Abstract
Objective
To describe the clinical outcomes of refractory chronic cough (RCC) diagnosis and management at a tertiary care chronic cough clinic.
Patients and Methods
This is a prospective study of all eligible patients referred to the Mayo Clinic Chronic Cough Clinic between October 6, 2020 and April 9, 2021. All adult patients aged 18 years or older with cough persisting beyond 8 weeks in accordance with the American College of Chest Physicians definition were screened. Only participants with research authorization and consent were included in this study.
Results
A total of 278 patients were screened; 100 patients were enrolled in this study. On the initial visit, 56 patients who were considered to have RCC were invited for a 3-month follow-up survey. Of those 56 patients, electronic health record review clarified that 35 (62%) had etiology-confirmed chronic cough 21 (37%) patients had unexplained chronic cough.
Conclusion
This study shows that RCC needs further attentiveness toward diagnosis and trials of therapy to truly ascertain those who have unexplained chronic cough such as at specialized chronic cough centers.
Chronic cough—defined as a cough persisting for more than 8 weeks—remains a frequent yet complex clinical presentation. The burden of chronic cough among patients presenting to respiratory clinics in the United States is variable, ranging from 10% to 38% of visits.1, 2, 3, 4 In response to its prevalence and clinical impact, multiple professional societies—including the American College of Chest Physicians (ACCP), the European Respiratory Society, and national societies in Korea and Japan—have issued guidelines that converge on a tiered diagnostic approach.5, 6, 7, 8 In the absence of overt lung disease, the most identified causes include cough variant asthma (CVA), eosinophilic bronchitis (EB), upper airway cough syndrome (UACS), and gastroesophageal reflux disease (GERD). Increasing attention has also been given to evaluating comorbidities such as obstructive sleep apnea and dynamic airway collapse (eg, tracheobronchomalacia), which can perpetuate or mimic chronic cough.9
Despite these structured frameworks, diagnostic and therapeutic challenges persist for both patients and clinicians. Most diagnostic tests serve to exclude potential causes rather than confirm a definitive etiology. Aside from an elevated fractional-exhaled nitric oxide (FeNO),10 few tools offer high positive predictive value to directly attribute findings to symptomatology. Even when abnormalities are detected, causality is typically inferred only through a positive clinical response to empiric therapy. This uncertainty is compounded by the lack of consistently effective, evidence-based treatments for common contributors such as GERD with extraesophageal manifestations.11 Furthermore, a substantial and sustained placebo effect has been well documented in patients with chronic cough, complicating the interpretation of treatment outcomes.
Another layer of complexity lies in the recognition that, in some cases, chronic cough arises from neurosensory dysregulation—specifically, an upregulation or hypersensitization of the afferent pathways mediating the cough reflex. In such cases, where cough is refractory to treatment or remains unexplained despite a thorough diagnostic evaluation, terms like cough hypersensitivity syndrome have been used alongside others such as idiopathic cough, neurogenic cough, and neuropathic cough.12, 13, 14, 15, 16 The overlapping nature and lack of standardization among these terms have contributed to diagnostic ambiguity and inconsistent treatment strategies.
Intervention fidelity has been proposed as a crucial component in chronic cough research, emphasizing the need to standardize study design, provider training, treatment delivery, patient engagement, and implementation.17 However, incorporating these elements into real-world practice and using them to measure meaningful clinical outcomes remain a significant challenge. In this study, we aimed to evaluate diagnostic and therapeutic outcomes of patients initially considered as refractory chronic cough (RCC) for etiology-confirmed chronic cough versus unexplained chronic cough (UCC).
Patients and Methods
This was a single-center, observational mixed-methods study conducted at the Chronic Cough Clinic at Mayo Clinic Rochester. The study consisted of an initial cross-sectional phase, followed by a prospective phase. Adult patients (>18 years) with cough persisting for more than 8 weeks, as defined by the ACCP, were enrolled between October 2020 and April 2021. The study was approved by the Mayo Clinic institutional review board (IRB# 20-001443). Patients were screened via electronic health record (EHR) and on the day of their initial visit to the Mayo Clinic Rochester cough center for inclusion criteria and approached for consent for the cross-sectional and for the potential need to be in the prospective phase of the study. An overview of our clinically practiced Chronic Cough Protocol is provided in Supplemental Appendix 1 (available online at http://www.mcpiqojournal.org). For this study, we defined the categories of chronic cough as described further.
Definitions and Diagnostic Criteria
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Refractory chronic cough: Persistent cough despite targeted treatment of identified causes.
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Etiology-confirmed chronic cough: Defined by symptom resolution with therapy for 1 or a combination of the specific diagnosis of CVA, EB, GERD, and UACS as per chronic cough guidelines.
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Unexplained chronic cough: Assigned when no objective cause was found and patients failed to improve with empiric therapy.
Inclusion and Exclusion Criteria
All patients seen in the Chronic Cough Clinic between October 1, 2020, and April 30, 2021, who met the inclusion criteria and none of the exclusion criteria, were included. Patients were excluded if they had no research authorization, active tobacco use, and angiotensin-converting enzyme inhibitor use; had no prior diagnosis of bronchiectasis, lung cancer, pulmonary fibrosis, chronic obstructive pulmonary disease, active respiratory infection, dysphagia, cognitive impairment, aspiration, and acute heart failure; or were under palliative care (Figure).
