it pertains to diagnosis. In-depth discussion on treatment of cough is discussed in chapters to follow.

In addition to framing the discussion for subsequent chapters on the various causes and diagnosis of cough, this chapter presents the economic impact of chronic cough. Above all else, this chapter intends to relate this organic pathology back to the patients treated for the condition. By emphasizing the human toll of chronic cough, the purpose of this text is to educate the wide array of practitioners who treat chronic cough for the benefit of their patients.

PHYSIOLOGY OF COUGH

Pathophysiology of Cough

A reflex is defined as an involuntary or nearly instantaneous movement in response to a stimulus.⁵ As defined, cough is indeed a reflex serving to clear the tracheal bronchial tree for gas exchange. Cough, unlike other human reflexes such as pupillary light or palmar grasp reflex, is critical for the preservation of life.

The physiologic basis of cough is broken into four distinct phases defined by distinct actions within the phase. Inspiration to fill the lungs is the first action of cough. In the second phase, subglottic pressure increases as there is compression of air against a closed glottis. The third action is marked by the explosive opening of the glottis, leading to rapid increase in airflow. During this phase, the rapid airflow moving through the airway causes a distinctive acoustic emission, which is the hallmark “cough.” The sound of a cough is universally recognized and is used to differentiate between other similar expiratory respiratory efforts such as sneezing and throat clearing.⁶ The final phase is the restorative phase, in which a final resting breath is taken. The act of coughing is an extraordinary physiologic event capable of producing intrathoracic pressured measured up to 300 mm Hg and airspeed up to 500 miles per hour.^{7, 8} This particularly violent response can result in urinary and fecal incontinence, pneumothorax, syncope, and even broken ribs.

Neurophysiology of Cough

To understand how cough becomes pathologic, it is useful to understand the neurophysiology of cough in its normative state.

In its essence, cough can be broken down into three constituents: input, processing, and output. The cough reflex involves stimulation of the afferent limb of the cough reflex, then transmission of the stimulation to the cortical cough center and, finally, the efferent pathway, which causes the muscles of expiration to contract, producing cough.

Airway sensory nerves originate within either the nodose or jugular vagal ganglia,9, 10 as evident by the fact that a vagotomy or local anesthesia applied to the vagus nerve will abolish the cough reflex.^{11, 12} The nerve terminals can have endings either in the pulmonary airway and parenchyma or in the extrapulmonary airway, including the carina, trachea, and large bronchi. There is currently no classification schema that neatly characterizes airway afferent nerves given the degree of heterogeneity within the group. This being said, there is consensus that within primary afferent cough fibers, there are nociceptors stimulated by chemical irritants and others stimulated through mechanical means, forming a division where afferents are divided by their physiologic responsiveness to stimuli.

Stretch receptors are well-described intrapulmonary afferents stimulated by mechanical means. When activated by changes in lung volume, airway edema, or smooth muscle constriction, stretch receptor afferents within the lower tracheobronchial tree and parenchyma conduct action potentials at 10 to 20 m/s to cell bodies located in the inferior nodose ganglion. Stretch receptors are further divided into rapid adapting receptors and slowly adapting receptors. The former are more active in the dynamic phase of the respiratory cycle and the latter are more active throughout the respiratory cycle. Stretch receptors help regulate the respiratory cycle, but their role in cough remains uncertain.¹³

A third type of receptor sensitive to mechanical stimulation was first described by Widdicombe in 1954.¹⁴ Unlike stretch receptors, these fibers are found exclusively in the extrapulmonary airway and adapt to punctate mechanical stimuli rather than stretch stimuli. These receptors precipitate an action potential in myelinated vagal afferents at a much slower velocity of 5 m/s, arguing to the uniqueness of these receptors from stretch receptors. Since the first description, the receptors have been eponymously referred to as Widdicombe receptors, then irritant receptors, but are now commonly referred to simply as cough receptors.

Chemical receptors, as the name would suggest, are relatively nonre-sponsive to mechanical stimulation, requiring 100 times the threshold required for mechanoreceptors. Instead, chemical receptors are sensitive to mediators found during inflammation, irritation, and changes in pH. Customarily, chemical nociceptors are defined by the presence of the ion channel transient receptor potential vanilloid 1 (TRPV1). The TRPV1 receptor binds capsaicin, the active component in chili pepper extracts and a known potent tussigenic agent. The binding affinity of TRPV1 is increased with mediators found during inflammation including bradykinins, prostaglandins, adenosine, and serotonin, as well irritants including nicotine and ozone. An overexpression of TRPV1 can be seen in chronic cough patients.15

Chemoreceptors are stereotypically associated with C-fiber afferents, which are classified by their action potential conduction velocity, ranging from 1 to 2 m/sec.¹⁶ Though C-fibers are most common type of afferent associated with chemoreceptors, afferents with a conduction velocity of 6 m/s, known as alpha-delta afferents, have been shown to conduct action potentials from chemoreceptors.⁹

Table 1–1 provides a summary of the thoracic and extrathoracic afferents that have been associated with cough.

