Airway Receptors Research Articles

Interactions of cholinergic agonists with pulmonary neuroepithelial bodies using an in situ mouse lung slice model

Pulmonary neuroepithelial bodies (NEBs), occurring as densely innervated groups of neuroendocrine cells in the airway epithelium, were recently suggested to represent complex sensory airway receptors. Despite the considerable amount of morphological and neurochemical data, none of the functional hypotheses have so far been fully established because reliable in vitro models are not available. Recently, our research group has developed an in situ lung model for the functional study of NEBs in a fluorescent live cell imaging set-up.

Review Series: Chronic cough: Future directions in chronic cough: mechanisms and antitussives

Cough is an important defensive reflex of the respiratory tract needed to clear and protect the upper airways; however, it may become exaggerated and interfere with quality of life. Although chronic cough may be successfully treated when associated with the common causes such as asthma and eosinophilic bronchitis, gastrooesophageal reflux disease and post-nasal drip syndrome or rhinosinusitis, increasingly, idiopathic cough or cough with no associated cause is recognised. Chronic cough is often associated with an increased response to tussive agents such as capsaicin, used as an index of the cough reflex. Some airway receptors mediate or influence cough through activation of vagal afferent pathways which converge on brain stem respiratory networks and of supramedullary centres. Plastic changes in intrinsic and synaptic excitability at the brain stem, spinal or ganglionic level may be the mechanism by which the cough reflex is enhanced in chronic cough. Subjective and objective measurements of cough in the clinic are now available but a major unmet need in chronic cough is the availability of effective antitussives. Future directions in chronic cough include the pathophysiological mechanisms of the enhanced cough reflex, and the discovery of effective antitussives that can successfully alleviate chronic cough.

Proteases and Protease‐activated receptors signalling: at the crossroads of acquired and innate immunity

Protease-activated receptors (PARs) are seven-transmembrane G-protein coupled receptors activated by serine proteases (Fig. 1). Proteases cleave the extracellular Nterminus of the molecule to expose a new tethered ligand, which in turn binds and activates the cleaved receptor. Four PARs have been cloned and each has a unique cleavage site amino acid sequence. Tryspin activates PAR2 and PAR4. Thrombin activates PAR1 and PAR3. Of particular interest for allergic disease, mast cell tryptase activates PAR2. Much that is known about PARs and their function in the respiratory system comes from studies in the lower airways. All four PARs are expressed in airway epithelium and smooth muscle. PAR2 expression is increased in the asthmatic epithelium [1]. In isolated mouse airways, activation of epithelial PAR1, PAR2 and PAR4 by the proteases trypsin and thrombin, as well as by specific activating peptides corresponding to each receptor’s tethered ligand amino acid sequence, cause airway relaxation via release of a cyclooxygenase product, probably prostaglandin E2 (PGE2) [2, 3]. PAR2 activation also causes relaxation of isolated rat, guinea pig and human bronchi, and induces bronchodilation in mice in vivo [2]. On the other hand, thrombin stimulates airway smooth muscle contraction, likely by activation of airway smooth muscle PAR1 [4]. Activation of PAR1, PAR2 and PAR4 stimulates IL-6, IL-8/CXCL8 and PGE2 release from airway epithelial cells [5, 6]. Activation of PAR2 also induces airway epithelial cell release of granulocyte-macrophage-colony stimulating factor (GM-CSF), eotaxin/CCL11 and matrix metalloproteinase (MMP)-9 [7–9]. Basolateral stimulation of PAR2 receptors in mouse and human airways results in phospholipase C and Ca-dependent inhibition of amiloride-sensitive Na conductance and stimulation of both luminal Cl channels and basolateral K channels, leading to a secretory response [10]. PAR2 activation interrupts E-cadherin adhesion and compromises the airway epithelial barrier [11]. PARs are also present on mast cells, eosinophils, neutrophils, alveolar macrophages, monocytes and lymphocytes [12]. Thrombin and the PAR1 activating peptide induce b-hexosaminidase, IL-6 and MMP-9 release from mouse bone marrow mast cells, as well as mast cell adhesion to fibronectin [13]. Trypsin induces activation and superoxide release from human eosinophils through PAR2 [14]. PAR2 stimulation of peripheral blood monocytes induces Ca flux and production of IL-1b, IL-6, and IL-8/CXCL8 [15]. Stimulation of human peripheral monocytes and monocyte-derived macrophages with thrombin or PAR1 activating peptide triggers expression of monocyte chemoattractant protein (MCP)-1/CCL2 [16]. Thrombin, trypsin and the PAR2 activating peptide induce calcium flux in human T cell lines [17]. The abundant effects of PAR2 activation on airway cell and leucocyte function are consistent with the notion that PAR2 plays a critical role in the pathogenesis of allergic airways disease. To test this, Schmidlin et al. [18] examined the response to ovalbumin (OVA) sensitization and challenge in PAR2 knockout mice, as well as mice undergoing intranasal administration of the PAR2 activating peptide SLIGRL-NH2. Compared with wild-type animals, eosinophil infiltration was inhibited by 73% in mice lacking PAR2 and increased by 88% in mice overexpressing PAR2. Similarly, compared with wild-type animals, airway cholinergic responsiveness was diminished 38% in mice lacking PAR2 and increased by 52% in mice overexpressing PAR2. PAR2 deletion also reduced IgE levels to OVA sensitization by fourfold compared with those of wild-type animals. Thus, PAR2 significantly contributes to the development of acquired immunity and allergic inflammation in the airways. Correspondence: Marc B. Hershenson, Department of Pediatrics and Communicable Diseases, Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA 48109. E-mail: mhershen@umich.edu doi: 10.1111/j.1365-2222.2007.02738.x Clinical and Experimental Allergy, 37, 963–966

