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Competing Interests: SBM holds grants from the Australian Research Council and the National Health and Medical Research Council of Australia; he declares honoraria from Merck, NeRRe Therapeutics, Reckitt Benckiser, and Bellus Health, and grant support from Merck and Bellus Health. IS is currently supported by the EJ Moran Campbell Early Career Award from the Department of Medicine, McMaster University (Hamilton, ON, Canada); he is the recipient of a European Respiratory Society RESPIRE3 Marie Sklodowska-Curie fellowship and he declares grants and personal fees from Merck Canada and GlaxoSmithKline (GSK), grants from Bayer and Bellus, and personal fees from Respiplus, Genentech, and AstraZeneca. LM reports grant support from Merck, and honoraria for lectures and advisory board participation from Chiesi, GSK, Merck, NeRRe Therapeutics, Shionogi, AstraZeneca, Nocion, Boehringer Ingelheim, and Reckitt Benckiser. W-JS declares grants from Merck and AstraZeneca, consulting fees from Merck, AstraZeneca, Shionogi, and GSK, and lecture fees from Merck, AstraZeneca, GSK, and Novartis. KFC has received honoraria from GSK, AstraZeneca, Novartis, Merck, Nocion, Shionogi, and Reckitt Benckiser for advisory board participation, and from Haleon for scientific advisory board participation for the Clean Breathing Institute; he has also been remunerated for speaking engagements by AstraZeneca, Novartis, and Merck. KFC is supported by grants from the UK Medical Research Council and Engineering Physical Sciences Research Council, and is Senior Investigator of the UK National Institute for Health Research. The Twelfth London International Cough Symposium was supported by an educational grant from Merck, with contributions from Bellus Health, Bionorica, NeRRe Therapeutics, Nocion Therapeutics, Reckitt Benkiser, Shionogi, and Trevi Therapeutics. The funders had no role in developing the programme for the Symposium.

Background: Cough characteristics vary between patients, and this can impact clinical diagnosis and care. The purpose of part two of this state-of-the-art review is to update the American College of Chest Physicians (CHEST) 2006 guideline on global physiology and pathophysiology of cough., Study Design and Methods: A review of the literature was conducted using PubMed and MEDLINE databases from 1951 to 2019 using prespecified search terms., Results: We describe the demographics of typical patients with cough in the clinical setting, including how cough characteristics change across age. We summarize the effect of common clinical conditions impacting cough mechanics and the physical properties of mucus on airway clearance., Interpretation: This is the second of a two-part update to the 2006 CHEST cough guideline; it complements part one on basic phenomenology of cough by providing an extended clinical picture of cough along with the factors that alter cough mechanics and efficiency in patients. A greater understanding of the physiology and pathophysiology of cough will improve clinical management., (Copyright © 2021. Published by Elsevier Inc.)

