Medical Hypotheses xxx (2014) xxx–xxx

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The biological impact of living with chronic breathlessness – A role for the hypothalamic–pituitary–adrenal axis? R. Ryan ⇑, A. Spathis, A. Clow, M. Fallon, S. Booth Palliative Care Department, Box 63, Elsworth House, Cambridge University Hospitals NHS Foundation Trust, Hill’s Road, Cambridge CB2 0QQ, United Kingdom

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Article history: Received 30 November 2013 Accepted 2 April 2014 Available online xxxx

a b s t r a c t Breathlessness is a common and distressing symptom in advanced cardiorespiratory disease, with recognised psychological, functional and social consequences. The biological impact of living with chronic breathlessness has not been explored. As breathlessness is often perceived as a threat to survival, we propose that episodic breathlessness engages the stress-response, as regulated by the hypothalamic–pituitary–adrenal (HPA) axis. Furthermore, we hypothesise that chronic breathlessness causes excessive stimulation of the HPA axis, resulting in dysfunctional regulation of the HPA axis and associated neuropsychological, metabolic and immunological sequelae. A number of observations provide indirect support for this hypothesis. Firstly, breathlessness and the HPA axis are both associated with anxiety. Secondly, similar cortico-limbic system structures govern both breathlessness perception and HPA axis regulation. Thirdly, breathlessness and HPA axis dysfunction are both independent predictors of survival. There is a need for direct observational evidence as well as experimental data to investigate this hypothesis which, if plausible, could lead to the identification of a new biomarker pathway to support breathlessness research. Ó 2014 Elsevier Ltd. All rights reserved.

Introduction Breathing is a basic instinct essential to survival. It is not surprising, therefore, that the symptom of breathlessness is often perceived as a threat to survival and is commonly associated with a fear of dying [1]. The psychological, functional and social consequences of living with this chronic stressor, in the context of advanced cardiorespiratory disease, have been prolifically described in the literature, with evidence, across a range of diagnoses, indicating that it causes significant psychological distress, physical disability and social isolation [2–4]. The biological impact of living with chronic breathlessness has not been explored, however. Due to the survival threat associated with breathlessness, one would intuitively expect the sensation of breathlessness to engage the physiological stress-response system and that the biological

Grants: This report is independent research arising from a doctoral research fellowship programme award supported by the National Institute for Health Research. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health. ⇑ Corresponding author. Address: Palliative Care Department, Box 63, Elsworth House, Cambridge University Hospitals NHS Foundation Trust (Addenbrooke’s Hospital), Hill’s Road, Cambridge CB2 0QQ, United Kingdom. Tel.: +44 1223274404. E-mail addresses: [email protected], richellacryan@hotmail. com (R. Ryan).

consequences of breathlessness might be effectuated through this system. On the basis of this presumption, an understanding of stress biology might provide clues about the biological impact of breathlessness. The biological consequences of living with chronic stress are being increasingly elucidated in the psychoneuroendocrinological literature. The ability to measure the function of the hypothalamic–pituitary–adrenal (HPA) axis, an important regulator of the stress-response, has been a key advance in the understanding of this area. It is now recognised that the prolonged or repeated exposure to stressful triggers may actually result in a dysregulated or dysfunctional HPA axis [5]. This state is characterised by a disrupted circadian pattern of cortisol secretion, with loss of normal rhythm and responsiveness [6,7]. This pattern of HPA axis dysfunction is believed to result in a range of metabolic, immunological and neuropsychological consequences [8] and has been found to be associated with important health outcomes including psychiatric morbidity [9], increased cardiovascular mortality [10] and reduced survival in cancer patients [11,12]. As breathlessness is a chronic stressor, we hypothesise that living with breathlessness causes a dysregulated HPA axis and that this, by extension, may result in important adverse biological and clinical outcomes, independent of the underlying disorder inducing the breathlessness. While a relationship between breathlessness and HPA axis function might seem intuitive, there is no evidence

http://dx.doi.org/10.1016/j.mehy.2014.04.011 0306-9877/Ó 2014 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Ryan R et al. The biological impact of living with chronic breathlessness – A role for the hypothalamic–pituitary–adrenal axis? Med Hypotheses (2014), http://dx.doi.org/10.1016/j.mehy.2014.04.011

