- Author: Henry Haipei Chen, MD, MBA; Chief Editor: Arlen D Meyers, MD, MBA more...
The management of chronic cough presents a challenge for the clinician. Typically defined as a cough that persists for longer than 8 weeks, this is the most common presenting symptom in adults who seek medical treatment in an ambulatory setting.[1, 2] Chronic cough is estimated to occur in up to 40% of the population.
Traditionally, a dichotomy has separated the upper and lower airways, with the upper airway being the domain of the otolaryngologist and the lower airway being the domain of the pulmonologist. Recent research that shows a high proportion of patients with asthma and coexisting allergic rhinitis has paved the way for the “one airway” theory, in which a continuum of inflammation that involves the entire airway can be thought of as the underlying mechanism for disorders that start from the nose and mouth and extend to the most distal aspects of the lungs.[4, 5, 6]
Indeed, inflammatory mediators in the lower airways are elevated in patients with postnasal drip syndrome, cough variant asthma, and gastroesophageal reflux disease (GERD). Since the etiology of chronic cough can arise from anywhere in the tracheobronchial tree, a multidisciplinary approach is often needed, with the primary care provider coordinating care with appropriate referrals to the otolaryngologist, pulmonologist, or both, as appropriate. Additional specialists also important in the workup include the gastroenterologist, allergist and immunologist, neurologist, and speech therapist.
Mechanism of Cough
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[8, 9, 10] :
Rapidly adapting receptors (RARs) that respond to mechanical stimuli, cigarette smoke, ammonia, acidic and alkaline solutions, hypotonic and hypertonic saline, pulmonary congestion, 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.[11, 12, 13] 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.
Causes of Chronic Cough
The etiologies of chronic cough are numerous and may include pathology from the nose and nasopharynx to the distal bronchial tree. Obvious causes such as smoking and angiotensin-converting enzyme (ACE) inhibitor use can be easily ascertained from the history. After this, the challenge for the clinician lies in how to efficiently and systematically evaluate the patient without an overly exhaustive workup. Further compounding this is the fact that oftentimes more than one condition is simultaneously present.
Prospective studies have shown that 3 conditions account for the etiologic cause of chronic cough in 92-100% of immunocompetent, nonsmoking patients with normal chest radiograph findings. In order of frequency, they are as follows:
- Upper airway cough syndrome (UACS), previously referred to as postnasal drip syndrome (PNDS)
- Gastroesophageal reflux disease (GERD)
These 3 conditions make up what is called the pathogenic triad of chronic cough.
A fourth etiology that deserves mention is nonasthmatic eosinophilic bronchitis (NAEB), which is relatively common, easy to diagnose and treat, and should be considered early on in the diagnostic evaluation.
Another way to categorize the etiologies is to draw a distinction between cough due to eosinophilic airway diseases (asthma and NAEB) and noneosinophilic chronic cough. Eosinophilic airway diseases have airway inflammation due to eosinophils, which can be diagnosed by raised induced sputum eosinophil counts and increased exhaled nitric oxide levels. They are also associated with good steroid responsiveness.
The physician who focuses on diagnosing and treating these conditions can very successful at treating chronic cough.
A study by Cash et al found that of 58 pediatric patients with chronic cough presenting to otolaryngology clinics at a single tertiary care academic medical center, the primary causes of their condition were infection (39.7%), airway hyperreactivity (24.1%), and GERD (24.1%).
Upper airway cough syndrome
PNDS refers to the sensation of secretions from the nose or sinuses that drain into the pharynx in addition to nasal discharge and frequent throat clearing. Unfortunately, this is largely based on patients’ subjective symptoms, which frequently do not show any significant physical examination findings. In fact, 20% of patients with PNDS-induced cough are unaware of the presence of postnasal drip or its link to their cough. Even the presence of mucus in the oropharynx or cobblestoning of the oropharyngeal mucosa only suggest this as a cause. These findings are sensitive but not specific.
PNDS has recently been broadened to UACS, referring to a myriad of rhinosinus conditions that are related to cough, including:
UACS is considered the most common cause of chronic cough and has been implicated as the cause in up to 87% of patients. Mucoid secretions containing inflammatory mediators are thought to stimulate pharyngeal and laryngeal sites, inducing cough.
