Cough reflex is a vital protective mechanism against aspiration, but when becomes dysregulated, it can become hypersensitive.
The cough reflex is a vital protective mechanism against aspiration. It relies on a complex vagally mediated neuronal pathway which is still only partially understood.
The cough hypersensitivity syndrome, is defined as a clinical entity characterized by cough as a major component, which is often triggered by low levels of thermal, mechanical, or chemical exposure.
Cough hypersensitivity syndrome is a clinical entity in which chronic cough is a major presenting problem, regardless of the underlying condition.
In some disease states, both acutely as in a viral respiratory tract infection and chronically, a state of hypersensitivity is created.
Evidence suggests that aberrant neurophysiology is the common etiology of this syndrome.
“Three things cannot be hidden: coughing, poverty, and love.” An originally Yiddish proverb, refers to the hypersensitive nature of cough.
The cough reflex is an airway defense mechanism against aspiration, but dysregulated cough presents as irresistible bouts with hypersensitivity to even trivial environmental stimuli.
The cough reflex is a complex protective mechanism that serves to clear the airways of irritants, secretions, and foreign particles.
Initiation: The cough reflex is initiated by the stimulation of cough receptors, which are located in the trachea, main carina, and branching points of large airways.
These receptors can be activated by mechanical or chemical irritants.
Reflex Arc: The cough reflex involves a reflex arc that includes sensory afferent nerves, a central processing center in the brainstem, and motor efferent pathways.
The sensory signals are primarily carried by the vagus nerve to the brainstem.
Central Processing: In the brainstem, the sensory input is processed in the nucleus tractus solitarius (NTS), which then coordinates the cough response by sending signals to the respiratory muscles.
The efferent signals are transmitted to the muscles involved in coughing, including the diaphragm, intercostal muscles, and abdominal muscles.
This results in a coordinated series of events: a deep inhalation, closure of the glottis, and a forceful exhalation against the closed glottis, followed by the sudden opening of the glottis to expel air and any irritants.
The cough reflex is crucial for protecting the lungs from aspiration and facilitating the clearance of secretions and noxious substances.
The cough reflex can be modulated by various factors, including inflammation, infection, and certain medications, which can either enhance or suppress the reflex.
Cough is a common medical problem, and cough is the single most common symptom for seeking medical consultation.
Chronic cough is also a globally prevalent problem, affecting ~10% of adults in the general population.
Correlations between older age and chronic cough prevalence suggest that the epidemiological burden is on the rise.
Cough can seriously impair quality of life, as it includes psychological, social, and physical consequences.
A survey among elderly individuals found that the impact of chronic persistent cough on mental health was comparable to that of stroke or Parkinson’s disease.
Despite a meticulous diagnostic protocol for chronic cough, 12%–42% of patients remain unexplained or refractory.
Additionally, anti-tussive medicines with proven efficacy and safety are nearly lacking.
In a European study most subjects with chronic cough responded that their cough medication had limited or no effectiveness (57% and 36%, respectively).
Previously, chronic cough was thought to be primarily a consequence of chronic disease conditions, such as reactive airways (asthma and eosinophilic bronchitis), rhinosinusitis, or reflux disease, the “three Rs.”
However, a large proportion of patients with these conditions do not complain of chronic cough.
Many patients with chronic cough did not fit into any disease category, resulting in common diagnoses of idiopathic, refractory, or unexplained cough.
It is suggested that cough is not always related to another disease condition but rather is a clinical entity with a distinct pathophysiology.
The cough reflex has its own neural pathways of regulation, and disease conditions, such as the 3Rs, could be associated with or act as triggers, rather than direct causes of cough.
Cough hypersensitive syndrome encompasses various cough-related conditions or unexplained cough.
Cough hypersensitivity syndrome represents a clinical entity where chronic cough is a major presentation, irrespective of underlying conditions.
The main mechanism of cough hypersensitivity syndrome has been suggested to be dysregulated sensory neural pathways and central processing in cough reflex regulation: direct evidence for neural dysfunction is lacking.
Cough hypersensitivity syndrome clinical profile: Cough triggered by trivial stimuli such as cold air, perfume, stress, exercise, singing, or talking.
Chronic cough patients frequently report that their cough is triggered by innocuous stimuli, such as perfume, cold air, exercise, stress, singing, or talking.
Cough is frequently preceded by an urge-to-cough, a sensation of irritation or itching in the throat, which is also called laryngeal paresthesia.
The frequency of allotussia or urge-to-cough varies according to population, but it is reported to occur in ~99% of these patients.
The left-shift of the tussigen-cough response curve (hypertussia: increased cough sensitivity is another example of cough reflex hypersensitivity.
The cough response to capsaicin inhalation can be enhanced by administration of angiotensin-converting enzyme (ACE) inhibitor.
Enhanced cough reflex sensitivity can commonly be observed in various conditions presenting as cough, such as cough variant asthma, reflux-associated cough, and idiopathic cough, but not observed in asthma without cough.
Furthermore, control of these factors-ACE inhibition or associated disease conditions usually normalizes the hypersensitivity in the cough reflex.
Several types of inputs-viruses, allergens, and irritants, can induce phenotypic switches in sensory neurons and up-regulate host cough responses.
Respiratory viruses infect and replicate in airway epithelial cells, leading to proinflammatory responses from the host to clear the invaders.