Figure.
CONSORT diagram. CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; CVA, cough variant asthma; EB, eosinophilic bronchitis; GERD, gastroesophageal reflux disease; ILD, interstitial lung disease; NTM, non- tuberculous mycobacterium; UCC, unexplained chronic cough.
Patients diagnosed during the initial encounter as having a high probability of RCC, per clinician judgment (Supplemental Appendix 2, available online at http://www.mcpiqojournal.org), were followed up prospectively for 3 months. EHRs of the initial 100-patient cohort were reviewed independently by at least 2 reviewers (Va.A., Vi.A., K.J., and S.A.), and the CONSORT diagram was revised accordingly.
Data Collection
Baseline demographic characteristics, comorbidities, and standardized questionnaire data were collected at the time of enrollment. Key clinical data collected included cough duration; dry vs productive cough; patient-reported wheezing, heartburn, and regurgitation; and sensation of postnasal drainage. Allotussia (cough triggered by nontussive stimuli), hypertussia (increased sensitivity to cough-inducing stimuli), and the urge to cough (described as throat tickle, scratch, or laryngeal irritation) were also documented.
Patients completed the Leicester Cough Questionnaire (LCQ),18 visual analog scale,19 and Punum Ladder20 on initial encounter. A 5-question numerical cough severity questionnaire administered routinely in our clinic. Same survey and including “Patient impression of change in chronic cough”21,22 was distributed to the RCC cohort in 3 months.
Follow-up
Follow-up surveys for patients suspected of having RCC and enrolled in the prospective phase of the study were sent the same surveys as on initial encounter, including patient impression of change in cough. Reminders up to 3 times were attempted, including phone call follow-ups. The EHR was explored for a range of notes, including communication notes to physicians and nurses, even if patients were unable to physically return to original cough clinic physician.
Outcomes
The outcomes were as follows:
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Evaluate diagnostic outcomes of patients initially labeled with RCC for etiology-confirmed chronic cough vs UCC
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Assess outcomes of therapy in the RCC cohort
Statistical Analyses
Patient characteristics and outcomes were summarized using medians and interquartile ranges (IQRs) for continuous variables and frequencies and percentages for categorical variables. Patients were grouped into the etiology-confirmed chronic cough or UCC group at the follow-up.
LCQ responses were grouped owing to small sample sizes as follows:
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Frequency responses (eg, all/most/a good bit vs some/little vs hardly/none)
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Severity/timing responses similarly collapsed
Wilcoxon signed-rank tests compared differences between baseline and the 3-month follow-up for Punum Ladder, cough severity questionnaire, and LCQ scores by the diagnosis group at the follow-up (etiology-confirmed chronic cough or UCC). Fisher exact test assessed categorical differences in perceived improvement by the diagnosis group at the follow-up. Exploratory χ2 tests were used to compare LCQ responses at the follow-up between diagnosis groups. If expected cell count thresholds were not met for LCQ response comparisons, Fisher exact test P values were reported.
A 2-tailed P value of <.05 was considered statistically significant. All analyses were conducted using SAS, version 9.4 (SAS Institute Inc).
Results
A total of 278 patients were screened, and 165 were approached for written consent. Of these, 100 suspected of having chronic cough per ACCP guidelines and approached for enrollment provided consent. Further exclusions were applied based on reviewing criteria, leaving 86 patients in the final cohort, with 28 (33%) being diagnosed with etiology-confirmed chronic cough in initial encounter history and diagnostics and 58 (67%) suspected to have RCC (Figure).
These 58 patients considered to have RCC were approached with follow-up surveys in 3 months, with 2 missing data, hence leaving 56 patients with RCC. The entire 100 patients were reviewed in the EHR; 35 (40%) patients with RCC were found to have explained reasons for chronic cough, and 21 (24%) were assessed to have UCC.
RCC Demographic Characteristics
Of the 56 patients in the final cohort of RCC, 57% were women, with a median age of 62 years and a median cough duration of 26 months. Prior consultations included combinations of general internal medicine; pulmonary medicine; ear, nose, and throat including speech language pathology; allergy, and gastroenterology; 68% of these patients had more than 1 diagnosis for chronic cough such as UACS, GERD, and asthma (Table 1).
Table 1.
Patient Characteristics of Those Considered RCC at Index Visit
| Characteristic | RCC (n=56) |
|---|---|
| Age (y) | 62.0 (55.0-68.5) |
| Sex | |
| Female | 32 (57) |
| Male | 24 (43) |
| BMI (kg/m2), n=54 | 29.0 (24.9-34.3) |
| Ethnicity | |
| Non-Hispanic | 56 (100) |
| Cough duration (mo) | 26.0 (12.0-96.0) |
| Prior etiologies of chronic cougha | |
| Asthma | 17 (30) |
| Eosinophilic bronchitis | 1 (2) |
| GERD | 38 (68) |
| UACS | 39 (70) |
| CHS | 7 (13) |
| Prior medical conditions | |
| Sleep apnea | 10 (18) |
| Obesity | 24 (43) |
| Depression/anxiety | 10 (18) |
| GERD | 23 (41) |
| Cardiovascular disease | 15 (27) |
| Fibromyalgia | 9 (16) |
| Prior consultation | |
| General medicine | 14 (25) |
| Pulmonary medicine | 14 (25) |
| ENT/SLPb | 24 (44) |
| GI | 16 (29) |
| Allergy | 11 (20) |
Values are n (%) or median (IQR).
