Cough Hypersensitivity Syndrome: Advancements in Care

A persistent, unexplained cough can be frustrating and disruptive, especially when standard treatments fail. Cough Hypersensitivity Syndrome (CHS) is increasingly recognized as a key mechanism in chronic coughing, shifting the focus from symptom management to addressing an overly sensitive cough reflex.

Recent research has improved understanding of CHS and led to potential new treatment approaches.

Pathophysiological Processes

CHS is marked by an exaggerated cough reflex triggered by otherwise harmless stimuli, stemming from complex neurophysiological changes. At its core is the dysregulation of sensory nerve pathways in the airways, particularly vagal afferents that transmit signals to the brainstem. These nerves, composed of Aδ and C fibers, become hyperresponsive due to persistent stimulation, leading to an amplified cough reflex even without clear pathology. Capsaicin challenge tests show that individuals with CHS have lower cough thresholds than healthy controls, reinforcing the role of neural sensitization.

Neuroplastic changes in the central nervous system further contribute to this hypersensitivity. Functional imaging studies reveal increased activity in brainstem regions responsible for cough regulation, suggesting that repeated exposure to irritants or inflammation leads to maladaptive central sensitization. This mirrors mechanisms seen in chronic pain syndromes, where persistent signals create an exaggerated perception of discomfort. Transient receptor potential (TRP) channels, particularly TRPV1 and TRPA1, play a key role, as they mediate responses to environmental irritants and inflammatory mediators. Increased expression and activation of these receptors in CHS patients suggest a potential therapeutic target.

Epithelial dysfunction may also contribute to CHS. The airway epithelium serves as a protective barrier, but in CHS patients, its integrity may be compromised, increasing permeability and allowing irritants to reach sensory nerves. Chronic exposure to pollutants, allergens, or acid reflux can worsen this sensitivity. Research indicates that epithelial-derived mediators like prostaglandins and ATP can directly activate sensory neurons, perpetuating cough hypersensitivity.

Airway Sensory Receptors

The heightened cough reflex in CHS stems from abnormal airway sensory receptor activity. These receptors, located in the larynx, trachea, and bronchi, detect inhaled stimuli and trigger protective reflexes. Among the most studied are transient receptor potential (TRP) ion channels, particularly TRPV1 and TRPA1. TRPV1, the capsaicin receptor, responds to heat, acid, and inflammatory mediators, while TRPA1 detects reactive chemicals like cigarette smoke and air pollutants. CHS patients exhibit an upregulation of these receptors, making them more susceptible to mild airway stimuli.

Activation of these receptors initiates nerve signaling through unmyelinated C fibers and myelinated Aδ fibers, both components of the vagus nerve. C fibers, primarily involved in chemical sensitivity, release neuropeptides such as substance P and calcitonin gene-related peptide (CGRP), amplifying local inflammation and further sensitizing the airway. Aδ fibers mediate rapid mechanosensitive responses, such as those triggered by particulate matter or airflow changes. Electrophysiological studies show increased excitability in these fibers in CHS patients, reinforcing the idea that heightened sensory nerve activity drives persistent cough.

Beyond direct cough initiation, airway sensory receptors influence central neural pathways, altering the perception of airway irritation. Functional MRI studies show heightened activity in brainstem and cortical regions associated with sensory processing in CHS patients. This explains why many report a persistent tickling or burning sensation in the throat, even without an obvious irritant. The interplay between peripheral receptor sensitivity and central neural processing creates a feedback loop, reinforcing cough hypersensitivity.

Contributing Respiratory Conditions

Respiratory conditions often contribute to CHS by amplifying airway sensitivity. Chronic inflammation, epithelial injury, or mucus hypersecretion can make sensory nerves more reactive. Asthma is a well-documented contributor, with up to 30% of chronic cough patients exhibiting features of cough-variant asthma. Persistent bronchial inflammation increases sensory nerve receptor expression, particularly TRP channels, heightening cough reflex sensitivity. Patients with poorly controlled asthma frequently report a dry, persistent cough triggered by temperature changes, strong odors, or exertion.