Although oftentimes a causative etiology for the rhinitis might be suggested from the patient’s history and symptomatology, the hallmark of UACS is that this syndrome has no pathognomonic findings, and the diagnosis is made based on response to specific therapy, which includes antihistamines and decongestants.
The hallmarks of asthma are variable airflow obstruction and airway hyperresponsiveness, which manifest as shortness of breath, wheezing, dyspnea, and cough. Cough occurs in all asthmatics, and in a subset of patients with cough-variant asthma (CVA), it is the only presenting symptom. The treatment of asthma, regardless of whether it is of the cough variant or not, includes beta-2 agonists and corticosteroids.
Gastroesophageal reflux disease
The following 2 mechanisms have been postulated for GERD-associated cough:
Distal esophageal acid exposure that stimulates an esophageal-tracheobronchial cough reflex via the vagus nerve
Microaspiration of esophageal contents into the laryngopharynx and tracheobronchial tree
The second entity refers to laryngopharyngeal reflux (LPR) or extraesophageal GERD, and it differs from traditional GERD in that it does not manifest as heartburn and tends to occur when the patient is upright as opposed to lying flat. This silent GERD can be present in as many as 75% of patients with chronic cough. Symptoms of LPR include throat clearing, hoarseness, and globus sensation. Empiric treatment includes acid suppression and lifestyle and dietary modifications.
Nonasthmatic eosinophilic bronchitis
NAEB has been implicated as an etiology of chronic cough in 13-33% of patients. It is characterized by eosinophilic infiltration of the bronchial tree as well as the absence of variable airflow obstruction and airway hyperresponsiveness. This disease is highly responsive to inhaled corticosteroids.
A plethora of other causes account for the remaining 5-10%. They include:
Congestive heart failure (CHF)
Interstitial lung disease
Workup and Management
Antitussives, such as codeine and dextromethorphan, have been shown to have limited or no efficacy in the treatment of chronic cough and any beneficial effect is largely due to placebo effect.[10, 3, 21] As such, the clinician should try to elucidate and identify the underlying cause of the cough to effectively manage it.
Every patient with chronic cough needs a thorough history taken and physical examination performed as part of their evaluation. Each patient should also have a chest radiograph taken.
Surprisingly, the medical history (in terms of the patient’s description of the character, timing, and presence or absence of sputum production) has been shown to have little or no diagnostic value.[22, 23] What is of value from the medical history is whether or not the patient is or has been a smoker; is taking an ACE inhibitor; is living in a geographic area where tuberculosis or certain fungal diseases are endemic; has any systemic symptoms, a history of cancer, tuberculosis, or AIDS; or has a large pulmonary mass visible on chest radiograph.
Management should begin with cessation of smoking or ACE inhibitor use in those patients whose history indicates such action. Most patients have a resolution of their cough within 4 weeks of smoking cessation. Cough related to ACE inhibitor use usually subsides within 2 weeks, but the median time has been reported to be 26 days.
If the chest radiograph findings are abnormal, further workup depends on the specific finding. Chest CT scan, bronchoscopy, needle biopsy, and sputum studies are all potentially warranted studies if a pulmonary lesion is found.
For the immunocompetent nonsmoker who does not use ACE inhibitors and has normal chest radiograph findings, a systematic approach to the most common causes of chronic cough is warranted, keeping in mind that more than one cause may be present. The body of literature regarding specific treatments and the expected time frame of response is extensive, and the accuracy of the diagnosis is confirmed by the patient’s response to these treatments. From both theoretical and cost effectiveness standpoints, empiric treatment of the 3 most common causes of cough is favored over extensive testing at the outset.[24, 25] Further, sequential and additive therapy may be needed because more than one cause of cough is often present.
A randomized, placebo-controlled trial by Vertigan et al indicated that treatment of chronic refractory cough with a combination of speech pathology therapy and pregabalin (300 mg daily) is more effective than treatment with speech pathology therapy plus placebo. The study involved 40 patients, with improvement measured using the visual analogue scale, the Leicester Cough Monitor, and the Leicester Cough Questionnaire.
Upper airway cough syndrome
Because upper airway cough syndrome (UACS) is the most common cause of chronic cough, it should be treated first. In patients in whom the cause of the UACS-induced cough is apparent, specific therapy directed at this condition should be instituted. This includes avoiding environmental irritants and offending antigens, treating sinusitis with antibiotics, and weaning patients off nasal decongestants for rhinitis medicamentosa. Further workup may include allergy testing for allergic rhinitis or sinus CT scan for sinusitis, as indicated.
