Materiały źródłowe

• #1 Chronic Cough – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK430791/

  Cough is a complex reflex involving coordination between various muscles and neural pathways. Coughing is a protective mechanism for the respiratory system, helping to keep the airways clear of substances that could potentially cause harm or hinder normal breathing. While coughing is generally a healthy response, persistent or chronic coughing can be a symptom of an underlying health issue and may require further investigation and management. […] Chronic cough is a widespread yet underappreciated condition that imposes substantial illness on affected individuals. […] Chronic cough is a persistent cough that lasts 8 weeks or longer in adults, while subacute cough usually lasts 3 to 8 weeks, and acute cough typically lasts for less than 3 weeks. […] The cough reflex is not a fixed, unchanging response but rather a dynamic process that can be influenced by various inputs and stimuli, a phenomenon called „cough plasticity.” Vagal afferent fibers, part of the vagus nerve (cranial nerve X), play a crucial role in sensing and transmitting information from the airways to the brainstem, particularly the nucleus tractus solitarius (NTS).

• #1 Chronic Cough – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK430791/

  A chronic cough may also be brought about by abnormalities of the cough reflex and sensitization of its afferent and central components with exaggerated cough reflex sensitivity to stimuli that generally do not cause a cough (cough hypersensitivity syndrome). […] The mechanism of cough in ILD is complex and may involve multiple factors. Cough in IPF can be attributed to mechanical distortion associated with lung parenchymal fibrosis. The scarring and lung fibrosis may lead to irritation and cough reflexes. This heightened sensitivity can contribute to the persistent cough seen in these patients. Additionally, gastroesophageal reflux is another potential contributor to cough in IPF. […] The initiation and control of cough involve a complex interplay of neural pathways, including the activation of vagal afferents and central processing in the NTS. The central projections of vagal afferents, specifically those involved in the cough reflex, terminate in the brainstem. The NTS is a critical nucleus in the medulla oblongata, where these afferents synapse with second-order neurons.

• #2 Prevalence, pathogenesis, and causes of chronic cough – PubMed

  https://pubmed.ncbi.nlm.nih.gov/18424325/

  Cough is a reflex action of the respiratory tract that is used to clear the upper airways. Chronic cough lasting for more than 8 weeks is common in the community. The causes include cigarette smoking, exposure to cigarette smoke, and exposure to environmental pollution, especially particulates. Diseases causing chronic cough include asthma, eosinophilic bronchitis, gastro-oesophageal reflux disease, postnasal drip syndrome or rhinosinusitis, chronic obstructive pulmonary disease, pulmonary fibrosis, and bronchiectasis. […] Chronic cough is often associated with an increased response to tussive agents such as capsaicin. Plastic changes in intrinsic and synaptic excitability in the brainstem, spine, or airway nerves can enhance the cough reflex, and can persist in the absence of the initiating cough event. Structural and inflammatory airway mucosal changes in non-asthmatic chronic cough could represent the cause or the traumatic response to repetitive coughing. Effective control of cough requires not only controlling the disease causing the cough but also desensitisation of cough pathways.

• #3 Chronic Cough: Practice Essentials, Mechanism of Cough, Causes of Chronic Cough

