Diagnosis and Treatment of Refractory Chronic Cough: An American Broncho‐Esophagological Association Expert Consensus Statement

ABSTRACT

Objective

To develop an expert consensus statement (ECS) on the diagnosis and treatment of refractory chronic cough (RCC) in adults. RCC was defined as cough lasting longer than 8 weeks and refractory to standard management of pulmonary, gastrointestinal, sinonasal, and medication‐induced etiologies.

Methods

An expert panel of otolaryngologists used published consensus statement methodology to develop statements guiding the diagnosis and management of RCC from an otolaryngologic perspective. A modified Delphi method was used to iteratively select, eliminate, and refine statements based upon accepted methodology until consensus was achieved.

Results

Three iterative Delphi surveys were performed with discussion rounds between each of the voting sessions. Twenty‐seven statements met consensus while six statements did not. The clinical statements were grouped into 9 categories: operational definition, pathophysiology, assessment of prior work‐up, phenomenology and symptomatology, four treatment categories (neuromodulators, superior laryngeal nerve blocks, behavioral cough suppression, and emerging treatments), and overall treatment approaches.

Conclusion

The panel reached consensus for 27 statements related to the diagnosis and treatment of adults with RCC from an otolaryngologic perspective. These statements may be used to standardize evaluation and improve quality of care, while also identifying areas for future investigation in the management of RCC.

1. Introduction

Cough is a normal, adaptive reflex designed to protect the airway from foreign material and remove obstructive secretions [1, 2]. Multilevel regulation of cough exists, beginning at chemoreceptors and mechanoreceptors at the level of the bronchi, trachea, larynx, pharynx, and ear, through vagal afferents to the brainstem, and then back through efferent fibers to the musculature of the larynx, respiratory musculature, and diaphragm [1, 3]. However, stimulation of this reflex at inappropriate times may result in frequent or bothersome cough that produces a significant social, emotional, and physical impact on patients, accounting for over 20 million clinician visits annually [4].

Chronic cough, defined by prior society guidelines as a cough lasting over 8 weeks, is a known manifestation of a number of cardiopulmonary, gastrointestinal, and sinonasal pathologies, as well as a medication side effect of a number of common medications [5, 6, 7]. A stepwise approach to diagnosis and treatment of these possible contributing etiologies is recommended for all cough patients and is backed by high‐quality evidence in multidisciplinary literature [6, 8].

However, even after accepted evaluation and management of these common etiologies, some patients continue to experience bothersome cough. Refractory chronic cough (RCC), also described as unexplained chronic cough or idiopathic chronic cough, is defined as a chronic cough that persists despite diagnostic elimination or treatment of possible contributing etiologies as described above [5, 6, 7, 8, 9, 10]. This remains a very common complaint, accounting for up to 46% of referrals in some subspecialty clinics [11]. However, what qualifies as a complete work‐up and trial of treatment varies significantly across clinicians, resulting in heterogeneous diagnosis and ultimately varying treatment of RCC [12, 13, 14]. Furthermore, while numerous methodologies exist to address RCC, many emerging treatments or protocols may be localized to subspecialty clinics, limiting their implementation by clinicians seeing RCC more broadly.

Given the ubiquitous nature of chronic cough and variability in its management, many patients stand to benefit from standardization of approach to diagnosis and treatment of RCC. Based on this need, the possibility of creating an expert consensus statement (ECS) on RCC was reviewed with the American Broncho‐Esophagologicial Association (ABEA), which has supported past consensus statements [15]. With ABEA support, the decision was made to proceed with an expert consensus statement on otolaryngologic approaches to RCC. The goal of this ECS was to establish actionable statements to guide clinicians of any specialty in the diagnosis and management of RCC. As there is wide variation in work‐up leading to diagnosis of RCC, this ECS aims to create clear statements guiding reasonable exclusion of other treat etiologies of chronic cough. Additionally, as a number of new treatments for RCC have emerged within the last several years, effort was made to highlight treatments with substantial evidence supporting their use in RCC. With these consensus statements, the panel members hoped to clarify areas in which experts agree on the standard of care, versus areas of controversy, and to identify future research needs to best treat patients suffering from RCC.

2. Methods

2.1. Literature Review

A state‐of‐the‐art literature review on chronic cough, conducted by the same research group, was published separately in the previous year to summarize current evidence [1]. This review was conducted by five practicing otolaryngologists and one speech‐language pathologist with extensive clinical experience in evaluating and treating chronic cough. The literature review identified a growing battery of treatment options for patients with RCC, but there was a notable dearth of consolidating work. We therefore proceeded with a modified Delphi approach to better characterize expert consensus, using the literature review to guide initial drafting of statements for eventual voting and discussion.

2.2. Conception and Expert Recruitment

This expert consensus statement (ECS) was developed using the methodology outlined in the American Academy of Otolaryngology – Head and Neck Surgery's (AAO‐HNSF) Expert Consensus Statements Development Manual [16]. A modified Delphi panel was convened with roles outlined according to the development manual, including a chair (LMA) and assistant chairs (TLC, PCB) responsible for committee leadership, non‐voting methodologists (REM, AS, MAR) with experience in ECS, and 11 fellowship‐trained academic laryngologists to make up the voting panel (GL, AB, KWA, MA, LM, AKO, CBS, JB, PCB, TLC, LMA). The voting members were recruited via email invitation, and all experts who received the invitation accepted and joined the panel. Panelists were chosen based on expertise in chronic cough as demonstrated by publications and presentations on the topic, as well as an effort to balance the panel by geographic representation and number of years in practice. First drafts of the explanatory paragraphs for statements were written by REM and AS before being edited by the rest of the authors. The statement was sponsored by the ABEA, so all recruited panelists practice in the United States. The target audience for the ECS was defined as otolaryngologists. Although management of RCC is often interprofessional with the otolaryngologist as part of the multi‐disciplinary team, this ECS was designed to target the otolaryngologist and therefore the panel was kept single specialty. This study was approved by the Johns Hopkins University School of Medicine institutional review board.

2.3. Preliminary Statement Compilation

A total of 18 preliminary statements were drafted by a “working group” before the first call, consisting of the methodologists (MAR, AS, REM) and lead authors (LMA, GL, TLC, PCB). These preliminary statements were then presented to the entire Delphi panel during a pre‐voting video conference call (Zoom, Zoom Communications, San Jose, CA). Several modifications were made to existing statements, and new statements were added in this call before the first round of formal voting.

2.4. Voting Rounds

The Qualtrics survey platform was used for voting rounds, and the results were anonymized when presented to the voting panel. Participants were asked to identify themselves solely to methodologists in order to track the completion of the survey. Three rounds of voting were completed. Each round began with a Qualtrics survey containing statements for review sent to the Delphi panel. Participants were asked to rate the statements on a 9‐point Likert scale (1 = Strongly Disagree; 3 = Somewhat Disagree; 5 = Neither Agree nor Disagree; 7 = Somewhat Agree; 9 = Strongly Agree). Participants could also submit comments along with their score rating for each statement. The AAO‐HNSF scoring criteria [16] were used to evaluate statements as follows:

• Consensus: Statements with a mean score ≥ 7.00 AND with 1 or fewer outlier scores (where outlier is defined as any rating ≥ 2 Likert points from the mean in either direction).

• Near Consensus: Statements NOT qualifying for consensus AND with a mean score ≥ 6.50 AND with 2 or fewer outliers.

• No Consensus: Statements with a mean score < 6.50 OR with 3 or more outliers.

After each round of voting, a video conference call was held with the methodologists and members of the Delphi panel to review anonymized, collated results. Statements that did not reach consensus were not discussed further and were discarded. Those reaching consensus were briefly reviewed for clarity and wording. Finally, statements scored as “near consensus” were discussed in depth for wording and message, with the goal of crafting an improved statement. Comments from voting rounds generated additional discussion that sometimes led to the generation of new statements in these discussion rounds. Any statements that were meaningfully changed (beyond minor grammatical changes) during a conference call were voted on again in the following round, and any new statements generated in discussion rounds were subject to voting in subsequent rounds as well. In Rounds 2 and 3, revised and new statements were presented for voting alongside statements that had already been accepted, allowing them to be interpreted in the context of the existing consensus.

3. Results

In this modified Delphi study, 11 fellowship‐trained academic laryngologists (n = 11) voted in three rounds to ultimately generate 27 accepted consensus statements about the diagnosis and management of refractory chronic cough in adults. 32 statements were voted on in Round 1, 18 of which reached consensus, 7 near consensus, and 7 no consensus. 15 statements based on the results of Round 1 were considered in Round 2, 14 of which reached consensus and 1 of which was near consensus. In Round 3, 3 statements were considered, and they all reached consensus. The sum of accepted statements, when added together round by round, exceeded the 27 total accepted statements because statements accepted in one round that had more than “minor grammatical edits” were subject to re‐voting in the subsequent round. Rewording was done to improve clarity and understanding and sometimes led to an already‐accepted statement being subject to re‐voting.