Selective visualisation of sensory receptors in the smooth muscle layer of ex-vivo airway whole-mounts by styryl pyridinium dyes

Recently, we established the location, morphology and neurochemical coding of vagal smooth-muscle-associated airway receptors (SMARs) in rat lungs. These receptors were characterised as branching laminar terminals that originated from myelinated nerve fibres and were intercalated between airway smooth-muscle bundles. To allow the direct physiological examination of these receptors, the present investigation aimed at visualising SMARs in airway whole-mounts of rat and mouse lungs ex vivo. Short incubation with various styryl pyridinium dyes (AM1-43, FM2-10, FM4-64 or 4-Di-2-ASP) gave a highly selective fluorescent visualisation of both laminar nerve terminals and myelinated fibres from which they originated throughout the intrapulmonary airway tree in mouse and in rat. The reliable and specific labelling of SMARs ex vivo with these lipophilic membrane dyes was confirmed via immunostaining for protein gene-product 9.5 and vesicular glutamate transporters. Similar to the intrapulmonary location of NEBs, these SMARs appeared to be even more explicitly located near airway bifurcations. Both the trachealis muscle and the smooth-muscle bundles of extrapulmonary bronchi were also shown to contain laminar nerve terminals that were morphologically similar to the SMARs reported in the intrapulmonary airways. Thus, this study provides an in-vitro model enabling, for the first time, the fast and reliable visualisation of SMARs and the myelinated nerve fibres from which they originate in airway whole-mount preparations ex vivo. As such, this model opens up further perspectives and creates a valid basis for direct physiological measurement and manipulation of the individually identified airway receptors.

Nerve growth factor mediates steroid‐resistant inflammation in respiratory syncytial virus infection

Neurotrophic factors and receptors are upregulated in the respiratory tract of humans and rodents infected by the respiratory syncytial virus, leading to airway inflammation and hyperreactivity. The contribution of neurotrophic pathways to the recruitment of immuno-inflammatory cells and their response to anti-inflammatory therapy remains unclear. We sought to determine whether selective nerve growth factor inhibition prevents the immuno-inflammatory response against infection, and explored the effect of inhaled corticosteroids on virus-induced neurotrophic upregulation and the consequent recruitment of immuno-inflammatory cells into the airways. We tried to inhibit the recruitment of lymphocytes and monocytes into the airways of infected weanling rats using immunologic inhibition of nerve growth factor with a specific blocking antibody, or chemical inhibition of receptor tyrosine kinase with K252a. The anti-inflammatory activity of inhaled corticosteroids was studied in infected rats treated with budesonide, fluticasone, or vehicle. Immunological or chemical inhibition of nerve growth factor or its high-affinity receptor tyrosine kinase pathway inhibited the recruitment of inflammatory cells triggered by nociceptive irritation of infected rat airways, thereby reducing local and systemic immuno-inflammatory responses against the virus. Neurotrophic upregulation in infected airways was not affected by inhaled corticosteroids. As a logical consequence, these commonly used drugs were also unable to stop the recruitment of immune and inflammatory effector cells into infected airways. Overexpression of neurotrophic factors and receptors in airways infected by respiratory syncytial virus is critical for the development of airway inflammation and hyperreactivity, which is resistant to the anti-inflammatory effect of inhaled corticosteroids.