For patients in whom the cause is not apparent, empiric therapy should be instituted with a combination of an antihistamine and decongestant. First-generation antihistamines such as azatadine and dexbrompheniramine plus pseudoephedrine have shown more effectiveness than newer, less-sedating antihistamines.[7, 27] Patients typically respond within 2 weeks of initiating therapy but may sometimes take several months.
Asthma should be considered only after the UACS evaluation and empirical treatment trial are complete. Ideally, patients should undergo spirometry and bronchoprovocation challenge with methacholine, which reveals reversible airflow obstruction. The negative predictive value for a negative challenge approaches 100%.
The initial treatment of asthma consists of beta-2 agonists and inhaled corticosteroids (ICS) and response is usually seen within 1 week, with complete resolution taking up to 8 weeks. Some patients may require a trial of oral corticosteroids before a response is seen. However, because leukotriene inhibitors have been shown to be effective in patients with asthma-induced cough, they should be tried prior to oral corticosteroid therapy.
Nonallergic eosinophilic bronchitis
Because its diagnosis is made easily, nonallergic eosinophilic bronchitis (NAEB) is the next etiology to consider, even though GERD is more common. An induced sputum test that reveals increased eosinophils is the diagnostic procedure of choice. Treatment includes ICS, with oral corticosteroids reserved for refractory cases. Response is usually seen within 4 weeks.
Gastroesophageal reflux disease
Prospective studies have shown that in a patient who has undergone empiric therapy for UACS, asthma, and NAEB and has had no response or only a partial response, a 92% probability exists that their chronic cough is due to GERD. The criterion standard for diagnosis of GERD is dual-channel 24-hour pH probe monitoring. Alternatively, flexible nasopharyngoscopy can reveal glottic changes associated with reflux. These include laryngeal edema and erythema, laryngeal pseudosulcus, and posterior commissure hypertrophy or pachydermia.
Simply because of the percentages, empiric therapy with acid suppression and lifestyle and dietary modification has been advocated as initial management instead of testing, which is reserved for refractory cases. Lifestyle modifications include limiting fat intake; avoiding caffeine, chocolate, mints, citrus products, alcohol, and smoking; and limiting vigorous exercise that increases intra-abdominal pressure.
The choice of acid suppressive medication can include histamine 2 (H2) blockers, proton pump inhibitors (PPIs), and prokinetic agents. However, note that maximal medical therapy refers to twice daily PPI in addition to a prokinetic agent with concurrent lifestyle and dietary modifications. Although response can be seen in as little as 2 weeks, at least a 6-8 week trial is needed to fully evaluate a response to treatment, with some patients requiring as long as 6 months.[27, 28]
Only when management of the most common causes has failed to yield a resolution of cough should a more extensive workup begin. This can include induced sputum testing for acid fast bacillus, high resolution CT scan of the chest, and bronchoscopy. Oftentimes, these tests should be performed by a cough specialist. If further testing does not reveal the cause, then the patient most likely has chronic cough hypersensitivity syndrome. Owing to inflammation and hyperresponsiveness of the airway from some inciting cause, tissue remodeling has occurred, leading to an enhanced cough reflex that maintains the cough even though the inciting cause has resolved. In these truly idiopathic cases, therapeutics are limited, but ongoing research is focusing on medicines that either directly or indirectly affect the cough reflex.
In the immunocompetent nonsmoking patient who does not take angiotensin-converting enzyme (ACE) inhibitors, the most common causes of chronic cough are upper airway cough syndrome (UACS), asthma, and gastroesophageal reflux disease (GERD). Together, these causes account for more than 90% of all cases of chronic cough. Frequently more than one of these etiologies is present, and cough may be the only presentation. Nonasthmatic eosinophilic bronchitis (NAEB) should also be considered early in the diagnostic evaluation because it is easily diagnosed and treated. Only after these most common causes of chronic cough are ruled out should more extensive testing be performed, usually after referral to a cough specialist. An empiric and integrative approach that uses sequential and additive therapy is needed to systematically evaluate and effectively treat patients with chronic cough.
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