Tables 1, 2, 3, 4, 5, 6, 7, 8, 9 present the 27 statements that reached consensus, organized into categories: operational definition, pathophysiology, assessment of prior work‐up, phenomenology and symptomatology, treatment using neuromodulators, treatment using superior laryngeal nerve block, treatment using behavioral cough suppression, emerging treatments, and overall treatment approaches. Table 10 lists statements that did not reach consensus. This Results section provides a narrative description of the process that created the list of consensus statements in each category. The Discussion section that follows will present background, supporting evidence, and clinical context for the accepted statements.

TABLE 1.

Operational definition of RCC in adults: Statements that reached consensus.

Number	Statement	Mean	Outliers
1	RCC should be diagnosed in adults when cough has been present for > 8 weeks in a patient > 18 years old and when it remains refractory to evaluation and management of the most common etiologies of chronic cough: asthma and non‐asthmatic eosinophilic bronchitis, ACE‐I, reflux (acidic and non‐acidic), and sinonasal disease/allergy.	8.4	1
2	Operationally speaking, otolaryngologists often see cough patients who—though having had prior evaluation and treatment—may not have had complete work‐up for these issues; as this consensus statement is meant to support Best Practices for Otolaryngologic management of these cough patients who reflect the types of patients seen in clinical practice, statements will review emerging paradigms as relate to overall treatment of cough.	8.4	1

Abbreviations: ACE‐I, angiotensin‐converting enzyme inhibitor; RCC, refractory chronic cough.

TABLE 2.

Pathophysiology of RCC in adults: Statements that reached consensus.

Number	Statement	Mean	Outliers
3	RCC is thought to result from both peripheral and central hypersensitization of the cough reflex.	8.5	0
4	Peripheral and central hypersensitization may result in provokable coughing from seemingly benign chemical or mechanical stimuli, such as speaking, noxious or chemical smells, ingestion of acidic or spicy foods, air temperature changes, or light mechanical pressure.	8.8	0
5	Though central and peripheral hypersensitization are thought to occur in RCC, specific biochemical and cellular mechanisms underlying these changes have yet to be fully elucidated.	8.5	1

Abbreviation: RCC, refractory chronic cough.

TABLE 3.

Assessment of prior work up of RCC in adults: Statements that reached consensus.

Number	Statement	Mean	Outliers
6	When approaching a patient with possible RCC, consider whether work‐up and evaluation for established causes of cough has been thorough, and consider re‐visiting pulmonary, reflux, sinonasal/allergy and other etiologies as needed.	9	0
7	When evaluating past pulmonary work‐up, consider whether prior work‐up had included pulmonary function testing, bronchoprovocation challenge as indicated, appropriate chest imaging, and/or an approach to assessing for eosinophilic airway disease.	8.6	0
8	When evaluating past reflux workup, consider length and dosing of any prior acid suppression trials, presence or absence of objective reflux testing, and presence or absence of trials of barrier therapy such as alginates.	8.7	0
9	An adequate acid suppression trial should be 2–3 months in duration and include either twice daily dosing of an appropriately‐timed PPI, once daily PPI dosing with adjuvant H2 blocker to cover the remainder of the 24‐h period, or an equivalent 24‐h acid suppression regimen.	7.8	1
10	Non‐acid reflux can contribute to cough, is not expected to respond to acid suppression medication, and requires assessment either with pH‐impedance testing and/or response to empiric trial of alginate (barrier) therapy.	7.7	1
11	When evaluating past sinonasal work‐up, consider patient complaints of rhinorrhea and nasal congestion, prior sinus imaging and/or allergy testing, sinonasal endoscopy, and results from any empiric management for allergic rhinitis and/or chronic sinusitis.	8.7	0
12	When evaluating medication side effect as related to cough, consider both ACE‐I and also ARB medications.	7.7	1

Abbreviations: ACE‐I, angiotensin‐converting enzyme inhibitor; ARB, angiotensin receptor blocker; H2, histamine 2 receptor; PPI, proton pump inhibitor; RCC, refractory chronic cough.

TABLE 4.

Phenomenology and symptomatology of RCC in adults: Statements that reached consensus.

Number	Statement	Mean	Outliers
13	Signs and symptoms suggesting laryngeal hypersensitivity might include history of viral prodrome, dry cough associated with throat irritation, or stimuli such as talking, laughing, or odors.	8.27	0
14	Patients being evaluated for RCC should be asked about impact of cough on their quality of life as relates to social interactions, social and professional handicap, and psychological wellbeing.	8.6	0

Abbreviation: RCC, refractory chronic cough.

TABLE 5.

Treatment using neuromodulators for RCC in adults: Statements that reached consensus.

Number	Statement	Mean	Outliers
15	Neuromodulators such as amitriptyline, nortriptyline, gabapentin, pregabalin, tramadol, and baclofen have a potential role in treatment of RCC.	8.8	0
16	Though no consensus on medication type, dosing, or titration regimen has emerged as superior to another, most neuromodulators for cough should be dose‐titrated over time to balance concerns for patient tolerance with goal of therapeutic effect.	8.2	0
17	Neuromodulators have significant side effect profiles which may limit patient tolerance and ability to durably treat RCC.	8.55	0

Abbreviation: RCC, refractory chronic cough.

TABLE 6.

Treatment using superior laryngeal nerve block for RCC in adults: Statements that reached consensus.

Number	Statement	Mean	Outliers
18	SLN block can be a safe and effective treatment option for appropriately selected patients with neurogenic RCC.	8.5	0
19	Superior laryngeal nerve blocks may be used unilaterally or bilaterally to treat patients.	8.7	0
20	The optimal regimen for SLN block medication, dose, and treatment frequency is not yet standardized.	8.5	0
21	Serial steroid injection can have side effects which can lead to considerations in patient counseling, frequency of injection, and medication choice.	8.6	0

Abbreviations: RCC, refractory chronic cough; SLN, superior laryngeal nerve.

TABLE 7.

Treatment with behavioral cough suppression for RCC in adults: Statements that reached consensus.

Number	Statement	Mean	Outliers
22	Behavioral cough suppression therapy with a qualified speech language pathologist is a low‐risk intervention that can benefit many patients with RCC.	9	0

Abbreviation: RCC, refractory chronic cough.

TABLE 8.

Emerging treatments for RCC in adults: Statements that reached consensus.

Number	Statement	Mean	Outliers
23	Vocal fold augmentation is a treatment option in patients with RCC who have concomitant glottic insufficiency.	8	0
24	Laryngeal botulinum toxin injections can be considered for some patients with RCC.	7.5	0

Abbreviation: RCC, refractory chronic cough.

TABLE 9.

Overall treatment approaches for RCC in adults: Statements that reached consensus.

Number	Statement	Mean	Outliers
25	Treatment of RCC should be individualized and guided by both patient‐specific considerations and a thorough understanding of the risk and efficacy of the various options. There is no single approach to be used for all patients, and multimodal treatment may be pursued.	8.91	0
26	As a broad set of tools to be used in treatment of RCC is developed, the use of prolonged opioid to suppress cough in non‐specific fashion is discouraged.	7.5	1
27	As understanding of RCC evolves, it is expected that the evidence base supporting some emerging treatments may grow and that new treatments will be developed.	8.5	1

Abbreviation: RCC, refractory chronic cough.

TABLE 10.

Statements that did not reach consensus for RCC in adults.

Number	Statement	Group	Mean	Outliers
21	Trigger point injection for RCC has not been fully described but may be offered to some patients with discrete mechanical stimuli zones.	Treatment—Superior Laryngeal Nerve Block	6.73	3
24	Patients with co‐morbid laryngeal disorders such as glottic insufficiency, muscle tension dysphonia, or inducible laryngeal obstruction are more likely to benefit from BCST.	Treatment—Behavioral Cough Suppression	5.73	4
25	Limited but emerging evidence supports the possibility of capsaicin to aid in behavioral cough suppression by helping patients with RCC to schedule cough.	Treatment—Behavioral Cough Suppression	5.64	1
26	Patients may be counseled and educated about a novel class of pharmacologic agents targeting P2X3 receptors that may eventually have a role in treatment of RCC, but currently available evidence about effect size and side effect profile are such that these are not yet approved by the FDA for routine clinical use.	Emerging Treatments	7.09	3
30	In choosing which RCC treatments to start with, decision‐making based on likely benefit and goal of limiting side effects favors trial of alginates as most patients have not had this, and it can effectively treat RCC in many patients	Overall Treatment Approaches	5.36	7
32	Consideration of tolerance and side effect profile means that treatment of neuropathic mechanisms in RCC might reasonably begin with SLN block rather than neuromodulators.	Overall Treatment Approaches	7.18	3

Abbreviations: BCST, Behavioral cough suppression therapy; FDA, Food and Drug Administration; RCC, refractory chronic cough; SLN, Superior laryngeal nerve.