Non-asthmatic eosinophilic bronchitis (NAEB) also plays a role. Marked by eosinophilic airway inflammation without airflow obstruction, NAEB shares an inflammatory profile with asthma, leading to cough hypersensitivity. Bronchial biopsies reveal elevated inflammatory mediators that sensitize airway nerves. Unlike asthma, NAEB does not involve bronchoconstriction, but corticosteroid treatment often alleviates cough, underscoring the role of inflammation in sensory nerve excitability.

Gastroesophageal reflux disease (GERD) is another significant factor. Acid reflux reaching the larynx and lower airways can directly irritate sensory nerve endings, triggering cough even in the absence of heartburn. Additionally, reflux-induced activation of esophageal vagal afferents can heighten airway sensitivity. Studies show proton pump inhibitor therapy reduces cough frequency in some CHS patients, though responses vary, highlighting the complexity of cough hypersensitivity.

Clinical Indicators

CHS patients typically experience a persistent, dry cough that remains unexplained despite thorough evaluation. Unlike coughs from infections or structural lung diseases, CHS-related cough is triggered by environmental or sensory stimuli that wouldn’t normally provoke a response. A defining characteristic is the persistent urge to cough, often described as a tickling or irritation in the throat. This sensation, known as laryngeal paresthesia, suggests sensory nerve dysfunction. Many patients report worsening symptoms with perfume, cold air, talking, or laughter, reflecting exaggerated airway nerve sensitivity.

CHS-related cough often persists for months or years, resisting conventional treatments such as antihistamines, bronchodilators, or antitussives. Unlike transient infections, it does not involve significant mucus production, fever, or systemic symptoms. Patients frequently undergo extensive testing, including imaging, pulmonary function tests, and allergy screenings, with inconclusive results. The unpredictability of symptoms and absence of structural abnormalities often delay diagnosis.

Common Triggers

Many CHS patients experience symptom exacerbation in response to environmental, chemical, and mechanical stimuli that wouldn’t typically provoke coughing. Strong odors like perfumes, cleaning products, or cigarette smoke frequently elicit coughing, likely due to TRPA1 activation. Air pollutants, including fine particulate matter (PM2.5) and ozone, worsen cough sensitivity by inducing oxidative stress and epithelial irritation. Seasonal allergens such as pollen and mold spores can also contribute, even in individuals without allergies, suggesting nerve sensitization beyond immune mechanisms.

Temperature fluctuations and mechanical stimuli also play a role. Sudden exposure to cold air, such as stepping outside in winter or inhaling air-conditioned air, is a common trigger. This may involve TRPM8, a cold-sensitive ion channel expressed on airway sensory nerves, which becomes hyperactive in sensitized individuals. Talking, laughing, or deep breathing can also provoke coughing, likely due to increased laryngeal sensitivity and altered neuromuscular control. Many patients report worsened symptoms with prolonged speech, supported by laryngeal hypersensitivity studies showing increased neural excitability in the upper airway.

Potential Management Strategies

Managing CHS requires addressing both peripheral nerve sensitization and central neural processing. Pharmacological interventions target excessive nerve excitability. Gabapentin and pregabalin, originally developed for neuropathic pain, have shown promise in reducing cough frequency. Clinical trials indicate gabapentin significantly reduces cough severity by modulating voltage-gated calcium channels involved in sensory nerve signaling. Emerging research on P2X3 receptor antagonists, such as gefapixant, suggests blocking purinergic signaling in airway nerves can alleviate cough hypersensitivity. Phase III trials report meaningful improvements with gefapixant, though some patients experience taste disturbances.

Non-pharmacological strategies also help, particularly for those with heightened laryngeal sensitivity. Speech therapy techniques, including vocal cord relaxation exercises and controlled breathing, improve symptom control by reducing laryngeal hyperreactivity and enhancing neuromuscular coordination. Environmental modifications, such as reducing exposure to known irritants and using air filtration systems, can minimize symptom exacerbation. Dietary adjustments, particularly for individuals with reflux-related cough hypersensitivity, may also provide relief. These strategies reflect a shift toward a more targeted approach in managing CHS.