Inflamed airway epithelial cells can produce soluble neurotrophic factors in response to viral infections.
Viral infections may also infect sensory neurons and rapidly induce a phenotypic switch, to produce neurotrophic factors
Neuronal phenotypic switches are significantly correlated with cough responses to tussigens, such as capsaicin and citric acid, and have also been associated with increased expression of neurotrophic factor receptors in the neurons.
Such phenotypic changes in peripheral sensory neurons may in turn provoke inflammatory responses from immune cells, so-called neurogenic inflammation.
Released neuropeptides, such as substance P and CGRP, may induce local vascular dilatation, chemotaxis, immune cell activation, and promote type 2 helper T-cell polarization.
The neuro-immune interactions, particularly in cases of repeated sensory inputs with viruses or allergens, would lead to a vicious cycle of hypersensitive responses, therefore functional up-regulation of airway sensory nerves is commonly found in chronic cough patients.
Bronchoalveolar lavage fluids contain inflammatory mediators, such as histamine, CGRP, cysteinyl leukotrienes, and prostaglandins E2 and D2, at significantly increased in patients with chronic cough, regardless of the underlying conditions.
Nerve staining density for CGRP, a common neuropeptide is significantly increased in biopsied peripheral lung tissues from idiopathic cough patients compared with healthy controls.
Expression of TRPV1 was also increased in the bronchial epithelial nerves of chronic cough patients compared with healthy controls, in one study.
The central neural processes of cough regulation are altered in chronic cough patients as demonstrated in functional brain imaging studies.
The sensation of laryngeal irritation or urge-to-cough following tussigen inhalation normally accompanies activation in diverse areas of brain networks both in cough patients and healthy controls.
Three areas of the midbrain—the nucleus cuneiformis, periaqueductal grey, and dorsal raphe—where cough hypersensitive patients showed marked increases in activation signals, whereas controls showed no such increases.
These midbrain component changes of the descending pain modulatory system may indicate altered central neural processing in cough control.
Also cough hypersensitive patients showed significantly lower activation levels in brain areas implicated in cough suppression.
A loss of cough inhibitory control may be a feature of chronic cough in patients as suggested by a functional study measuring capsaicin inhalation-induced maximum cough responses.
It is proposed that centrally acting anti-tussive agents, such as morphine and first-generation antihistamines, such as chlorpheniramine and diphenhydramine, act through agonist activity on these central inhibitory pathways.
It is suggested that repeated peripheral stimulation induces changes in the central nervous system.
Drugs with proven anti-tussive efficacy in unexplained cough patients, such as opioids, gabapentin, pregabalin have neuromodulatory properties, and they are also being used to alleviate neuropathic pain.
Speech pathology therapy can significantly benefit in relieving cough, which is also considered to act on both peripheral and central parts of the cough reflex pathway.
Capsaicin, the active ingredient of chilli pepper, is one of the most potent tussigens used in inhalation cough challenge tests.
TRPV1, a sensory receptor for capsaicin, is expressed primarily in sensory nerve C-fibers, and its expression is increased in chronic cough patients.
However, contrary to expectations, a TRPV1 antagonist failed to show any significant benefit in reducing cough frequency or improving cough-specific quality of life scores.
TRPA1 binds to a wide range of irritants, such as allyl isothiocyanate, cinnamaldehyde, and acrolein, which are abundant in pollutants and cigarette smoke, and was shown to mediate cough responses.
TRPA1 also acts as a thermosensor for cold temperatures (<17℃), and cough is frequently triggered by irritants and cold air exposure.
Adenosine triphosphate (ATP), is a major damage-associated molecule released during cellular injury.
Two types of ATP receptors have been described to date: the P2Y receptors respond mainly to adenosine and adenosine monophosphate, whereas the P2X receptors are relatively specific for ATP.
These latter receptors are located primarily on small afferent neurons of the C-fiber class, may play a role in the hypersensitivity of chronic cough.
P2X3 receptor is clearly an important mediator of cough hypersensitivity.
ATP is a ubiquitous component of intracellular metabolism, and is released into the extracellular space during cellular damage, signaling sensory neurons through the P2X3 receptor which is then responsible for the promotion of hypersensitivity.
Cough frequency monitoring study: the mean total cough counts per 24 hours were 16.8 in healthy subjects, 33 in smokers, 107 in asthmatic patients, 321 in cough variant asthmatic/eosinophilic bronchitis patients, and 477 in unexplained chronic cough patients.
The prevalence of chronic cough, defined by the presence of cough for longer than 3 months per year, in the community population shows an inconsistent pattern of gender association, but it frequently reflected a male predominance.
Almost homogeneous female preponderance was observed in a multi-national survey of about 10,000 chronic cough patients recruited at referral clinics.
Population levels show significant correlations with the smoking rate,
A considerable proportion of chronic cough is smoking-related.
Cigarette smoke acts as an irritant for the cough reflex.
There is a female predominance in clinic population in females showing increased cough/urge-to-cough responses and also more activation in the somatosensory cortex after tussigen inhalation.
There is a gender discrepancy in prevalence between community and clinical populations.
The major impact of cough is the deterioration in the quality of life, and the treatment goal is to resume a normal daily life but not to completely inhibit the cough reflex.
Cough frequency could be a useful index for distinguishing pathological cough from physiologic cough.