3.1. Operational Definition Statements

Two statements established an operational definition for RCC. The first statement defined RCC based upon prior literature. A second statement justifying the use of this ECS to establish adequate diagnostic criteria for RCC based on typical patient presentation to subspecialty clinics was made to guide further discussion. Both statements were rapidly accepted in the first round of voting, with minimal grammatical edits.

3.2. Pathophysiology Statements

Three statements were developed to clarify the current accepted pathophysiology of RCC to guide future RCC discussion. Notably, the third statement clarifies our knowledge of the specific pathophysiologic mechanisms behind RCC as an area that is poorly understood. All three statements were accepted in the first round of voting with few edits.

3.3. Assessment of Prior Work‐Up Statements

The panel developed 7 statements regarding an appropriate work‐up for a patient with chronic cough prior to designating this cough “refractory.” This was an area of significant deliberation for the panel, particularly surrounding appropriate diagnostic modalities and trial of treatment to suggest for exclusion of reflux as a contributing factor to chronic cough. The panel wanted to lay out a minimum standard for appropriate work‐up, while accepting that some physicians and patients employ more than this “minimum” work‐up, on a case‐by‐case basis. Discussion of what was a reasonable minimum work‐up before declaring cough “refractory” resulted in extensive discussion, with three rounds of voting and editing between each round, and voting on revised statements in subsequent voting rounds. Six of the 7 statements reached consensus in the first round, and one did not reach consensus. Three of the statements meeting consensus and the one that had not were voted on again in the second round after changes were made in discussion, and all reached consensus in Round 2.

3.4. Phenomenology and Symptomatology Statements

Two statements were evaluated regarding common symptomatology among RCC patients. One reached consensus on the first round of voting, and the second reached near consensus in both Rounds 1 and 2 before reaching consensus in Round 3. The panel intended this section to guide clinicians on recognition of features of RCC, without establishing these symptoms as definitional.

3.5. Treatment Using Neuromodulators Statements

Three statements regarding neuromodulator treatment for RCC were developed, two of which reached consensus and one near consensus in the first round of voting. One statement reaching consensus was voted on again in the second round due to minor changes, while the near consensus statement did not reach consensus until the third round. These statements sought to clarify specific medications accepted under the umbrella term “neuromodulator” as well as reinforce awareness of systemic side effect profiles as they might impact clinical use.

3.6. Treatment Using Superior Laryngeal Nerve Block Statements

Overall, 4 of 5 statements developed regarding superior laryngeal nerve (SLN) block for RCC eventually reached consensus. 2 of these statements were accepted in the first round, and 2 were accepted in the second round after reaching near consensus in the first. One statement did not reach consensus in the first round and was not discussed further. These statements sought to support SLN block as a well‐described treatment for RCC, as well as to highlight modifications clinicians may employ to the originally described SLN block protocol.

3.7. Treatment With Behavioral Cough Suppression Statements

The panel included 3 statements regarding behavioral cough suppression therapy (BCST). Two of these did not reach consensus in the first round and were not discussed further, and one reached consensus in the second round after modification. This was intended to both remind clinicians about the utility of a low‐risk therapy for treating RCC, as well as to highlight that BCST is best performed by a speech‐language pathologist familiar with this treatment.

3.8. Emerging Treatments Statements

Two statements on emerging treatments for RCC met consensus, while one did not. The two reaching consensus focused on repurposing therapies for treatment of other laryngeal pathologies—specifically glottic insufficiency and laryngeal dystonia—that may contribute to RCC management. These therapies were included as they have shown evidence of reducing cough symptoms when used to treat these underlying pathologies, and they serve as a reminder to clinicians that other laryngeal pathologies may contribute significantly to laryngeal hypersensitization seen in RCC. The statement not meeting consensus addressed a family of medications (P2X3 and TRPV1 inhibitors) postulated to improve RCC symptoms but not yet approved in the United States for this indication, as of the writing of this statement.

3.9. Overall Treatment Approaches Statements

Four statements regarding overall treatment approaches were discussed by the panel in the first round toward the proposal of a context for incorporating potentially unfamiliar treatments into routine clinical practice. These were included to reinforce the need for individualized implementation of the listed techniques in treating RCC, with consideration of particular patient needs and with recognition of a risk/benefit approach to organizing utilization of the discussed treatments. Two statements in the first round did not meet consensus, and two were near consensus. In the second round, two new statements were fashioned based on the discussion and met consensus. One statement that met consensus was further refined and accepted in the third round.

4. Discussion

This section is meant to provide background, supporting evidence, and clinical context for the 27 accepted statements. As above, it is also organized into categories.

4.1. Operational Definition

The clinical scope of this ECS is established in Statement 1 (Table 1), as RCC in adults age 18 or older with greater than 8 weeks of cough having been specifically worked up for the most common sources of cough: “RCC should be diagnosed in adults when cough has been present for > 8 weeks in a patient > 18 years old and when it remains refractory to evaluation and management of the most common etiologies of chronic cough: asthma and non‐asthmatic eosinophilic bronchitis, ACE‐i, reflux (acidic and non‐acidic), and sinonasal disease/allergy.” These definitions have been established with multiple interdisciplinary guidelines and publications, most notably the American College of Chest Physicians (CHEST) guidelines from 2006, 2016, and 2018 [5, 6, 7]. These most common etiologies of chronic cough have been identified in prior prospective studies showing approximately 95% of chronic cough was associated with asthma or bronchitis/bronchiectasis, postnasal drip, and/or gastroesophageal reflux (GER) [9, 10]. Subsequent studies demonstrated cough as a significant side effect of angiotensin‐converting enzyme inhibitors (ACE‐Is) and, to a lesser degree possibly also angiotensin receptor blockers (ARBs), adding medication adverse reaction to the list of common etiologies [17, 18, 19]. However, the practical reality of patients presenting to otolaryngology clinics is that much or all of the recommended work up may not have been completed adequately to rule out most common sources of chronic cough—therefore, to make this guideline more clinically relevant and practical for those treating RCC, this document encompasses all chronic cough patients (i.e., adults with cough lasting longer than 8 weeks) by specifically addressing recommended work up for pulmonary, sinonasal, gastrointestinal, and systemic medication contributions to RCC with Statement 2 (Table 1): “Operationally speaking, otolaryngologists often see cough patients who—though having had prior evaluation and treatment—may not have had complete work‐up for these issues; as this consensus statement is meant to support Best Practices for Otolaryngologic management of these cough patients who reflect the types of patients seen in clinical practice, statements will review emerging paradigms as related to overall treatment of cough.”

4.2. Pathophysiology

Cough is a reflexive protective mechanism that exists to defend the airway from foreign debris and noxious irritative stimuli, and to clear the airway [1]. The cough reflex arc consists of two limbs. The afferent limb carries sensory signals from the laryngeal, pharyngeal, tracheal, and bronchial mucosa to the medulla via the vagus nerve. Sensory signals are also carried afferently from the ear by the auricular branch of the vagus nerve. After processing in the nucleus tractus solitarius of the medulla, as well as in higher cortical structures, the reflex arc transmits an output signal through its efferent limb to the larynx, respiratory muscles, and diaphragm, which execute the cough response [20]. Current research suggests that both peripheral and central limbs of the reflex arc can lead to refractory chronic cough [21, 22, 23]. This hypersensitization model explains why many RCC patients can be provoked to cough through otherwise benign stimuli such as speaking or laughing, strong odors, ingestion of acidic or spicy foods, air temperature changes, or light mechanical pressure.

The afferent limb is composed of two types of sensory fibers. Aδ fibers are fast‐responding mechanoreceptors that respond to stretch, as well as to the acidity and osmolarity of the airway mucosa. C‐fibers are slower‐responding nociceptive fibers that detect chemical irritants such as capsaicin, nicotine, ozone, and some cytokines [21]. Two main receptors have been implicated in increasing the sensitivity of afferent sensory fibers: transient receptor potential (TRP) receptors and purinergic P2X3 receptors. These are cation channels located on the C‐fiber afferent terminals of airway sensory nerve endings, and their activation can result in signal transmission to the medulla. TRP receptors have been shown to be upregulated in animal models of chronic airway inflammation, and this upregulation has been associated with a lowered cough threshold [24]. Higher levels of TRP receptors have also been identified in human bronchial biopsies from patients with chronic cough [25]. P2X3 is a receptor within the broader P2X family of ion channels and is expressed almost exclusively on sensory neurons [26]. Activation of P2X3 on airway sensory nerves has been shown to cause depolarization of both human and guinea pig vagus nerves [3]. Several novel chronic cough therapeutics, such as gefapixent and camlipixant, act as P2X3 receptor antagonists. Gefapixent is approved for use in Europe, the United Kingdom, Switzerland, and Japan but was not approved in the United States because of FDA concerns because of modest efficacy. Camlipixant is currently undergoing clinical trials with the goal of improving this therapeutic profile [27]. Similarly, trials of TRPV1 antagonists in RCC have not shown improvement in cough severity or frequency, suggesting a more complex signaling pathway [28, 29]. Finally, it has been shown that inflammatory mediators like bradykinin and prostaglandins can lower the activation threshold of these fibers and increase cough hypersensitivity [21].