BMI, body mass index; CHS, cough hypersensitivity syndrome; ENT, ear, nose, and throat; GERD, gastroesophageal reflux disease; GI, gastrointestinal; IQR, interquartile range; RCC, refractory chronic cough; SLP, speech language pathology; UACS, upper airway cough syndrome.
Thirty-eight patients had >1 prior etiology of chronic cough.
ENT/SLP includes chronic cough evaluation in ENT clinics and behavioral speech therapy.
RCC Diagnostics
Our overview of testing in 56 patients is summarized in Table 2. This includes a summary of prior testing patients came with and those pursued for initial encounters. Diagnostics at initial encounter or following it included pulmonary function test with methacholine challenge (25%), FeNO (93%), chest computed tomography (CT; 14%), rhinoscopy (27%), and barium swallow/esophagram (14%) as the most common diagnostics. Moreover, FeNO is used in our institution in the place of sputum eosinophils and bronchoalveolar lavage as a reasonable guideline-supported alternative.7,15
Table 2.
Summary of Patient Diagnostics with RCC
| Workup | Previous to index visit evaluation (n=56) | At or after index visit evaluation (n=56) |
|---|---|---|
| PFT with methacholine | 8 (14) | 14 (25) |
| Chest CT | 19 (34) | 8 (14) |
| Sinus CT | 9 (16) | 4 (7) |
| Swallow/esophagram study | 7 (13) | 8 (14) |
| pH test | 8 (14) | 3 (5) |
| Bravo capsule | 2 (4) | 1 (2) |
| Sleep apnea test | 0 (0) | 1 (2) |
| ECG | 15 (27) | 5 (9) |
| Bronchoscopy (n=55) | 3 (5) | 1 (2) |
| Rhinoscopy | 12 (21) | 15 (27) |
| Exhaled nitric oxide | 10 (18) | 52 (93) |
| Overnight oximetry | — | 7 (13) |
Values are n (%).
CT, computed tomography; PFT, pulmonary function test; RCC, refractory chronic cough.
RCC Therapeutics
Neuromodulator use was trialed in the general cohort of RCC (N=56), with amitriptyline (19%) and duloxetine (16%) being the most common choices, followed by gabapentin and pregabalin (5% each). Changes in choices of medication were also noted (Supplemental Table 3, available online at http://www.mcpiqojournal.org). Tetracaine was used as a topical anesthetic in 36% of patients with RCC. Narcotics such as morphine are not used in our practice for RCC. Speech therapy referral was 5% and superior laryngeal nerve block 4% (Table 3). Cough suppression methods instructions during visit were provided by clinician in 21%, including with the use of educational handout. Because UACS was most common in 37% of patients found to have etiology-confirmed chronic cough, and in combination with asthma and GERD, we observed treatment directed toward those etiologies (Supplemental Table 2, available online at http://www.mcpiqojournal.org).
Table 3.
Summary of Treatments in Patients with RCC Before and After Visit
| Treatment after evaluation | Previous to index visit evaluation (n=56) | At or after index visit evaluation (n=56) |
|---|---|---|
| Trial of inhalers | 25 (45) | 9 (16) |
| Nasal regimen | 30 (54) | 39 (70) |
| Acid suppressive medications | 31 (55) | 3 (5) |
| Sinus surgery | 6 (11) | 0 (0) |
| Fundoplication | 5 (9) | — |
| GERD diet and lifestyle modification | 7 (13) | 7 (13) |
| Neuromodulators | 10 (18) | 18 (32) |
| Speech therapy | 3 (5) | 3 (5) |
| Superior laryngeal nerve block | 2 (4) | 2 (4) |
| Allergy shots | 2 (4) | 0 (0) |
| Treatment for sleep apnea | 3 (5) | 1 (2) |
| Airway clearance method | 2 (4) | 1 (2) |
| Cough suppression techniques | — | 12 (21) |
| Antibiotics | 4 (7) | 0 (0) |
| Corticosteroids | 4 (7) | 0 (0) |
| Antihistamines | 10 (18) | 2 (4) |
| Tetracaine/lidocaine/benzocaine | 4 (7) | 20 (36) |
| OTC medications | 6 (11) | — |
| Weight loss | — | 3 (5) |
GERD, gastroesophageal reflux disease; OTC, over-the-counter; RCC, refractory chronic cough.
