Unexplained cough is a diagnosis of exclusion that should not be made until a thorough validated diagnostic evaluation is performed, specific and appropriate validated treatments have been tried and failed, and uncommon causes have been ruled out. When chronic cough remains troublesome after the initial work up, determine that a protocol has been used that has been shown to lead to successful results. If such a protocol has been used, next consider whether or not pitfalls in management have been avoided. If they have been, the frequency of truly unexplained chronic cough usually should not exceed 10%. While patients with truly unexplained coughs have an overly sensitive cough reflex, the mere presence of an overly sensitive cough reflex does not by itself explain why they do not get better, because most patients with chronic cough, even those who respond to treatment and get better, have demonstrable heightened cough sensitivity. Management options include referral to a cough clinic with interdisciplinary expertise, speech therapy, and self-limited trials of drugs, preferentially with those shown to be effective in randomized, double-blind placebo-controlled trials in patients with unexplained chronic cough.
As stated in the 2006 American College of Chest Physicians (ACCP) Evidenced-Based Clinical Practice Guidelines on diagnosis and management of cough
“the diagnosis of unexplained (idiopathic) cough is a diagnosis of exclusion. It should not be made until a thorough diagnostic evaluation is performed, specific and appropriate treatment (according to the management protocols that have performed the best in the literature) has been tried and has failed, and uncommon causes have been ruled out”
In essence, the unexplained cough is a variant of chronic cough (ie, a cough of more than 2 months duration) that has remained persistently troublesome to the patient. This article, expands upon this definition by discussing why unexplained cough is a better term than idiopathic cough to characterize treatment failures and then poses and answers a series of questions:
How often is chronic cough unexplained, and what are the potential explanations?
How should clinicians and researchers approach the problem?
What are the pitfalls in management, and have they been avoided?
How often will chronic cough remain truly unexplained after the recommended management protocol has been followed?
The article also discusses the potential pathogenetic mechanisms to explain the truly refractory unexplained cough and the available options to manage it.
Unexplained versus idiopathic cough
I agree with the ACCP cough guidelines that unexplained is a better descriptor than idiopathic when referring to the persistently troublesome cough and that the distinction is important, because the difference in terms might affect how the problem is approached. For instance, the term unexplained implies that the cause is yet to be determined and that there might be multiple reasons to consider and reconsider; on the other hand, the term idiopathic implies that while the cause is unknown, it is likely due to a single condition that has yet to be described. This has the potential to truncate any further work-up. The literature supports the preferential use of the term unexplained, because it has suggested that some of the variation in successful treatment of chronic cough could be explained by investigators using inadequate management protocols. For example, in some countries in Europe, the putatively most effective treatment for upper airway cough syndrome, the older first-generation H 1 -antagonists, are generally unavailable, leading to the preferential prescribing of the newer-generation H 1 -antagonists that are considered to be less effective, or, in the case of cough caused by the common cold, ineffective.
How often is chronic cough unexplained, and what are the potential explanations?
Based upon the published results of prospective and retrospective before and after intervention trials, treatment failures for chronic cough have ranged from 0% to 46% of patients referred for specialist management. Although there has been a wide range of unexplained cough reported in the literature, most of the time (approximately 90%) chronic cough has been explained and successfully treated. Possible explanations to account for coughs that remain persistently troublesome are multiple and include
The previously mentioned failure to follow a successful, validated protocol (eg, failing to use the most effective medication)
Failure of patients to follow treatment recommendations
Patients not being willing to be contacted or refusing to complete evaluations
Investigators reporting results in a group of patients with a different spectrum of pretreatment, presumptive causes
Investigators reporting results in a group of patients with different phenotypic or airway histopathologic profiles or referral sources
Development of serious, comorbid illnesses that force patients to drop out of studies or not follow prescribed treatment plans
The diagnosis is correct, but the cough is refractory to the prescribed treatment regimen(s)
Combinations of the above
The cough is truly unexplained.
How often is chronic cough unexplained, and what are the potential explanations?