Central processing of the cough reflex is not well understood. From a molecular perspective, while neurotransmitters such as glutamate and substance P have been implicated, the underlying mechanisms remain poorly elucidated. NK1 receptors, which bind substance P, may represent targets for emerging therapies [5]. More is understood at the macro level, as neuroimaging studies have begun to map the brain structures involved in cough hypersensitization. Functional magnetic resonance imaging (fMRI) studies have shown increased cortical and midbrain activity in patients with RCC during capsaicin challenge [30, 31]. These studies have also demonstrated hyperactivation within the nucleus cuneiformis and higher brain centers, as well as the periaqueductal gray—also implicated in chronic pain [32]. This connection with chronic pain may explain why neuromodulators, such as gabapentin, show efficacy in treating chronic cough [33, 34, 35, 36]. It further supports a central sensitization component in the model of refractory chronic cough, through the development of enhanced central gain or reduced inhibitory control, which amplifies weak peripheral signals. This model could explain why some patients have persistent symptoms despite treatment of peripheral causes [21, 22, 32].

This current understanding of both peripheral and central elements of cough hypersensitization led panelists to accept statements 3 and 4 (Table 2). Statement 3 states that, “RCC is thought to result from both peripheral and central hypersensitization of the cough reflex” and Statement 4 that, “peripheral and central hypersensitization may result in provokable coughing from seemingly benign chemical or mechanical stimuli, such as speaking, noxious or chemical smells, ingestion of acidic or spicy foods, air temperature changes, or light mechanical pressure.” In an acknowledgment that there is yet significant progress to be made in our conceptualization of these mechanisms, Statement 5 (Table 2) concedes that “though central and peripheral hypersensitization are thought to occur in RCC, specific biochemical and cellular mechanisms underlying these changes have yet to be fully elucidated.”

4.3. Assessment of Prior Work Up

Evaluating the rigor of prior work‐up in patients presenting with chronic cough is crucial to avoid missing potentially treatable etiologies unrelated to cough hypersensitivity [37]. Retrospective reviews of patients with chronic cough presenting to primary care physicians reveal marked heterogeneity in referral patterns, initial treatment attempts, and diagnostic testing [12, 13, 14]. Pulmonary and sinonasal work‐up often excludes formal allergy testing, pulmonary function testing, or empiric trial of medical management, and an estimated 15%–25% of patients do not receive chest imaging like a radiograph or chest CT. Additionally, work‐up for reflux etiologies varies vastly, with surveys suggesting that less than half of patients are treated empirically for GER, and up to a third of those patients are treated for less than a month [12]. Disappointingly, published guidelines directing physicians on the management of chronic cough often exclude assessment for occupational or environmental exposures altogether [38]. Consequently, physicians treating chronic cough should be well‐versed in a complete work‐up for common treatable etiologies before designating symptoms “refractory.” This led to the acceptance of Statement 6 (Table 3), stating, “When approaching a patient with possible RCC, consider whether work‐up and evaluation for established causes of cough has been thorough, and consider re‐visiting pulmonary, reflux, sinonasal/allergy and other etiologies as needed.”

Pulmonary etiologies of chronic cough include lesions, parenchymal lung disease, asthma, and pulmonary eosinophilic disease, which should all be ruled out during pulmonary work‐up [39, 40]. Statement 7 (Table 3) addresses this, listing specific options for testing and empiric treatment, while allowing for variations in treatment preference and diagnostic availability: “When evaluating past pulmonary work‐up, consider whether prior work‐up had included pulmonary function testing, bronchoprovocation challenge as indicated, appropriate chest imaging, and/or an approach to assessing for eosinophilic airway disease.” Specifically, a screen for mass, lesion, or other evidence of infectious or structural lung pathology with at least a chest radiograph is widely recognized as a first step and safety check in patients with chronic cough [5, 7, 12]. After this, asthma has historically been considered the most common pulmonary etiology of chronic cough, classically reported as accounting for between 24% and 29% of chronic cough cases [10, 12, 41]. While classic asthma presents primarily with dyspnea and wheezing, isolated chronic cough has been described as a significant proportion of patients with airway hyperreactivity, termed cough‐variant asthma (CVA) [40]. An intermediate asthma subtype termed “cough‐predominant asthma (CPA),” presenting with significant cough complaints in addition to wheezing and dyspnea, has also been described [42]. While concomitant structural disease such as bronchiectasis or chronic obstructive pulmonary disease is more frequently seen with classical asthma subtype, patients with any subtype of asthma may present with chronic cough [42]. Thus, a complete work‐up for asthma with pulmonary function testing, with subsequent assessment for airway hyperreactivity with bronchoprovocation testing as indicated, is recommended [6, 41]. Bronchoprovocation testing is specifically indicated in scenarios in which asthma is suspected but spirometry is normal, or in cases in which cough‐variant asthma is suspected [43, 44]. This is typically performed using a methacholine challenge, though histamine, hypertonic saline, mannitol, or exercise challenges may also be used, depending upon patient symptomatology and pulmonologist recommendation [44].

Additionally, eosinophilic airway disease in the absence of concurrent asthma, coined non‐asthmatic eosinophilic bronchitis (NAEB), has been described with increasing frequency in patients with chronic cough [39, 41, 45]. This disease process was initially discovered by sputum sample analysis in a cohort of chronic cough patients without asthma but responsive to inhaled corticosteroid therapy, presenting primarily with increased sputum eosinophil count compared to patients with asthma [39]. While initially thought to comprise about 10% of chronic cough patients, the relative proportion of NAEB compared to asthma may be underestimated, with some studies showing a relatively equal proportion of NAEB and CVA in patients explicitly tested for both etiologies [41, 46]. Gold standard for diagnosis remains sputum analysis showing > 3% eosinophils; however, as this can be onerous to obtain and is often masked by temporary neutrophil exacerbations, other mechanisms to diagnose have been developed [45]. Elevated levels of fractional exhaled nitric oxide (FeNO) have been validated in multiple studies as an adequate biomarker of NAEB, though both sensitivity and specificity are lower than with cough‐variant asthma [47]. Given the difficulty with definitive diagnostics and patient responsiveness to inhaled corticosteroids, a simple therapeutic trial of inhaled corticosteroids for patients with negative spirometry and suspected eosinophilic airway disease may also be considered [45]. Regardless of diagnostic choice, the specific assessment of eosinophilic airway disease separate from asthma work‐up is recommended in the chronic cough population (Table 3, Statement 7).

Laryngeal inflammation and hypersensitization due to GER‐related irritation are expected to account for approximately 21%–22% of chronic cough [10, 12]. This symptom constellation is often designated laryngopharyngeal reflux (LPR) when primarily presenting with hoarseness, globus pharyngeus, throat clearing, or cough instead of traditional heartburn symptoms [48, 49]. As these symptoms and corresponding signs of laryngeal inflammation are nonspecific, LPR is frequently misdiagnosed prior to dedicated work‐up or empiric testing, with at least 64% of patients ultimately receiving a different explanatory diagnosis [50]. Additionally, there is evidence that GER‐induced cough can occur with both acid and non‐acid reflux, and empiric antacid‐alone trials and pH‐only probes can miss non‐acid reflux [51]. Thus, a provider treating chronic cough must be able to critically review prior diagnostic and empiric testing to assess whether adequate for ruling out GER as a significant contributor to cough, rather than relying on the presence of traditional heartburn symptoms alone. This led to the acceptance of Statement 8 (Table 3): “When evaluating past reflux workup, consider length and dosing of any prior acid suppression trials, presence or absence of objective reflux testing, and presence or absence of trials of barrier therapy such as alginates.”

When assessing quality of acid suppression therapy, one should consider the medication type, timing, and duration of therapy. Proton pump inhibitor (PPI) therapy has been recommended by the American Gastroenterological Association (AGA) at a minimum once daily for the treatment of typical GERD symptoms [52]. However, twice‐daily acid suppression therapy has been demonstrated as superior to once‐daily administration in controlling both acid reflux events and specifically extraesophageal reflux symptoms [51, 52, 53]. More than twice‐daily administration of acid suppressive medications has not demonstrated increased efficacy and is not recommended [54].

