Brendan J. Canning

Diagnosis and management of cough executive summary: ACCP evidence-based clinical practice guidelines

Recognition of the importance of cough in clinical medicine was the impetus for the original evidence-based consensus panel report on “Managing Cough as a Defense Mechanism and as a Symptom,” published in 1998,1 and this updated revision. Compared to the original cough consensus statement, this revision (1) more narrowly focuses the guidelines on the diagnosis and treatment of cough, the symptom, in adult and pediatric populations, and minimizes the discussion of cough as a defense mechanism; (2) improves on the rigor of the evidence-based review and describes the methodology in a separate section; (3) updates and expands, when appropriate, all previous sections; and (4) adds new sections with topics that were not previously covered. These new sections include nonasthmatic eosinophilic bronchitis (NAEB); acute bronchitis; nonbronchiectatic suppurative airway diseases; cough due to aspiration secondary to oral/pharyngeal dysphagia; environmental/occupational causes of cough; tuberculosis (TB) and other infections; cough in the dialysis patient; uncommon causes of cough; unexplained cough, previously referred to as idiopathic cough; an empiric integrative approach to the management of cough; assessing cough severity and efficacy of therapy in clinical research; potential future therapies; and future directions for research.

Identification of the tracheal and laryngeal afferent neurones mediating cough in anaesthetized guinea‐pigs

We have identified the tracheal and laryngeal afferent nerves regulating cough in anaesthetized guinea‐pigs. Cough was evoked by electrical or mechanical stimulation of the tracheal or laryngeal mucosa, or by citric acid applied topically to the trachea or larynx. By contrast, neither capsaicin nor bradykinin challenges to the trachea or larynx evoked cough. Bradykinin and histamine administered intravenously also failed to evoke cough. Electrophysiological studies revealed that the majority of capsaicin‐sensitive afferent neurones (both Aδ‐ and C‐fibres) innervating the rostral trachea and larynx have their cell bodies in the jugular ganglia and project to the airways via the superior laryngeal nerves. Capsaicin‐insensitive afferent neurones with cell bodies in the nodose ganglia projected to the rostral trachea and larynx via the recurrent laryngeal nerves. Severing the recurrent nerves abolished coughing evoked from the trachea and larynx whereas severing the superior laryngeal nerves was without effect on coughing. The data indicate that the tracheal and laryngeal afferent neurones regulating cough are polymodal Aδ‐fibres that arise from the nodose ganglia. These afferent neurones are activated by punctate mechanical stimulation and acid but are unresponsive to capsaicin, bradykinin, smooth muscle contraction, longitudinal or transverse stretching of the airways, or distension. Comparing these physiological properties with those of intrapulmonary mechanoreceptors indicates that the afferent neurones mediating cough are quite distinct from the well‐defined rapidly and slowly adapting stretch receptors innervating the airways and lungs. We propose that these airway afferent neurones represent a distinct subtype and that their primary function is regulation of the cough reflex.

Synergistic interactions between airway afferent nerve subtypes regulating the cough reflex in guinea-pigs

Cough initiated from the trachea and larynx in anaesthetized guinea‐pigs is mediated by capsaicin‐insensitive, mechanically sensitive vagal afferent neurones. Tachykinin‐containing, capsaicin‐sensitive C‐fibres also innervate the airways and have been implicated in the cough reflex. Capsaicin‐sensitive nerves act centrally and synergistically to modify reflex bronchospasm initiated by airway mechanoreceptor stimulation. The hypothesis that polymodal mechanoreceptors and capsaicin‐sensitive afferent nerves similarly interact centrally to regulate coughing was addressed in this study. Cough was evoked from the tracheal mucosa either electrically (16 Hz, 10 s trains, 1–10 V) or by citric acid (0.001–2 m). Neither capsaicin nor bradykinin evoked a cough when applied to the trachea of anaesthetized guinea‐pigs, but they substantially reduced the electrical threshold for initiating the cough reflex. The TRPV1 receptor antagonist capsazepine prevented the increased cough sensitivity induced by capsaicin. These effects of topically applied capsaicin and bradykinin were not due to interactions between afferent nerve subtypes within the tracheal wall or a direct effect on the cough receptors, as they were mimicked by nebulizing 1 mg ml−1 bradykinin into the lower airways and by microinjecting 0.5 nmol capsaicin into nucleus of the solitary tract (nTS). Citric acid‐induced coughing was also potentiated by inhalation of bradykinin. The effects of tracheal capsaicin challenge on cough were mimicked by microinjecting substance P (0.5–5 nmol) into the nTS and prevented by intracerebroventricular administration (20 nmol h−1) of the neurokinin receptor antagonists CP99994 or SB223412. Tracheal application of these antagonists was without effect. C‐fibre activation may thus sensitize the cough reflex via central mechanisms.