Reply to Yu

reply: Dr. Jerry Yu is a well-respected investigator in the field of sensory airway receptor physiology, and we would like to thank him for his interest in our work and for the valuable expert comments. The Letter to the Editor ([7][1]) mainly relates to items discussed in our recent publications ([

Functional morphology and neurochemical characterization of diverse sensory receptors in mouse lungs

Because of the importance of genetically modified mice for functional studies, and the present lack of data, aim of this study was the identification and neurochemical coding of sensory nerve terminals related to neuroepithelial bodies (NEBs) and other sensory receptors in mouse lungs. Antibodies against known selective markers for sensory nerve terminals in rat lungs were used in control and vagotomized mouse lungs. Mouse pulmonary NEBs were found to receive at least two populations of myelinated vagal afferents with intraepithelial terminals: immunoreactive (IR) for vesicular glutamate transporters (VGLUTs) and calbindin D28k; expressing P2X3 ATP receptors. CGRP IR was seen in thin vagal nerve fibers and in delicate non-vagal fibers, both in close proximity to NEBs. VGLUT 1 and P2X3 IR were further found both in receptor complexes reminiscent of the visceral pleura receptors (VPRs) and the smooth muscle-associated airway receptors (SMARs) that we characterized in rat lungs. The presented data revealed that mouse lungs harbor VPRs, SMARs and several populations of sensory nerve terminals that selectively contact NEBs. The neurochemical information on diverse sensory receptors in mouse lungs will be essential for the interpretation of functional data obtained from our recently developed in situ mouse lung slice model. Support: FWO grant G.0085.04 (D.A.); UA grants NOI-BOF 2003 (D.A.) and KP-BOF 2006 (I.B.)

Transient receptor potential vanilloid receptor-1 does not contribute to slowly adapting airway receptor activation by inhaled ammonia

Inhalation of ammonia influences the activity of slowly adapting airway receptors (SARs), but the mechanism(s) is uncertain. Release of inflammatory mediators by transient receptor potential vanilloid receptor-1 (TRPV1) containing nerve endings could affect SAR response to ammonia. We examined how sensitization and subsequent desensitization of the TRPV1 by resiniferatoxin (RTX), affected the responses of SARs to inhaled ammonia. In pentobarbital-anesthetized, paralyzed and artificially ventilated rats, the left cervical vagus nerve was exposed, sectioned rostrally, and desheathed. Single fibers of SARs were identified and recorded. Two milliliters of ammonia vapor (from a 30% NH 4OH solution) was inhaled over 20 s and responses to ammonia were measured. RTX was injected intravenously at 2 μg/Kg. Twenty minutes later, ammonia inhalation was repeated. Isoproterenol (ISO, 100 μg/kg, i.v.) was used in another set of experiments to block possible ammonia-induced bronchoconstriction. Ammonia increased tonic activity of SARs ( n = 10, P < 0.0001), with complex changes in ventilator-related activity. SAR firing rate began to increase 2.3 ± 0.2 min after RTX and returned to control levels at 13.6 ± 1.4 min ( n = 10). By 20 min after RTX cardiovascular responses to ammonia were abolished, but effects on SAR activity were essentially unchanged. ISO did not modify the response of SARs to ammonia ( n = 8). These data suggest that responses of SARs to ammonia in rats do not depend on release of mediators by nerve endings containing TRPV1 and are not secondary to bronchoconstriction. However, when TRPV1 containing nerve endings were initially activated by RTX, the release of mediators may have affected SAR discharges.

Cough and ventilatory adjustments evoked by aerosolised capsaicin and distilled water (fog) in man

Airway receptors mediate cough and ventilatory adjustments. Simultaneous assessment of cough sensory-motor components and changes in breathing pattern may provide insights into the receptor(s) prevailingly stimulated by inhaled irritants. Nineteen subjects inhaled capsaicin and fog up to threshold concentrations for cough. Cough intensity, respiratory sensations and changes in breathing pattern induced by the two irritants were compared. Capsaicin and fog cough threshold values did not correlate. Coughing induced by both agents was preceded by qualitatively similar sensations and by significant increases in minute ventilation and respiratory drive due to selective increases in tidal volume (P<0.01). Cough intensity was similar with both agents. Cough frequency and the intensity of the urge to cough were higher with capsaicin (P<0.01). The lack of correlation between fog and capsaicin cough threshold values suggests differences in the neural mechanisms activated. The selective increase in tidal volume suggests prevailing involvement of rapidly adapting receptors. The stronger sensations evoked by capsaicin may contribute to the higher cough frequency observed with this agent.