Based upon the published results of prospective and retrospective before and after intervention trials, treatment failures for chronic cough have ranged from 0% to 46% of patients referred for specialist management. Although there has been a wide range of unexplained cough reported in the literature, most of the time (approximately 90%) chronic cough has been explained and successfully treated. Possible explanations to account for coughs that remain persistently troublesome are multiple and include
The previously mentioned failure to follow a successful, validated protocol (eg, failing to use the most effective medication)
Failure of patients to follow treatment recommendations
Patients not being willing to be contacted or refusing to complete evaluations
Investigators reporting results in a group of patients with a different spectrum of pretreatment, presumptive causes
Investigators reporting results in a group of patients with different phenotypic or airway histopathologic profiles or referral sources
Development of serious, comorbid illnesses that force patients to drop out of studies or not follow prescribed treatment plans
The diagnosis is correct, but the cough is refractory to the prescribed treatment regimen(s)
Combinations of the above
The cough is truly unexplained.
How should clinicians and researchers approach the problem?
The first step in approaching the adult patient with an unexplained cough is to review the patient’s work-up to be certain that an appropriate and comprehensive management protocol has been followed such as that shown in Fig. 1 . This protocol was developed by the ACCP Cough Guideline Committee based upon
The known relative frequency of the disorders (singly and in combination) that have been reported to cause chronic cough
The known sensitivity and specificity of most diagnostic tests in predicting the cause(s) of chronic cough
The known timeframe of response to appropriate therapy
This protocol summarizes guidance on how to effectively manage chronic cough by:
Initially recommending that the commonest causes of chronic cough be sequentially evaluated and treated using a combination of selected diagnostic tests and empiric therapy
Reminding that sequential and additive therapy is important, because more than one cause of cough is frequently present
Considering evaluating for uncommon causes when the commonest causes have been adequately addressed
Referral to a cough specialist or cough clinic when cough remains undiagnosed after all of the recommendations have been followed.
After determining that a protocol has been used that has been shown to lead to successful results, the next step to take when cough continues to remain troublesome, even when one thinks that the management has been appropriate and adequate, is to consider whether pitfalls in management have been avoided.
What are the pitfalls in management, and have they been avoided?
Although a comprehensive discussion on how to use the protocol outlined in algorithmic form in Fig. 1 can be found elsewhere, the answers to this question reassure in specific terms whether specific and appropriate treatment has been prescribed or a thorough diagnostic evaluation work-up has been performed. While the author initially introduced this pitfall avoidance strategy in 1998 and revisited it in 2000 and 2002, it is much more robustly expressed here.
Upper Airway Cough Syndrome (Previously Referred to as Postnasal Drip Syndrome) Caused by Various Rhinosinus Conditions
This condition may not be considered or correctly treated due to the following potential failures:
Recognizing that it can present as a cough–phlegm syndrome that can lead to the incorrect diagnose of chronic bronchitis
Appreciating that all H 1 -antagonists are not the same when treating cough. For example, the newer, relatively nonsedating agents are primarily useful when the upper airway cough syndrome (UACS) is caused by a histamine-mediated condition such as allergic rhinitis and the older agents have been shown to be efficacious in conditions like the common cold when the newer agents failed
Considering sinusitis because it is silent (eg, no discolored nasal discharge, pain, or fever) from a clinical standpoint or the usefulness of endoscopy that might reveal its presence ( Fig. 2 )
Fig. 2
Endoscopic view revealing evidence of suppuration due to sinusitis that was clinically silent and about to drip onto vocal cords.
Considering allergic rhinitis or recommending the avoidance of allergens because symptoms are perennial
Considering that this diagnosis can be silent (eg, no complaint of postnasal drip or throat clearing) up to 20% of the time
Considering aspirin-exacerbated disease or the usefulness of endoscopy that might uncover nasal polyposis ( Fig. 3 ). In aspirin-sensitive patients, aspirin therapy following desensitization has been shown to be effective in preventing the reoccurrence of nasal polyposis.
Fig. 3
Endoscopic view of a nasal polyp in a patient with chronic cough who was subsequently determined to have aspirin sensitivity during a monitored aspirin challenge.