From one’s personal experience with volitional cough and conscious cough suppression, it should be clear there is a layer of cortical control in the physiology of cough. Located in the caudal brainstem, the central cough generator receives the vagal afferents via the nucleus tractus solitarius. The ability of cough to undergo central processing is also demonstrated in the efficacy of placebo therapy, which often decreases cough.

COMMON CAUSES OF CHRONIC COUGH

The following discussion serves as a precursory introduction to familiarize the reader to common causes of chronic cough. In-depth appraisal of each etiology is included in subsequent chapters. Furthermore, although the following descriptions discuss common etiologies of chronic cough as singular entities, it is paramount for the reader to appreciate the multifactorial nature of chronic cough. As up to 93% of troublesome coughs are multifactorial, recognition of this salient concept mitigates delay in diagnosis as well as both clinician and patient frustration.17

Asthma as a source of chronic cough should always be in the differential. Asthmatic patients classically present with wheezing, dyspnea, and cough of an intermittent reversible nature. These symptoms, though, are not unique to asthmatics, and are found in many other respiratory diseases. Some readers are familiar with the term Reactive Airway Disease, an imprecise term used to describe transient symptoms of cough and wheeze when confirmation of a diagnosis of asthma is lacking. The majority of adult patients will already have a diagnosis of asthma since 75% of patients are diagnosed before the age of 7, though asthma can be diagnosed at any age.18 Therefore, it is not the definition of asthma or necessarily the diagnosis that is important as much as the recognition of the relationship between cough and asthma.

Chronic cough may be the only manifestation of asthma in a condition called cough-variant asthma. Irwin and partners found that, in their prospective study of 102 patients with chronic cough, 28% of asthmatics had only cough as a symptom.¹⁷

Eosinophilic asthma, distinguished by a high level of eosinophils in the serum, sputum, and tissue, is a particularly severe form of asthma.¹⁹ Though it accounts for only 5% of asthma cases, it is the most common cause of a severe asthma and is most commonly diagnosed in adults between the ages of 35 and 50. Eosinophilic bronchitis is a condition similarly presenting with elevated eosinophils, yet differs in the fact that patients do not exhibit typical variable airway restriction and responsiveness to bronchodilators, which is the defining hallmark of asthma.^{20, 21} As eosinophilic bronchitis does not respond to bronchoprovocation testing, diagnosis is based on responsiveness to empiric inhaled corticosteroids. It is unclear whether eosinophilic bronchitis is separate from asthma or represents a condition along the spectrum of asthma.²² Regardless, eosinophilic bronchitis patients invariably present with cough, triggered by inhaled allergens.

Gastroesophageal Reflux and Laryngopharyngeal Reflux

Gastroesophageal reflux disease (GERD) describes the condition where long-term flow of gastric contents flows retrograde from the stomach into the esophagus. Up to 50 episodes of reflux is considered physiologic and, therefore, in order to be classified as GERD, reflux must also cause tissue changes or produce symptoms.23 Familiarly referred to as heartburn, symptoms of GERD often present with a burning sensation in the chest. It is not uncommon for the pain to be referred to the throat with accompanying globus pharyngeus. More importantly, GERD is a common cause of chronic cough. When refluxate reaches the laryngopharynx (aka both the larynx and hypopharynx), the term laryngopharyngeal reflux (LPR) is used.²⁴ Unlike GERD, LPR is never considered physiologic.²³

Reflux is further classified as acidic or nonacidic based upon whether the reflux has a pH less than 4 or greater, respectively. The DeMeester score is an attempt to objectively quantify the results of a pH study and is usually included in results of a reflux study. The DeMeester score is based on calculations from six parameters, including percent total time pH is less than 4, pH less than 4 while in the upright and supine positions, number of reflux episodes, reflux episodes greater than 5 minutes, and the longest reflux episode. A composite score of 14.72 indicates reflux.^{25, 26} This distinction is important as patients with well-controlled acidic reflux can still have chronic cough in the presence of nonacidic reflux.