Updated guidelines on cough launched

Updated guidelines on cough launched

Effect of aging on respiratory system physiology and immunology

With the looming expansion of the elderly population of the US, a thorough understanding of "normal" aging-related changes on the respiratory system is paramount. The respiratory system undergoes various anatomical, physiological and immunological changes with age. The structural changes include chest wall and thoracic spine deformities which impairs the total respiratory system compliance leading to increase work of breathing. The lung parenchyma loses its supporting structure causing dilation of air spaces: "senile emphysema". Respiratory muscle strength decreases with age and can impair effective cough, which is important for airway clearance. The lung matures by age 20-25 years, and thereafter aging is associated with progressive decline in lung function. The alveolar dead space increases with age, affecting arterial oxygen without impairing the carbon dioxide elimination. The airways receptors undergo functional changes with age and are less likely to respond to drugs used in younger counterparts to treat the same disorders. Older adults have decreased sensation of dyspnea and diminished ventilatory response to hypoxia and hypercapnia, making them more vulnerable to ventilatory failure during high demand states (ie, heart failure, pneumonia, etc) and possible poor outcomes.

The rapidly adapting receptors in mammalian airways and their responses to changes in extravascular fluid volume

In this short review, we shall focus on some recent findings on the physiological stimulus for the rapidly adapting receptors (RAR) of the airways. They are readily activated by a sustained inflation of the lungs and they are usually identified by their rapid adaptation to this stimulus. They are also activated by both tactile stimuli and irritant gases applied to the epithelium of the airways. The investigations reviewed here suggest that these receptors are activated by changes in extravascular fluid volume. The principal factors governing fluid flux from the microcirculation are identified in the Starling equation. These are the hydrostatic pressure, plasma oncotic pressure and capillary permeability. Findings from recent studies suggest that all these factors increase the activity of RAR. In addition, these receptors are also activated by obstruction of lymph drainage from the lung. Evidence is presented to show that manipulation of Starling forces also increases the extravascular fluid volume of the airways in areas where the RAR are located. On the basis of these findings, it is suggested that, along with mechanosensitivity to stimuli such as stretch, inflation and deflation, another physiological stimulus to the RAR is a change in extravascular fluid volume in the regions of the airways where these receptors are located.

Evidence for a role of neuroepithelial bodies as complex airway sensors: comparison with smooth muscle-associated airway receptors

The epithelium of intrapulmonary airways in many species harbors diffusely spread innervated groups of neuroendocrine cells, called neuroepithelial bodies (NEBs). Data on the location, morphology, and chemical coding of NEBs in mammalian lungs are abundant, but none of the proposed functions has so far been fully established. Besides C-fiber afferents, slowly adapting stretch receptors, and rapidly adapting stretch receptors, recent reviews have added NEBs to the list of presumed sensory receptors in intrapulmonary airways. Physiologically, the innervation of NEBs, however, remains enigmatic. This short overview summarizes our present understanding of the chemical coding and exact location of the receptor end organs of myelinated vagal airway afferents in intrapulmonary airways. The profuse populations that selectively contact complex pulmonary NEB receptors are compared with the much smaller group of smooth muscle-associated airway receptors. The main objective of our contribution was to stimulate the idea that the different populations of myelinated vagal afferents that selectively innervate intraepithelial pulmonary NEBs may represent subpopulations of the extensive group of known electrophysiologically characterized myelinated vagal airway receptors. Future efforts should be directed toward finding out which airway receptor groups are selectively coupled to the complex NEB receptors.

Reflexes from the lungs and airways: historical perspective

Historical aspects of respiratory reflexes from the lungs and airways are reviewed, up until about 10 yr ago. For most of the 19th century, the possible reflex inputs into the "respiratory center," the position of which had been identified, were very speculative. There was little concept of reflex control of the pattern of breathing. Then, in 1868, Breuer published his paper on "The self-steering of respiration via the Nervus Vagus." For the first time this established the role of vagal inflation and deflation reflexes in determining the pattern of breathing. Head later extended Breuer's work, and Kratschmer laid a similar basis for reflexes from the nose and larynx. Then, 50-60 yr later, the development of the thermionic valve and the oscilloscope allowed recording action potentials from single nerve fibers in the vagus. In 1933, Adrian showed that slowly adapting pulmonary stretch receptors were responsible for the inflation reflex. Later, Knowlton and Larrabee described rapidly adapting receptors and showed that they mediated deep augmented breaths and the deflation reflex. Still later, it was established that rapidly adapting receptors were, at least in part, responsible for cough. In 1954, Paintal began his study of C-fiber receptors (J receptors), work greatly extended by the Coleridges. Since approximately 10 yr ago, when the field of this review stops, there has been an explosion of research on lung and airway receptors, many aspects of which are dealt with in other papers in this series.