  https://emedicine.medscape.com/article/1048560-overview

  Cough is a protective reflex serving a normal physiologic function of clearing excessive secretions and debris from the pulmonary tract. The cough reflex has 3 components: an afferent sensory limb, a central processing center, and an efferent limb. The trigeminal, glossopharyngeal, and vagus nerves supply the afferent pathways for cough receptors; the vagus, through its pharyngeal, superior laryngeal, and pulmonary branches, supplies the large majority of these receptors. Receptors are located throughout the airway from the pharynx to the terminal bronchioles, with the greatest concentration located in the larynx, carina, and the bifurcation of larger bronchi. Three types of receptors are predominant: Rapidly adapting receptors (RARs) that respond to mechanical stimuli, cigarette smoke, ammonia, acidic and alkaline solutions, hypotonic and hypertonic saline, pulmonary congestion, atelectasis, and bronchoconstriction; Slowly adapting receptors (SARs); Nociceptors on C-fibers that respond to chemical stimuli as well as inflammatory and immunological mediators such as histamine, bradykinin, prostaglandins, substance P, capsaicin, and acidic pH. Afferent impulses are transmitted to the cough center of the brain, located in the nucleus tractus solitarius of the medulla of the brainstem, which is connected to the central respiratory generator. To complete the reflex arc, efferent impulses leave the medulla and travel to the larynx and tracheobronchial tree via the vagus while the phrenic and spinal motor nerves of C3 to S2 supply the intercostals muscles, abdominal wall, diaphragm, and pelvic floor. This cough reflex has been shown to have neuroplasticity such that a hypersensitive response is elicited over time due to the cough itself inducing chronic irritation and inflammation and tissue remodeling. Both peripheral (increase in sensitivity of cough receptors) and central (changes in central processing in the brainstem) sensitization can account for an exaggerated cough response that is common in patients and further contributes to the maintenance of chronic cough. Recently, the term chronic cough hypersensitivity syndrome has been proposed as the new way to label chronic cough owing to the fact that the underlying abnormality leading to chronic coughing is an abnormally sensitive cough reflex. Indeed, evidence suggests that members of the transient receptor potential (TRP) ion channel family, specifically the vanilloid 1 (TRPV1) and ankyrin 1 (TRPA1) channels, are receptors that mediate cough. Patients with chronic cough hypersensitivity syndrome have a negative workup and lack of response to common treatments and are characterized by having a sensation of a tickle or itch in the throat, as well as being sensitive to triggers such as cold air, eating, and odors.

• #4 Anatomy and neuro-pathophysiology of the cough reflex arc | Multidisciplinary Respiratory Medicine | Full Text

  https://mrmjournal.biomedcentral.com/articles/10.1186/2049-6958-7-5

  Coughing is an important defensive reflex that occurs through the stimulation of a complex reflex arc. […] The aim of this review is to provide the anatomic and pathophysiologic elements of evaluation of the complex and multiple etiologies of cough. […] Each cough occurs through the stimulation of a complex reflex arc. This is initiated by the irritation of cough receptors which are found in the trachea, main carina, branching points of large airways, and more distal smaller airways; also, they are present in the pharynx. […] Impulses from stimulated cough receptors traverse an afferent pathway via the vagus nerve to a cough center in the medulla, which itself may be under some control by higher cortical centers. […] The cough reflex arc is constituted by: Afferent pathway: Sensory nerve fibers (branches of the vagus nerve) located in the ciliated epithelium of the upper airways (pulmonary, auricular, pharyngeal, superior laryngeal, gastric) and cardiac and esophageal branches from the diaphragm.

• #4 Anatomy and neuro-pathophysiology of the cough reflex arc | Multidisciplinary Respiratory Medicine | Full Text

  https://mrmjournal.biomedcentral.com/articles/10.1186/2049-6958-7-5

  The important observation that cough does not appear to occur with increased frequency in patients treated with angiotensin II receptor antagonists (which do not increase kinin levels) is consistent with the kinin hypothesis. […] Chronic cough and Holmes-Adie syndrome. […] The mechanical events of a cough can be divided into three phases: Inspiratory phase: Inhalation, which generates the volume necessary for an effective cough. […] Since cough is an important defensive reflex, required to maintain the health of the lungs, people who do not cough effectively are at risk of atelectasis, recurrent pneumonia, and chronic airways disease from aspiration and retention of secretions. […] Many disorders can impair the ability to cough effectively, which may result in persistent cough. […] Based on this complex mechanism, the treatment often requires an early symptomatic approach in order to prevent the vicious cycle of cough perpetuating cough.

