenocortical function: an indicator of severity of disease and survival in chronic critically ill patients. Intensive Care Med 1992;18:93–96. 7. Annane D, Sebille V, Troche G, Raphael JC, Gajdos P, Bellissant E. A 3-level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotropin. JAMA 2000;283:1038–1045. 8. Sam S, Corbridge TC, Mokhlesi B, Comellas AP, Molitch ME. Cortisol levels and mortality in severe sepsis. Clin Endocrinol 2004;60:29–35. 9. Burchard K. A review of the adrenal cortex and severe inflammation: quest of the ‘‘eucorticoid’’ state. J Trauma 2001;51:800–814. 10. Schein RM, Sprung CL, Marcial E, Napolitano L, Chernow B. Plasma cortisol levels in patients with septic shock. Crit Care Med 1990; 18:259–263. 11. Hamrahian AH, Oseni TS, Arafah BM. Measurements of serum free cortisol in critically ill patients. N Engl J Med 2004;350:1629–1638. 12. Mortensen EM, Coley CM, Singer DE, Marrie TJ, Obrosky DS, Kapoor WN, Fine MJ. Causes of death for patients with community-acquired pneumonia: results from the Pneumonia Patient Outcomes Research Team cohort study. Arch Intern Med 2002;162:1059–1064. 13. Niederman MS, Mandell LA, Anzueto A, Bass JB, Broughton WA, Campbell GD, Dean N, File T, Fine MJ, Gross PA, et al. Guidelines for the management of adults with community-acquired pneumonia: diagnosis, assessment of severity, antimicrobial therapy, and prevention. Am J Respir Crit Care Med 2001;163:1730–1754. 14. Bartlett JG, Dowell SF, Mandell LA, File TM Jr, Musher DM, Fine MJ; Infectious Diseases Society of America. Practice guidelines for the management of community-acquired pneumonia in adults. Clin Infect Dis 2000;31:347–382. 15. Mandell LA, Marrie TJ, Grossman RF, Chow AW, Hyland RH; Canadian Community-acquired Pneumonia Working Group. Canadian guidelines for the initial management of community-acquired pneumonia: an evidence-based update by the Canadian Infectious Diseases Society and the Canadian Thoracic Society. Clin Infect Dis 2000;31:383–421. 16. Christ-Crain M, Stolz D, Bingisser R, Muller C, Miedinger D, Huber PR, Zimmerli W, Harbarth S, Tamm M, Muller B. Procalcitonin guidance of antibiotic therapy in community-acquired pneumonia: a randomized trial. Am J Respir Crit Care Med 2006;174:84–93. 17. Christ-Crain M, Stolz D, Sukhdeep J, Couppis O, Muller C, Bingisser R, Schuetz P, Tamm M, Edwards R, Mueller B, et al. Free and total cortisol levels as predictors of severity and outcome in communityacquired pneumonia. Presented at the 89th Meeting of the Endocrine Society (Endo 07), June 2–5, 2007, Toronto, ON, Canada. 18. Fine MJ, Auble TE, Yealy DM, Hanusa BH, Weissfeld LA, Singer DE, Coley CM, Marrie TJ, Kapoor WN. A prediction rule to identify lowrisk patients with community-acquired pneumonia. N Engl J Med 1997;336:243–250. 19. Christ-Crain M, Jutla S, Widmer IE, Couppis O, Ko¨ nig C, Pargger H, Puder JJ, Edwards R, Mueller B, Grossman AB. Measurement of serum free cortisol shows discordant responsivity to stress and dynamic evaluation. J Clin Endocrinol Metab 2007;92:1729– 1735. 20. Korbonits M, Trainer PJ, Edwards R, Besser GM, Grossman AB. Benzodiazepines attenuate the pituitary–adrenal responses to corticotrophin-releasing hormone in healthy volunteers, but not in patients with Cushing’s syndrome. Clin Endocrinol 1995;43: 29–36.