The pathophysiologic mechanism by which GERD/LPR causes chronic cough is not well understood, though are several proposed theories.²⁷ Gastric reflux, in addition to containing hydrochloric acid, also contains proteolytic digestive enzymes, most notably pepsin. Pepsin is formed from its inactive precursor pepsinogen in a process requiring a low pH and, therefore, most efficiently occurs in the stomach. Experiments demonstrate that this conversion of pepsinogen into its active state can occur in a weakly acidic environment up to a pH of 6, a value that would be considered well-treated reflux.²⁸ Furthermore, pepsin remains in the larynx after a reflux event, and could become activated when a true acidic reflux event occurs. Pepsin may also cause harm through a novel independent mechanism, as proposed by Johnston et al.²⁹ In Johnston’s study, inactivated pepsin is taken in through endocytosis by extraesophageal tissue; once taken into the cell, the pepsin becomes reactivated, leading to mitochondrial and intracellular damage.

Upper Airway Cough Syndrome

Upper airway cough syndrome (UACS) is now the preferred term for the condition previously classified as postnasal drip and is the most common etiology for chronic cough.³⁰ The latter term is now disfavored, as up to 20% of patients with UACS may not sense and report retrograde flow of mucus into the upper airway.³¹ In fact, chronic cough may be the only manifestation of UACS. The transport of sinonasal secretions into the pharynx is a normal physiologic process in heathy individuals, and postnasal drip alone is inadequate to explain the mechanism for chronic cough.

The definition of UACS remains a topic of debate. The American College of Chest Physicians defines UACS as a syndrome characterized by chronic cough related to upper airway abnormalities. As stated above, it is the amalgamation of symptoms including postnasal drip, hence the use of the term syndrome. This difficulty in determining a definition is exacerbated by the fact that there is no objective test to confirm the diagnosis of UACS. Ultimately, it is the response to treatment that defines UACS. Interestingly, postnasal drip is considered by many a symptom rather than a stand-alone condition, and the etiology may be multifactorial, including LPR, allergies, and environmental causes of inflammation with resultant mucus production.32–34

Chronic Bronchitis

Chronic bronchitis, along with emphysema, represents a continuum of a condition known as chronic obstructive pulmonary disease (COPD). Emphysema describes a condition where the alveolar walls in the lung weaken and progressively trap air, producing shortness of breath, while chronic bronchitis is defined as the presence of a productive cough lasting at least 3 months for at least 2 consecutive years.³⁵ Many patients will have features of both chronic bronchitis and emphysema and, therefore, the more encompassing term of COPD is used.

Smoking, either directly or by passive means, is a major risk factor for the development of chronic bronchitis, hence the term “smoker’s cough” that is usually associated with this condition.²⁰ Toxins in cigarette smoke result in inflammation in the lower bronchials. This inflammation then leads to increased mucus production from goblet cells and decreased ciliary function, both of which lead to the distinctive hacking, productive cough.³⁶ Paradoxically, patients need to be counseled that their cough severity and frequency may worsen temporarily after smoking cessation. Smoking cessation allows cilia to recover their normative function of pulmonary clearance from the lower tracheal bronchial tree into upper airway larynx stimulation cough.

Other Causes of Chronic Cough

Although GERD/LPR, asthma, and upper airway cough syndrome remain the most common causes of chronic cough, clinicians should maintain a broad differential, as there are numerous other pathologies and conditions associated with cough.

In some patients, even after an extensive workup, the etiology of chronic cough cannot be deciphered. Terms used to describe this circumstance include idiopathic, unexplained, refractory, intractable, treatment-resistant, and postviral vagal neuropathic cough.37 Regardless of the term used, this diagnosis is one of exclusion. More evidence emerges that nonacidic reflux into the proximal esophagus and pharynx that is missed by classic pH-only testing is being discovered on hypopharyngeal-esophageal multichannel intraluminal impedance with dual pH testing and is likely revealing previously missed diagnoses of reflux-induced cough.^{38, 39}

HISTORY

As a result of the long-standing nature of their symptoms and resulting frustration, it is not uncommon for patients to provide a tangential history, obscuring more relevant details. The history should be focused on the most common causes of chronic cough, maintaining an appreciation for less-frequent sources of chronic cough.