Response to Therapy
In the cohort of 56 patients with RCC, in those subsequently diagnosed with etiology-confirmed chronic cough at the follow-up (n=35), Punum Ladder score decreased (improved) from a median of 4.5 (IQR, 2-7) at screening to 2 (IQR, 0-4) at follow-up, which was statistically significant (P=.001). Among patients diagnosed with UCC at follow-up (n=21), Punum Ladder score improved from a median of 6 (IQR, 4-7) at screening to 3.5 (IQR, 1-5) at follow-up, but that difference was not statistically significant (P=.08). Overall state of cough ratings decreased, an improvement, for the etiology-confirmed diagnosis group from screening (6.0 [IQR, 4.0-7.0]) to follow-up (3.0 [IQR, 2.0-7.0]; P=.003). LCQ increased (improved) significantly for both patients with etiology-confirmed chronic cough and those with UCC from screening to follow-up (Table 4 and Supplemental Table 1, available online at http://www.mcpiqojournal.org). A higher percentage of patients with etiology-confirmed chronic cough had the impression their cough had resolved or was much improved compared with those with UCC (P=.017) (Table 5).
Table 4.
Comparison of Cough Scores for Patients With RCC (N=56), With Explained Chronic Cough and UCC at 3 Mo Follow-up
| Cough score | Index visit evaluation |
Follow-up |
P | Index visit evaluation |
Follow-up |
P |
|---|---|---|---|---|---|---|
| RCC (n=35) | Explained chronic cough (n=35) | RCC (n=21) | UCC (n=21) | |||
| Punum ladder (n=47/n=41) | 4.5 (2.0-7.0) | 2.0 (0-4.0) | .001 | 6.0 (4.0-7.0) | 3.5 (1.0-5.0) | .08 |
| Cough severity questionnairea | ||||||
| Cough severity (how bad is it now?) (n=47/n=40) | 6.0 (3.0-8.0) | 3.0 (2.0-8.0) | .06 | 8.0 (5.0-8.0) | 6.0 (3.0-7.0) | .05 |
| Cough frequency (how often is it now?) (n=47/n=40) | 6.0 (4.0-7.0) | 3.0 (2.0-5.0) | .002 | 7.0 (5.0-8.0) | 5.0 (3.0-6.0) | .016 |
| Nighttime cough (how often is your sleep disrupted by cough?) (n=47/n=41) | 2.0 (1.0-5.0) | 1.0 (0-3.0) | .002 | 1.0 (1.0-5.0) | 2.0 (0-5.0) | .66 |
| Disabling cough (interferes with day-to-day activities now) (n=46/n=41) | 4.0 (2.0-7.0) | 1.0 (0-5.0) | .023 | 5.5 (1.0-8.0) | 4.5 (1.0-7.0) | .21 |
| Urge to cough (rate the strength of the sensation you need to cough) (n=47/n=41) | 7.0 (4.0-8.0) | 4.0 (1.0-7.0) | .005 | 7.0 (5.0-8.0) | 5.5 (2.0-8.0) | .037 |
| Please indicate the overall state of your cough—visual analog scale (n=46/n=41) | 6.0 (4.0-7.0) | 3.0 (2.0-6.0) | .003 | 8.0 (7.0-8.0) | 5.5 (2.0-7.0) | .058 |
| Leicester cough questionnaire (n=46/n=36) | 11.6 (8.4-14.8) | 15.5 (12.1-19.0) | .004 | 11.7 (8.1-13.4) | 12.9 (10.8-18.2) | .005 |
Missingness is described as No. of screening total/No. of follow-up. All data presented as median (IQR).
IQR, interquartile range; RCC, refractory chronic cough; UCC, unexplained chronic cough.
Scale of 0-10 (0 being no cough and 10 being worst cough).
Table 5.
Impression of Change in Cough in RCC
| Change in cough | Etiology-confirmed chronic cough found (n=35) | UCC (n=21) | P |
|---|---|---|---|
| Patients (n=41) | .017a | ||
| Resolved/much improved | 15 (65) | 5 (28) | |
| Minimal change/no change | 6 (26) | 12 (67) | |
| Much worse | 2 (9) | 1 (6) |
RCC, refractory chronic cough; UCC, unexplained chronic cough.
Fisher exact test used. Sample size was 23 for etiology-confirmed chronic cough, and 18 for UCC.
Discussion
This mixed-method study evaluating the diagnostic and therapeutic outcomes of patients considered to have RCC between October 2020 and April 2021 is among a few to elucidate the real-world experience of challenges in diagnosis and treatment of chronic cough.23 The spectrum of chronic cough referrals in our tertiary care referral center remains diverse because, of the 278 patients screened over a 6-month period, 31% (86) who met diagnosis of chronic cough per ACCP criteria were included in the study, including 10% with the etiology-confirmed reasons for chronic cough and 21% were screened further as having RCC. In the final cohort of 56 patients with RCC, an EHR review showed that at least 62% of those considered to have RCC had explanations for chronic cough needing to be addressed more carefully, including CVA, GERD, and UACS. The other 37% of those with RCC appeared most consistent with UCC. Follow-up of RCC cohort revealed that improvement in chronic cough was more likely in those with etiology-confirmed chronic cough than that in those with UCC as, seen in the Punum Ladder, cough severity questionnaire, and LCQ scores and patient impression of change in cough. Yet, for the 35% who did not have change or worsened despite an explanation being found, further EHR review is needed. The diagnosis of UCC remains a diagnosis of exclusion after a careful workup and adequate trial of therapy. The diagnosis of RCC merits evaluation at a specialized cough center despite persistent challenges.