919 21. Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, Schein RM, Sibbald WJ; American College of Chest Physicians/ Society of Critical Care Medicine. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest 1992;101:1644–1655. 22. American College of Chest Physicians/Society of Critical Care Medicine. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992;20:864–874. 23. Cooper MS, Stewart PM. Corticosteroid insufficiency in acutely ill patients. N Engl J Med 2003;348:727–734. 24. Annane D, Maxime V, Ibrahim F, Alvarez JC, Abe E, Boudou P. Diagnosis of adrenal insufficiency in severe sepsis and septic shock. Am J Respir Crit Care Med 2006;174:1319–1326. 25. Beishuizen A, Thijs LG. Endotoxin and the hypothalamo–pituitary– adrenal (HPA) axis. J Endotoxin Res 2003;9:3–24. 26. Dickstein G. On the term ‘‘relative adrenal insufficiency’’—or what do we really measure with adrenal stimulation tests? J Clin Endocrinol Metab 2005;90:4973–4974. 27. Confalonieri M, Urbino R, Potena A, Piattella M, Parigi P, Puccio G, Della Porta R, Giorgio C, Blasi F, Umberger R, et al. Hydrocortisone infusion for severe community-acquired pneumonia: a preliminary randomized study. Am J Respir Crit Care Med 2005;171: 242–248. 28. Arafah BM. 2006. Hypothalamic–pituitary–adrenal function during critical illness: limitations of current assessment methods. J Clin Endocrinol Metab 2006;91:3725–3745. 29. Aronsky D, Dean NC. How should we make the admission decision in community-acquired pneumonia? Med Clin North Am 2001;85:1397– 1411. 30. Wipf JE, Lipsky BA, Hirschmann JV, Boyko EJ, Takasugi J, Peugeot RL, Davis CL. Diagnosing pneumonia by physical examination: relevant or relic? Arch Intern Med 1999;159:1082–1087. 31. Stolz D, Christ-Crain M, Gencay MM, Bingisser R, Huber PR, Muller B, Tamm M. Diagnostic value of signs, symptoms and laboratory values in lower respiratory tract infection. Swiss Med Wkly 2006;136:434– 440. 32. McIvor RA. Plasma D-dimer for outcome assessment in patients with CAP: not a replacement for PSI. Chest 2004;126:1015–1016. 33. Muller B, Harbarth S, Stolz D, Bingisser R, Mueller C, Leuppi J, Nusbaumer C, Tamm M, Christ-Crain M. Diagnostic and prognostic accuracy of clinical and laboratory parameters in community-acquired pneumonia. BMC Infect Dis 2007;7:10. 34. Farr BM, Sloman AJ, Fisch MJ. Predicting death in patients hospitalized for community-acquired pneumonia. Ann Intern Med 1991;115:428– 436. 35. Fine MJ, Singer DE, Hanusa BH, Lave JR, Kapoor WN. Validation of a pneumonia prognostic index using the MedisGroups Comparative Hospital Database. Am J Med 1993;94:153–159. 36. Garcia-Ordonez MA, Garcia-Jimenez JM, Paez F, Alvarez F, Poyato B, Franquelo M, Colmenero JD, Juarez C. Clinical aspects and prognostic factors in elderly patients hospitalised for community-acquired pneumonia. Eur J Clin Microbiol Infect Dis 2001;20:14–19. 37. Lim WS, van der Eerden MM, Laing R, Boersma WG, Karalus N, Town GI, Lewis SA, Macfarlane JT. Defining community acquired pneumonia severity on presentation to hospital: an international derivation and validation study. Thorax 2003;58:377–382. 38. Aronsky D, Haug PJ. Assessing the quality of clinical data in a computer-based record for calculating the pneumonia severity index. J Am Med Inform Assoc 2000;7:55–65. 39. Ewig S, de Roux A, Bauer T, Garcia E, Mensa J, Niederman M, Torres A. Validation of predictive rules and indices of severity for community acquired pneumonia. Thorax 2004;59:421–427. 40. American Thoracic Society, Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med 2005;171:388–416. 41. Almirall J, Bolibar I, Toran P, Pera G, Boquet X, Balanzo X, Sauca G. Contribution of C-reactive protein to the diagnosis and assessment of severity of community-acquired pneumonia. Chest 2004;125:1335– 1342. 42. Kolsuz M, Erginel S, Alatas O, Alatas F, Metintas M, Ucgun I, Harmanci E, Colak O. Acute phase reactants and cytokine levels in unilateral community-acquired pneumonia. Respiration 2003;70:615– 622.

920


43. Luna CM. C-reactive protein in pneumonia: let me try again. Chest 2004;125:1192–1195. 44. Querol-Ribelles JM, Tenias JM, Grau E, Querol-Borras JM, Climent JL, Gomez E, Martinez I. Plasma D-dimer levels correlate with outcomes in patients with community-acquired pneumonia. Chest 2004;126: 1087–1092. 45. Masia M, Gutierrez F, Shum C, Padilla S, Navarro JC, Flores E, Hernandez I. Usefulness of procalcitonin levels in communityacquired pneumonia according to the Patients Outcome Research Team pneumonia severity index. Chest 2005;128:2223–2229.

2007

46. Christ-Crain M, Muller B. Procalcitonin in bacterial infections: hype, hope, more or less? Swiss Med Wkly 2005;135:451–460. 47. Venkatesh B, Mortimer RH, Couchman B, Hall J. Evaluation of random plasma cortisol and the low dose corticotropin test as indicators of adrenal secretory capacity in critically ill patients: a prospective study. Anaesth Intensive Care 2005;33:201–209. 48. Vanhorebeek I, Peeters RP, Vander Perre S, Jans I, Wouters PJ, Skogstrand K, Hansen TK, Bouillon R, Van den Berghe G. Cortisol response to critical illness: effect of intensive insulin therapy. J Clin Endocrinol Metab 2006;91:3803–3813.