The airways receive a dense supply of sensory nerve fibers that are responsive to damaging or potentially injurious stimuli. These airway nociceptors are mainly derived from the jugular and nodose vagal ganglia, and when activated they induce a range of reflexes and sensations that play an essential role in airway protection. Jugular nociceptors differ from nodose nociceptors in their embryonic origins, molecular profile and termination patterns in the airways and the brain, and recent discoveries suggest that excessive activity in jugular nociceptors may be central to the development of chronic cough. For these reasons, targeting jugular airway nociceptor signaling processes at different levels of the neuraxis may be a promising target for therapeutic development. In this focused review, we present the current understanding of jugular ganglia nociceptors, how they may contribute to chronic cough and mechanisms that could be targeted to bring about cough suppression., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Cough is one of the most common presenting symptoms of COVID-19, along with fever and loss of taste and smell. Cough can persist for weeks or months after SARS-CoV-2 infection, often accompanied by chronic fatigue, cognitive impairment, dyspnoea, or pain-a collection of long-term effects referred to as the post-COVID syndrome or long COVID. We hypothesise that the pathways of neurotropism, neuroinflammation, and neuroimmunomodulation through the vagal sensory nerves, which are implicated in SARS-CoV-2 infection, lead to a cough hypersensitivity state. The post-COVID syndrome might also result from neuroinflammatory events in the brain. We highlight gaps in understanding of the mechanisms of acute and chronic COVID-19-associated cough and post-COVID syndrome, consider potential ways to reduce the effect of COVID-19 by controlling cough, and suggest future directions for research and clinical practice. Although neuromodulators such as gabapentin or opioids might be considered for acute and chronic COVID-19 cough, we discuss the possible mechanisms of COVID-19-associated cough and the promise of new anti-inflammatories or neuromodulators that might successfully target both the cough of COVID-19 and the post-COVID syndrome., Competing Interests: Declaration of interests KFC has received honoraria for participating in advisory board meetings for GlaxoSmithKline, AstraZeneca, Novartis, Merck, Boehringer Ingelheim, Nocion, Shionogi, Roche, and TEVA Pharmaceutical regarding treatments for asthma and chronic obstructive pulmonary disease; he has recieved honoraria for participating on the scientific advisory board of the Clean Breathing Institute, supported by GlaxoSmithKline Health Care Consumer Products; and he has been remunerated for speaking engagements by AstraZeneca, Novartis, and Merck. SBM reports grants from Merck and personal fees from Merck and NeRRe Therapeutics. SSB reports personal fees from Nocion, Merck, Nerre, Bayer, Bellus, and Shionogi; and grants from Merck, all outside the submitted work. LM reports personal fees from GlaxoSmithKline, Merck, Shionogi, Bayer, Bellus Health, Nocion, Chiesi, and Applied Clinical Intelligence; and grants from Merck and Chesi, all outside the submitted work. JHH has received grant funding and advisory fees from MSD pharmaceuticals and is a member of the advisory board for Bellus health. The other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Cough is a defense mechanism that protects the airways and lungs in response to airway irritation. The sensory neurons involved in detecting airway irritants and the neural pathways mediating cough share similarities with those that encode pain from the body. Painful conditioning stimuli applied to one body site are known to reduce the perception of pain at another. However, whether the neural regulation of cough is influenced by painful stimuli is not known., Research Question: What are the behavioral and neural outcomes of painful conditioning stimuli on urge-to-cough (UTC) and cough evoked by inhaled capsaicin?, Study Design and Methods: Sixteen healthy participants underwent psychophysical testing and functional MRI while completing a series of capsaicin inhalations to induce UTC and cough. The responses associated with capsaicin inhalation without pain were compared with those after the application of painful conditioning stimuli., Results: Significant decreases were seen behaviorally of 18.7% ± 17.3% (P < .001) and 47.0% ± 30.8% (P < .001) in participants' UTC ratings and cough frequencies, respectively, during the application of pain. UTC ratings were reduced by 24.2% ± 36.5% (P < .005) and increased by 67% ± 40% (P < .001) for capsaicin and saline inhalation, respectively, during the scanning session. Painful conditioning stimuli were associated with widespread decreases in regional brain responses to capsaicin inhalation (P < .001). Several brain regions showed levels of reduced activation attributable to painful conditioning that correlated with related changes in behavioral responses during scanning (R 2  = 0.53)., Interpretation: Pain-related decreases of cough and UTC are accompanied by widespread changes in brain activity during capsaicin inhalation, suggesting that pain can modify the central processing of inputs arising from the airways. A mechanistic understanding of how cough and pain processing interact within the brain may help develop more effective therapies to reduce unwanted coughing., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

The purpose of this state-of-the-art review is to update the American College of Chest Physicians 2006 guideline on global physiology and pathophysiology of cough. A review of the literature was conducted using PubMed and MEDLINE databases from 1951 to 2019 and using prespecified search terms. We describe the basic phenomenology of cough patterns, behaviors, and morphological features. We update the understanding of mechanical and physiological characteristics of cough, adding a contemporary view of the types of cough and their associated behaviors and sensations. New information about acoustic characteristics is presented, and recent insights into cough triggers and the patient cough hypersensitivity phenotype are explored. Lastly, because the clinical assessment of patients largely focuses on the duration rather than morphological features of cough, we review the morphological features of cough that can be measured in the clinic. This is the first of a two-part update to the American College of Chest Physicians 2006 cough guideline; it provides a more global consideration of cough phenomenology, beyond simply the mechanical aspects of a cough. A greater understanding of the typical features of cough, and their variations, may allow a more informed interpretation of cough measurements and the clinical relevance for patients., (Copyright © 2020. Published by Elsevier Inc.)