In a previous assessment for prognosis of chronic cough, almost half of those patients at 5 years continued to have chronic cough, including from common reasons of chronic cough such as postnasal drainage and GERD.24 This resonates with our experience, where ongoing evaluation for those considered refractory still had gaps in methods to address explained reasons. Similarly, in a Japanese cohort over 2 years of 334 patients, CVA, sinobronchial syndrome, atopic cough, and GERD continued to prevail, and cough related to GERD ended up becoming refractory and more difficult to treat.23 Another experience from Warsaw of 201 patients, UCC was 1.5%, and for those monitored for response to therapy, RCC was found in 27.1%, with a variety of routine chronic cough etiologies such as asthma, GERD, and UACS.25 A similar proportion of possible RCC of 27.9% was observed in a secondary analysis across 4 European countries.26 Yet, in a cohort from China, RCC accounted for 38.1% of chronic cough referrals, with GERD being a main etiology, and UCC accounted for 68.1% of the cases, highlighting the diagnostic and therapeutic challenges in real word.27
There have been robust efforts focusing on treatment of RCC over the years, which have included a myriad of interventions and trials. There has been an established role of neuromodulator therapy such as gabapentin, amitriptyline, pregabalin, baclofen, and opiates, as well as speech language and pathology for management of RCC.28, 29, 30, 31, 32, 33, 34, 35 Gabapentin and baclofen have also been studied for having similar efficacy in GERD-related RCC.36, 37, 38 In our study, a limited experience of neuromodulators was observed, including the need to trial alternative agents and side-effects. Duloxetine and amitriptyline were among the most common choices used to treat chronic cough, with the other ones being gabapentin and pregabalin. Trials of neuromodulator therapy could entail common adverse effects of drowsiness and fatigue, limiting their use. A number of clinical trials, including recently studying antagonists of purinergic receptors of P2X2/3, have also been attempted to focus on treatment of RCC, usually with a large placebo effect that has been itself of interest.39, 40, 41 To counteract the side-effect profile, there has been a proliferation of studies including a variety of purinergic antagonists, but, because benefit has been marginal, they have not been approved by the Food and Drug Administration.11,39, 40, 41, 42, 43, 44, 45, 46
Among the challenges of clinical studies and trials focusing on RCC remains the lack of consensus on methods to include aspects of fidelity to intervention including training of providers, delivery of treatment, receipt of treatment, enactment of treatment.17 In our experience, all physicians are trained respiratory physicians inclusive of subspecialty chronic cough practice. Yet, the utilization of testing for the group considered to have RCC revealed heterogeneity of practice of the algorithmic approach to test for chronic cough, such as 25% of patients had bronchoprovocation test with methacholine, 14% had a contrast esophagram/swallow study, and only 7% had 24-hour pH impedance testing/Bravo test to assess for GERD, providing opportunities for reevaluations and testing for patients coming after layers of prior consultations and testing. In this limited cohort, evaluation for sleep apnea appears limited and excessive dynamic airway collapse (EDAC) was not noted, which is performed with the help of dynamic airway CT protocol at our institution. Sleep apnea is an important evaluation in the multimodal approach toward chronic cough, as is the recognition of EDAC.9,47,48 Dynamic airway CT has since been increasingly used in our practice to recognize EDAC.
Our study has several limitations. First, it happened to be conducted during the COVID-19 pandemic, which affected referrals in a time when clinical and research efforts were redistributed in focus toward pandemic care. This period could have also affected our recruitment of the number of patients because 49% of those screened declined to participate in the study. It also overlapped with a period when there was shortage of methacholine for bronchoprovocation. The time of the pandemic could have also affected the limited utilization of testing in general, where gastrointestinal focused testing was limited. Therefore, this snapshot experience may not accurately reflect all trends of diagnostics in our clinical practice. Another limitation is that the EHR capabilities used to study charts have evolved over the years since this study. It is important to note that, with most patients accomplishing travel to our cough center for their clinical visit, recommendations for some testing may lag. The follow-up using EHR chart review was a surrogate to the other elements of fidelity of intervention, although is not validated for it. There is an opportunity for future studies to build on research using EHR data base and large language models through an institutional chronic cough registry, which can also provide longer-term follow-up beyond 3 months. Such data platforms if built on robust quality data could be coalesced for the recruitment of patients for clinical trials. Lastly, it is challenging to account for the heterogeneity of clinical judgment of physicians as well as the etiologies of chronic cough. The strength of this study is that it was conducted at a tertiary care cough referral center, where all physicians are trained and knowledgeable to major society guideline algorithms. Follow-up communications were helpful in most cases because they were documented in EHR.