• #4 Anatomy and neuro-pathophysiology of the cough reflex arc | Multidisciplinary Respiratory Medicine | Full Text

  https://mrmjournal.biomedcentral.com/articles/10.1186/2049-6958-7-5

  The terminations of the vagal afferents are found in abundance in the airway mucosa and in the airway wall from the upper airways to the terminal bronchioles and lung parenchyma. […] A nonproductive cough is a well-recognized complication of treatment with angiotensin converting enzyme (ACE) inhibitors, occurring in up to 15% of patients treated with these agents. […] Although the pathogenesis of the cough is not known with certainty, it has commonly been hypothesized that accumulation of bradykinin, which is normally degraded in part by ACE, may stimulate afferent C-fibers in the airway. […] Laryngeal sensory neuropathy has been identified as the cause of chronic cough in 18 of 26 patients with acute onset of cough that was often associated with laryngospasm or throat clearing. […] Chronic tonsillar enlargement has been proposed as a cause of chronic cough, but clinical evidence of this association is limited.

• #5 Mechanism of disease – MSDinsight.se

  https://www.msdinsight.se/therapeutic-areas/chronic-cough/mechanism-of-disease/

  C-fibers can be activated in response to inflammation or tissue irritation. […] Signaling molecules (e.g. ATP), inflammatory mediators (e.g. PGE2) or chemical irritants (e.g. acrolein) may originate from airway cells or environmental sources. […] These substances, acting as ligands (e.g. ATP, PGE2 and acrolein) can activate the sensory receptors expressed on C-fibers. […] Cough signals are transmitted along the C-fibers of the vagus nerve and patients may show increased sensitivity to otherwise harmless cough triggers, such as cold air, strong odors or speech and laughter. […] Activation of these sensory C-fibers sends signals to the brainstem, which in turn sends signals to the respiratory muscles, resulting in a persistent cough.

• #5

• #6

  https://www.meddean.luc.edu/lumen/meded/elective/pulmonary/cough/cough.htm

  The approach to a chronic cough requires consideration of the anatomical distribution of the cough receptors and the knowledge of the likely of the various etiologies of chronic cough. […] Reflex begins with deep inspiration, followed by glottic closure, diaphragmatic relaxation, and thoracic and abdominal expiratory muscle contraction. Posterior wall of airway invaginates and causes shearing of mucus. […] Positive pleural pressure generated up to 100-300 mm Hg; peak flows of 12 L/sec.

• #7 Peripheral and central mechanisms of cough hypersensitivity – Singh – Journal of Thoracic Disease

  https://jtd.amegroups.org/article/view/43624/html

  Chronic cough is a difficult to treat symptom of many respiratory and some non-respiratory diseases, indicating that varied pathologies can underpin the development of chronic cough. […] A strong argument has emerged that changes in the excitability and/or normal regulation of the peripheral and central neural circuits responsible for cough are instrumental in establishing cough hypersensitivity and for causing excessive cough in disease. […] Chronic cough is now widely considered a syndrome (cough hypersensitivity syndrome) characterised by troublesome coughing to low level stimuli, consistent with an upregulation of activity in the neural circuits that ordinarily regulate coughing. […] Neural hypersensitivity is argued to reflect the clinical observation that cough can be more easily triggered by tussive stimuli (hypertussivity) as well as by stimuli that would be considered innocuous in healthy people such as talking, laughing or eating (allotussivity).

• #7 Peripheral and central mechanisms of cough hypersensitivity – Singh – Journal of Thoracic Disease

  https://jtd.amegroups.org/article/view/43624/html

  This argues that changes in cough neural activity can occur at multiple locations within the neural circuits that ordinarily regulate coughing. […] The description of the neural networks and processes governing airway sensory processing and cough above provides a framework to help understand how cough can become sensitised or upregulated in disease. […] The clinical phenotype of patients with cough hypersensitivity is increased cough frequency and enhanced cough sensitivity, which suggests that changes in two fundamental neural processes may be at play. […] Enhanced central nervous system (CNS) processing may involve neuroinflammatory mechanisms that activate glial cells, the primary cells regulating inflammatory states in the brain. […] Essentially, behavioural and regional brain signal changes during tussive challenges in patients show a common pattern, whereby the relationship between stimulus and response is shifted toward heightened sensitivity relative to outcomes from healthy people.