The initial approach to acid suppression therapy in the work‐up of chronic cough historically has comprised twice‐daily PPI therapy, taken 30–60 min before meals. Practitioners concerned about limiting PPI exposure may replace the second dose of PPI with histamine‐2 receptor blocker therapy such as famotidine or ranitidine [48]. Duration of treatment is recommended to be at least 2–3 months based upon clinical guidelines from AAO‐HNSF, AGA, and CHEST [52, 55, 56]. Thus, for practitioners who prefer an empiric trial of medication over diagnostic exclusion of reflux, Statement 9 (Table 3) was included, stating “an adequate acid suppression trial should be 2‐3 months in duration and include either twice daily dosing of an appropriately‐timed PPI, once daily PPI dosing with adjuvant H2 blocker to cover the remainder of the 24‐hour period, or an equivalent 24‐hour acid suppression regimen.”

As alluded to previously, non‐acid reflux events have been correlated with triggering cough in this patient population [51]. Lasting effects from refluxate, specifically pepsin, on laryngeal and hypopharyngeal mucosa have also been proposed as a mechanism of reflux‐mediated inflammation [57, 58, 59, 60]. This led the panel to accept a separate statement (Statement 10, Table 3) regarding adequate assessment of non‐acid reflux: “Non‐acid reflux can contribute to cough, is not expected to respond to acid suppression medication, and requires assessment either with pH‐impedance testing and/or response to empiric trial of alginate (barrier) therapy.” Objective testing for GER/LPR contribution to chronic cough should therefore assess for reflux at both the distal esophagus and proximally—at either the upper esophagus or pharynx—when appropriate technologies such as hypopharyngeal‐esophageal dual probe study are available [48, 61]. Additionally, assessment of both acid and non‐acid reflux events requires impedance testing [48, 49]. Some literature supports a hypopharyngeal‐esophageal multichannel impedance with dual pH probe (HEMII‐pH) with impedance testing as the objective testing tool of choice in patients with chronic cough [62]. However, this degree of pH testing is not always readily available, leading panelists to vote specify only pH probe testing without further qualification. It should additionally be noted that assessment for sequelae of gastroesophageal reflux disease (GERD) with tools such as upper gastrointestinal endoscopy does not rule in or rule out GERD or LPR, but rather show if reflux has continued to a point where mucosal changes are seen. Thus, patients presenting with unremarkable endoscopy as presumed evidence of lack of reflux contribution to cough should either undergo objective reflux testing or subsequent empiric therapy trial.

As an alternative to pH impedance testing, a trial of barrier therapy to prevent both acid and non‐acid reflux events may be performed. Alginates, which have become popular as an over‐the‐counter, non‐medication alternative for GER, are a primary type of barrier therapy and can treat both acid and non‐acid reflux [63]. A 2017 meta‐analysis and systematic review of 15 RCTs found that alginate therapy significantly reduced symptoms of GER compared to placebo or antacid‐alone [64]. Patients seeking heartburn management may choose to use alginates as needed (e.g., at night or after a large meal); however, when attempting to rule out potentially silent reflux contribution to chronic cough, alginate therapy should ideally be used any time mechanical pressure of gastric contents on the lower esophageal sphincter increases, namely after each meal and before bedtime.

Sinonasal disease and postnasal drip, sometimes termed “upper airway cough syndrome” (UACS) or “postnasal drip syndrome” (PNDS) as it pertains to inciting cough symptoms, are believed to trigger cough through both mechanical stimulation and chemosensory signaling [4, 65]. Sinonasal disease is estimated to comprise the largest single contributing pathology in these patients, contributing to over 40% of cough cases in some retrospective reviews [10]. Similar to pulmonary and reflux‐related etiologies, assessment of sinonasal workup can comprise diagnostic exclusion of significant sinonasal disease or an adequate empiric trial of treatment of allergic rhinitis and/or chronic rhinosinusitis. This is specifically stated in Statement 11 (Table 3): “When evaluating past sinonasal work‐up, consider patient complaints of rhinorrhea and nasal congestion, prior sinus imaging and/or allergy testing, sinonasal endoscopy, and results from any empiric management for allergic rhinitis and/or chronic sinusitis.” The majority of patients presenting with UACS report post‐nasal drip, anterior rhinitis, and nasal congestion, which were shown to respond to a 4–8 week trial of daily first‐generation antihistamine [66]. Notably, when considering an adequate empiric trial, choice of antihistamine should also be considered; first‐generation H1 blockers have been demonstrated more efficacious in improving cough symptoms in these patients compared to second‐generation antihistamines, which is thought to be due to some additional anticholinergic activity [67, 68]. Leukotriene inhibitors have shown variable results in treating cough, and they appear to have the most impact in patients suffering from CVA as opposed to UACS/PNDS [68]. Alternative use of intranasal topical steroid therapy may be considered alone or in combination with topical antihistamine, particularly in patients with significant rhinitis and nasal congestion complaints [69, 70]. However, this data is more robust in the allergic rhinitis literature than for managing chronic cough alone, and for cough, intranasal therapy is backed by significantly less data than oral antihistamine therapy.

Diagnostic assessment for sinonasal disease should be reserved for chronic cough patients with a history suggestive of significant additional sinonasal symptoms. Sinus findings in patients with chronic cough associated with UACS are most commonly a deviated nasal septum, inferior turbinate hypertrophy, and mucosal thickening, which are non‐specific and can be normal variants [66].

Early rigid nasal endoscopy, as opposed to just anterior rhinoscopy, may be of benefit in patients with nasal symptoms, such as rhinitis and nasal congestion, that are more suggestive of chronic rhinosinusitis, but data regarding routine nasal endoscopy improving UACS/PNDS diagnosis is lacking [71]. Either skin prick testing (SPT) or serum‐specific IgE bloodwork can be considered for allergy testing, but they should be reserved for patients with a history more specific to chronic rhinitis/rhinosinusitis or asthma [5, 6, 71]. Additional diagnostic testing, such as sinus or maxillofacial CT or allergy testing, is not recommended as a first‐line diagnostic in patients with isolated chronic cough due to low pretest probability, and they should be reserved for patients with persistent sinonasal symptoms refractory to medical management or sinonasal symptoms outside of isolated chronic cough [72].

While a number of medications including calcium channel blockers, immunosuppressants, and even omeprazole have been associated with chronic cough, the incidence of cough as a significant medication side effect is low [73]. However, ACE‐Is have demonstrated cough as a side effect in 20% or more of patients [17, 18, 19]. Notably, this may begin at any time, including in patients who have tolerated the medication for years previously without issue [74]. Patients on ARBs have been found to develop cough at much lower rates than those on ACE‐Is. While early evidence suggested an over 20% incidence of cough in side‐by‐side comparison with ACE‐Is (which, in these studies, notably showed higher rates of ACE‐I cough approaching 70%), subsequent systematic review and meta‐analysis have found patients taking ARBs exhibit cough rates slightly higher but not significantly different from those on placebo [18]. While acknowledging the markedly reduced risk in cough compared to ACE‐Is, in light of this admittedly heterogenous data, this panel did want to suggest at least consideration of ARBs when evaluating patients with chronic cough, and included both medications in Statement 12 (Table 3): “When evaluating medication side effect as related to cough, consider both ACE‐I and also ARB medications.”

4.4. Phenomenology and Symptomatology

Many survey studies of patients with RCC have addressed common cough triggers, addressed in Statement 13 (Table 4): “Signs and symptoms suggesting laryngeal hypersensitivity might include history of viral prodrome, dry cough associated with throat irritation, or stimuli such as talking, laughing, or odors.” Multiple survey studies support this statement. A 2011 survey of RCC patients revealed that many perceived an abnormal throat sensation to be a trigger for their cough. Perfumes, aerosols, cold air, and talking or laughing have also been noted to trigger dry cough in these patients [75]. Over 60% of patients in another survey reported that chemical scents such as smoke or bleach, as well as cold air, triggered their cough. Exercise was a trigger in over 50% of patients [76]. Very often, RCC begins after an upper respiratory illness.

This type of cough has been noted to significantly interfere with patients' quality of life (QoL). Cough often limits verbal communication and physical activity, and 64% of patients have reported that it interferes with their social life [77]. Studies assessing both global health‐related QoL—such as the Sickness Impact Profile—as well as cough‐specific instruments, such as the Leicester Cough Questionnaire and the Cough Quality of Life Questionnaire, have noted significant reductions in reported QoL [78, 79, 80, 81]. Interestingly, this impact appears to be mediated by gender. Not only are females known to have increased cough reflex sensitivity—both in healthy individuals and in those with chronic cough—when challenged with capsaicin, but chronic cough presents a unique psychosocial burden in middle‐aged women due to cough‐related urinary incontinence [82, 83]. This often results in embarrassment and avoidance of social situations. Fortunately, studies of RCC have shown that effective cough treatment can improve the QoL of affected patients [33, 84]. These important studies reviewing the effects of chronic cough on patients' QoL led panelists to accept Statement 14 (Table 4): “Patients being evaluated for RCC should be asked about impact of cough on their quality of life as relates to social interactions, social and professional handicap, and psychological well‐being.”

