Nonasthmatic eosinophilic bronchitis (NAEB)
Obstructive sleep apnea
Drug induced: ACEI, sitagliptin
Chronic exposure to environmental and occupational irritants
Bronchogenic and metastatic carcinoma
Foreign body or endobronchial suture
Infectious tracheobronchitis (e.g., tuberculosis, Aspergillus)
Infectious pneumonias (e.g., bacterial, tuberculous, fungal, parasitic)
Sjogren’s syndrome with xerotrachea
Chronic interstitial lung disease (e.g., sarcoidosis, HSP, asbestosis, drugs)
Idiopathic interstitial pneumonias (e.g., IPF, NSIP, DIP, LIP, RB-ILD, OP)
Pulmonary vasculitis (e.g., granulomatosis with polyangiitis)
Transvenous pacemaker stimulation
Left ventricular failure
Premature ventricular complexes
Enlarged left atrium
Aberrant innominate artery
Pericardial stimulation by transvenous pacemaker
Head and neck
Rhinitis and sinusitis (UACS)
Laryngeal disorders (e.g., vocal fold dysfunction, laryngomalacia)
Postviral vagal neuropathy
Neurilemmoma of vagus nerve
Neuroma of internal laryngeal nerve
Ascending palatine artery aneurysm
Osteophytes of cervical spine
Syngamus laryngeus infection
Gastroesophageal reflux disease (GERD)
Esophageal cyst or diverticulum
Celiac disease (and other organ-specific or systemic autoimmune diseases)
Tic disorders (e.g., Gilles de la Tourette’s syndrome)
The general approach to the evaluation of chronic cough begins with a medical history and physical examination that defines the duration of cough, smoking status, and current use of angiotensin-converting enzyme inhibitors (ACEI) or sitagliptin . If the patient is a smoker, chronic bronchitis and irritant effects of cigarette smoke are the most likely diagnoses and further diagnostic studies and empiric therapy should not be attempted until the patient has ceased smoking for at least 4 weeks. Similarly, if the patient is taking an ACEI or sitagliptin, the medication should be discontinued for 4 weeks before attempting further diagnostic studies.
The next important step in the evaluation of chronic cough is a chest radiograph. If the chest radiograph is abnormal, the radiographic findings should be pursued as a possible cause of the cough. However, if the chest radiograph is normal, or near normal, then most cases of chronic cough are due to upper airway cough syndrome (UACS; formerly called postnasal drip syndrome or PNDS), asthma/NAEB, and/or gastroesophageal reflux disease (GERD). Confirmation of one or more of these diagnoses then depends on whether or not the cough resolves during sequential, empiric treatment trials that are specifically aimed at each suspected diagnosis. Depending on the response to empiric treatments, additional diagnostic studies may be helpful and these include sinus imaging, spirometry, methacholine inhalation challenge (MIC) testing, allergy evaluations, barium esophagography, 24-h esophageal pH/impedance monitoring, sputum for microbiology and/or cytology, flexible bronchoscopy, chest computed tomography (CT) scan, and noninvasive cardiac studies [5, 6, 21].
The goal of a systematic, medical evaluation, focusing on the most common causes of chronic cough, is to identify and confirm the underlying cause by observing the complete resolution of cough while on specific therapy. In most cases, and depending on the clinical setting, a systematic approach that faithfully follows a trustworthy, evidence-based guideline (such as the American College of Chest Physicians cough guidelines of 2006 with subsequent updates) will identify the causes of cough more than 90% of the time [12, 22]. When the cough has completely resolved on specific therapy, the cause of chronic cough may be considered “explained.”
