Chronic refractory breathlessness is a distinct clinical syndrome

Thomas Sydenham ‘I watched what method Nature might take, with intention of subduing the symptom by treading in her footsteps.’ Rigorous, systematic and empiric observations of the manifestations of diseases have formed the bedrock of clinical practice since Sydenham reintroduced this into medical thinking in the 17th century. His conviction that meticulous description of the natural history of disease would eventually lead to an understanding of the appropriate treatment for that ailment was particularly apparent in his wide ranging observations about fever, gout, hysteria and attention to psychological health as a public health measure (‘The arrival of a good clown exercises a more beneficial influence upon the health of a town than of twenty asses laden with drugs.’ Thomas Sydenham), many of which still hold relevance today. Such an approach has served clinical medicine well. The delineation of a clinical syndrome, that is a constellation of clinical findings often accompanied by laboratory or imaging abnormalities, on many occasions has been the start of the road to develop effective interventions targeted at specific pathological process(es). This situation is illustrated by the clinical syndrome of heart failure because of left ventricular dysfunction, itself the final common pathway for a variety of pathological insults. Although the definition is still debated, a consensus working description has allowed systematic clinical recognition and assessment alongside research to understand the pathophysiological mechanisms involved and to develop and evaluate drug and device therapies. This process has resulted in targeted treatments, the widespread implementation of which has dramatically improved both quality and quantity of life for people with heart failure seen in successive national audits and the improved outcomes in the usual care ± placebo arms in controlled trials over time [1]. As many of the articles in this issue state, breathlessness is a common symptom of common chronic medical conditions. The same steps of clinical observation, recognition of patterns and changes over time resulted in the identification of the underlying disease's pathological processes, such as chronic obstructive pulmonary disease. Algorithms to guide the investigation of breathlessness are available, and aid diagnosis and management of the underlying condition, usually leading to improvement of breathlessness [2,3]. However, for most, treatment of the underlying condition only partly relieves the breathlessness, and in many people, it will continue unalleviated despite treatment of the disease. Such breathlessness, which persists despite the best tailored treatment for the cause, is termed ‘chronic refractory breathlessness’ [4]. Meticulous observation and study of breathlessness itself has been slow to develop. However, over the past decades, as a result of painstaking work by groups including clinical academics from respiratory medicine, palliative care, cardiology and oncology, and respiratory and neurophysiologists, the picture is becoming clearer, emphasizing the crucial importance of recognizing chronic refractory breathlessness as a distinct clinical syndrome [5,6]. FEATURES OF THE SYNDROME Breathlessness is a subjective sensation with distinguishable dimensions. The model of perceived intensity and unpleasantness of breathlessness, followed by an emotional response and a variety of functional consequences is borne out by detailed clinical and laboratory observation [7]. Assessment tools based on the complex sensation that is breathlessness such as the multidimensional dyspnea profile [8] and the Dyspnoea-12 [9] have robust clinimetric validation and confirm that people living with refractory breathlessness because of medical conditions can distinguish intensity, unpleasantness, quality and emotional response. Ongoing daily breathlessness results in a functional response. For many patients, there is a predictable pattern of breathlessness related to physical and emotional exertion. Many develop adaptive coping strategies, which enable continued function at some level, and may delay deterioration [10], whereas others respond by increasing restrictions and limitations. However, over time, episodes of exertion-induced breathlessness become worse as the disease progresses, and people are able to do less and less. Thus, patients exist in an ever shrinking world, accelerated by a vicious cycle of physical de-conditioning. One way, therefore, to describe the severity of the breathlessness is to relate it to the degree of exertion allowed before the breathlessness stops the activity – the basis of the Medical Research Council (MRC) dyspnea scale [11]. In addition to predictable patterns of exertion-induced breathlessness, many people experience episodes of breathlessness not associated with any particular trigger causing fear and distress [12]. NEUROPHYSIOLOGY The model of primary perception followed by emotional response is supported by neuroimaging studies of acutely induced breathlessness in healthy volunteers, which can map brain activity to the distinct sensations identified by the breathless person [13]. This may indicate a final common pathway of the perception of breathlessness independent of the causative disease. Emerging data from people with chronic breathlessness owing to respiratory disease confirm similar spatial patterns of brain activity to that seen with acutely induced breathlessness, regardless of the underlying cause [14]. Additionally, central processing of chronic breathlessness appears to involve processing of memory and expectation [14,15]. These early findings indicate that there are features of central perception and processing of chronic breathlessness, which are distinct from acutely induced breathlessness in people who do not experience ongoing breathlessness. Such neural activity is a potential pathophysiological marker of the clinical syndrome of refractory breathlessness. However, although this indicates a final common pathway of perception (and thus independent of underlying disease), peripheral targets (dependent on underlying disease) for breathlessness interventions should also be explored. For example, pursed lip expiration, by providing positive end expiratory pressure, may be more beneficial for people with COPD than for those with interstitial lung disease, although both groups may benefit from opioids. CHRONIC REFRACTORY BREATHLESSNESS: A DISTINCT CLINICAL SYNDROME We therefore propose a new clinical syndrome of chronic refractory breathlessness: an unpleasant sensation of breathlessness caused by an underlying disease or disease, which persists despite optimum treatment directed at the underlying disease; can be ameliorated by pharmacological and nonpharmacological interventions, which modulate the perception (both via central and peripheral mechanisms) and the person's response; is associated with neurophysiological evidence of altered central neural processing of breathlessness. IMPORTANCE FOR CLINICAL PRACTICE Breathlessness is associated with poor clinical outcomes (emergency department attendance, hospital admission, in-hospital adverse events, poorer short and long-term survival). As described by Janssen in this issue, for the individual patients and their families, it represents serious, frightening, physical and psychosocial distress, which deserves serious attention [16] and for which there are evidence-based treatments. IMPORTANCE FOR RESEARCH A recognition of chronic refractory breathlessness as a distinct clinical syndrome will encourage appropriate focus for research and funding priorities. Given the impact of this syndrome on millions of people each day around the world, such emphasis is long overdue. Acknowledgements None. Financial support and sponsorship None. Conflicts of interest There are no conflicts of interest.