As with any patient assessment, a detailed history and careful physical examination are paramount in the evaluation of chronic cough. The most important information gathered in developing a differential diagnosis for cough is the duration. To review, acute cough is defined by the presence of cough for less than 3 weeks, while chronic cough has a duration of greater than 8 weeks, with subacute cough in between these intervals.

Patients should be queried on inciting triggers of cough. Common triggers include exposure to noxious fumes and perfumes, changes in air temperature, environmental allergens, and posture. Given the numerous etiologies of cough, triggers when pertinent can help to narrow the differential. For example, in a patient with cough exacerbated after eating or laying in the recumbent position, laryngopharyngeal reflux is a more likely diagnosis than asthma.^{40, 41}

Scrutinizing the family or personal history for atopic disease can favor a diagnosis of allergic rhinitis, asthma, or UACS, given the right clinical context.

Review of Medications

Angiotensin-converting-enzyme (ACE) inhibitors are a class of antihypertensive medication utilized as primary treatment replacing beta-blockers and diuretics. The literature reports an incidence rate of 2% to 33% of chronic cough in those taking ACE inhibitors.^42–44 As such, even when considering the most conservative estimates in prevalence, with the 162 million ACE-inhibitor prescriptions dispensed annually in the United States, the number of patients with chronic cough secondary to ACE inhibitors is substantial.⁴⁵ In patients presenting specifically for evaluation of cough, a more recent prospective study cites ACE inhibitors as the etiology in 1% to 3% of cases.46–48 It is important to note that cough can present at any time while using an ACE inhibitor, even after many years without meaningful cough side effects, and cough is not dose dependent.⁴⁹ The only effective means of mitigating ACE-induced cough is complete cessation of medication.⁵⁰ ACE inhibitor-induced chronic cough can persist after cessation of therapy and, as such, cannot be excluded as an etiology until a period of weeks has passed.

Social History

Questions regarding alcohol use, recreational drug use—especially those that are inhaled—and tobacco exposure are important when accessing new patients presenting with chronic cough. These questions can be uncomfortable, sensitive, and anxiety provoking for patients and need to be levied in a straightforward, nonjudgmental fashion.

The association between tobacco use and chronic conditions such as lung cancer, emphysema, asthma, heart disease, and, of course, cough is well known. Accordingly, patients should be asked to quantify tobacco use by asking about duration of use, method of delivery, and amount. Patients who smoke are 3 times more likely to develop chronic cough,⁵¹ and multiple studies involving guinea pigs exposed to tobacco smoke have demonstrated increased sensitivity to capsaicin.^{52, 53} It is also important to be cognizant of passive and environmental tobacco exposure, known more ubiquitously as “secondhand smoke.” In a cross-sectional analysis of more than 700 nonsmoking patients, Iribarren et al found that 64% of patients were exposed to at least 9 hours of passive smoke per week, carrying a significant increase in the odds of chronic cough.⁵⁴

A through history necessitates a social history. Tobacco smoke, inhaled either actively or passively, is an obvious interrogation point, but clinicians should also inquire about occupational history as many workers, especially those in industry, are exposed to chemical irritants. Studies estimate 10% of new diagnoses of asthma are the direct result of workplace exposure, highlighting the importance of the occupational history.⁵⁵

PHYSICAL EXAMINATION

Physicians should perform a comprehensive neck examination during the evaluation of a patient with chronic cough. Furthermore, a head and neck examination is not exclusive to an otolaryngologist, nor does it necessitate special equipment. A general examination performed in the office can reveal a supratip crease on the nasal dorsum or venous congestion underneath the eyes, suggestive of allergies. In fact, these physical examination findings are referred to colloquially as the allergic salute and allergic shiners, respectively.

Visualization of the larynx, most commonly performed with a flexible fiberoptic laryngoscope, can reveal signs indicative of GERD/LPR. The Reflux Finding Score is a validated instrument utilized by otolaryngologists to rate the severity of common clinical findings such as subglottic edema, erythema, and excessive mucus.56 External validation of the RSI affirms good inter- and intrarater reliability though the findings are still subjective and not specific for reflux, but rather serve mainly to support a diagnosis based on history.^{57, 58} Flexible fiberoptic examination is not only useful in visualizing the effects of GERD/LPR, but many systemic diseases also present with endolaryngeal findings. Sarcoidosis most commonly affects the supraglottic larynx with the vocal cords, also known as the glottis, being the most common site of deposits in amyloidosis. Meanwhile, granulomatosis with polyangitis (Wegener’s) deposits are most commonly deposited on the subglottis. One can remember the systemic disease of the larynx with the mnemonic S-A-W, which also conveniently describes the most common location of disease from a cranial caudal direction—sarcoid in the supraglottis, amyloid in the glottis, and Wegener’s in the subglottis.