• #7 Peripheral and central mechanisms of cough hypersensitivity – Singh – Journal of Thoracic Disease

  https://jtd.amegroups.org/article/view/43624/html

  Cough hypersensitive participants show reduced levels of activation in the central network that is enlisted during voluntary cough suppression during tussive challenges with capsaicin. […] Together these data suggest that changes in the efficacy of central inhibitory systems may play a significant role in determining cough in response to airway irritant stimuli. […] Restoring normal cough sensitivity and reducing excessive cough is preferred over complete cough suppression, given the important role cough plays in normal pulmonary health.

• #8

  https://link.springer.com/article/10.1007/s40136-019-00239-9

  The term Cough Hypersensitivity Syndrome was first proposed by a European Respiratory Society Task Force and is defined as a clinical syndrome characterised by troublesome coughing triggered by low levels of thermal, mechanical or chemical exposure. […] Although the causes of chronic cough vary, cough reflex hypersensitivity is likely to be a shared clinical and mechanistic characteristic. […] The recognition that chronic cough is characterised by hypersensitivity of the peripheral and central neural pathways involved in cough has expanded the range of potential therapeutic targets currently under evaluation. […] The mechanisms underpinning the development of CHS may be akin to those described in pain where disordered peripheral and central neurophysiology are thought to be responsible for a variety of chronic pain syndromes. […] Chronic cough patients appear to have altered brain activity with evidence of both central sensitisation and dysfunctional inhibitory control.

• #9 Chronic Cough | Archivos de Bronconeumología

  https://www.archbronconeumol.org/en-chronic-cough-articulo-S1579212915003006

  Hypertussia or allotussia are clinical conditions that are now grouped under the heading of chronic cough hypersensitivity syndrome (CCHS). […] The cough circuit is unquestionably complex, and may involve interaction between the different stimuli from the very start. […] The neurological mechanism of cough in humans originates from stimulation of 2 types of neuron terminals that converge in the cough center: unmyelinated C fibers and myelinated A fibers. […] Excitability of the CNS cough center is increased by 3 mechanisms: peripheral, central and secondary hypersensitivities. […] When central hypersensitivity has developed, a mechanism that is much more sensitive to mild peripheral stimuli is established, and this may be the cause of the phenomenon known as visceral hypersensitivity, also called secondary hypersensitivity.

• #10 Chronic cough hypersensitivity syndrome | ENT & Audiology News

  https://www.entandaudiologynews.com/features/ent-features/post/chronic-cough-hypersensitivity-syndrome

  Chronic cough can result in significant morbidity and affects quality of life. The treatment of chronic cough often requires multidisciplinary input. Of increasing interest is the role of cough receptors in cough pathogenesis which will be discussed in the review. […] Cough is a protective automatic arc reflex and has three components: an afferent sensory limb, a central processing centre, and an efferent limb. […] The cough reflex has been shown to have neuroplasticity such that a hyper-sensitive response is elicited over time due to the cough itself inducing chronic irritation and inflammation and tissue remodelling. Both peripheral and central sensitisation can account for an exaggerated cough response that is common in patients and further contributes to the maintenance of chronic cough.

