Abstract
Aim
To examine the relationship between cortisol suppression and asthma symptoms in patients with difficult asthma.
Methods
Patients, referred to a specialist difficult asthma service and who fulfilled the criteria for difficult asthma, were recruited to the study in a sequential, unselected manner. At each clinic visit, all patients completed a validated asthma control questionnaire. For measuring cortisol suppression, early morning urinary cortisol [corrected for creatinine to give urinary cortisol creatinine ratio (UCC ratio)] was used. The urine samples were collected and stored at −70 °C until ready for analysis. Urinary cortisol was extracted (solid-phase extraction) and analysed using high-performance liquid chromatography. The Pearson correlation coefficient was used for correlation analysis while t-tests were used for between-group differences for normally distributed data. If the data were not normally distributed, nonparametric statistics were used. A P-value < 0.05 was considered statistically significant.
Results
During the study period all the patients who attended the difficult asthma clinic and fulfilled the criteria for difficult asthma (n = 66) agreed to take part in the study. There were moderate to strong and significant associations between several measures of asthma control and UCC ratio. The correlation coefficient with five indicators of asthma control ranged between 0.3 and 0.5 (P < 0.05).
Conclusions
We have demonstrated a relationship between cortisol suppression and asthma control in difficult asthmatics on high-dose steroid therapy. We have proposed a model based on the relationship between symptom control and cortisol suppression, whereby both adherence and therapeutic adjustments could potentially be made. A properly controlled prospective clinical trial should examine the utility of this approach in clinical practice.
Keywords: adherence, asthma, cortisol suppression, inhaled steroids, prednisolone
Introduction
National and international treatment guidelines for asthma management stress the importance of anti-inflammatory agents [1, 2], in particular inhaled corticosteroids. There remains, however, a small but important subgroup of patients who are inadequately controlled on high-dose inhaled steroids [steps 4 and 5 of the British Thoracic Society (BTS) guidelines [1]]. These patients are a cause of concern because of continued impaired lung function and disability and increased risk of asthma deaths. A number of factors may contribute to the lack of adequate control in these subjects (difficult asthmatics), including poor adherence to medications [3].
Asthma control varies with time and is primarily determined by background disease severity, contact with exacerbating factors (such as allergens and infectious agents) and adherence to therapy [4]. It is generally accepted that if inhaled steroids are taken in sufficient dose and adequately deposited in the lung, they will cause endogenous cortisol suppression and it has previously been proposed that due to this effect, evaluation of adherence to inhaled steroids could be accomplished by examining suppression of early morning cortisol [5, 6]. However, it has been suggested that the degree of cortisol suppression resulting from inhaled steroids is variable due to an individual propensity to cortisol suppression [7]. Some of the observed variability may also be due to the different assay methods used for measuring cortisol and to the different methods used to quantify cortisol suppression. Furthermore, medication adherence within studies, inhaler device and inhalation techniques are also likely to be important [8, 9].
No previous study has examined the association between asthma symptoms and cortisol suppression. The aim of the present study was to examine the relationship between cortisol suppression and asthma symptoms in patients with difficult asthma [prescribed oral prednisolone and/or high-dose inhaled steroids (HDIS)]. Our hypothesis was that if patients on HDIS adhered to therapy and used their inhalers correctly, inhaled steroids would reach the systemic circulation in sufficient concentrations to cause cortisol suppression. We also hypothesized that those with more suppression may have achieved more therapeutic benefit than those with less suppression.
Methods
Patients, referred to a specialist difficult asthma service and who fulfilled the criteria for difficult asthma, were recruited to the study in a sequential, unselected manner. The subjects consented to the study after full explanation of what was involved.
The definition of difficult asthma was [10]: (i) persisting refractory symptoms prompting specialist referral, (ii) minimal maintenance therapy of long-acting β2-agonist and inhaled steroids [>800 µg beclomethasone dipropionate (BDP) or equivalent], and (iii) at least one course of systemic steroids in the preceding 12 months. Asthma was defined on the basis of typical symptoms together with current or recently documented reversibility in forced expiratory volume in 1 s (FEV1) of >12%[11].
Patients were contacted by phone before the scheduled clinics visit and were asked to bring their first morning urine sample at the day of clinic visit. Asthma was managed according to BTS guidelines with treatment being stepped up and down as appropriate [1]. At each clinic visit, all patients completed a validated asthma control questionnaire and performed spirometry. As part of the difficult asthma management protocol, all patients received instructions on medication adherence, inhaler technique and spacer use (if required). The study was approved by the local Research Ethics Committee.