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R. Ryan et al. / Medical Hypotheses xxx (2014) xxx–xxx

in the literature to indicate that a direct relationship between the two actually exists. There is much to suggest that such a relationship might exist, however, given the many intersections between the neuroscience of the respiratory system and that of the stresssystem, as extensively reviewed by Abelsen et al. [13]. In the absence of evidence of a direct relationship, we have explored the literature for associations that might be suggestive of the co-existence of HPA axis dysfunction and breathlessness. We have identified three factors which appear to be associated with both breathlessness and HPA axis dysfunction, providing a link between the two. Firstly, we have identified that anxiety is associated with both breathlessness and HPA axis dysregulation. Secondly, related to this, we have noted that the areas of the cortico-limbic system involved in breathlessness processing are similar to the areas involved in regulating the HPA axis. Finally, we have observed that both breathlessness and HPA dysregulation are independent predictors of survival. For each factor linking breathlessness and the HPA axis, we present the evidence, first in relation to breathlessness and then in relation to the HPA axis. We then postulate various mechanisms by which the mutual association of interest might causally link breathlessness and HPA axis dysregulation. We wish to highlight from the outset that we are not attempting to prove causality through the presentation of these indirect associations and are simply evaluating the scientific plausibility of our hypothesis, as well as generating related hypotheses about potential causal mechanisms involved. We hope that this exploration will ultimately facilitate the design of an experimental study to test our hypothesis.

Anxiety is associated with both breathlessness and HPA axis dysregulation Association between breathlessness and anxiety Anxiety appears to be a prominent part of the experience of breathlessness, regardless of the underlying disease. Qualitative studies report anxiety, panic and fear as significant features of the breathlessness experience in COPD and lung cancer [3,4], as well as in heart failure and motor neurone disease [4]. Anxiety disorders are also highly prevalent in respiratory disease. In COPD, generalised anxiety disorder has a prevalence ranging from 10% to 15.8% [14–17] compared with a lifetime rate of 5.1% in the general public [18], and panic disorder has a prevalence of 8–32% [17,19,20] compared with a lifetime prevalence rate of 1.5% in the general population [17,21]. Within COPD, breathlessness level has been shown to be positively correlated with anxiety level, independent of demographics and disease severity [22], suggesting that the high prevalence of anxiety seen in COPD may, in part, be explained by breathlessness. Interestingly, respiratory disorders also appear to be more prevalent in patients suffering from anxiety disorders. The life-time prevalence rate of respiratory disorder has been shown to be as high as 47% in patients with panic disorder compared to 13% in obsessive compulsive disorder [17,23]. In addition, intrinsically irregular breathing patterns have been demonstrated in patients suffering from panic disorder [24]. Theoretical knowledge of breathlessness genesis and evidence of anxiety-related changes in breathlessness perception support the possibility of a causal relationship between breathlessness and anxiety, the temporal nature of which appears to be complex. Theoretically, breathlessness perception is understood to have both sensory and affective dimensions [25], which may be measured using separate subjective scales in experimental studies [26] and which may be distinguished clinically by different breathlessness descriptors [27]. Accordingly, anxiety may be understood