‘Free’ surfactant in gastric aspirates and bronchoalveolar lavage in children with and without reflux oesophagitis

Dipalmitoylphosphatidycholine (DPPC) is the characteristic and main constituent of surfactant. Adsorption of surfactant to epithelial surfaces may be important in the masking of receptors. The aims of the study were to (i) compare the quantity of free DPPC in the airways and gastric aspirates of children with gastroesophageal reflux disease (GORD) to those without and (ii) describe the association between free DPPC levels with airway cellular profile and capsaicin cough sensitivity. Children aged <14 years were defined as 'coughers' if a history of cough in association with their GORD symptoms was elicited before gastric aspirates and nonbronchoscopic bronchoalveolar lavage (BAL) were obtained during elective flexible upper gastrointestinal endoscopy. GORD was defined as histological presence of reflux oesophagitis. Spirometry and capsaicin cough-sensitivity test was carried out in children aged >6 years before the endoscopy. Median age of the 68 children was 9 years (interquartile range (IQR) 7.2). Median DPPC level in BAL of children with cough (72.7 microg/mL) was similar to noncoughers (88.5). There was also no significant difference in DPPC levels in both BAL and gastric aspirates of children classified according to presence of GORD. There was no correlation between DPPC levels and cellular counts or capsaicin cough-sensitivity outcome measures. We conclude that free DPPC levels in the airways and gastric aspirate is not influenced by presence of cough or GORD defined by histological presence of reflux oesophagitis. Whether quantification of adsorbed surfactant differs in these groups remain unknown. Free DPPC is unlikely to have a role in masking of airway receptors.

Influenza virus receptors in the human airway

Although more than 100 people have been infected by H5N1 influenza A viruses, human-to-human transmission is rare. What are the molecular barriers limiting human-to-human transmission? Here we demonstrate an anatomical difference in the distribution in the human airway of the different binding molecules preferred by the avian and human influenza viruses. The respective molecules are sialic acid linked to galactose by an alpha-2,3 linkage (SAalpha2,3Gal) and by an alpha-2,6 linkage (SAalpha2,6Gal). Our findings may provide a rational explanation for why H5N1 viruses at present rarely infect and spread between humans although they can replicate efficiently in the lungs.

The Role of RGS16 in T lymphocyte responses

Asthma is a Th2-mediated inflammatory disease resulting from the cooperation of many cell types, receptors, and cellular events, many of which are caused by signal transduction through G Protein Coupled Receptors (GPCRs). Current therapies for asthma target GPCRs but prolonged use results in increased airway hyperreactivity and receptor desensitization. RGS (Regulator of G protein Signaling) proteins negatively regulate signaling through GPCRs by accelerating the rate of GTP hydrolysis of the α subunit of the heterotrimeric G protein. RGS 16 was originally identified as an IL-2 responsive gene in human T cells. Th2 cytokine production is increased in transgenic mice expressing RGS16 in CD4+ and CD8+ T lymphocytes in a mouse model of allergic inflammation and trafficking of these cells to the lung is reduced. High RGS16 levels are found in germinal center T cells, and upregulation of RGS16 mRNA results in impaired migration towards CXCL12. RGS16 is hypothesized modulate T cell trafficking to the lung in response to inflammation. We are currently assessing the role of RGS16 in T cell responses. We have characterized RGS16 expression by intracellular flow cytometry. We have knocked down RGS16 expression in Jurkats and assessed effects on Ca2+ mobilization, CD69 and T Cell Receptor (TCR) expression levels, intracellular localization by immunofluorescence and immunohistochemistry, and tyrosine phosphorylation levels. Preliminary results show no change in expression levels of the α/β TCR when RGS16 is knocked down, but higher phosphorylation levels of ZAP70 and ERK. Taken together, these results suggest that RGS16 has a negative effect on signaling through an activated TCR. Determination of a role for RGS16 in T cell responses may provide another mechanism by which therapeutics can be developed and administered in the treatment and control of asthma and allergic inflammation.