Cough is a troublesome and difficult-to-treat symptom that accompanies a diverse range of pulmonary and extrapulmonary conditions. Although considerable advances have been made over recent years in basic cough biology, this has not translated into improved clinical management. A major challenge has been in understanding the heterogeneity underlying the development and persistence of chronic cough in different patients. We present evidence that such heterogeneity begins with the multiple peripheral and central neural pathways capable of eliciting cough and associated respiratory behaviours, and extends to incorporate the diversity of diseases that underlie cough and the clinical phenotypic and pathological endotypic presentations that can vary substantially between individual patients with cough. A better understanding of how these sources of heterogeneity are expressed across individual patients with chronic cough is needed to better predict the efficacy of clinical management strategies and of specifically targeted therapies, which will facilitate the development of more personalised clinical approaches to treat patients with chronic cough., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: In bronchiectasis due to cystic fibrosis (CF) and other causes, airway clearance is one of the mainstays of management. We conducted a systematic review on airway clearance by using non-pharmacological methods as recommended by international guidelines to develop recommendations or suggestions to update the 2006 CHEST guideline on cough., Methods: The systematic search for evidence examined the question, "Is there evidence of clinically important treatment effects for non-pharmacological therapies in cough treatment for patients with bronchiectasis?" Populations selected were all patients with bronchiectasis due to CF or non-CF bronchiectasis. The interventions explored were the non-pharmacological airway clearance therapies. The comparison populations included those receiving standard therapy and/or placebo. Clinically important outcomes that were explored were exacerbation rates, quality of life, hospitalizations, and mortality., Results: In both CF and non-CF bronchiectasis, there were systematic reviews and overviews of systematic reviews identified. Despite these findings, there were no large randomized controlled trials that explored the impact of airway clearance on exacerbation rates, quality of life, hospitalizations, or mortality., Conclusions: Although the cough panel was not able to make recommendations, they have made consensus-based suggestions and provided direction for future studies to fill the gaps in knowledge., (Copyright © 2018 American College of Chest Physicians. All rights reserved.)

Chronic cough is a significant problem, and in many patients cough remains refractive to both disease-specific therapies and current cough-suppressing medicines, creating a need for improved antitussive therapies. Most patients with chronic cough also display heightened sensitivity so that they experience a persistent sense of the need to cough, and often innocuous stimuli can trigger their coughing. This hypersensitivity underpins the newly described concept of cough hypersensitivity syndrome (CHS), a term that encapsulates the notion of common underlying mechanisms producing neuronal activation, sensitization and/or dysfunction, which are at the core of excessive coughing. Understanding these mechanisms has been a focus of recent research efforts in the field in the hope that new therapies can be developed to selectively target sensitized unproductive cough while maintaining the reflexive cough essential for airway protection. However, efforts to achieve this have been slower than expected, in part because of some significant challenges and limitations translating current cough models. In this review, we summarize recent advances in our understanding of the sensory circuits innervating the respiratory system that are important for cough, how cough sensory pathways become hypersensitive, and some of the recently described neural targets under development for treating chronic cough. We present the case that better use of current cough models or the development of new models, or both, is ultimately needed to advance our efforts to translate the discovery of basic cough mechanisms into effective medicines for treating patients with chronic cough., (Copyright © 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Bronchopulmonary C-fibers and a subset of mechanically sensitive, acid-sensitive myelinated sensory nerves play essential roles in regulating cough. These vagal sensory nerves terminate primarily in the larynx, trachea, carina, and large intrapulmonary bronchi. Other bronchopulmonary sensory nerves, sensory nerves innervating other viscera, as well as somatosensory nerves innervating the chest wall, diaphragm, and abdominal musculature regulate cough patterning and cough sensitivity. The responsiveness and morphology of the airway vagal sensory nerve subtypes and the extrapulmonary sensory nerves that regulate coughing are described. The brainstem and higher brain control systems that process this sensory information are complex, but our current understanding of them is considerable and increasing. The relevance of these neural systems to clinical phenomena, such as urge to cough and psychologic methods for treatment of dystussia, is high, and modern imaging methods have revealed potential neural substrates for some features of cough in the human.