This study serves to lay foundation to build more rigorous methods for clinical and research purposes for evaluating diagnoses in chronic cough. The EHR can be successfully used for this purpose and improved in its utility for this to incorporate all aspects of fidelity to intervention. These methods can not only help improve the quality of recruitment of patients with RCC in clinical trials but also prompt clinicians to continue with diligence in addressing known reasons for explained chronic cough.
Conclusion
The diagnosis of UCC remains one of exclusion when evaluating patients with RCC, most of whom will still have etiology-confirmed chronic cough needing recurrent clinical assessments. It is best to consider reevaluation and careful trials of therapies at a tertiary care cough clinic.
Potential Competing Interests
The authors report no competing interests.
Ethics Statement
The study was approved by the Mayo Clinic institutional review board (IRB# 20-001443). Patients were screened via EHR and, on the day of their initial visit to the Mayo Clinic Rochester cough center for inclusion criteria, approached for consent for the cross-sectional and for the potential need to be in the prospective phase of the study.
Footnotes
Grant Support: This study was supported by a small grant from Mayo Clinic CCaTS (grant number UL1TR000135).
Supplemental material can be found online at http://www.mcpiqojournal.org. Supplemental material attached to journal articles has not been edited, and the authors take responsibility for the accuracy of all data.
Supplemental Online Material
References
- 1.Macedo P., Zhang Q., Saito J., et al. Analysis of bronchial biopsies in chronic cough. Respir Med. 2017;127:40–44. doi: 10.1016/j.rmed.2017.04.001. [DOI] [PubMed] [Google Scholar]
- 2.Chung K.F., Pavord I.D. Prevalence, pathogenesis, and causes of chronic cough. Lancet. 2008;371(9621):1364–1374. doi: 10.1016/s0140-6736(08)60595-4. [DOI] [PubMed] [Google Scholar]
- 3.Irwin R.S., Curley F.J., French C.L. Chronic cough. The spectrum and frequency of causes, key components of the diagnostic evaluation, and outcome of specific therapy. Am Rev Respir Dis. 1990;141(3):640–647. doi: 10.1164/ajrccm/141.3.640. [DOI] [PubMed] [Google Scholar]
- 4.Irwin R.S., Corrao W.M., Pratter M.R. Chronic persistent cough in the adult: the spectrum and frequency of causes and successful outcome of specific therapy. Am Rev Respir Dis. 1981;123(4 Pt 1):413–417. doi: 10.1164/arrd.1981.123.4.413. [DOI] [PubMed] [Google Scholar]
- 5.Mukae H., Kaneko T., Obase Y., et al. The Japanese respiratory society guidelines for the management of cough and sputum (digest edition) Respir Investig. 2021;59(3):270–290. doi: 10.1016/j.resinv.2021.01.007. [DOI] [PubMed] [Google Scholar]
- 6.Joo H., Moon J.Y., An T.J., et al. Revised Korean Cough Guidelines, 2020: recommendations and summary statements. Tuberc Respir Dis (Seoul) 2021;84(4):263–273. doi: 10.4046/trd.2021.0038. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Morice A.H., Millqvist E., Bieksiene K., et al. ERS guidelines on the diagnosis and treatment of chronic cough in adults and children. Eur Respir J. 2020;55(1) doi: 10.1183/13993003.01136-2019. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Irwin R.S., Baumann M.H., Bolser D.C., et al. Diagnosis and management of cough executive summary: ACCP evidence-based clinical practice guidelines. Chest. 2006;129(1 Suppl):1s–23s. doi: 10.1378/chest.129.1_suppl.1S. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Good J.T., Jr., Rollins D.R., Kolakowski C.A., Stevens A.D., Denson J.L., Martin R.J. New insights in the diagnosis of chronic refractory cough. Respir Med. 2018;141:103–110. doi: 10.1016/j.rmed.2018.06.024. [DOI] [PubMed] [Google Scholar]
- 10.Hahn P.Y., Morgenthaler T.Y., Lim K.G. Use of exhaled nitric oxide in predicting response to inhaled corticosteroids for chronic cough. Mayo Clin Proc. 2007;82(11):1350–1355. doi: 10.4065/82.11.1350. [DOI] [PubMed] [Google Scholar]
- 11.Irwin R.S., Madison J.M. Unexplained or refractory chronic cough in adults. N Engl J Med. 2025;392(12):1203–1214. doi: 10.1056/NEJMra2309906. [DOI] [PubMed] [Google Scholar]