4.5. Treatment Using Neuromodulators

Use of neuromodulator medications—medications which are thought to modulate sensory nerve signaling pathways either as primary intended effect or significant side effect—was first recognized in treatment of RCC in the early 2000s [85, 86]. Tricyclic antidepressants (TCAs) have received the most investigation, with one study examining nortriptyline and four studies establishing amitriptyline as a treatment of RCC [84, 85, 87, 88]. The first two of these by Jeyakumar et al. (a randomized controlled trial) and Bastian et al. (a prospective cohort series) came out in 2006, with both showing at least 40%–50% improvement in subjective cough symptoms in a majority (> 85%) of patients with 10 mg of amitriptyline taken every evening [84, 85]. While encompassing small cohorts of 28 and 12 patients, respectively, these established amitriptyline as efficacious in RCC. Subsequent examination of escalating dosing of amitriptyline in RCC patients by Norris et al. demonstrated 78% symptom improvement within 5 months, with only 25% requiring escalating dose of amitriptyline (from 25 mg to a maximum of 75 mg daily) or a change to gabapentin [88]. Long‐term efficacy of amitriptyline in RCC treatment was established by Ryan and Cohen in 2016, showing 53% of patients demonstrating greater than 50% improvement in cough at 2–3 years, and 66% of patients no longer taking the medication [87]. Bowen et al. compared TCA (either amitriptyline or nortriptyline) and gabapentin, demonstrating both to be efficacious, though with reduced tolerance and increased tachyphylaxis to TCAs in their patient cohort, limiting long‐term efficacy [89]. Subsequently in 2020, Song et al. reported a 72% patient‐reported improvement rate in cough symptoms with dosing of nortriptyline, started at 10 mg nightly but escalating up to 100 mg nightly as needed [90]. Recently, Chen et al. have examined the TCA melitracen (in conjunction with an antipsychotic flupentixol) in the treatment of RCC with promising results; however, antidepressant medication other than amitriptyline and nortriptyline have not been extensively evaluated outside of this study [91].

Four primary studies established gabapentin as effective in reducing patient symptoms of RCC. The first of these was in 2005 by Lee and Woo, which showed 68% of patients reporting some symptomatic relief by escalating gabapentin dosing from 100 to 900 mg daily for at least 4 weeks [86]. Notably, all patients in their prospective series underwent videostroboscopy and laryngeal electromyography (EMG) to diagnose any superior laryngeal or recurrent laryngeal neuropathy, and the response rate was higher in those with evidence of neuropathy. A year later, Mintz and Lee published a case report detailing the resolution of RCC in a patient who began taking gabapentin for migraine headache [36]. In 2012, Van de Kerkhove et al. described a regimen of 600 mg gabapentin three times daily for a minimum of 4 weeks, which improved cough in 57% of patients by an average of 2.8 points on a 10‐point patient‐reported cough severity scale [34]. The same year, Ryan et al. published a randomized controlled trial of 62 patients, comparing a 10‐week trial of gabapentin 600 mg three times daily to placebo, which demonstrated significant improvement in LCQ (inter‐group difference of 1.8 points) on gabapentin compared to placebo [33].

Pregabalin, another gabapentinoid with stronger GABA‐ergic receptor binding, faster onset, higher oral bioavailability, and reduced renal excretion compared to gabapentin, has been described in the neuropathic pain literature as an alternative to gabapentin, with similar or superior results [92]. Pregabalin application to RCC was first described by Vertigan et al. in 2016 as a neuromodulator addition to behavioral cough suppression therapy, showing improved cough control with dual therapy compared to therapy and placebo [93]. A subsequent 2019 case report described pregabalin monotherapy (75 mg twice daily for treatment of post‐herpetic neuralgia) as efficacious in RCC symptom management [94]. The largest trial of pregabalin for RCC was performed by Adeli et al. in 2023, comparing pregabalin with dextromethorphan to dextromethorphan with placebo, showing significant improvement in LCQ after 8 weeks of therapy in the pregabalin group [95]. Interestingly, subsequent analysis of patients with chronic cough with incompletely treated pulmonary origin (obstructive lung pathology or interstitial lung disease) showed improved cough symptom response with pregabalin compared with patients without other explanatory pathophysiology, suggesting that there exists a neurosensory component that can be targeted in these patients [96].

Tramadol, an atypical opioid which limits serotonin and norepinephrine reuptake in addition to conferring mild μ‐receptor activity, was originally described as efficacious for chronic cough in a case report in 2009 [97]. A subsequent 2017 prospective study by Dion et al. demonstrated significant improvement in both Cough Severity Index (CSI) and LCQ scores with tramadol 50 mg every 8 h as needed for a minimum of 14 days [98]. No further studies evaluating tramadol efficacy in RCC have been published as of the writing of this ECS.

Baclofen, a GABA_B receptor agonist with known muscle relaxant properties, has been described in the treatment of chronic cough primarily in patients in whom GER is considered a primary etiology of cough but is refractory to PPI therapy. Baclofen was first described to improve chronic cough symptoms as early as 1998, with two patients showing improvement in cough severity and frequency with baclofen 10 mg three times daily for 14 days compared to placebo. This was revisited in 2012, with a case series of three patients by Xu et al. reporting that baclofen improved GER‐associated cough symptoms [99]. Shortly thereafter, the same group published a prospective trial with 16 patients, assessing the efficacy of adding baclofen 20 mg daily to a regular daily PPI regimen for 8 weeks; it showed that > 50% of patients subjectively reported cough improvement and significantly lower laryngeal sensitivity with capsaicin testing [100]. The largest study to date assessing baclofen is Dong et al.'s 2019 randomized controlled trial of 234 patients with suspected GER‐related cough refractory to PPI and promotility agent therapy [35]. The study compared baclofen 60 mg daily to gabapentin 900 mg daily for 8 weeks of therapy and showed similar rates of cough resolution (greater than 50% in both cohorts) and similar reduction in cough sensitivity. However, gabapentin was associated with fewer reports of somnolence and dizziness side effects compared to baclofen. A recent randomized controlled trial evaluating lesogaberan—another GABA_B agonist similar to baclofen but preferentially acting on peripheral receptors and thus with fewer central side effects—compared to placebo demonstrated decreased capsaicin‐induced cough and overall cough episodes after 2 weeks of therapy in patients with GER‐associated cough [101]. Notably, whether historical features alone or formal pH probe studies establish reflux varies across studies, and none of the studies evaluating baclofen for GER‐associated cough evaluated the impact of barrier therapy.

Based on these data in aggregate, Statement 15 (Table 5) was accepted: “Neuromodulators such as amitriptyline, nortriptyline, gabapentin, pregabalin, tramadol, and baclofen have a potential role in treatment of RCC.” Notably, however, these studies demonstrated a wide variety of dosing regimens, leading to the acceptance of Statement 16 (Table 5): “Though no consensus on medication type, dosing, or titration regimen has emerged as superior to another, most neuromodulators for cough should be dose‐titrated over time to balance concerns for patient tolerance with goal of therapeutic effect.”

One of the primary concerns with neuromodulator therapy is systemic side effects, and indeed these medications' efficacy is often limited by patient tolerance. In a retrospective observational study specifically examining medication side effects in neuromodulator therapy, adverse effects are reported in 29%–60% of patients, with up to 50% of those patients stopping therapy altogether due to intolerable side effects [102]. Sedation, followed by xerostomia and dizziness, was the most common side effects of both TCAs and gabapentin, while tramadol had nausea, headaches, and constipation as its most common side effects. Tachyphylaxis—the need for continually escalating doses of therapy due to diminishing therapeutic benefit—has also been observed in an average of 26% of patients on neuromodulators, with amitriptyline exhibiting the highest tachyphylaxis rate (34%) and gabapentin the lowest (13%). Dependence, defined as either being unable to stop the medication after attempts at de‐escalation or recurrence of symptoms after medication cessation, was also noted in 27% of patients. This led to the acceptance of Statement 17 (Table 5): “Neuromodulators have significant side effect profiles which may limit patient tolerance and ability to durably treat RCC.”

4.6. Treatment Using Superior Laryngeal Nerve Block

The superior laryngeal nerve (SLN) block is a peripheral nerve block targeting the internal branch of the SLN. This nerve carries sensory input from the larynx and pharynx, and the technique, adapted from the pain management and anesthesia literature by Simpson et al., aims to reduce hypersensitization of the cough reflex by blocking afferent nerve signals in patients with cough hypersensitivity [103]. Patients are typically selected based on a presumptive diagnosis of cough hypersensitivity specific to the larynx, often referred to as “neurogenic cough,” which is refractory to other treatment modalities, as outlined in previous sections of this document. This has, in recent years, been widely performed for cough, and on the strength of growing literature concerning efficacy of this approach, panelists accepted Statement 18 (Table 6): “SLN block can be a safe and effective treatment option for appropriately selected patients with neurogenic RCC.”