Many pulmonary diseases are characterized by inflammatory pathologies which in turn are responsible for obstruction, mucus hypersecretion, dyspnea, cough and other clinical symptoms of lung disease. Understanding processes that regulate inflammation will therefore provide insights into mechanisms that contribute to pulmonary dysfunction. The airways and lungs are densely innervated by autonomic and sensory nerves which might regulate aspects of pulmonary inflammation. In this review we provide a critical appraisal of the available literature on the topic of neuro-immune interactions in the airways and ask the question 'how strong is the evidence that pulmonary nerves regulate inflammation?', (Copyright © 2013 Elsevier B.V. All rights reserved.)

Chronic cough is a common symptom that can be a daunting challenge for clinicians since treatment of the underlying cause does not always provide adequate relief, an obvious cause can remain elusive, and current antitussives have fairly poor efficacy and undesirable side-effects. Patients with chronic cough typically describe a range of sensory symptoms suggestive of upper-airway and laryngeal neural dysfunction. Additionally, patients often report cough triggered by low-level physical and chemical stimuli, which is suggestive of cough-reflex hyperresponsiveness. Pathophysiological mechanisms underlying peripheral and central augmentation of the afferent cough pathways have been identified, and compelling evidence exists for a neuropathy of vagal sensory nerves after upper-respiratory viral infections or exposure to allergic and non-allergic irritants. In this Personal View, we argue that chronic cough is a neuropathic disorder that arises from neural damage caused by a range of inflammatory, infective, and allergic factors. In support of this idea, we discuss evidence of successful treatment of chronic cough with agents used for treatment of neuropathic pain, such as gabapentin and amitriptyline. Regarding cough as a neuropathic disorder could lead to new, more effective antitussives., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The airways and lungs are innervated by both sympathetic and parasympathetic nerves. Cholinergic parasympathetic innervation is well conserved in the airways while the distribution of noncholinergic parasympathetic and adrenergic sympathetic nerves varies considerably amongst species. Autonomic nerve function is regulated primarily through reflexes initiated upon bronchopulmonary vagal afferent nerves. Central regulation of autonomic tone is poorly described but some key elements have been defined., (© 2013 Elsevier B.V. All rights reserved.)

Background: The urge to cough is a clinical symptom of respiratory disease that precedes the motor act of coughing. Although previous studies have shown that cough is particularly susceptible to placebo suppression, it is unclear whether the perception of an urge to cough is also modifiable by placebo. Therefore, we tested the hypothesis that capsaicin-evoked urge to cough could be suppressed by placebo conditioning., Methods: Eleven healthy participants were unknowingly conditioned to believe that an inert inhaler temporarily suppressed capsaicin-induced urge to cough by deceptively modifying the challenge concentration of capsaicin. In subsequent testing, capsaicin-evoked urge-to-cough subjective ratings were assessed in four challenges with a single dose of inhaled capsaicin following no treatment or the placebo metered-dose inhaler. An additional 10 participants were informed that the inhaler therapy was inert prior to receiving capsaicin challenges with and without inhaler treatment., Results: There was a significant decrease in mean urge-to-cough ratings to capsaicin challenge following placebo compared with no treatment followed by capsaicin challenge (P < .001), with a peak decrease of 45%. The placebo inhaler alone had no effect on urge-to-cough subjective ratings when participants were aware that it contained no active medication., Conclusions: These data confirm that the urge to cough is susceptible to placebo inhibition. This provides further evidence that higher brain networks are involved in the processing of respiratory sensations related to airway irritation.

The autonomic nervous system plays a primary role in regulating airway smooth muscle tone. Here, we describe the development of an in vivo guinea pig model that permits systematic studies of the autonomic control of airway smooth muscle. The model is based on preparations previously described and utilizes measurements of isometric tension in a perfused segment of extrathoracic guinea pig trachea in situ. It has the advantage that the autonomic innervation to the tracheal segment under study can be physiologically or pharmacologically isolated and studied independently from other mechanisms regulating airway smooth muscle tone. Initial experiments were conducted to optimize model conditions. Subsequent experiments were designed to highlight the usefulness of this preparation for studying parasympathetic regulation of airway caliber. The results of the study demonstrate the utility of this model for future studies into the neural regulation of bronchomotor tone and the mechanisms of airway obstruction and hyperreactivity associated with disease.