- 12.Chung K.F., McGarvey L., Song W.J., et al. Cough hypersensitivity and chronic cough. Nat Rev Dis Primers. 2022;8(1):45. doi: 10.1038/s41572-022-00370-w. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Sundar K.M., Stark A.C., Hu N., Barkmeier-Kraemer J. Is laryngeal hypersensitivity the basis of unexplained or refractory chronic cough? ERJ Open Res. 2021;7(1):00793–2020. doi: 10.1183/23120541.00793-2020. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Morice A., Dicpinigaitis P., McGarvey L., Birring S.S. Chronic cough: new insights and future prospects. Eur Respir Rev. 2021;30(162) doi: 10.1183/16000617.0127-2021. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Irwin R.S., French C.L., Chang A.B., Altman K.W. Classification of cough as a symptom in adults and management algorithms: CHEST Guideline and Expert Panel Report. Chest. 2018;153(1):196–209. doi: 10.1016/j.chest.2017.10.016. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Vertigan A.E., Murad M.H., Pringsheim T., et al. Somatic cough syndrome (previously referred to as psychogenic cough) and tic cough (previously referred to as habit cough) in adults and children: CHEST Guideline and Expert Panel Report. Chest. 2015;148(1):24–31. doi: 10.1378/chest.15-0423. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.French C.T., Diekemper R.L., Irwin R.S., et al. Assessment of intervention fidelity and recommendations for researchers conducting studies on the diagnosis and treatment of chronic cough in the adult: CHEST Guideline and Expert Panel Report. Chest. 2015;148(1):32–54. doi: 10.1378/chest.15-0164. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Birring S.S., Prudon B., Carr A.J., Singh S.J., Morgan D., Pavord I.D. Development of a symptom specific health status measure for patients with chronic cough: Leicester Cough Questionnaire (LCQ) Thorax. 2003;58(4):339–343. doi: 10.1136/thorax.58.4.339. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Martin Nguyen A., Bacci E.D., Vernon M., et al. Validation of a visual analog scale for assessing cough severity in patients with chronic cough. Ther Adv Respir Dis. 2021;15 doi: 10.1177/17534666211049743. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Fletcher K.E., French C.T., Irwin R.S., Corapi K.M., Norman G.R. A prospective global measure, the Punum Ladder, provides more valid assessments of quality of life than a retrospective transition measure. J Clin Epidemiol. 2010;63(10):1123–1131. doi: 10.1016/j.jclinepi.2009.09.015. [DOI] [PubMed] [Google Scholar]
- 21.Mackay E.C., Turner R.D., Cho P.S.P., Birring S.S. Patient-reported assessments of chronic cough in clinical trials: accessory or primary endpoints? J Thorac Dis. 2024;16(10):7165–7181. doi: 10.21037/jtd-24-705. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Rhatigan K., Hirons B., Kesavan H., et al. Patient global impression of severity scale in chronic cough: validation and formulation of symptom severity categories. J Allergy Clin Immunol Pract. 2023;11(12):3706–3712.e1. doi: 10.1016/j.jaip.2023.08.046. [DOI] [PubMed] [Google Scholar]
- 23.Ishiura Y., Fujimura M., Ogawa H., et al. Prevalence and causes of chronic cough in Japan. Respir Investig. 2024;62(3):442–448. doi: 10.1016/j.resinv.2024.02.017. [DOI] [PubMed] [Google Scholar]
- 24.Koskela H.O., Lätti A.M., Purokivi M.K. Long-term prognosis of chronic cough: a prospective, observational cohort study. BMC Pulm Med. 2017;17(1):46. doi: 10.1186/s12890-017-0496-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Kukiełka P., Moliszewska K., Białek-Gosk K., Grabczak E.M., Dąbrowska M. Prevalence of refractory and unexplained chronic cough in adults treated in cough centre. ERJ Open Res. 2024;10(5):00254–2024. doi: 10.1183/23120541.00254-2024. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Domínguez-Ortega J., Virchow J.C., Guilleminault L., et al. Prevalence and burden of possible refractory chronic cough in four European countries. ERJ Open Res. 2025;11(4):00888–2024. doi: 10.1183/23120541.00888-2024. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Zhang M., Morice A.H., Si F., et al. New insights into refractory chronic cough and unexplained chronic cough: a 6-year ambispective cohort study. Allergy Asthma Immunol Res. 2023;15(6):795–811. doi: 10.4168/aair.2023.15.6.795. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Chamberlain Mitchell S.A., Garrod R., Clark L., et al. Physiotherapy, and speech and language therapy intervention for patients with refractory chronic cough: a multicentre randomised control trial. Thorax. 2017;72(2):129–136. doi: 10.1136/thoraxjnl-2016-208843. [DOI] [PubMed] [Google Scholar]
- 29.Vertigan A.E., Kapela S.L., Ryan N.M., Birring S.S., McElduff P., Gibson P.G. Pregabalin and speech pathology combination therapy for refractory chronic cough: a randomized controlled trial. Chest. 2016;149(3):639–648. doi: 10.1378/chest.15-1271. [DOI] [PubMed] [Google Scholar]
- 30.Cohen S.M., Misono S. Use of specific neuromodulators in the treatment of chronic, idiopathic cough: a systematic review. Otolaryngol Head Neck Surg. 2013;148(3):374–382. doi: 10.1177/0194599812471817. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Ryan N.M., Birring S.S., Gibson P.G. Gabapentin for refractory chronic cough: a randomised, double-blind, placebo-controlled trial. Lancet. 2012;380(9853):1583–1589. doi: 10.1016/S0140-6736%2812%2960776-4. [DOI] [PubMed] [Google Scholar]
