Cough is among the most common symptoms for which medical attention is sought. It represents 10 to 38 percent of outpatient practice visits1,2 totaling over 26 million medical visits in the U.S. annually, and has a point prevalence of 9 to 33 percent in U.S. and European populations3. Most cough results from viral upper respiratory infection and is self-limited. Chronic cough, however, is a refractory condition that can be attributed to a variety of pulmonary and nonpulmonary etiologies.
Cough evaluation and management is resource intensive with significant economic burden4. Varied etiology results in affected patients undergoing extensive diagnostic testing associated with pulmonary, allergy, otolaryngology and gastroenterology consultations, which further escalates costs. Furthermore, many commonly used medications can potentiate or exacerbate cough including ACE inhibitors and drying medications. As clinicians, it is difficult to differentiate whether cough relates primarily to gastroesophageal reflux disease (GERD) or to other causes. We will discuss circumstances when GERD or other conditions are likely to represent the primary etiologic factor.
Why it Could be GERD
Mechanistically, there is evidence that reflux events can be related to cough. GERD is thought to mediate cough through noxious refluxate stimulation of the distal esophagus via the esophagobronchial reflex or activation of sensory nerve receptors in the upper airway, which trigger the afferentloop of the cough reflex. Evaluating clinicians rarely have a simple approach to differentiate the particular etiology of reflux-related cough or even to determine if reflux is the culprit. While it is plausible that reflux is the primary cause of idiopathic chronic cough, it is less common than previously presumed.
Cough is more likely to be triggered by reflux if associated with classic GERD symptoms. In a recent study of patients with laryngopharyngeal reflux symptoms post fundoplication, we found that chronic cough response to surgery is more likely in those with concomitant typical GERD symptomatology — heartburn ± reflux.5 Those who improved also had pathological reflux on pH monitoring and endoscopic presence of hiatal hernia. This highlights the importance of volume regurgitation as a trigger for cough. Thus, presence of concomitant classic GERD symptoms and a moderate degree of reflux by pH monitoring off therapy may guide whose chronic cough symptoms may be reflux related. Another recent study, employing a novel cough monitor device synchronized with 24-hour pH-impedance testing, showed that even physiologic reflux events may be temporally associated with cough events.6 This suggests that in patients with chronic cough, irritation from physiological reflux can also initiate coughing spells. It also indicates that once someone has chronic cough, it can be perpetuated by normal physiologic reflux events into the esophagus. In the context of these studies, it is important to recognize that the associated therapeutic benefit of acid suppression is modest compared to the effects on classic GERD symptoms (i.e., heartburn, regurgitation). Although commonly practiced, acid-suppression therapy is not a sensitive test, thus caution should be exercised when attributing the cough to reflux even among responders.7
Why it May Not be GERD
One must not be too simplistic when considering the etiology of chronic cough. It is easy to attribute cough to allergies, asthma, GERD or other sources without demonstrable evidence. Empiric treatment of these conditions may be effective. However, in many situations, particularly in patients with chronic cough, it is a disservice to overly simplify their disease. Each specialty approaches chronic cough differently from within the lens of their experience, training and biases. It is important to carefully listen to the patient’s triggers, and to be open minded and approach this process with a degree of humility to avoid the tendency toward furor medicus (or misdirected medical activity). There is a reason that nearly half of patients with chronic cough have etiologies deemed idiopathic. In many patients, chronic cough is multifactorial in etiology and that cough’s precipitating inciting event is distant history. Additionally, it might no longer have management-related relevance at the patient’s presentation. For example, patients often state that the inciting event was an upper respiratory infection, but as other associated symptoms resolved, the cough persisted. They did not have pathological cough prior to the upper respiratory infection, so is it fair to attribute the cough to asthma, allergies or even GERD? Some argue that the act of coughing may have caused some damage to the esophagus or diaphragm that resulted in a predisposition to GERD. It is difficult to conceptualize how the vast number of patients with this condition would all suffer this fate. In this scenario, it is also difficult to understand how anyone with this degree of damage could have symptom resolution. Thus, it is important to recognize that other etiologies for chronic cough exist beyond those routinely espoused, including adult-onset asthma, allergies and GERD. The same study mentioned previously that synchronized the cough monitor to pH-impedance also was illustrative of what other etiologies may be contributing to the chronic cough6. The strongest predictor of cough in this study was the occurrence of a prior cough. While this may seem intuitive, it is a critically important point. Chronic coughing involves repeated trauma to the vocal folds as they close, as manifested by the cough sound. Its chronicity can result in what is termed laryngeal sensory neuropathy or irritable larynx syndrome. The proposed pathophysiology is abnormal, repeated stimulation of sensory receptors causing neuroplastic changes in brainstem laryngeal controlling networks, inducing them into a perpetually hyperexcitable state, which increases the epithelial sensitivity to sensory stimuli. Depending on the coughing frequency and severity, it can stimulate further cough with lesser and typically nonstimulating inciting factors (e.g., breathing, laughing, talking, certain smells, throat mucus). Thus, we found that cough strongly begets cough, thereby explaining the paroxysmal nature of cough in these patients. Furthermore, this study found that phonation was a trigger for cough, providing more evidence that typically physiologic activities can act as an effector of cough in patients who are hypersensitive.
These findings underscore the importance of a careful history and understanding what the triggers are for these patients. If chronic cough patients complain of concomitant typical GERD symptoms or show evidence of pathologic reflux on pH testing, then the probability is higher that GERD is playing a role in their cough. In the absence of these findings, it is incumbent on the physician to have an understanding of the complex differential diagnosis, including careful consideration of whether this could be a hypersensitivity phenomenon triggered by typically nonnoxious physiological processes. Idiopathic chronic cough remains a difficult condition for patients and providers. Patients recognize how debilitating it is for their quality of life, and it is important that we as providers are sympathetic and not dismissive of its severity. It’s also important that we continue to better understand specific underpinnings as we move toward a cogent understanding of its complex pathophysiology and development of effective treatment approaches.
Dr. Francis has no conflicts to disclose.
Dr. Vaezi has no conflicts to disclose.
1. Irwin RS, Madison JM. The diagnosis and treatment of cough. N Engl J Med. 2000;343(23):1715-21.
2. Irwin RS, Curley FJ, French CL. Chronic cough. The spectrum and frequency of causes, key components of the diagnostic evaluation, and outcome of specific therapy. The American review of respiratory disease. 1990;141(3):640-7.
3. Chung KF, Pavord ID. Prevalence, pathogenesis, and causes of chronic cough. Lancet. 2008;371(9621):1364-74.
4. Francis DO, Rymer JA, Slaughter JC, Choksi Y, Jiramongkolchai P, Ogbeide E, et al. High economic burden of caring for patients with suspected extraesophageal reflux. The American journal of gastroenterology. 2013;108(6):905-11. 5. Francis DO, Goutte M, Slaughter JC, Garrett CG,
5. Hagaman D, Holzman MD, et al. Traditional reflux parameters and not impedance monitoring predict outcome after fundoplication in extraesophageal reflux. Laryngoscope. 2011;121(9):1902-9.
6. Francis DO, Slaughter JC, Ates F, Higginbotham T,Stevens KL, Garrett CG, et al. Airway Hypersensitivity, Reflux, and Phonation Contribute to Chronic Cough. Clinical Gastroenterology and Hepatology : the official clinical practice journal of the American Gastroenterological Association. 2015.
7. Kahrilas PJ, Howden CW, Hughes N, Molloy-Bland M. Response of chronic cough to acid-suppressive therapy in patients with gastroesophageal reflux disease. Chest. 2013;143(3):605-1