• #11 Chronic cough: new concepts and therapeutic possibilities

  https://otorhinolaryngologypl.com/seo/article/01.3001.0009.5278/en

  Mechanisms responsible for the onset of cough in the natural history of UACS include: the runoff of secretion, direct irritation of laryngeal and pharyngeal structures featuring numerous cough receptors by the flowing secretion, respiratory tract inflammation (joint inflammation of the upper and lower airways) and extrathoracic airway hyperresponsiveness (EAHR) manifested by hyperintense cough responses to various stimuli. […] Following the growing understanding of CC-related mechanisms, a concept of excessive cough reflex response that defines patients with Cough Hypersensitivity Syndrome was proposed as possibly explaining the etiology of cough in patients previously diagnosed as idiopathic cough patients. […] TRPV1 appears to be the most important receptor: up-regulation of TRPV1 expression was observed in CC patients;

• #12 Tobacco Smoke Induced Cough: Mechanisms Driving Acute and Chronic Cough Pathology | IntechOpen

  https://www.intechopen.com/chapters/18583

  Chronic cough is reported as a troublesome symptom by 7% of the population (Ford et al., 2006). […] The mechanisms driving chronic cough have been elusive. […] There is some evidence to suggest that an increase in receptor expression may be involved in the development of cough hypersensitivity, as evidenced by an increase in TRPV1 expression in the lungs of chronic coughers compared to healthy controls (Groneberg et al., 2004). […] The findings discussed in this chapter represent a breakthrough in the field of cough, and could hold major implications for understanding the pathogenesis of chronic cough.

• #13 Overview of Chronic Cough

  https://www.ajmc.com/view/overview-of-chronic-cough

  A cough is caused by a vagal reflex, with receptive neuronal fields in the larynx, airways, alveolar septa, and lung parenchyma. The nerves regulating the cough response respond to various chemical and mechanical stimuli. Receptors along these pathways, such as purinergic 2X3 (P2X3) receptors, transient receptor potential vanilloid type 1 (TRPV1), and transient receptor potential ankyrin type 1 (TRPA1), are some of the targets for drug therapy. The P2X3 receptors, for example, are ATP-regulated and induce cough when activated. The goal of treatment is to suppress a pathologic cough without suppressing the protective cough reflex. […] CC is related to an increased number of coughs due to inhaled stimuli compared with non-coughers. This response may result from increased sensitivity of cough receptors or central changes in the brain stem. Changes in neurotransmitters or neuromodulators, the excitability of the postsynaptic neuron, and the nerve structure may lead to sensitization. A cough may be caused by excessive stimulation of a normal cough response; however, most people presenting with CC have cough reflex hypersensitivity and complaints of sensitivity to environmental irritants that leads to a tickling sensation in the throat and the urge to cough. Cough reflex hypersensitivity causes a response to a low level of stimuli from thermal, chemical, or mechanical means. This suggests a heightened sensitivity of the neuronal pathways controlling the cough reflex.

• #14

  https://link.springer.com/article/10.1007/s00408-023-00666-y

  The study designs and endpoints utilised to evaluate therapies for chronic cough have evolved substantially in the last 10 to 15 years. […] The first novel therapy found to have significant effects in patients with RCC was gefapixant, a first in class P2X3 antagonist. […] At present it is unclear whether ATP concentrations are elevated or P2X3 receptor expression increased in the airways of patients with RCC or how antagonism of P2X3 plays a role in reducing coughing to a range of chemical irritants, temperature changes, and mechanical stimuli. […] Nonetheless, in clinical trials P2X3 receptor antagonism has provided robust reductions in cough frequency and patient-reported outcomes. […] Following the taste side effects reported for gefapixant, more selective P2X3 antagonists were evaluated for the treatment of RCC; however, there was some uncertainty about whether effects at both P2X3 and P2X2/3 channels were both contributing to antitussive efficacy and hence whether more selective agents would have similar efficacy.

• #14

  https://link.springer.com/article/10.1007/s00408-023-00666-y

  In humans, the inhalation of cough-evoking stimuli such as capsaicin produce widely distributed brain activity in functional brain imaging studies, including the primary and secondary sensory cortex and cingulate, insula, and orbitofrontal cortices. […] Moreover, RCC patients seem to be indiscriminately hyperresponsive to a wide range of tussive challenges and report triggering of cough with many different environmental irritants. […] Centrally acting drugs to treat cough may act to reduce amplification of action potentials at synapses in the central nervous system and or activate deficient inhibitory control mechanisms. […] There is a risk in patients with productive cough, for example, chronic bronchitis and bronchiectasis and those within impaired swallow, that reducing coughing could impair the clearance of airway secretions and airway protection, leading to lower respiratory tract infections.