Broadly categorizing the causes of chronic cough with excessive throat clearing, there are causes that originate from above the throat (e.g., from centrally mediated neurologic reflexes or from secretions dripping down from nasal passages or sinuses); from below (e.g., from GERD or from airway inflammation due to asthma/NAEB); from the environment (e.g., cigarette smoke); or from intrinsic disease processes, either systemic or local, that irritate the laryngopharyngeal mucosa (e.g., mucositis caused by autoimmune diseases) (Fig. 15.1). When chronic cough is associated with a predominant complaint of throat clearing, we suggest that the differential diagnosis remains similar to that of chronic cough except that the likelihood of various possible etiologies is skewed in favor of environmental irritant factors such as cigarette smoke, UACS , and GERD . The implications of this are that, among nonsmokers without environmental irritant exposures, it is probable that the presence of excessive throat clearing, as a predominant complaint, makes UACS and GERD more likely the causes of a patient’s chronic cough. Conversely, when excessive throat clearing is a predominant complaint it is less likely that asthma and NAEB and other pulmonary disorders are the underlying cause of a patient’s chronic cough as long as there is not any associated rhinosinus disease and NAEB is not associated with environmental inhalations. Finally, although chronic cough due to somatic or tic disorders is relatively uncommon in adults, and best diagnoses of exclusion, throat clearing and other phonic or vocal sounds are common in tic disorders such as Tourette’s syndrome  and, therefore, it is plausible that the diagnosis of a tic disorder may be more likely when chronic cough is associated with a predominant complaint of excessive throat clearing.
Major etiologies of chronic cough when there is a predominant, associated complaint of excessive throat clearing. For a patient with a normal or near-normal chest radiograph and not smoking or taking an angiotensin-converting enzyme inhibitor or sitagliptin, the possible causes of chronic cough and of throat clearing, as separate symptoms, are broadly similar. Causes can be from above (upper airways or brain), from environmental irritations originating outside the body, from below (GERD/LPR or lower airways), or from intrinsic disease processes irritating the mucosa of the larynx or upper airway. However, compared to chronic cough alone, it is proposed that when chronic cough is associated with a predominant complaint of excessive throat clearing, the underlying etiologies of both symptoms are more likely to be UACS or GERD/LPR or a somatic/tic disorder (red shading), and less likely asthma/NAEB (blue shading) when asthma is not associated with allergic rhinitis and NAEB is not associated with environmental air pollution. Direct environmental stimuli are more likely the underlying etiology when throat clearing is associated with chronic cough because cigarette smoking is so common and frequently causes both symptoms (red shading). Intrinsic diseases, such as organ-specific or systemic autoimmune diseases, that involve the laryngopharyngeal mucosa (purple shading) may or may not be similar in frequency when compared to chronic cough alone. Abbreviations: GERD gastroesophageal reflux disease, LPR laryngopharyngeal reflux, UACS upper airway cough syndrome, NAEB nonasthmatic eosinophilic bronchitis
Common Causes of Chronic Cough with Throat Clearing
Gastroesophageal Reflux Disease (GERD)
Cough consensus and evidence-based guidelines recognize GERD as the third most common cause of chronic cough in adults with the following clinical profile: nonsmoking, not on an ACEI or a sitagliptin and with a normal chest radiograph. Guidelines also emphasize that chronic cough can be the sole manifestation of GERD (so-called silent GERD ) [8, 11, 12]. Although there are many controversies, chronic cough due to GERD can be diagnosed with the help of 24-h esophageal pH and impedance recordings that correlate instances of reflux before cough events. It is also generally agreed that cough due to GERD usually resolves on specific medications, lifestyle changes, and diet changes that are directed at preventing gastroesophageal reflux (Fig. 15.2) . It has been suggested that GERD causes chronic cough due to the direct mechanical and chemical irritation of the larynx, vocal cords, or airways by acid and nonacid reflux that reaches hypopharyngeal and laryngeal structures and/or by neurally mediated reflex pathways stimulated by a bolus of refluxate into the distal esophagus . The successful suppression of reflux with medications, diet, and lifestyle changes, and, when indicated, surgical intervention, usually results in complete resolution of chronic cough due to GERD, although medical treatment can sometimes take many months to be successful. It is important to stress that treatment limited only to acid suppression will usually fail to control the cough [8, 11].
