Clinical ReviewPhenotypic approaches to obstructive sleep apnoea – New pathways for targeted therapy
Introduction
Obstructive sleep apnoea (OSA) is an increasingly common disorder characterised by repetitive narrowing and collapse of the pharyngeal airway during sleep [1], [2]. This results in a substantial decrease (hypopnoea) or complete cessation (apnoea) of airflow despite increased effort to breathe. Each breathing disturbance or ‘respiratory event’ continues for at least 10 s but can last for 60 s or more. Clinically, greater than five events per hour of sleep in adults is often considered the lower level of abnormal. However, in extreme cases, more than 100 breathing disturbances per hour of sleep can occur. Respiratory events transiently increase carbon dioxide levels and reduce oxygenation. The extent of blood gas changes vary according to the duration of each event and other modifiers such as obesity status [3]. Termination of most respiratory events is associated with a brief (usually <15 s) awakening or a ‘cortical arousal’ [4], ∗[5]. Thus, OSA fragments sleep and many people with OSA feel sleepy and find it difficult to remain alert and maintain concentration throughout the day.
Recent polysomnographic data from a community sample of over 2000 individuals aged 40–85 years in Switzerland, indicate that 23% of women and nearly 50% of men have moderate to severe OSA, defined as ≥15 obstructive breathing events per hour of sleep [1]. Similarly, the estimated prevalence of moderate to severe OSA from the Wisconsin sleep cohort study in the United States has increased by 14–55% over the past two decades [2]. While as many as 50% of OSA patients are not obese [6], obesity is a major risk factor for OSA. It is responsible, at least in part, for the continual increase in the prevalence of OSA. The majority of people with OSA remain undiagnosed and untreated. This is a major public health and safety concern as untreated OSA has multiple adverse cardiovascular [7], metabolic [8], neurocognitive [9], quality of life [10], and safety consequences [11]. Links have also recently been established between OSA and cancer [12].
Development of the first-line therapy, continuous positive airway pressure (CPAP), in the early 1980s in Sydney, Australia, by Professor Sullivan and colleagues [13] completely transformed the treatment of OSA and facilitated the growth of sleep medicine. CPAP therapy involves the patient wearing either a nasal or oro-nasal breathing mask or interface attached to a positive pressure source. Positive pressure is delivered continuously throughout the night to act as a pneumatic splint to keep the upper airway open and maintain adequate airflow. The pressure is titrated to the minimal level required to keep the upper airway open according to each patient's specific requirement (up to 20 cmH2O). This is performed either manually during an overnight sleep study or via an auto-titration device. CPAP is highly efficacious in resolving the breathing disruptions associated with OSA. Indeed, millions of people with OSA worldwide now benefit from CPAP therapy. However, it is often poorly tolerated [14]. Approximately 50% or more of all OSA patients who are prescribed CPAP either do not use it at all or on average, use it for less than four hours per night [14], [15]. Another substantial proportion of people who are diagnosed with OSA refuse to even try CPAP therapy. Others who suspect that they may have OSA do not seek formal diagnosis and treatment due to a lack of enthusiasm for CPAP therapy. Second-line therapies such as dental devices and upper airway surgery have variable and unpredictable efficacy. Other approaches such as weight loss are often challenging and also have variable and unpredictable efficacy. Thus, there is a need for new treatments for OSA and to develop effective strategies to accurately predict and optimise treatment outcomes for existing non-CPAP therapies.
To address these key challenges and move OSA management beyond the current one-size-fits-all trial and error approach, upper airway and respiratory phenotyping approaches for OSA have been developed. This review summarises the recent advances in knowledge of OSA pathogenesis that have emerged from these developments and implications for treatment. Specifically, the concepts of how different phenotypic traits contribute to OSA and how understanding their pathogenic role in individual patients could lead to new targeted therapies are discussed. The potential role of phenotypic approaches, including new diagnostic tools to optimise existing second-line therapies, is also covered. Finally, research priorities for OSA phenotypic approaches to translate these concepts to the clinic are highlighted.
Section snippets
Overview
OSA is a heterogeneous disorder. Indeed, even though the ten patients studied in the seminal OSA pathogenesis work by Remmers and colleagues in the late 1970s were homogeneous in that they were all very obese with severe OSA [16], clear between-patient differences in breathing and neuromuscular responses during airway closure were noted. While this poses challenges for a one-size-fits-all management approach to treat OSA, the heterogeneity in the pathogenesis and manifestations of OSA also
‘Impaired upper airway anatomy’: the main cause of OSA
There is no doubt that a crowded, narrow or inherently collapsible upper airway, i.e., ‘impaired upper airway anatomy’, is the key cause of OSA. Multiple studies using a variety of imaging techniques consistently show that, on average, the static cross-sectional area of the pharyngeal airway in people with OSA is smaller when compared to their non-OSA counterparts (Fig. 2 and for review see [23]). It is therefore not surprising that most existing therapies for OSA are directed towards reversing
Non-anatomical contributions to OSA
The role of non-anatomical phenotypes that contribute to OSA has only been characterised quite recently. When combined with some degree of upper airway narrowing due to anatomical factors, impairment in one or more of the non-anatomical traits outlined below can cause OSA and mediate its severity. However, the opposite also applies such that favourable non-anatomical phenotypes can protect people with vulnerable upper airway anatomy from OSA. Accordingly, non-anatomical phenotypes are potential
PALM scale categorisation to inform development of targeted therapies
As described in the sections above, the key determinant of OSA is impaired upper airway anatomy. Thus, therapies for OSA that target this trait are, and likely always will be, important. Accordingly, optimisation of existing therapies to increase pharyngeal dimensions is a priority. This includes, but is not limited to, strategies to increase CPAP adherence as well as lifestyle and surgical weight loss interventions which can improve upper airway collapsibility and alleviate OSA in obese people
Beyond the AHI: development of new tools to diagnose OSA according to a phenotypic approach
The detailed upper airway and respiratory phenotyping approaches described throughout this review have been, and will continue to be, essential to understand the mechanisms that underpin each phenotype and identify new therapeutic targets. However, their use in routine clinical practice is not feasible. Thus, to translate the concepts outlined in the PALM scale to the clinic, simplified methodology to estimate each trait is required.
At present, the gold standard for the diagnosis of OSA is
Conclusions
Until recently, the heterogeneity of OSA pathogenesis was poorly defined. Impairment in upper airway anatomy is the most important variable. However, other non-anatomical phenotypes such as impaired upper airway muscle function during sleep, unstable respiratory control and a low respiratory arousal threshold play a contributory role. These phenotypes are potential therapeutic targets. There is also scope to combine existing non-CPAP therapies (e.g., mandibular advancement splints and upper
Conflict of interest
The author has no relevant conflicts of interests to declare in relation to the content of this manuscript.
Acknowledgements
The author would like to thank the NeuRA sleep and breathing team and other colleagues and collaborators who have contributed to the evolution of the science behind the concepts outlined in this review article. The author would also like to acknowledge and thank Dr Lauriene Juge for preparing the MRIs for Fig. 2, Dr Jason Amatoury and Dr Jayne Carberry for their valuable feedback on the manuscript, and Associate Professor Peter Catcheside for preparing the Venn diagram for Fig. 9. The author is
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