Asthma control questionnaire
Patients were asked to record their symptoms (night waking, morning symptoms, activity limitation, shortness of breath and wheezing) during the previous week. The questions were scored on a 7-point scale (0, good control/no symptoms; 6, poor control/severe symptoms). The mean score of the five symptom questions is the total asthma control score (ACS). A score <3 indicates well-controlled asthma with no or mild exacerbations. A score of ≥3 indicates poorly controlled asthma with more frequent symptoms and exacerbations. The asthma control questionnaire has been shown to have good validity and reliability [12–14]. In one longitudinal study both reliability and responsiveness tended to be better for the asthma control questionnaire when compared with a daily diary recording of asthma symptom frequency [14].
Cortisol suppression
For measuring cortisol suppression, early morning urinary cortisol [corrected for creatinine to give urinary cortisol creatinine ratio (UCC ratio)] was used. It has previously been evaluated and shown to be as sensitive as the 24-h urinary free cortisol collection and is more sensitive than a single measurement of a 09.00 h plasma cortisol [15, 16].
Chromatographic analysis
The urine samples were collected and stored at −70°C until ready for analysis. Urinary cortisol was extracted (solid-phase extraction) and analysed using high-performance liquid chromatography (HPLC) [17]. This method has been shown to have high specificity for cortisol measurement without interference from prednisolone or inhaled steroids and has been shown to be superior to radioimmunoassay and enzyme-linked immunosorbent assay [18] due to a higher degree of specificity. The limit of detection of cortisol in urine (using 3-ml samples) was 0.33 ng ml−1. The intraday and interday precision (measured by CV%) for cortisol was always <7%. The accuracy (measured by relative error percentage) for cortisol was always <8%. Urinary creatinine was measured using a rate blanked and compensated Jaffe method. The lower limit of detection was 0.2 mmol l−1 and the CV was 3%. Samples were analysed in batches. Calibration curves and quality control standards were prepared in every batch. All analyses were carried out in triplicate.
Statistical analysis
Data were coded and entered into SPSS® version 11 (SPSS Inc., Chicago, IL, USA). The Pearson correlation coefficient was used for correlation analysis, while t-tests were used for between-group differences for normally distributed data. If the data were not normally distributed nonparametric statistics were used (Spearman correlation coefficient for correlation, Mann–Whitney U-test for independent group differences). χ2 analysis was used for categorical data. A P-value < 0.05 was considered statistically significant. Cortisol concentrations below the limit of detection were given a value of a half of the limit of detection [19, 20]. In general, correlation coefficient (r) 0–0.1 is considered as a very weak correlation, 0.1–0.29 is weak, 0.3–49 is considered to be moderate correlation and 0.5–1 is a strong correlation [21, 22].
Results
Study population
During the study period all the patients who attended the difficult asthma clinic and fulfilled the criteria for the definition of difficult asthma (n = 66) agreed to take part in the study. The study population [25 male, median age 40.5 years (19–72), 11 smokers] had had asthma for a median duration of 17 years (1–52) with 18 (27%) of the population on oral prednisolone at the time of study (median dose 20 mg, range 5–40 mg). FEV1 prebronchodilator (% predicted) mean ± SE was 66.5 ± 2.9 while FEV1/forced vital capacity (FVC) prebronchodilator, % mean ± SE was 67.8 ± 1.9. The median standardized bio-equivalent dose of inhaled steroid (beclomethasone dipropionate equivalent) was 2000 µg (range 1000–4000 µg) administered by metered dose inhaler. Fifty patients (71.4%) were on fluticasone, six (8.6%) were on beclomethasone and 14 (20%) were on budesonide.
Asthma control
Four patients did not fill in the asthma control questionnaire (two receiving prednisolone and two receiving inhaled steroid only). The results for the remaining 62 patients are shown in Table 1. Almost all indicators of disease control show that this group of patients have disease which is difficult to control.
Table 1.
Asthma control questionnaire
| Parameter | Prednisolone | HDIS | All |
|---|---|---|---|
| Night awaking | 3 (2–5) | 2 (0–3) | 2 (1–3) |
| Morning symptoms | 4 (1–4) | 2 (2–4) | 3 (2–4) |
| Activity limitation | 3 (1–4) | 3 (1–4) | 3 (1–4) |
| Shortness of breath | 4 (3–5) | 3 (2–4) | 4 (2–4) |
| Wheezing | 4 (1–5) | 3 (2–4) | 3 (2–5) |
| ACS | 3.6 (2.4–4.4) | 2.9 (1.6–3.8) | 3.3 (1.9–3.8) |
| Reliever use | 4 (3–6) | 2 (1–3) | 3 (2–4) |
| FEV1% | 60.9 (20.1) | 69.3 (22.8) | 66.7 (22.2) |
The response options for each of the items are on a 7-point scale, ranging from 1 (totally limited) to 7 (not at all limited). Data are shown as median (25–75% iles) except for forced expiratory volume in 1 s (FEV1) %, where data shown as mean (SD). Prednisolone, Patients on prednisolone and high-dose inhaled steroids; HDIS, patients on high-dose inhaled steroids only; ACS, asthma control score.