- 32.Vertigan A.E., Theodoros D.G., Gibson P.G., Winkworth A.L. Efficacy of speech pathology management for chronic cough: a randomised placebo controlled trial of treatment efficacy. Thorax. 2006;61(12):1065–1069. doi: 10.1136/thx.2006.064337. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Mintz S., Lee J.K. Gabapentin in the treatment of intractable idiopathic chronic cough: case reports. Am J Med. 2006;119(5):e13–e15. doi: 10.1016/j.amjmed.2005.10.046. [DOI] [PubMed] [Google Scholar]
- 34.Jeyakumar A., Brickman T.M., Haben M. Effectiveness of amitriptyline versus cough suppressants in the treatment of chronic cough resulting from postviral vagal neuropathy. Laryngoscope. 2006;116(12):2108–2112. doi: 10.1097/01.mlg.0000244377.60334.e3. [DOI] [PubMed] [Google Scholar]
- 35.Dicpinigaitis P.V., Rauf K. Treatment of chronic, refractory cough with baclofen. Respiration. 1998;65(1):86–88. doi: 10.1159/000029232. [DOI] [PubMed] [Google Scholar]
- 36.Zhang L., Aierken A., Zhang M., Qiu Z. Pathogenesis and management of gastroesophageal reflux disease-associated cough: a narrative review. J Thorac Dis. 2023;15(4):2314. doi: 10.21037/jtd-22-1757. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Zhu Y., Xu X., Zhang M., et al. Pressure and length of the lower esophageal sphincter as predictive indicators of therapeutic efficacy of baclofen for refractory gastroesophageal reflux-induced chronic cough. Respir Med. 2021;183 doi: 10.1016/j.rmed.2021.106439. [DOI] [PubMed] [Google Scholar]
- 38.Dong R., Xu X., Yu L., et al. Randomised clinical trial: gabapentin vs baclofen in the treatment of suspected refractory gastro-oesophageal reflux-induced chronic cough. Aliment Pharmacol Ther. 2019;49(6):714–722. doi: 10.1111/apt.15169. [DOI] [PubMed] [Google Scholar]
- 39.Irwin R.S., Madison J.M. Gefapixant for refractory or unexplained chronic cough? JAMA. 2023;330(14):1335–1336. doi: 10.1001/jama.2023.18508. [DOI] [PubMed] [Google Scholar]
- 40.McGarvey L.P., Birring S.S., Morice A.H., et al. Efficacy and safety of gefapixant, a P2X(3) receptor antagonist, in refractory chronic cough and unexplained chronic cough (COUGH-1 and COUGH-2): results from two double-blind, randomised, parallel-group, placebo-controlled, phase 3 trials. Lancet. 2022;399(10328):909–923. doi: 10.1016/s0140-6736(21)02348-5. [DOI] [PubMed] [Google Scholar]
- 41.Smith J.A., Kitt M.M., Morice A.H., et al. Gefapixant, a P2X3 receptor antagonist, for the treatment of refractory or unexplained chronic cough: a randomised, double-blind, controlled, parallel-group, phase 2b trial. Lancet Respir Med. 2020;8(8):775–785. doi: 10.1016/s2213-2600(19)30471-0. [DOI] [PubMed] [Google Scholar]
- 42.Smith J.A., Birring S.S., Blaiss M.S., et al. Camlipixant in refractory chronic cough: a phase 2b, randomized, placebo-controlled trial (SOOTHE) Am J Respir Crit Care Med. 2025;211(6):1038–1048. doi: 10.1164/rccm.202409-1752OC. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43.Yamamoto S., Horita N., Hara J., et al. Benefit-risk profile of P2X3 receptor antagonists for treatment of chronic cough: dose-response model-based network meta-analysis. Chest. 2024;166(5):1124–1140. doi: 10.1016/j.chest.2024.05.015. [DOI] [PubMed] [Google Scholar]
- 44.Friedrich C., Francke K., Birring S.S., et al. The P2X3 receptor antagonist filapixant in patients with refractory chronic cough: a randomized controlled trial. Respir Res. 2023;24(1):109. doi: 10.1186/s12931-023-02384-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 45.Morice A.H., Kitt M.M., Ford A.P., et al. The effect of gefapixant, a P2X3 antagonist, on cough reflex sensitivity: a randomised placebo-controlled study. Eur Respir J. 2019;54(1) doi: 10.1183/13993003.00439-2019. [DOI] [PubMed] [Google Scholar]
- 46.Garceau D., Chauret N. BLU-5937: a selective P2X3 antagonist with potent anti-tussive effect and no taste alteration. Pulm Pharmacol Ther. 2019;56:56–62. doi: 10.1016/j.pupt.2019.03.007. [DOI] [PubMed] [Google Scholar]
- 47.Sundar K.M., Stark A.C., Dicpinigaitis P. Chronic cough and obstructive sleep apnea. Sleep Med Clin. 2024;19(2):239–251. doi: 10.1016/j.jsmc.2024.02.004. [DOI] [PubMed] [Google Scholar]
- 48.Kim T.H., Heo I.R., Kim H.C. Impact of high-risk of obstructive sleep apnea on chronic cough: data from the Korea National Health and Nutrition Examination Survey. BMC Pulm Med. 2022;22(1):419. doi: 10.1186/s12890-022-02222-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
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