as an emotional response to the affective dimension of the sensation. There is also evidence to suggest that breathlessness occurs in response to anxiety. Qualitative studies of breathlessness experience suggest that breathlessness triggers anxiety and anxiety triggers breathlessness, resulting in a self-perpetuating cycle [28]. In addition, an induced negative affective state, such as anxiety, has been shown to increase the affective component of breathlessness perception in COPD patients [29]. Furthermore, distraction techniques, which are often used in anxiety management, have been shown to reduce the affective component of breathlessness perception both in healthy volunteers experiencing induced breathlessness [30] and in exercising COPD patients [31]. Thus, the theory and the evidence suggest that a bidirectional relationship between breathlessness and anxiety is likely. Association between HPA axis dysregulation and anxiety As well as being associated with breathlessness, anxiety has also been shown to be associated with HPA axis dysregulation. Cross-sectional large-scale population studies have demonstrated that the normal distinct pattern of cortisol secretion is absent in those suffering from anxiety disorder [32,33], though the pattern of disruption has been inconsistent across studies. Hek et al. [33] demonstrated that the cortisol awakening response, which is calculated by measuring the cortisol rise after 30 min of awakening, was significantly reduced in 145 community-based patients with a variety of chronic anxiety disorders (>65 years) compared to 1643 normal controls. By contrast, Vreeburg et al. [32] demonstrated that the one-hour cortisol awakening level was significantly higher in a group of 774 patients with a current diagnosis of anxiety disorder in comparison with 342 normal controls. Both of these large studies suggest that anxiety is associated with HPA dysregulation but the reported pattern of dysregulation appears to conflict. The determinants of the pattern of HPA dysregulation observed in association with anxiety disorder are not known but factors which may be implicated include subdiagnosis, population and chronicity. In relation to chronicity, for example, it is postulated that a recent diagnosis of anxiety disorder may be associated with a hyperactive HPA axis which, over time, becomes hypoactive [33]. Further studies are necessary in order to better interpret these findings. The evidence of an association between anxiety disorder and HPA axis dysregulation is strengthened by recent longitudinal data in which 837 patients with anxiety disorder (42.8%), depression (22.2%) or both (35%) were followed over 2 years [34]. In this study, a lower cortisol awakening response at baseline was independently associated with a significantly more unfavourable course of disease after 2 years of follow-up [34], suggesting that HPA axis dyregulation may be implicated in anxiety disorder progression. This finding suggests that the association between anxiety and HPA axis dysregulation is worthy of further investigation. Could breathlessness cause HPA axis dysregulation through its association with anxiety? Clearly, it is not possibly to prove a causal association between breathlessness and HPA axis dysregulation outside of an experimental study. However, the intimate, bidirectional relationship between breathlessness and anxiety suggests that they might operate together along a causal chain of common effects, one potential effect being HPA axis dysregulation. As anxiety is a product of the limbic system, it is likely that any impact which breathlessness might have on HPA axis function, through its relationship with anxiety, is effected by modulation of the cortico-limbic control of the HPA axis. The potential role for the cortico-limbic sys-

Please cite this article in press as: Ryan R et al. The biological impact of living with chronic breathlessness – A role for the hypothalamic–pituitary–adrenal axis? Med Hypotheses (2014), http://dx.doi.org/10.1016/j.mehy.2014.04.011

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tem in mediating the relationship between breathlessness and HPA axis function is further explored in the next section. Breathlessness is processed in parts of the limbic system which regulate HPA axis function Association between breathlessness and the limbic system The cortical and subcortical structures involved in breathlessness perception are increasingly being identified in neuro-imaging studies of experimental breathlessness in healthy volunteers. In general, these studies suggest the importance of the insular cortex, the anterior cingulate cortex (ACC) and the amygdala in the central processing of breathlessness, though findings are inconsistent across studies due to differences in experimental methods used [35]. It is postulated that these areas are particularly important in processing the affective dimension of breathlessness, which appraises its aversive nature. Von Leupoldt et al. [36] showed that pain and breathlessness shared a common emotion-regulating network which included the anterior and mid-insula, the dorsal ACC, the amygdala and the medial thalamus. The insula and the ACC have also been shown to be activated in response to hunger [37] and thirst [38]. These particular areas are thought to be important in the conscious processing of interoceptive inputs requiring context-dependent responses [38], suggesting an important role in motivation-to-action behavioural responses [39]. Together, these findings suggest that the affective dimension of breathlessness is processed in a non-specific fashion, with an anatomical pattern similar to that of other aversive threatening sensory stimuli that require homeostatic regulation [36]. This suggests that breathlessness perception may activate a common pathway which co-ordinates responses to stressful physical stimuli. The hippocampus, another limbic system structure, is also believed to have a role in breathlessness processing, but this role appears to be distinct from the role of the other limbic system structures. It has been shown to be activated in response to hypercapnia in a number of studies [39,40], though it is less consistently activated across imaging studies than the aforementioned limbic system structures. It is believed that the hippocampus, along with the thalamus, has a critical role in the gating of respiratory sensory signals, determining their distribution to specific brain areas for cognitive processing [41]. Association between the limbic system and HPA axis regulation The recent development of non-invasive neuro-imaging methods has also allowed cortico-limbic regulation of the human HPA axis to be studied. Under stimulated conditions, this work has been limited to the context of psychological rather than physical stressors [42–47]. Such work has also been conducted under unstimulated, stress-free basal conditions [48,49]. All of these studies suggest that the hippocampus, the prefrontal cortex, which includes the ACC, and the amygdala are involved in the central stress response in humans [47]. The nature of this limbic-HPA axis relationship depends on the particular limbic anatomical structure or neuronal network being studied (see Fig. 1). The strongest evidence appears to exist for the role of the hippocampus in limbic-HPA axis regulation, particularly in the context of psychological or anticipatory stressors [47]. Pruessner et al. (2005) demonstrated an inverse correlation between hippocampal volume and the cortisol response to a stress task [42]. In addition, Pruessner et al. (2008) showed a linear relationship between the degree of hippocampal deactivation and the amount of cortisol released in response to stress [43]. Another study demonstrated that those participants that secreted a desirably greater