Urinary cortisol suppression
Blood and urine samples were collected from all 66 patients; 18 samples were from patients on prednisolone with HDIS and 48 samples were from patients on HDIS only. Table 2 shows the distribution of UCC values in patients with prednisolone and those taking HDIS. UCC values were significantly lower in subjects taking HDIS with controlled asthma compared with those who had uncontrolled disease. There was also a significant difference in cortisol suppression between those who used inhaled steroids only and those who were also on prednisolone (data not shown; P = 0.0001).
Table 2.
Distribution of urinary cortisol corrected for creatinine values in patients on prednisolone plus high-dose inhaled steroids (HDIS) and patients on HDIS only
| N | Mean | SE | Median | Min. | Max. | P-value | |
|---|---|---|---|---|---|---|---|
| Prednisolone | |||||||
| Controlled | 7 | 0.1 | 0.06 | <0.33 | <0.33 | 0.5 | 0.1 |
| Uncontrolled | 11 | 5.8 | 3.2 | 0.7 | <0.33 | 39.8 | |
| HDIS | |||||||
| Controlled | 26 | 3.5 | 0.7 | 2.0 | <0.33 | 7.6 | 0.01 |
| Uncontrolled | 22 | 15.9 | 6.6 | 5.7 | <0.33 | 140 | |
Values are in nmol/mmol (cortisol/creatinine). Statistical comparison is made using the Mann–Whitney U-test. Controlled asthma was defined as an asthma control score <3.
Relationship between urinary cortisol suppression and asthma control
We examined the relationship between asthma control and urinary cortisol in a cross-sectional study sample. For the remaining subjects (n = 62), there were moderate to strong and significant associations between several measures of asthma control and UCC (Table 3; Figure 1). In addition, the reliever use was inversely associated with UCC. These associations remained when patients on HDIS and patients taking prednisolone were examined separately (Table 3). The associations were also present for urinary cortisol (UC), uncorrected for urinary creatinine.
Table 3.
Correlation between asthma control score, reliever use, lung function and urinary cortisol (UC) and urinary cortisol creatinine ratio (UCC)
| Prednisolone (N = 16) | HDIS (N = 46) | All (N = 62) | ||||
|---|---|---|---|---|---|---|
| Parameter | UC | UCC | UC | UCC | UC | UCC |
| Night awaking | 0.68 (0.01)* | 0.63 (0.02)* | 0.24 (0.12) | 0.21 (0.16) | 0.17 (0.21) | 0.10 (0.46) |
| Morning symptoms | 0.70 (0.008)* | 0.66 (0.02)* | 0.35 (0.02)* | 0.35 (0.02)* | 0.33 (0.01)* | 0.30 (0.02)* |
| Activity limitation | 0.54 (0.05)* | 0.57 (0.04)* | 0.42 (0.004)* | 0.39 (0.007)* | 0.42 (0.001)* | 0.38 (0.003)* |
| Shortness of breath | 0.73 (0.005)* | 0.68 (0.01)* | 0.36 (0.02)* | 0.35 (0.02)* | 0.36 (0.005)* | 0.30 (0.02)* |
| Wheezing | 0.88 (<0.0005)* | 0.82 (0.001)* | 0.52 (<0.0005)* | 0.49 (0.001)* | 0.58 (<0.0005)* | 0.51 (<0.0005)* |
| ACS | 0.86 (<0.0005)* | 0.79 (0.001)* | 0.48 (0.001)* | 0.41 (0.004)* | 0.46 (<0.0005)* | 0.38 (0.003)* |
| Reliever use | 0.77 (0.002)* | 0.78 (0.002)* | 0.22 (0.14) | 0.11 (0.47) | 0.24 (0.07) | 0.14 (0.30) |
| FEV1% | −0.09 (0.76) | −0.09 (0.77) | −0.17 (0.27) | −0.23 (0.13) | −0.08 (0.56) | −0.10 (0.46) |
Correlation was performed using the Spearman rank method. A P-value of <0.05 was regarded as significant.