The SLN block targets the insertion point of the internal branch of the SLN through the thyrohyoid membrane; the injection is performed just anterior to the superior cornu of the thyroid cartilage, inferior to the greater cornu of the hyoid bone [103]. The injected medication typically consists of a 1:1 mixture of a long‐acting corticosteroid—most commonly triamcinolone 40 mg/mL—with a local anesthetic, often 0.5% bupivacaine or 1% lidocaine [103, 104]. There is some variation in this, however. In the original Simpson description, methylprednisolone 80 mg/mL was also used, and in both the Simpson and Duffy descriptions, 0.5% bupivacaine has been used in place of lidocaine [105]. Some physicians perform single‐component SLN blocks as well, with one study reporting use of 20 mg/mL triamcinolone acetonide alone [106]. More recently, some physicians anecdotally report performing anesthetic‐only injections to reduce steroid exposure, with some brief mentions in subgroup analyses of SLN injection studies [106, 107]. Injection frequency also varies widely across studies, ranging from single injections to repeat sessions every 2, 4, or 6 weeks. In a scoping review, McClutchy et al. reported a total injection range of 1 to 17 per patient [108]. Long‐term de‐escalation strategies remain undefined and are currently under investigation. With this uncertainty about the specifics of the technique, panelists accepted Statement 20 (Table 6): “The optimal regimen for SLN block medication, dose, and treatment frequency is not yet standardized.”

The decision to use unilateral versus bilateral injections is also not standardized. Some physicians perform unilateral injections based on symptom laterality and advocate alternating sides with each session [108]. Alternating sides may impact outcomes, as Talbot et al. reported that 20%–40% of patients in their series who did not experience improvement after the first block reported benefit after a contralateral injection [109]. Quinton et al. focused their study on bilateral blocks and found that they led to statistically significant improvement in cough‐related quality‐of‐life scores [106]. Variation in laterality of the technique led to the acceptance of Statement 19 (Table 6): “Superior laryngeal nerve blocks may be used unilaterally or bilaterally to treat patients.”

Despite this variability, multiple studies have demonstrated the efficacy of SLN blocks for appropriately selected patients. In the original 2018 study, Simpson et al. showed a reduction in CSI scores from 26.8 to 14.6 [103]. Dhillon et al. reported a mean 16.3‐point improvement in CSI [110, 111]. Larger retrospective reviews in subsequent years showed similar improvements in subjective cough severity, with subjective improvement in approximately 75% of patients across an average of three injections per patient [106, 112, 113]. In a randomized controlled trial, Tipton et al. demonstrated improvement in Leicester Cough Questionnaire (LCQ) scores from 10.09 to 13.15 in the treatment group, while the placebo group showed no change. The largest improvement was in the social domain [104].

Adverse effects have been reported with SLN injections, though they are rare. The most common are transient throat anesthesia or paresthesia, which are more frequently observed with bilateral injections. In one study, 30% of patients reported altered sensation at the injection site, and 7% experienced transient throat pain [109]. There are theoretical concerns for change in metabolism, weight gain, change in hypertension control, change in glycemic control, and other systemic side effects with repeated steroid injections; however, evidence for serious SLN block‐related side effects is rare. Minor side effects, however, do occur, with Peachman et al. reporting that 40%–50% of patients report mild and self‐limited side effects when considering all the injections they have received, including 56% reporting altered throat sensation and 11% reporting anxiety [114]. Dhillon et al. described one case of transient hyperglycemia in a patient with type 1 diabetes requiring additional insulin [111]. Scattered case reports have also described transient post‐injection globus and self‐limited bruising at the injection site [108]. Of note, steroid injections in laryngology are also done for serial intralesional steroid injections (SILSI) in patients with idiopathic subglottic stenosis, and a prospective study of steroid injection in this population noted menstrual irregularities in 30%–40% of women of reproductive age [115]. Anecdotally, concern over potential steroid side effects with repeated injection is what has led many of the panelists who use this technique regularly in their own practice to limit the number of injections in a given 12‐month period—using a set schedule for injection, spreading injections out as possible, and/or switching to anesthetic‐only injections as necessary. These poorly described but potential side effects of SLN injection led panelists to reach consensus on Statement 21 (Table 6): “Serial steroid injection can have side effects which can lead to considerations in patient counseling, frequency of injection, and medication choice.”

4.7. Treatment With Behavioral Cough Suppression

Behavioral Cough Suppression Therapy (BCST) was first described in 1988 as an adaptation of voice therapy techniques for hyperfunctional dysphonia to patients with cough [116]. Described initially as an intervention for “habitual cough,” or “tic cough,” BCST has consistently been shown to help patients reduce severity, frequency, and duration of RCC symptoms, regardless of whether a behavioral component features strongly in the patient's history [117, 118, 119, 120]. Two randomized controlled trials exist as of the writing of this ECS supporting BCST monotherapy over verbal education alone [117, 120]. Both studies consisted of four sessions of weekly BCST compared to weekly placebo therapy (comprising general healthy lifestyle counseling), and demonstrated reduction in patient‐reported outcome measures (PROMs) in the BCST group compared to placebo. A third randomized controlled trial of online BCST delivery showed similar improved cough severity scores compared with telehealth counseling on healthy lifestyle [121]. Subsequent studies have demonstrated objective cough frequency reduction and reduced laryngeal sensitivity (as measured with response to capsaicin irritant), and at least 9 additional self‐controlled case series have similarly supported BCST monotherapy as an efficacious treatment modality for chronic cough [119, 122]. Therapy duration of at least 4 weekly sessions has been demonstrated efficacious, and demonstrates significant symptom improvement with both individualized and group telehealth options [123, 124]. Patient improvement with entirely asynchronous digital delivery of pre‐recorded videos has additionally been demonstrated, suggesting this therapy modality can be beneficial to patients who do not have ready access to trained speech language pathologists [121]. Therapeutic effect lasting over a year has additionally been described [125].

BCST may be recommended as monotherapy or in conjunction with other treatment modalities. Vertigan et al. demonstrated in a randomized controlled trial of 40 patients that patients treated with BCST in conjunction with pregabalin neuromodulator therapy had reduced cough severity on standardized PROMs when compared with BCST and placebo, though notably this difference was no longer seen after 18 weeks [93]. While this study comprises the only published literature on BCST concurrent with other medical therapy for cough suppression, Slovarp et al. have additionally described BCST with laryngeal irritant stimulation as more efficacious than BCST alone [126]. In this study, improved PROM scores, objective urge‐to‐cough scores, and cough frequency testing performance were achieved with nebulized capsaicin during BCST sessions, suggesting a desensitization component to BCST. These data in aggregate led the panel to accept Statement 22 (Table 7): “Behavioral cough suppression therapy with a qualified speech language pathologist is a low‐risk intervention that can benefit many patients with RCC.” Notably, though quality evidence supporting its efficacy already exists, more data supporting BCST duration of effect and use in multimodal treatment plans is expected in the future.

4.8. Emerging Treatments

Vocal fold augmentation and laryngeal botulinum toxin injection are two emerging treatments for refractory chronic cough (RCC). While not yet widely employed specifically for cough, both are widely used for other laryngeal pathologies and have a growing body of literature supporting their impact on patients with chronic cough. In vocal fold augmentation, the goal is to compensate for glottic insufficiency, thereby reducing compensatory hyperfunction. Crawley et al. proposed three potential mechanisms by which injection laryngoplasty may improve RCC in patients with glottic insufficiency [127]. First, they suggest that augmentation reduces microaspiration and associated irritation that drives the cough reflex. Second, they propose that augmentation may alter sensory signaling: with increased bulk, the required closing force during cough or phonation is reduced, resulting in less vocal fold trauma and, consequently, less afferent cough reflex activation. Finally, they acknowledge the placebo effect as a potential mechanism. This is particularly relevant in the study of chronic cough, where placebo responses are known to be strong; one randomized study of cough suppressants found the placebo arm to be more effective than the experimental treatment [128].

Several recent studies have investigated vocal fold augmentation for RCC. Crawley et al., in a retrospective series of six patients with glottic insufficiency who had failed multiple medical and behavioral treatments, demonstrated subjective improvement in five of six patients following augmentation with temporary filler [127]. All patients showed improvements in CSI scores, with a mean improvement of 7.3 points. Notably, one patient received three injections due to symptom recurrence as the filler resorbed and then experienced consistent benefit with each subsequent treatment. Litts et al. reviewed 23 patients with glottic insufficiency and cough symptoms lasting more than 8 weeks who underwent injection augmentation. They reported a significant decrease in CSI scores from pre‐ to post‐injection, and 78.2% of patients noted a ≥ 50% improvement in cough symptoms [129]. In the largest cohort reported to date, Dwyer et al. presented 28 patients who underwent a total of 30 temporary vocal fold augmentation procedures—each with a complete cough workup and documented glottic insufficiency [130]. They reported an average CSI decrease of 1.4 points, which did not reach statistical significance. However, they showed that 13 patients reported satisfactory improvement in cough, 5 reported partial improvement, and 7 reported no improvement. The remaining patients lacked documented changes in their cough symptoms on chart review. It is interesting that some RCC patients in vocal fold augmentation studies experienced resolution of their chronic cough after a single injection, while others required repeated injections as the effects of the temporary augmentation wore off. This pattern suggests a potential role for augmentation in addressing underlying cough hypersensitivity mechanisms driving the aberrant cough reflex in select patients. These data support the panelists' decision to reach consensus on Statement 23 (Table 8): “Vocal fold augmentation is a treatment option in patients with RCC who have concomitant glottic insufficiency.”