Neural regulation of airway smooth muscle tone

Airway smooth muscle is innervated by sympathetic and parasympathetic nerves. When activated, airway nerves can markedly constrict bronchi either in vivo or in vitro, or can completely dilate a precontracted airway. The nervous system therefore plays a primary role in regulating airway caliber and its dysfunction is likely to contribute to the pathogenesis of airways diseases. The predominant contractile innervation of airway smooth muscle is parasympathetic and cholinergic in nature, while the primary relaxant innervation of the airways is comprised of noncholinergic (nitric oxide synthase- and vasoactive intestinal peptide-containing) parasympathetic nerves. These parasympathetic nerves are anatomically and physiologically distinct from one another and differentially regulated by reflexes. Sympathetic-adrenergic nerves play little if any role in directly regulating smooth muscle tone in the human airways. Activation of airway afferent nerves (rapidly adapting receptors, C-fibers) can evoke increases in airway smooth muscle parasympathetic nerve activity, or decreases in parasympathetic nerve activity (through activation of slowly adapting receptors). Extrapulmonary afferents can also modulate nerve mediated regulation of airway smooth muscle tone. In guinea pigs and rats, peripheral activation of tachykinin-containing airway afferent nerves evokes bronchospasm via release of substance P and neurokinin A. This effect of airway afferent nerve activation appears to be unique to guinea pigs and rats. The actions and interactions between the components of airway innervation are discussed.

Cholinergic chemosensory cells in the trachea regulate breathing

In the epithelium of the lower airways, a cell type of unknown function has been termed “brush cell” because of a distinctive ultrastructural feature, an apical tuft of microvilli. Morphologically similar cells in the nose have been identified as solitary chemosensory cells responding to taste stimuli and triggering trigeminal reflexes. Here we show that brush cells of the mouse trachea express the receptors (Tas2R105, Tas2R108), the downstream signaling molecules (α-gustducin, phospholipase Cβ2) of bitter taste transduction, the synthesis and packaging machinery for acetylcholine, and are addressed by vagal sensory nerve fibers carrying nicotinic acetylcholine receptors. Tracheal application of an nAChR agonist caused a reduction in breathing frequency. Similarly, cycloheximide, a Tas2R108 agonist, evoked a drop in respiratory rate, being sensitive to nicotinic receptor blockade and epithelium removal. This identifies brush cells as cholinergic sensors of the chemical composition of the lower airway luminal microenvironment that are directly linked to the regulation of respiration.

Anatomy and Neurophysiology of the Cough Reflex : ACCP Evidence-Based Clinical Practice Guidelines

OBJECTIVES To describe the anatomy and neurophysiology of the cough reflex. METHODS A review of the literature was carried out using PubMed and the ISI Web of Knowledge from 1951 to 2004. Most of the referenced studies were carried out in animals CONCLUSIONS Studies carried out in animals provide suggestive but inconclusive evidence that C-fibers and rapidly adapting receptors (RARs) arising from the vagus nerves mediate coughing. Recent studies also have suggested that a vagal afferent nerve subtype that is not readily classified as a RAR or a C-fiber may play an important role in regulating cough. Afferent nerves innervating other viscera, as well as somatosensory nerves innervating the chest wall, diaphragm, and abdominal musculature also likely play a less essential but important accessory role in regulating cough. The responsiveness and morphology of the airway vagal afferent nerve subtypes and the extrapulmonary afferent nerves that regulate coughing are described.

Reflex mechanisms in gastroesophageal reflux disease and asthma.

This article presents a brief description of the reflex mechanisms responsible for cough and bronchospasm, and identifies several potential mechanisms by which gastroesophageal reflux (GER) may precipitate these reflexes. Airway and esophageal reflexes related to various mechanoreceptors and chemoreceptors have been elucidated, primarily in animal studies. Central nervous system (CNS) reflex pathways as well as local axon reflexes may each contribute to the pathogenesis of both asthma and GER disease (GERD). When activated, airway nociceptors precipitate defensive reflexes such as cough, bronchospasm, and mucus secretion. Nociceptors innervating both the airways and the esophagus respond to similar stimuli with defensive manuevers. The pathways of some esophageal and airway sensory nerves terminate in the same regions of the CNS. It appears possible that synergistic interactions between esophageal nociceptors and airway sensory nerves may precipitate the asthma-like symptoms associated with GERD.