Treatment of chronic cough with excessive throat clearing due to GERD. The general treatment recommendations and common pitfalls in treating GERD are summarized. Abbreviation: GERD gastroesophageal reflux disease
Subspecialists in ear, nose, and throat (ENT) often evaluate throat clearing and other laryngeal symptoms. When these symptoms are attributable to the retrograde movement of gastric contents into the esophagus, a diagnosis of reflux laryngitis due to laryngopharyngeal reflux (LPR) is often made [25–28]. As with chronic cough caused by GERD, the stimulus causing throat clearing may be direct irritation of the laryngeal and pharyngeal structures by acid and/or pepsin or the indirect effect of neural reflexes triggered by a bolus of refluxate in the esophagus . How LPR is different from GERD is controversial in the ENT and gastrointestinal literature and it is possible that they represent the same general phenomenon [30, 31]. However, some have suggested that LPR is primarily due to failure of the upper esophageal sphincter while GERD is different and due to poor integrity of the lower esophageal sphincter [28, 32]. Supporting a potential difference between LPR and GERD is the observation that patients with LPR less commonly have heartburn or evidence of esophagitis on biopsy and that LPR more commonly occurs in an upright body position during exertion instead of a recumbent position, as is common in GERD [13, 28, 32, 33]. However, the controversy is likely to persist until there is a solid definition of LPR that is based on firm diagnostic criteria.
While some believe that physical findings can help the physician determine whether LPR and GERD are the potential causes of a patient’s chronic cough with excessive throa t clearing, others disagree. For example, finding edema and erythema of the posterior commissure, cobblestone appearance of the posterior pharyngeal wall, vocal cord ulcers, interarytenoid changes, medial arytenoid wall edema and erythema, vocal cord granulomas, and subglottic stenosis all have been cited as supportive physical findings . However, none of these findings are diagnostic and some are visualized in 64–86% of normal controls [35, 36].
For chronic cough due to GERD , 24-h esophageal pH and impedance and manometry monitoring to correlate reflux events with instances of coughing is an established diagnostic method. However, for the symptom of throat clearing the correlation is not as clear. Although 24-h double-probe pH monitoring may be more specific than the physical examination for establishing a diagnosis of laryngeal reflux, the technique still may not be sufficiently reliable to qualify as a gold standard of LPR. In one study, dual-sensor pH probe testing did not predict the severity of symptoms or signs of reflux pharyngitis and only the symptom of heartburn correlated with recorded instances of reflux . In a systematic review, only a minority of patients diagnosed with reflux laryngitis had pharyngeal reflux events on dual-probe monitoring and, comparing patients with reflux laryngitis to controls, there was no difference in the number of pharyngeal reflux events recorded . These findings certainly challenge the whole concept of LPR causing laryngo pharyngitis. Multiple factors contribute to the difficulties in linking LPR to the commonly made diagnosis of reflux laryngitis, and these include the lack of widely agreed-upon definitions, the lack of consensus on normal pH limits when interpreting recordings, the fact that indirect neural mechanisms may contribute to LPR, and the fact that the number and severity of reflux events needed to establish clinically significant inflammation in the laryngopharynx are not known.
Considering these diagnostic challenges, when GERD-induced chronic cough is associated with prominent and excessive throat clearing, we suggest that the throat clearing is likely due to GERD as well. For a given patient, we suggest that the mechanisms underlying the two symptoms are probably very similar, or closely related, and that both symptoms can be confidently attributed to a diagnosis of GERD when both resolve on specific treatment for GERD. However, to resolve symptoms, GERD treatment frequently needs to be prolonged to be effective. In one study, chronic cough due to GERD only responded to medical treatment after an average of 161–179 days [9, 21].
Medical treatment of GERD is usually effective [8, 11]. The recommended treatment regimen is a high-protein, low-fat (45 g/day), antireflux diet of three daily meals and no foods, beverages, or medications that lower esophageal sphincter tone or have high acidity. There should be nothing to eat between meals or 2 h prior to reclining and at least 10 cm head of bed elevation. What seems to be most important about the diet is that it targets weight loss [8, 11]. Proton pump inhibitors and prokinetic agents are prescribed to suppress acid and enhance motility, respectively. One randomized, placebo-controlled double-blind study showed that, although omeprazole was no better than placebo in treating reflux laryngitis in general, the specific symptoms of hoarseness and throat clearing were effectively treated by omeprazole . Because GERD is a chronic problem, some form of treatment (e.g., diet) is usually required indefinitely. If, despite adherence to diet and maximal pharmacologic therapy, the chronic cough continues and reflux events are shown to persist on 24-h esophageal pH and impedance and manometry monitoring in spite of therapy, then surgical intervention with antireflux surgery can be considered [8, 11, 39].