• #15 Prevalence, pathogenesis, and causes of chronic cough. | Read by QxMD

  https://read.qxmd.com/read/18424325/prevalence-pathogenesis-and-causes-of-chronic-cough

  Chronic cough lasting for more than 8 weeks is common in the community. […] Chronic cough is often associated with an increased response to tussive agents such as capsaicin. Plastic changes in intrinsic and synaptic excitability in the brainstem, spine, or airway nerves can enhance the cough reflex, and can persist in the absence of the initiating cough event. Structural and inflammatory airway mucosal changes in non-asthmatic chronic cough could represent the cause or the traumatic response to repetitive coughing. Effective control of cough requires not only controlling the disease causing the cough but also desensitisation of cough pathways.

• #16 How does rhinovirus cause the common cold cough? | BMJ Open Respiratory Research

  https://bmjopenrespres.bmj.com/content/3/1/e000118

  The primary inflammatory cytokines reported in HRV infection are interferon (IFN), interleukin (IL) 1, IL-6, IL-8, tumour necrosis factor (TNF), granulocyte-macrophage colony-stimulating factor and RANTES. […] The infection leads to massive upregulation, and, consequently, it is often described as a cytokine disease. […] Many symptoms are thought to occur as a result of the effects of inflammatory cytokines releasing of mediators. […] The proinflammatory mediator bradykinin has been suggested as a potent tussive modulator of TRPA1 and TRPV1. […] Elevated levels of bradykinin are found in the BAL fluid of patients with inflammatory airway conditions. […] Bradykinin has also been suggested to mediate ACE inhibitor cough which affects 15% of patients. […] Tachykinin peptides, neurokinin A and B, and substance P, are inflammatory neuropeptides, which collectively induce airway hyper-responsiveness, bronchial constriction, and increased vascular permeability.

• #17

  https://journals.lww.com/lungindia/fulltext/2015/32010/chronic_dry_cough__diagnostic_and_management.11.aspx

  Chronic dry cough may present as a predominant symptom or even the only symptom (as in the case of cough-variant asthma) in patients with asthma. The pathophysiology of dry cough in asthma can be explained by two mechanisms: Sensitization of cough receptors by increased levels of inflammatory mediators, such as, bradykinin, tachykinin, or prostaglandins. These sensitized cough receptors then cause an increased cough reflex. Stimulation of cough receptors through constriction of the bronchial smooth muscle. […] Gastroesophageal reflux disease-associated cough has been postulated to occur through three major mechanisms: (a) Intraesophageal reflux (stimulation of the esophageal-tracheobronchial cough reflex), (b) laryngopharyngeal reflux, and (c) microaspiration. Each of these three mechanisms may act directly by triggering cough events or indirectly by sensitization of the cough reflex.

• #17

  https://journals.lww.com/lungindia/fulltext/2015/32010/chronic_dry_cough__diagnostic_and_management.11.aspx

  Cough is the most common symptom for which medical treatment is sought in the outpatient setting. Chronic dry cough poses a great diagnostic and management challenge due to myriad etiologies. Chronic cough has been commonly considered to be caused by gastroesophageal reflux, post-nasal drip or asthma. However, recent evidences suggest that many patients with these conditions do not have cough, and in those with cough, the response to specific treatments is unpredictable at best. This raises questions about the concept of a triad of treatable causes for chronic cough. This article discusses the mechanism and etiology of cough, along with recent advances in the field of cough, highlighting some of the diagnostic and management challenges. […] Chronic cough can be caused by a myriad of different respiratory or non-respiratory conditions. The common causes of chronic cough include viral infections of the upper respiratory tract, upper airway cough syndrome (UACS; postnasal drip syndrome), gastroesophageal reflux disease (GERD), cough-variant asthma, eosinophilic bronchitis, mediastinal tumors, pleural diseases, early interstitial fibrosis, use of an angiotensin converting enzyme-inhibitor (ACEI), and psychogenic and idiopathic (or unexplained) cough.