The second emerging treatment for RCC is injection of Botulinum toxin A (BtxA) into laryngeal musculature. The exact mechanisms for BtxA injection in chronic cough are not well understood but could relate to effects on afferent nerve signaling and reduction of slow C‐fiber activation [131]. In addition, BtxA may modulate signaling in sensory neurons by modulating TRP signaling, and reduced cough threshold is known to be associated with increases in TRP receptor expression [20, 25, 132, 133]. Finally, there could be a mechanical mechanism in temporary laryngeal muscular weakness through BtxA's inhibition of presynaptic neural signal transduction that could reduce laryngeal hyperfunction and improve local mucosal irritation and resultant hypersensitivity.

Multiple studies have recently investigated the use of botulinum toxin A (BtxA) in the treatment of RCC. Sasieta et al. reported on 22 patients who underwent 31 EMG‐guided thyroarytenoid BtxA injection sessions [131]. Their primary outcome was self‐reported improvement of ≥ 50% in cough severity, which was achieved in 16 of 31 (52%) sessions. After the first injection, 11 patients (50%) reported > 50% improvement. Interestingly, post‐procedural mild dysphagia to liquids appeared to predict treatment response (positive predictive value of 84% and a negative predictive value of 100%). All patients initially received 2.5 units of Botox into each thyroarytenoid muscle (total dose 5 units), though some doses were adjusted in subsequent sessions. Dose changes at the second treatment did not correlate with treatment outcome. Chu et al. reported a case series of four patients treated with BtxA injections for chronic cough, with a mean dose of 4.0 units per session [134]. All patients experienced significant symptom relief after a median of 7 injections. Novakovic et al. used BtxA for what they defined as “laryngeal sensory dysfunction,” a broader category that included both RCC and abnormal throat sensation [135]. 14 patients underwent 25 supraglottic injections into the false vocal folds (19 unilateral, 6 bilateral), with a mean total dose of 7.74 units. They reported an average improvement of 2.6 points on the Newcastle Laryngeal Hypersensitivity Questionnaire, and improvements of 8 and 5 points on the Reflux Symptom Index (RSI) and CSI, respectively. Voice Handicap Index‐10 (VHI‐10) scores did not change. Finally, Campbell et al. studied 47 RCC patients who underwent a total of 197 BtxA injections [136]. Of those, 69.8% of injections resulted in subjective improvement in cough symptoms. Mean CSI improved by 2.12 points, though this did not meet a minimally clinical important difference threshold; voice, as measured by the VHI‐10, was not changed negatively. Post‐injection self‐limited dysphagia occurred in 7.6% of cases. These data led panelists to approve Statement 24 (Table 8): “Laryngeal botulinum toxin injections can be considered for some patients with RCC.”

In summary, both vocal fold augmentation and laryngeal BtxA injection may alleviate symptoms in appropriately selected patients with RCC, but significant work remains to be done in assessing patient selection and longer‐term treatment efficacy. In particular, further research is needed to better define optimal dosing, injection frequency, and predictive factors for treatment response with BtxA. As shown in the literature on laryngeal dystonia, BtxA dosing can be highly variable and technically challenging, and when performed with EMG guidance, the procedure is notably operator dependent.

4.9. Overall Treatment Approaches

The pathophysiology of RCC is complex, involving multiple mechanosensory and chemosensory pathways within the airway and with contributions from disparate anatomic sites. Patient symptomatology and history can vary markedly and include findings from multiple common etiologies simultaneously. Additionally, multimodal treatment and treatment escalation plans have demonstrated improved efficacy in treating RCC [137]. Thus, this panel wanted to emphasize with Statement 25 (Table 9) that RCC treatment should be tailored to the individual, and often includes multimodal treatment: “Treatment of RCC should be individualized and guided by both patient‐specific considerations and a thorough understanding of the risk and efficacy of the various options. There is no single approach to be used for all patients, and multimodal treatment may be pursued.”

Additionally, in guiding a practitioner's overarching approach to treating RCC, the panel did want to specifically address opioid use, particularly in light of the recent opioid addiction epidemic. While temporary opioid use (such as codeine or morphine) has been described as efficacious in managing cough symptoms, these medications have high addictive potential and a high rate of serious, often life‐threatening side effects [138, 139]. Thus, extended treatment with opioids is not recommended and should be discontinued in preference for treatment of underlying etiology/etiologies or use of another long‐term medical management with fewer side effects, addressed in Statement 26 (Table 9): “As a broad set of tools to be used in treatment of RCC is developed, the use of prolonged opioid to suppress cough in non‐specific fashion is discouraged.” Here, by “non‐specific fashion,” the statement refers to an opioid prescription with the goal of broadly suppressing cough without identifying or treating an underlying mechanism and potentially exposing patients to inappropriate long‐term opioid risk. Notably, this excludes the use of tramadol as a neuromodulator in the treatment of RCC, as this is often referred to as an “atypical opioid” given its lower μ‐receptor agonist activity, alternate pathway action limiting serotonin and norepinephrine uptake, and ultrarapid metabolism [140, 141].

Finally, and as highlighted throughout this ECS, while a significant body of literature exists surrounding the pathophysiology and treatment of RCC, there are a number of emerging treatments expected in this field in the future. The panel welcomes new additions to our armamentarium in treating RCC and improving the quality of life in these patients with Statement 27 (Table 9): “As understanding of RCC evolves, it is expected that the evidence base supporting some emerging treatments may grow and that new treatments will be developed.”

5. Strengths and Limitations

This ECS is based on the opinions of carefully chosen content experts and is provided for informational and educational purposes only. The purpose of the development group is to synthesize information, along with possible conflicting interpretations of the data, into clear and accurate answers to the question of interest. ECSs may reflect uncertainties, gaps in knowledge, opinions, or minority viewpoints. The goal is that through a consensus development process, many of the uncertainties are overcome, a consensual opinion is reached, and statements are formed. ECSs are not clinical practice guidelines and do not follow the same procedures as clinical practice guidelines. ECSs do not purport to be a legal standard of care. The responsible physician, in light of the circumstances presented by the individual patient, must determine the appropriate treatment, diagnosis, and management. Consideration of ECSs will not ensure successful patient outcomes in every situation. The ABEA emphasizes that these ECSs should not be deemed to include all proper diagnosis, management, or treatment decisions or methods of care, or to exclude other treatment decisions or methods of care reasonably directed to obtaining the same results.

6. Conclusions

A development group of fellowship‐trained laryngologists with significant experience treating RCC developed consensus statements on diagnosis and management of RCC based upon available evidence using an established protocol. The definition of RCC and specific criteria for appropriate work‐up to rule out alternative etiologies of chronic cough were elucidated. Specifically, statements identified what constitutes appropriate trial of therapy and diagnostic testing for sinonasal, pulmonary, and gastrointestinal etiologies of chronic cough. The mechanism and associated symptomatology surrounding laryngeal hypersensitization underlying RCC pathophysiology were described. Treatment options for RCC that are currently recommended based upon significant bodies of evidence were identified, and potential pitfalls or complications associated with these treatment modalities were described. Future avenues of research were highlighted, particularly with regard to targeted blockade at the level of upper respiratory afferent sensory receptors. The panel hopes this ECS will standardize thorough diagnostic work‐up and improve standard of care for treating patients with RCC.

Funding

The authors have nothing to report.

Disclosure

The view(s) expressed herein are those of the author(s) and do not reflect the official policy or position of Brooke Army Medical Center, the U.S. Army Medical Department, the U.S. Army Office of the Surgeon General, the Department of the Army, the Department of the Air Force and Department of Defense or the U.S. Government.

Conflicts of Interest

Milan Amin—Ampliovox, ownership stake; Merck, advisory board (former). Laura Matrka—Amgen, consultant; Inovio, consultant; Precigen, consultant. Lee M. Akst—GlaxoSmithKline Inc., clinical advisory board for chronic cough. Thomas L. Carroll—GlaxoSmithKline Inc., consultant; N‐Zyme Biomedical, scientific advisory board and stock options; Sofregen Medical, stock options and scientific advisory board.

Malka R. E., Saraswathula A., Lilly G., et al., “Diagnosis and Treatment of Refractory Chronic Cough: An American Broncho‐Esophagological Association Expert Consensus Statement,” The Laryngoscope 136, no. S5 (2026): S7–S26, 10.1002/lary.70598.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.