Expression of IL-13 Receptors in Human Airway and Skin Cells

Expression of IL-13 Receptors in Human Airway and Skin Cells

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. To mitigate future diagnostic confusion, two new diagnostic terms have been introduced to replace two older terms that may represent misnomers. The committee unanimously recommends that the term upper airway cough syndrome (UACS) be used in preference to postnasal drip syndrome (PNDS) when discussing cough that is associated with upper airway conditions because it is unclear whether the mechanism of cough is postnasal drip, direct irritation, or inflammation of the cough receptors in the upper airway. The committee also recommends using the term unexplained cough rather than idiopathic cough because it is likely that more than one unknown cause of chronic cough will be discovered. The term idiopathic implies that one is dealing with only one disease. For managing adult patients with cough, the committee recommends an empiric, integrative diagnostic approach, which is presented in the section entitled “An Empiric Integrative Approach to the Management of Cough”.3 Guidelines for managing acute, subacute, and chronic cough are presented in algorithmic form (Fig 1–3). Guidelines with algorithms for evaluating chronic cough in pediatric patients < 15 years of age are presented in the section entitled “Guidelines for Evaluating Chronic Cough in Pediatrics”2,4 [Fig 4, ​,5].5]. For a full discussion on how to use the algorithms, please refer to these sections. Figure 1 Acute cough algorithm for the management of patients ≥ 15 years of age with cough lasting < 3 weeks. For diagnosis and treatment recommendations refer to the section indicated in the algorithm. PE = pulmonary embolism; Dx = diagnosis; ... Figure 3 Chronic cough algorithm for the management of patients ≥ 15 years of age with cough lasting > 8 weeks. ACE-I = ACE inhibitor; BD = bronchodilator; LTRA = leukotriene receptor antagonist; PPI = proton pump inhibitor. See the legend of ... Figure 4 Approach to a child 6 years of age and in some children ... Figure 5 Approach to a child ≤ 14 years of age with chronic specific cough (ie, cough associated with other features suggestive of an underlying pulmonary and/or systemic abnormality). Children > 14 years of age should be managed as outlined in ...

Postinfectious Cough: ACCP Evidence-Based Clinical Practice Guidelines

Patients who complain of a persistent cough lasting >3 weeks after experiencing the acute symptoms of an upper respiratory tract infection may have a postinfectious cough. Such patients are considered to have a subacute cough because the condition lasts for no >8 weeks. The chest radiograph findings are normal, thus ruling out pneumonia, and the cough eventually resolves, usually on its own. The purpose of this review is to present the evidence for the diagnosis and treatment of postinfectious cough, including the most virulent form caused by Bordetella pertussis infection, and make recommendations that will be useful for clinical practice. Recommendations for this section of the guideline were obtained from data using a National Library of Medicine (PubMed) search dating back to 1950, which was performed in August 2004, of the literature published in the English language. The search was limited to human studies, using the search terms "cough," "postinfectious cough," "postviral cough," "Bordetella pertussis," "pertussis infection," and "whooping cough." The pathogenesis of the postinfectious cough is not known, but it is thought to be due to the extensive inflammation and disruption of upper and/or lower airway epithelial integrity. When postinfectious cough emanates from the lower airway, this is often associated with the accumulation of an excessive amount of mucus hypersecretion and/or transient airway and cough receptor hyperresponsiveness; all may contribute to the subacute cough. In these patients, the optimal treatment is not known. Except for bacterial sinusitis or early on in a B pertussis infection, therapy with antibiotics has no role, as the cause is not bacterial infection. The use of inhaled ipratropium may be helpful. Other causes of postinfectious cough are persistent inflammation of the nose and paranasal sinuses, which leads to an upper airway cough syndrome (previously referred to as postnasal drip syndrome), and gastroesophageal reflux disease, which may be a complication of the vigorous coughing. One type of postinfectious cough that is particularly virulent is that caused by B pertussis infection. When the cough is accompanied by paroxysms of coughing, posttussive vomiting, and/or an inspiratory whooping sound, the diagnosis of a B pertussis infection should be made unless another diagnosis is proven. This infection is highly contagious but responds to antibiotic coverage with an oral macrolide when administered early in the course of the disease. A safe and effective vaccine to prevent B pertussis is now available for adults as well as children. It is recommended according to CDC guidelines. In patients who have a cough lasting from 3 to 8 weeks with normal chest radiograph findings, consider the diagnosis of postinfectious cough. In most patients, a specific etiologic agent will not be identified, and empiric therapy may be helpful. A high degree of suspicion for cough due to B pertussis infection will lead to earlier diagnosis, patient isolation, and antibiotic treatment.