• #17

  https://journals.lww.com/lungindia/fulltext/2015/32010/chronic_dry_cough__diagnostic_and_management.11.aspx

  The growing numbers of patients with unexplained cough, who are resistant to treatment, and evidences of a large number of patients with UACS, GERD, and asthma, who do not complain of cough at all, indicates that these diseases are not fundamental in the etiology of cough. […] The term cough hypersensitivity syndrome views chronic cough from a more mechanistic standpoint. In this view, chronic cough is considered as a single syndrome with a common intrinsic mechanism of cough hypersensitivity. Furthermore, common diseases, such as rhinitis, eosinophilic bronchitis, asthma or gastroesophageal acidic refluxes are believed to be triggers rather than causes. There is increased expression of cough receptors in the airways of patients with cough. The important features of the cough hypersensitivity syndrome are depicted in Table 1.

• #18 Refractory chronic cough due to gastroesophageal reflux: Definition, mechanism and management

  https://www.wjgnet.com/2222-0682/full/v5/i3/149.htm

  Refractory chronic cough due to gastroesophageal reflux is a troublesome condition unresponsive to the standard medical anti-reflux therapy. Its underlying mechanisms may include incomplete acid suppression, non-acid reflux, transient lower esophageal sphincter relaxations and esophageal hypersensitivity. […] The mechanisms underlying the refractory GERC is poorly understood. It may be associated with the incomplete acid suppression, non-acid reflux, transient lower esophageal sphincter relaxations (TLESRs) and esophageal hypersensitivity. […] Incomplete acid suppression has been documented in patients with persistent symptoms despite the therapy with PPIs at a standard dose. Several studies have shown 4%-17% patients presented with abnormal acid reflux and 7%-11% patients had a positive symptom index as revealed by 24-h esophageal pH monitoring when they were on PPIs.

• #19 Drug-induced chronic cough and the possible mechanism of action – Ding – Annals of Palliative Medicine

  https://apm.amegroups.org/article/view/50825/html

  According to the Guidelines for Diagnosis of Chronic Cough in China, patients with chronic cough should first exclude drugs as a cause. […] It is important for diagnosis and treatment to determine the history of the patient with regard to any medications that can induce chronic cough. […] The mechanism of ACEI-inducing cough mainly includes the following aspects. […] The cough induced by lisinopril was reversed by bradykinin B2 and NK1 receptor antagonists. […] These results indicated that bradykinin/substance P might be involved in ACEI-associated cough through the upregulation of vagal nerve excitability. […] The mechanism underlying omeprazole-induced cough is still unclear, and whether it has a direct pharmacological effect on the receptors involved in the cough reflex remains to be determined.

• #19 Drug-induced chronic cough and the possible mechanism of action – Ding – Annals of Palliative Medicine

  https://apm.amegroups.org/article/view/50825/html

  Chronic cough is defined as a cough lasting for 8 weeks with a normal chest radiograph. […] Drug-induced chronic cough, a rare cause of chronic cough, refers to a chronic cough caused by certain drugs. […] An important step in the diagnosis and treatment of chronic cough is to determine the history of the patient with regard to any drugs that can induce chronic cough. […] If the cough resolution occurs within 1 to 4 weeks after drug withdrawal, it would be considered as a side effect of the medication. […] This article reviews the relevant drugs that may cause cough and their possible mechanisms of action. […] Drug-induced chronic cough is a relatively rare cause of chronic cough caused by certain drugs and resolves on its own within 1 to 4 weeks after the withdrawal of the relevant drugs, although it may linger for up to 3 months.