Common pitfalls in the management of chronic cough due to GERD include relying only on acid-suppression therapy, a failure to recognize that it may take 2–3 months of medical therapy before cough begins to improve and 5–6 months before cough resolves (Fig. 15.2) . Another error is to assume that cough cannot be due to GERD because cough remains unchanged when gastrointestinal symptoms improve . Finally, other pitfalls include a failure to assess the effectiveness of medical therapy using 24-h monitoring of esophageal pH and impedance when cough fails to resolve on an intensive medical regimen and failure to recognize and treat coexisting diseases that can worsen GERD, such as sleep apnea.
Upper Airway Cough Syndrome (UACS)
In nonsmoking adults not on an ACEI or sitagliptin and having a normal, or near-normal, chest radiograph, UACS is the single most common cause of chronic cough in the United States . The underlying pathophysiology is not established and controversial, but one possibility is that excessive or thick nasopharyngeal secretions containing mucus and inflammatory mediators may drain posteriorly (i.e., postnasal drip) and directly irritate the mucosa and structures of the hypopharynx and larynx to stimulate cough. Alternatively, normal amounts and thickness of secretions may stimulate coughing because the larynx, vocal cords, and hypopharyngeal structures are abnormally sensitive, that is, hypersensitive, to normally innocuous chemical or mechanical stimulation [7, 40]. Because patients can complain of postnasal drip and throat clearing and not be coughing, a hypersensitive cough reflex must be present, in our opinion, for the UACS to become operative.
Throat clearing is commonly associated with rhinosinus disease causing UACS and is an important symptom to elicit in the evaluation of chronic cough . For example, among patients with chronic cough, the symptom of throat clearing is a highly sensitive predictor for the presence of rhinitis (100%) but poorly specific (37%); this is an indication that throat clearing can be caused by other disorders besides rhinosinus diseases . Therefore, when chronic cough is associated with a predominant complaint of excessive throat clearing, rhinosinus disease should be strongly considered in the differential diagnosis, but other common causes, such as GERD, should be considered as well.
The differential diagnosis of UACS due to rhinosinus disease , with or without throat clearing, includes any inflammatory disorder of the nasal or sinus passages and these include allergic rhinitis, perennial nonallergic rhinitis (either vasomotor rhinitis or nonallergic rhinitis with eosinophilia—NARES), postinfectious UACS, bacterial sinusitis, allergic fungal sinusitis, rhinitis associated with anatomic abnormalities (e.g., deviated nasal septum), rhinitis due to physical or chemical irritants, occupational rhinitis, and rhinitis medicamentosa and rhinitis of pregnancy (Fig. 15.3) [1, 7]. Any of these conditions can cause chronic cough due to UACS. The diagnostic approach to UACS is to start with the history and physical examination looking for complaints of a draining or dripping sensation in the back of the throat, a tickle in the throat, hoarseness, throat clearing, nasal congestion, or nasal discharge. Some patients may complain of wheezing. On physical examination, there may be evidence of drainage in the oropharynx, nasal secretions, and a cobblestone appearance or mucus on the mucosa in the posterior pharynx. When bacterial sinusitis is suspected, sinus imaging may be helpful. In a patient with chronic cough and excessive throat clearing, these supportive findings on initial evaluation would lead to a presumptive diagnosis of UACS and the diagnosis would be confirmed with resolution of the symptoms upon treatment for the underlying cause of the rhinosinus disorder causing UACS . The prevalence of throat clearing is as high as 37% among patients with documented respiratory allergies , but distinguishing between allergic, nonallergic non-infectious, and infectious causes of rhinosinus disease is important because each is treated differently. However, when the specific etiology of the rhinosinus disease is not identifiable clinically, a trial of empiric therapy is recommended before embarking on an extensive, additional evaluation. When excessive throat clearing is present with UACS, it should be expected that the symptom of throat clearing should resolve along with the chronic cough.
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