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amplitude of cortisol diurnally under basal conditions had less activity in the hippocampus when exposed to traumatic images, suggesting a healthy emotional response to stress [46]. These studies, together, suggest that the hippocampus and the HPA axis regulate each other. It is postulated that, under normal circumstances, hippocampal activity results in tonic inhibition of the HPA axis and that hippocampal deactivation results in disinhibition of the HPA axis in response to a stressor [43]. The prefrontal cortex (PFC), which includes the ACC, has also been shown to be associated with cortisol regulation [44,45,47]. Activity in the lateral PFC before and after a stress task has been shown to be positively correlated with stress-induced salivary cortisol production [44,45]. By contrast, inverse correlations have been found between stress-induced cortisol production and activity in the orbitofrontal PFC [43,44,47] and the medial PFC [45,47]. The pattern of activity in the ACC in relation to stress-induced cortisol production seems to vary across studies, which may relate to different stress tasks used [47]. Pruessner et al. [43] found that stress-induced cortisol production was associated with decreased activity in the ACC whereas Wang et al. [44] observed stressinduced cortisol production to be positively associated with ACC activity. Together, these correlations suggest a role for the PFC, including the ACC, in HPA axis regulation but the exact role appears to differ depending on the specific region of the PFC involved and the stress task used. Though animal studies have shown a direct relationship between the amygdala and stress-induced cortisol secretion [50], the evidence from human neuro-imaging studies is more limited [47]. Within the limbic system, it is postulated that the amygdala is more involved in the processing of anticipatory stress associated with physical threats rather than psychosocial threats and its role, therefore, may be underestimated by neuro-imaging studies limited to psychosocial stressors [47]. Electrical stimulation of the human amygdala in temporal lobe epilepsy has been shown to be associated with ACTH and cortisol release, suggesting that the availability of a suitable stressor in neuro-imaging studies might unmask the relationship [51]. Despite limited evidence of a relationship between the amygdala and the HPA axis under stressful conditions, neuro-imaging studies have shown a relationship between amygdala activity and endogenous cortisol levels under basal or stress-free conditions. Veer et al. [48] showed that the amygdala resting-state functional connectivity with the medial PFC (including the perigenual ACC and the medial frontal pole) is influenced by basal cortisol levels, as measured by the cortisol area under the curve (AUC). Though it is already well known that the medial PFC has an inhibitory effect on the amygdala, this finding suggests that basal cortisol levels may modulate this effect [48]. In addition, Kiem et al. [49], using the dexamethasone-suppression-CRH-stimulation test as a measure of HPA axis functionality, showed a positive correlation between resting-state amygdala activity and ACTH AUC, as well as a significant negative correlation between amygdala–hippocampal connectivity and cortisol AUC. Could breathlessness modulate the HPA axis through its effect on the limbic system? Together, these studies demonstrate that limbic system structures known to be involved in the processing of both breathlessness and psychological stress are associated with both the basal regulation and stimulation of the HPA axis. The limitation of neuro-imaging studies of breathlessness to healthy volunteers with induced breathlessness means that we do not have information on the functional activity of the brain in patients with chronic breathlessness. In addition, the limitation of neuro-imaging studies of the stress-response to the context of psychosocial stressors means that we have limited information about the central regula-