Discussion of the pulmonary physical examination as secondary to the head and neck physical exam may surprise some readers. Admittedly, the emphasis on the head and neck exam can be counterintuitive given cough is physiologically driven by the rapid expulsion of air from the lungs. Findings on lung examination are nonspecific. For instance, an expiratory wheezing can be a sign of asthma, but also presents in COPD, emphysema, or heart failure.

DIAGNOSTIC ADJUNCTS

Imaging

A chest roentgenogram constitutes the most basic diagnostic adjunct to determine cough. Radiographic findings on chest roentgenograms should be addressed expediently, especially when there is concern for malignancy. Low-dose computerized tomography (LDCT) has superior resolution when compared to chest roentgenograms. In a large clinical trial comparing LDCT to chest roentgenograms, LDCT was found to lower mortality in adults between ages 55 and 74 with a 30-pack-per-year history of smoking in fairly good health.⁵⁹ However, despite superior resolution, LDCT’s utility as a routine screening tool is limited by its high false-positive rate. These incidental false positives subject patients to obligatory invasive workups while incurring additional costs. There remains debate in the literature regarding the optimal screening test for lung cancer, with the American Cancer Society recommending LDCT as a screening tool in select patients, as opposed to chest x-rays, to be performed at centers performing high volumes of LDCT to limit false positive interpretations.60

Computerized tomography (CAT) of the paranasal sinus can be used as an adjunct, especially in patients with suspected UACS who previously failed empiric treatments. Pertinent findings on CAT scans include mucosal paranasal sinus thickening and nasal polyposis, strengthening a presumed diagnosis of UACS. CAT scan without contrast is the preferred imaging modality of the paranasal sinuses, as opposed to magnetic resonance imaging, which has a higher false-positive rate than CAT scans. CAT scans should be used judiciously given the healthcare cost and radiation exposure, and guided by history. For example, a CAT scan should not be ordered if the duration of sinonasal symptoms suggests an acute process.⁶¹

A double pH probe remains the gold standard for diagnosing LPR and should be combined with multichannel impedance testing. Dual probe monitoring demonstrates sensitivity ranging from 50 to 80%. Impedance testing allows for the diagnosis of nonacidic reflux.⁶²

Patient Inventories

The Leicester Cough Questionnaire (LCQ) is a validated inventory focused exclusively on health-related quality of life as it pertains to chronic cough.⁶³ The LCQ consists of 19 items scored on a 7-point Likert scale divided into social, physical, and psychological domains. The inventory is easily self-administered in the outpatient setting, taking less than 5 minutes to complete. An advantage of the LCQ is its repeatability and responsiveness to intervention, making it suitable also to track the progression of treatment efficacy.

The Cough-Specific Quality-of-Life Questionnaire (CQLQ) is another inventory published by the American College of Chest Physicians.⁶⁴ The CQLQ, like the LCQ, is a validated self-administered inventory and consists of 28 items scored on a 4-point Likert scale. The CQLQ can be administered to patients with either acute or chronic cough with good reliability and validity.

IMPACT OF COUGH

Bothersome cough is a ubiquitous experience, mainly in the setting of an acute upper respiratory tract infection. Annually, it is estimated that 27 million outpatient clinic visits will be attributed to cough and the most common reason for presentation to primary care.⁶⁵ Though extremely prevalent, cough and especially chronic cough remain a challenge for physicians with regard to both diagnosis and treatment. Chronic cough is extremely pervasive, with prevalence estimates ranging from 10% to 20% of the population affected.66 This is likely an underestimated prevalence given that some patients are unlikely to seek medical treatment, as cough in some patients can either be minimally bothersome or, because of the chronicity of the disease, something patients come to accept as a new normal.⁶⁷

Economic Impact

As stated previously, cough is the most common symptom leading to presentation to primary care physicians. Astonishingly, estimates from an almost 20-year-old report cites almost $250 million spent annually on cough lozenges in the United States—a remarkable figure that is assuredly higher given inflation alone.⁶⁸

A cost breakdown of the typical diagnostic tests and procedures for a patient with chronic cough is shown in Table 1–2. It should be mentioned that the testing listed focuses on the most common causes of cough, and a patient with a particularly elusive etiology or who is refractory to typical treatment assuredly would incur more health-care-related costs.

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