• #20 Idiopathic chronic cough: a real disease or a failure of diagnosis? | Cough | Full Text

  https://coughjournal.biomedcentral.com/articles/10.1186/1745-9974-1-9

  Despite extensive diagnostic evaluation and numerous treatment trials, a number of patients remain troubled by a chronic and uncontrollable cough. […] However, an alternative explanation is that a distinct diagnostic entity exists, namely idiopathic cough. […] If this is the case then almost nothing is known about the underlying pathophysiological processes responsible for this condition and at present there are no effective treatment options. […] The cough reflex can be modified at any point along this reflex and unraveling the mechanisms responsible is key to a more complete understanding of cough pathophysiology and its successful treatment. […] Afferent sensory nerves are not static entities and the term 'plasticity’ has been used to describe changes in function contributing to the sensitization that occurs in response to various stimuli, in particular those associated with airway inflammatory processes.

• #20 Idiopathic chronic cough: a real disease or a failure of diagnosis? | Cough | Full Text

  https://coughjournal.biomedcentral.com/articles/10.1186/1745-9974-1-9

  Although viral infections are a major cause of cough and appear to be frequently reported in patients with idiopathic cough, little is known regarding the effects of viruses on cough sensitivity. […] This 'phenotypic switch’ is one plausible mechanism whereby viral infection causes increased tachykinergic content in airway nerves which possibly contribute to persistent reflex hypersensitivity and cough. […] It is unknown if such processes occur in man, but abnormal intraepithelial nerves containing increased neuropeptide content have been reported in bronchial biopsies from patients with idiopathic cough. […] They suggested that the presence of increased lymphocytes within the airway reflected either an aberrant homing of lymphocytes from the primary site of autoimmune inflammation to the lung or a distinct autoimmune process within the lungs.

• #21 ‘My cough interferes with everything’: New research could help refractory chronic cough patients after decades of depression, pain, and sleep loss | GSK

  https://www.gsk.com/en-gb/behind-the-science-magazine/refractory-chronic-cough-patients-symptoms/

  We believe there is a significant dysfunction of the cough reflex such that it becomes overstimulated and keeps firing off cough signals to the body inappropriately, Lipson says. […] For decades, researchers sought to develop treatments that block the airway receptors linked to coughing, but despite an increased understanding of the science, they struggled to do so. […] Now, however, scientists are advancing in their effort to inhibit the stimulation of airway receptors that contribute to excessive coughing. […] The idea is that by blocking only that receptor you potentially have even greater reductions in cough frequency and potentially fewer side effects. […] In the last 10 years, we have learned a tremendous amount about the mechanism of the cough, and now new approaches will hopefully inhibit this maladaptive, hypersensitive component of the cough reflex while maintaining the important protective cough intact.

• #22 Chronic cough relief by allosteric modulation of P2X3 without taste disturbance | Nature Communications

  https://www.nature.com/articles/s41467-023-41495-0

  P2X receptors are cation channels that sense extracellular ATP. Many therapeutic candidates targeting P2X receptors have begun clinical trials or acquired approval for the treatment of refractory chronic cough (RCC) and other disorders. However, the present negative allosteric modulation of P2X receptors is primarily limited to the central pocket or the site below the left flipper domain. Here, we uncover a mechanism of allosteric regulation of P2X3 in the inner pocket of the head domain (IP-HD), and show that the antitussive effects of quercetin and PSFL2915 (our nM-affinity P2X3 inhibitor optimized based on quercetin) on male mice and guinea pigs were achieved by preventing allosteric changes of IP-HD in P2X3. While being therapeutically comparable to the newly licensed P2X3 RCC drug gefapixant, quercetin and PSFL2915 do not have an adverse effect on taste as gefapixant does. Thus, allosteric modulation of P2X3 via IP-HD may be a druggable strategy to alleviate RCC.

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