Please cite this article in press as: Ryan R et al. The biological impact of living with chronic breathlessness – A role for the hypothalamic–pituitary–adrenal axis? Med Hypotheses (2014), http://dx.doi.org/10.1016/j.mehy.2014.04.011

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Fig. 1. Brain areas involved in processing physical and psychological stressors [Reproduced by the kind permission of Elsevier from Dedovic et al. [47]]. HC = hippocampus, BS = brainstem, AG = amygdala, HY = hypothalamus, PFC = prefrontal cortex, oPFC = orbital PFC, mPFC = medial PFC, vlPFC = ventrolateral PFC, ACC = anterior cingulated cortex.

tion of the human HPA axis in the context of physical stressors. These research gaps make it difficult to make clear inferences about how breathlessness might affect the HPA axis. What we do know is that the hippocampus, the ACC and the amygdala are important in both breathlessness processing and HPA axis regulation. This shared functional neuro-anatomy warrants further investigation.

Breathlessness and HPA axis dysregulation are both independent predictors of survival Association between breathlessness and survival Clinically, breathlessness has connotations far beyond the distress associated with it. It is not merely a symptom of a disease but also a powerful independent predictor of mortality [52]. In a multicentre prospective study of 183 COPD patients, 5-year survival was found to be significantly correlated to level of breathlessness rather than pulmonary function [53]. Similar relationships between breathlessness and prognosis have been demonstrated in other disease contexts. In a prospective study of 93 patients with idiopathic pulmonary fibrosis, conducted over a median follow-up period of 40 months, breathlessness during daily activities at diagnosis was found to be a stronger predictor of survival than most physiological parameters of lung function in a multivariate analysis [54]. In addition, dyspnoea has been identified as a significant independent predictor of survival in heart failure [55], lung cancer [56] and advanced cancer of any primary [57]. The consistent association between breathlessness and prognosis independent of respiratory function and other indicators of disease severity across a range of diseases suggests that breathlessness is not just a marker of disease severity but a potential mediator of disease progression. Though breathlessness and lung function correlate to a degree, the correlation has been shown to be weak in numerous studies [58], which is in keeping with the well established theory that breathlessness is a highly subjective multidimensional symptom, comprised of both physical and psychosocial perceptual factors [52,59]. The observation that a patient’s own perception of their degree of breathlessness is a stronger indicator of survival than lung function suggests that breathlessness experience, whatever its components, may contribute to health status.

Association between HPA axis dysregulation and survival HPA axis dysregulation has also been shown to relate to survival both in healthy populations and in a variety of disease contexts. In a large population study of 4047 men and women, followed over a period of 6.1 years, loss of the normal rhythmicity of the diurnal pattern of cortisol secretion, manifested by a flatter slope in the decline of cortisol levels over the day, was found to be associated with increased cardiovascular disease mortality, independent of a wide range of covariates [10]. A similar finding was observed in an earlier study involving a cohort of 104 metastatic breast cancer patients followed over 7 years [11]. In this study, flatter diurnal cortisol slopes at baseline predicted shorter subsequent survival times and this relationship remained after controlling for potential confounders. This relationship has also been demonstrated for other cancer types. A cohort study involving 217 metastatic renal cell carcinoma patients found a significant association between a flattened cortisol slope and survival, controlling for a range of possible confounders [60]. It is noteworthy that cortisol slope was as predictive as disease risk category in relation to survival in this study. More recently, a prospective cohort study of 62 lung cancer patients, both early and advanced-stage, showed that flattening of the diurnal cortisol rhythm predicted early mortality over a period of 3 years [12]. Importantly, this relationship was found to be independent of known prognostic indicators including performance status and more advanced lung cancer stage. Evidence from both laboratory and clinical experimental studies lends support to a potential bidirectional causal relationship between HPA axis dysregulation and cancer progression [12,61]. Tumour growth has been shown to be doubled when the circadian glucocorticoid rhythm is disrupted under experimental conditions [62] but laboratory studies also suggest that tumours may themselves disrupt central and peripheral circadian regulation [61,63]. Evidence from clinical interventional studies which demonstrate a survival benefit following the delivery of psychosocial interventions to breast cancer patients [64,65] and malignant melanoma patients [66] lends further support to a causal relationship as these interventions target stress-related psychological parameters which may modulate HPA axis function. Not all studies of this nature have demonstrated a survival benefit, however, such that the role of psychosocial, stress-reducing interventions in modulating cancer disease outcomes remains a much contested subject [67]. The way in which HPA axis dysregulation might contribute to cancer