Data shown as r (P-value). Prednisolone, Patients on prednisolone and high-dose inhaled steroids (HDIS); HDIS, patients on HDIS only.
Figure 1.
Relationship between the urinary cortisol creatinine (UCC) ratio and asthma control (N = 62). The Pearson correlation coefficient was used
In order to ascertain the reproducibility of this relationship, we collected follow-up samples from 27 patients and re-examined the correlation (we could not obtain follow-up from all patients due to several issues including time and fund limitation). The clinical characteristics of the follow-up sample including the median doses of inhaled steroid and oral prednisolone were similar to those of the initial sample. The results were interesting and supported those obtained initially. In patients on HDIS only, who provided a follow-up sample and filled in a follow-up asthma control questionnaire (n = 17), the differences in urinary cortisol or/and UCC between the first and follow-up samples were correlated with the difference in night awaking (r = 0.67, P = 0.003), morning symptoms (r = 0.65, P = 0.004) and total asthma control (r = 0.61, P = 0.009). In patients on prednisolone who provided a follow-up sample and filled in a follow-up asthma control questionnaire (n = 10) there were medium to strong associations (r > 0.3) between the differences in urinary cortisol and/or UCC between the first and follow-up samples and the differences in several measures of asthma control; however, they were not significant due to the small sample size (n = 10; data not shown).
Discussion
The relationship between cortisol suppression and asthma symptoms in subjects with difficult asthma has not been reported previously. Theoretically, better asthma control should occur with adherence to inhaled/oral steroid therapy which, in turn, should be associated with a degree of cortisol suppression. Previous studies have reported considerable interindividual variation in the degree of adrenal suppression with inhaled and oral corticosteroids.
Multiple factors, including the particular corticosteroid prescribed, the drug delivery device, inhaler technique and dosing regimen, all effect adrenal suppression independently of adherence to therapy. By studying the end-point of all of these variables (namely cortisol suppression), our study has shown that there are moderate to strong, significant associations between most measures of asthma control and cortisol suppression in this population. These associations remained when patients on HDIS and patients taking prednisolone were examined separately. These associations were further supported in a follow-up sample. This suggests that the degree of cortisol suppression may be related to asthma control.
These results may be clinically useful; based on our results from this observational study, we would suggest patients may be classified into four groups according to their asthma symptom control and degree of suppression. In group 1, asthma symptoms are well controlled and the cortisol level is suppressed; this suggests the patient is adherent to treatment and the treatment is effective at the current dose and step-down therapy should be considered. In group 2, asthma symptoms are controlled and the cortisol level is not suppressed; this situation is complex, as the patient is possibly not completely adherent to prescribed medication or not using the inhaler correctly but asthma remains controlled. In this case, the patient may not need to use inhaled steroids regularly or requires lower doses of regular inhaled steroids. We suggest a discussion with the patient regarding adherence and their individual goals of asthma therapy. In group 3, asthma symptoms are not controlled and the cortisol level is suppressed; this suggests that the patient is taking medication and using the inhaler correctly but the treatment is not effective. This ineffectiveness may result from persisting symptoms not being all due to asthma (e.g. wrong or coexistent diagnosis), steroid resistance (e.g. due to predominantly neutrophilic inflammation) or other factors. In group 4, asthma symptoms are uncontrolled and the cortisol level is not suppressed. These patients have potentially poor adherence or poor inhaler technique problems and these should be considered, including educational intervention prior to increasing asthma therapy.
Adherence to inhaled steroid therapy in asthma is variable and has been reported to be 30–70%[3], but assessing adherence to inhaled therapy remains a significant problem in routine clinical practice. Basal cortisol secretion returns to normal levels 1–4 days after stopping treatment in subjects taking prednisolone or HDIS [23, 24] and thus cortisol suppression, particularly if compared with an individual’s baseline, has the potential to be used for adherence assessment in difficult asthmatics requiring HDIS or oral prednisolone.
A number of factors, e.g. time of awakening, premenopausal state and oral contraceptive use [25], can influence early-morning cortisol levels, and so some inter- and intraindividual variability in UCC values are to be expected. This variability will undoubtedly influence the precision of the UCC test when used in asthma patients and should be taken into account in their interpretation.
Conclusion
We have demonstrated a relationship between cortisol level and asthma control in difficult asthmatics on high dose steroid therapy. We have proposed a model based on the relationship between symptom control and cortisol suppression, whereby both adherence and therapeutic adjustments could potentially be made. A properly controlled prospective clinical trial should examine the utility of this approach in clinical practice.
Acknowledgments
Competing interests: None declared.
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