Salivary diurnal cortisol profiles in patients suffering from chronic breathlessness receiving supportive and palliative care services: A cross-sectional study
Introduction
Chronic breathlessness is a common symptom of advanced cardiorespiratory disease, affecting >90% of people with advanced COPD, >60% of people with advanced heart disease and 10–70% of people with advanced cancer (Solano et al., 2006). It is a considerable source of psychosocial and physical stress, being associated with fear, anxiety, social isolation and functional disability (Booth et al., 2003). It has also been shown to predict mortality, independent of lung function, in a range of conditions, including COPD (Nishimura et al., 2002), pulmonary fibrosis (Nishiyama et al., 2010), and older adulthood (Ahmed et al., 2012). These effects suggest a potential role for the stress hormone system in the experience of breathlessness.
The hypothalamic-pituitary-adrenal (HPA) axis is a major regulator of the physiological stress response, exerting its effects through its end-hormone, cortisol. Basal cortisol secretion has a marked circadian rhythm, characterised by a rapid rise in cortisol secretion upon awakening, followed by a fall in cortisol levels throughout the day (Smyth et al., 2013). This pattern becomes disrupted in the context of prolonged or repeated exposure to stressful triggers, often manifesting as loss or blunting of diurnal variation in cortisol secretion (Miller et al., 2007). Such dysregulation has been observed in a wide range of chronic diseases, both malignant (Abercrombie et al., 2004) and non-malignant (Hackett et al., 2014), and has been associated with negative disease outcomes and characteristics. Flatter diurnal rhythms have been shown to predict mortality secondary to cancer (Sephton et al., 2000, Cohen et al., 2012, Sephton et al., 2013) and cardiovascular disease (Kumari et al., 2011). They have also been associated with more advanced cancer stages (Sephton et al., 2000, Sephton et al., 2013), greater functional disability in cancer (Weinrib et al., 2011, Sephton et al., 2013) and worse physical performance in older adulthood (Gardner et al., 2013).
To date, the relationship of the HPA axis with the physical symptomatology of chronic progressive diseases has been explored to a limited degree only. A few studies have described diurnal cortisol profiles in relation to fatigue in patients with cancer, but findings have been inconsistent (Sephton et al., 2000, Weinrib et al., 2011, Bower et al., 2005, Sephton et al., 2013). One study has identified a relationship between HPA axis function and the cancer symptom cluster of pain, fatigue and depression, but it did not assess diurnal cortisol rhythmicity (Thornton et al., 2010). Symptoms are increasingly understood in the literature to be psychoneurological responses to disease, driven by pathophysiological mechanisms which are distinct from, though related to, the underlying associated disease (Miller et al., 2008, Dantzer et al., 2012, Kim et al., 2012). It is, thus, important to identify these pathophysiological mechanisms to allow therapeutic targeting of symptoms independent of disease.
No studies have examined the relationship between chronic breathlessness and HPA axis function. The literature points to a number of specific factors which are suggestive of a link, however. First, there is a well-established relationship between breathlessness and anxiety (von Leupoldt et al., 2011), which might promote a chronic stress response. Second, the perception of breathlessness is processed in the same parts of the cortico-limbic system (insula, amygdala and anterior cingulate cortex) as other aversive sensations such as pain, hunger and thirst (von Leupoldt et al., 2009), all of which are known to activate the stress response. Finally, the aforementioned independent relationship between breathlessness severity and mortality, across a range of contexts, is currently unexplained; HPA axis dysregulation, in the context of breathlessness, represents one possible explanation needing exploration.
We hypothesised that patients suffering from chronic breathlessness due to chronic progressive disease would have evidence of HPA axis dysregulation, represented by a flatter diurnal cortisol slope. To investigate this, we aimed to measure the salivary diurnal cortisol profile in patients under the care of supportive and palliative care services, who were experiencing moderate-to-severe disability due to breathlessness, comparing this profile against that of non-breathless patients and that of healthy adults. Specific objectives were:
1) To compare the mean diurnal cortisol slope (slope of the decline in cortisol across the day) in patients with moderate-to-severe breathlessness (Medical Research Council, MRC ≥3) against that of non-breathless patients (MRC ≤2) and that of healthy adults.
2) To compare pre-defined diurnal cortisol slope categories between patients with moderate-to-severe breathlessness and healthy adults.
Section snippets
Material and methods
Study procedures for patient participants were approved by the National Research Ethics Service Committee, East of England-Norfolk (13/EE/0021). It was part of a larger programme of research, registered on the ISRCTN registry (ISRCTN70836126). Study procedures for the healthy control group were approved by the ethics committee of the University of Westminster. Written informed consent was obtained from all participants prior to enrolment.
Mean diurnal cortisol slope with respect to health status
To investigate our primary hypothesis that the DCS for patients with moderate-to-severe breathlessness (MRC ≥3) was different from that for patients with mild/no breathlessness and from that of healthy controls, we used a two-stage analysis. First, we calculated the DCS for each patient using linear regression of log-transformed cortisol levels against collection time across the 2 days (6 samples). Second, we assessed whether there was a difference in mean DCS between the three study groups (MRC ≤
Compliance with the saliva collection protocol
In the patient group, of the 366 commissioned saliva samples from 61 patients, 330 (90.2%) were collected within 1 h of the time stipulated by the protocol, 3 (0.8%) were missing and 15 (4.1%) had no collection time recorded. In regard to the self-reported awakening time, which was the anchor for the subsequent collection times, this was within 15 min of the objective actigraphy-derived awakening time on 78% of the days recorded (n = 38).
Protocol-compliance in the patient group is summarised at a
Discussion
We have described the salivary diurnal cortisol profile, a surrogate marker of HPA axis activity, in patients suffering from moderate-to-severe breathlessness (MRC ≥3) secondary to a range of cardiorespiratory diseases. We have shown that patients with moderate-to-severe breathlessness had significantly flatter diurnal cortisol slopes compared to healthy adults. We have also shown that patients with moderate-to-severe breathlessness had a mixture of declining, flat and ascending slopes, a
Conclusion
In summary, this cross-sectional study provides novel evidence of HPA axis dysregulation in patients with moderate-to-severe breathlessness, manifesting as flatter diurnal cortisol decline slopes. The degree of dysregulation appears to relate to functional disability due to breathlessness, rather than psychological distress. Future longitudinal studies are necessary to explore the temporal relationship between breathlessness-induced disability and HPA axis dysregulation, as well as its
Acknowledgements
The authors would like to thank the following people for their support of the study: all patients who participated; past and present staff of the Cambridge Breathlessness Intervention Service and the Palliative Care Department of Cambridge University Hospitals NHS Foundation Trust, particularly those who helped with recruitment and administration (in particular, Dr. Rosemary Wade, Julie Burkin, Pauline Kleanthous, Catherine Moffat, Rhys Hurst, Malika Harboun, Natalie Brown and Dr. Sarah Grove);
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