Please cite this article in press as: Ryan R et al. The biological impact of living with chronic breathlessness – A role for the hypothalamic–pituitary–adrenal axis? Med Hypotheses (2014), http://dx.doi.org/10.1016/j.mehy.2014.04.011

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progression is not fully understood, though many mechanisms have been postulated, including effects on the tumour microenvironment, the immune system and the metabolic system [68]. Could the prognostic impact of breathlessness be mediated by HPA axis dysregulation?

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use in clinical trials of new breathlessness interventions, a research area currently lacking objective outcome measures. Overall, the indirect associations between breathlessness and the HPA axis appear worthy of further study. This intriguing interface is rich in hypothetical possibilities. It is now necessary to move from postulation toward experimentation.

The association between breathlessness and survival, independent of respiratory function, suggests that breathlessness operates along a biological axis which is at least partially independent of the underlying cardiorespiratory disease status. As the non-respiratory element to breathlessness perception resides in the brain, where emotional and behavioural responses are co-ordinated, it is reasonable to postulate that the central response to breathlessness could be driving its independent prognostic impact. For this to be true, however, the emotional and behavioural responses would need to exert biological effects. The biological correlates of such responses are not known but the HPA axis is one potential biological pathway through which breathlessness and survival could be linked.

The authors declare that they do not have any conflict of interest. This report is independent research arising from a doctoral research fellowship programme award supported by the National Institute for Health Research. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health. The research sponsor, Cambridge University Hospitals NHS Foundation Trust, has not had any involvement in the preparation or submission of this paper.

Discussion

Dr. Ryan is funded by a National Institute for Health Research (NIHR) doctoral research fellowships programme award.

This paper presents observed associations of breathlessness which have also been identified in relation to the HPA axis. In doing so, the possibility that breathlessness could be associated with HPA axis dysregulation is explored. We acknowledge that the mutual associations presented here provide, at most, only indirect support of our hypothesis that chronic breathlessness causes HPA axis dysregulation. Nonetheless, the similarities between the breathlessness and HPA axis literature are compelling and suggest that our hypothesis is not implausible. To progress this area of interest, we are designing a trial to test the impact of a breathlessness intervention on the salivary diurnal cortisol levels of patients suffering from breathlessness. The results of this trial will hopefully address, to some degree, the current research gap. The demonstration that breathlessness engages a biological system such as the HPA axis would be of significant theoretical importance as it would alter our current understanding of the symptom. Increasingly, neuro-imaging is being used to help elucidate the perceptual processes involved in breathlessness genesis but the adaptive processes that follow perception and their biological correlates have not been considered. At present, we understand breathlessness as a symptom of an underlying disease but the uncoupling of breathlessness severity from disease stage and its independent relationship to survival suggest that breathlessness is more than this and that it may exert its own pathological effects, rather like a separate disease entity. This observed phenomenon is currently unexplained. Evidence that breathlessness engages a measurable biological system, such as the HPA axis, might also have significant clinical and research implications. Firstly, it may aid the early identification of those patients who have developed or are particularly at risk of developing maladaptive emotional and behavioural responses to breathlessness. Early expensive psychological and behavioural therapies could then be targeted toward this subpopulation. Secondly, it may lead to potential new therapeutic advances. For example, a better understanding of the psychobiological effects of breathlessness may allow the identification of new therapeutic targets. In addition, the observed relationship between breathlessness and survival, which might be mediated by its psychobiological effects, ignites the possibility of modulating prognosis through breathlessness treatments. Finally, the demonstration of a direct association between breathlessness and HPA axis dysregulation may allow the development of a biomarker for

Conflict of interest statement

Acknowledgments

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Please cite this article in press as: Ryan R et al. The biological impact of living with chronic breathlessness – A role for the hypothalamic–pituitary–adrenal axis? Med Hypotheses (2014), http://dx.doi.org/10.1016/j.mehy.2014.04.011