Asthma
This disease may not be considered or correctly treated because of the following potential failures:
Recognizing that it can just present as a cough (cough variant asthma) or as a cough–phlegm syndrome that can lead to the incorrect diagnose of chronic bronchitis
Recognizing that inhaled medications may exacerbate cough
Assuming that a positive methacholine challenge that is only consistent with asthma is actually diagnostic of asthma as the cause of cough. Cough can only be diagnosed as being caused by asthma when the cough goes away with asthma treatment.
Nonasthmatic Eosinophilic Bronchitis
Pitfalls in managing this condition include the failure to consider the diagnosis, order the correct tests to diagnose it, or consider occupational/environmental causes.
Gastroesophageal Reflux Disease
Risks of misdiagnosis or improper treatment of gastroesophageal reflux disease (GERD) include the following potential failures:
Recognizing that it can present as a cough–phlegm syndrome that can lead to the incorrect diagnose of chronic bronchitis
Appreciating that silent reflux disease can be the cause of cough, that it may take 2 to 3 months of intensive medical treatment before cough starts to improve, and, on average, 5 to 6 months before cough resolves
Assuming that cough cannot be caused by GERD, because cough remains unchanged when gastrointestinal symptoms improve
Assuming that one can reliably make the diagnosis of GERD based upon the appearance of the vocal cords ( Fig. 4 )
Fig. 4
Endoscopic views of supraglottic and glottic structures just before and immediately after an approximate 5-second paroxysm of spontaneous coughing in a patient being evaluated for chronic cough of 5 years duration. Before the coughing episode, mucosal surfaces were normal. Immediately after coughing, mucosal surfaces appear red and swollen. Because the coughing paroxysm occurred spontaneously and was not provoked by the instillation of fluid or trauma from the endoscope or regurgitation or vomiting, the changes noted were thought to be caused by the act of coughing itself and most likely represent venous congestion. ( From Irwin RS, French CT. Cough and gastroesophageal reflux: identifying cough and assessing the efficacy of cough-modifying agents. Am J Med 2001;111(8A):45S–50S; with permission.)
Recognizing that coexisting diseases such as obstructive sleep apnea or their treatment such as calcium channel blockers or nitrates for coronary artery disease or progesterone as hormone replacement therapy may be making GERD worse, because these drugs can relax the lower esophageal sphincter
Considering nonacid reflux disease and assuming that cough always will respond to acid suppression
Considering the importance of diet, avoiding intense exercising, and prokinetic therapy
Treating adequately other coexisting causes of cough that perpetuate the cycle of cough and reflux, because coughing itself can provoke reflux events
Recognizing that surgery may help when intensive medical therapy has failed.
Triad of UACS, Asthma, and GERD
Because these three conditions commonly cause chronic cough singly or in combination, it is also a pitfall in management to fail to
Consider that more than one of these conditions may be contributing simultaneously to the cough.
Consider these common conditions because the patient has a seemingly obvious pre-existing disease such as a chronic interstitial pneumonia (eg, idiopathic pulmonary fibrosis) that can cause cough. Approximately 50% of the time, in patients with a chronic interstitial pneumonia, the cause will be due to one of these common diseases.
Appreciate that because these are chronic conditions, they will not be cured and will periodically flare especially with upper respiratory tract infections such as the common cold.
Re-evaluate the cough as a new problem when cough flares after a period of remission. For example, asthma may become a problem when it was not before, especially following a severe viral infection.
Angiotensin-Converting Enzyme Inhibitor
In patients taking angiotensin-converting enzyme inhibitors (ACEIs), it is a pitfall in management to fail to consider that these drugs may be causing cough, because the cough had already been present before the drug was initially prescribed or that stopping the drug for 1 to 3 weeks is enough time to see if cough is caused by the drug. The author advises always stopping the ACEIs in patients with chronic cough, because the original cause of the cough may have disappeared on its own or responded to treatment just when the ACEI was prescribed. Also, 4 weeks of abstinence from taking the ACEI may be required to start to see improvement or disappearance in ACEI-induced cough ( Fig. 5 ).