Regulation of baseline cholinergic tone in guinea‐pig airway smooth muscle

1 We quantified baseline cholinergic tone in the trachealis of mechanically ventilated guinea‐pigs and determined the influence of vagal afferent nerve activity on this parasympathetic tone. 2 There was a substantial amount of baseline cholinergic tone in the guinea‐pig trachea, eliciting contractions of the trachealis that averaged 24.6 ± 3.5 % (mean ± s.e.m.) of the maximum attainable contraction. This tone was essentially abolished by vagotomy or ganglionic blockade, suggesting that it was dependent upon on‐going pre‐ganglionic input arising from the central nervous system. 3 Cholinergic tone in the trachealis could be markedly and rapidly altered (either increased or decreased) by changes in ventilation (e.g. cessation of ventilation; hyperpnoea; slow, deep breathing) and by lung distention (via positive end‐expiratory pressure). These effects were not accompanied by marked alterations in blood gases and were abolished by vagotomy or atropine. By contrast, tachykinin receptor antagonists, which abolished capsaicin‐induced bronchospasm, were without effect on baseline cholinergic tone. This and other evidence suggests that capsaicin‐sensitive nerves have little if any influence on baseline parasympathetic tone. Likewise, while activation of afferent nerves innervating the larynx can alter airway parasympathetic nerve activity, transection of the superior laryngeal nerves was without effect on baseline cholinergic tone. 4 Cutting the vagus nerves caudal to the recurrent laryngeal nerves, thus leaving the preganglionic parasympathetic innervation of the trachealis intact but disrupting all afferent nerves innervating the lungs and intrapulmonary airways, abolished baseline cholinergic tone in the trachea. Sham vagotomy or cutting the vagi caudal to the lungs did not reduce baseline cholinergic tone. 5 The results indicate that baseline airway cholinergic nerve activity is necessarily dependent upon afferent nerve activity arising from the intrapulmonary airways and lungs. More specifically, the data are consistent with the hypothesis that on‐going activity arising from the nerve terminals of intrapulmonary rapidly adapting receptors determines the level of baseline airway cholinergic tone.

Evidence that distinct neural pathways mediate parasympathetic contractions and relaxations of guinea‐pig trachealis.

1. The guinea‐pig trachea was isolated with its extrinsic innervation intact and pinned to the bottom of a water‐jacketed dissecting dish filled with warmed, oxygenated Krebs solution. The trachea was not separated from the oesophagus. Isometric tension was measured in a segment of the rostral portion of the trachea. 2. Stimulation of the vagus nerves caudal to the nodose ganglia elicited contractions of the trachealis that were blocked by the muscarinic receptor antagonist atropine. Following addition of atropine and contraction of the trachealis with prostaglandin F2 alpha (PGF2 alpha), vagus nerve stimulation elicited non‐adrenergic, non‐cholinergic relaxations. Both responses elicited by stimulation of the vagi were abolished by cutting the recurrent laryngeal nerves and were considered parasympathetic in nature as they were sensitive to the autonomic ganglion blockers trimetaphan and hexamethonium. 3. Experiments were designed in which ganglionic blockers were added to the buffer bathing the entire preparation or, alternatively, added only to the buffer perfusing the tracheal lumen. When given equal access to the trachea and oesophagus, hexamethonium was 56‐fold more potent an inhibitor of vagally mediated relaxations of the trachealis than vagally mediated contractions. Selective administration of hexamethonium to the buffer perfusing the tracheal lumen did not decrease the potency of the ganglionic blocker versus vagally mediated contractions. By contrast, even at a concentration of 1 mM, intratracheally administered hexamethonium failed to inhibit vagally mediated relaxations by 50%. Comparable results were obtained using trimetaphan. 4. Consistent with previous observations, removing the portion of the oesophagus contiguous with the region of the trachea at which isometric tension was measured abolished parasympathetic relaxations of the trachealis. Oesophagus removal was without effect on parasympathetic nerve‐induced contractions. Removing the dorsal half of the oesophagus or the mucosa and submucosa of the oesophagus did not affect the parasympathetic relaxant innervation. 5. The compound action potential of guinea‐pig recurrent laryngeal nerves evoked by vagus nerve stimulation consisted of three distinct peaks representing populations of axons with fast, intermediate and slow conduction velocities. The voltage‐response characteristics of vagally mediated contractions were identical to those of the compound action potential peak representing fibres with intermediate (10 m/s) conduction velocities. By contrast, the voltage‐response characteristics of the vagally mediated relaxations were best correlated with the compound action potential peak representing fibres with slow (0.4‐3 m/s) conduction velocities.(ABSTRACT TRUNCATED AT 400 WORDS)

Central nervous system control of the airways: Pharmacological implications

Autonomic innervation of the airways is derived primarily from the parasympathetic nervous system. Preganglionic fibers originating in the brainstem project to parasympathetic ganglion neurons, which regulate airway smooth-muscle tone, glandular secretion and blood-vessel diameter. Airway preganglionic nerve activity is regulated by subsets of pulmonary and extrapulmonary afferent nerve fibers, which continuously provide polysynaptic input to brainstem preganglionic nuclei. Each of these synapses in the central nervous system is a potential site for therapeutic intervention. Potential targets include increasing opioid, GABAergic and serotonergic controls on central neurons, and blockade of tachykinin and glutamate receptors. Unfortunately, much is still unknown about the control of airway nerves at the level of the central nervous system. Recently, however, interaction between vagal afferent nerve subtypes regulating airway function has been described. This interaction, made possible by their convergence at key sites of integration in the brainstem, may lead to central sensitization analogous to that described in somatic pathways regulating pain sensation. Improved understanding of the central pharmacology of airway reflexes may provide novel therapeutics for treating symptoms associated with respiratory disorders such as chronic obstructive pulmonary disease, asthma and sleep-disordered breathing.