Lung (2023) 201:275–286 https://doi.org/10.1007/s00408-023-00620-y CHRONIC COUGH Characteristics and Management of Patients with Refractory or Unexplained Chronic Cough in Outpatient Hospital Clinics in Spain: A Retrospective Multicenter Study Ignacio Dávila1 · Luis Puente2 · Santiago Quirce3 · Ebymar Arismendi4 · Miguel Díaz‑Palacios5 · Antonio Pereira‑Vega6 · Alfredo de Diego7 · Juan Luis Rodriguez‑Hermosa8 · Luis Cea‑Calvo9 · Marta Sánchez‑Jareño9 · Pilar López‑Cotarelo9 · Christian Domingo10 Received: 3 March 2023 / Accepted: 18 April 2023 / Published online: 9 May 2023 © The Author(s) 2023 Abstract Purpose Chronic cough (cough that persists for ≥ 8 weeks) can cause a range of physical symptoms and psychosocial effects that significantly impair patients’ quality of life. Refractory chronic cough (RCC) and unexplained chronic cough (UCC) are challenging to diagnose and manage, with substantial economic implications for healthcare systems. Methods This retrospective multicenter non-interventional study aimed to characterize the profile and health resource consumption of patients with RCC or UCC who attended outpatient clinics at Spanish hospitals. Data were collected from medical records of patients with RCC or UCC for up to 3 years before study inclusion. Results The patient cohort (n = 196) was representative of the chronic cough population (77.6% female, mean age 58.5 years). Two-thirds of patients (n = 126) had RCC. The most frequently visited doctors were pulmonologists (93.4% of patients) and primary care physicians (78.6%), with a mean of 5 visits per patient over three years’ observation. The most common diag- nostic tests were chest x-ray (83.7%) and spirometry with bronchodilation (77.0%). The most commonly prescribed treatments were proton pump inhibitors (79.6%) and respiratory medications (87.8%). Antibiotics were prescribed empirically to 56 (28.6%) patients. Differences between RCC or UCC groups related mainly to approaches used to manage cough-associated conditions (gastroesophageal reflux disease, asthma) in patients with RCC. Conclusion RCC and UCC are responsible for high health resource utilization in Spanish hospitals. Specific treatments targeting the pathological processes driving chronic cough may provide opportunities to reduce the associated burden for patients and healthcare systems. Keywords Refractory chronic cough · Unexplained chronic cough · Noninterventional study · Health resource utilization · Spain 5 * Luis Cea‑Calvo Servicio de Alergia, Hospital Universitari I Politècnic La Fe, luis.cea@merck.com Valencia, Spain 6 1 Servicio de Neumología, Hospital Juan Ramón Jiménez, Servicio de Alergia, Departamento de Ciencias Biomédicas Huelva, Spain Y del Diagnóstico, Facultad de Medicina, Hospital 7 Universitario de Salamanca, Universidad de Salamanca, Servicio de Neumología, Hospital Universitari I Politècnic Salamanca, Spain La Fe, Valencia, Spain 2 8 Servicio de Neumología, Hospital Universitario Gregorio Servicio de Neumología, Departamento de Medicina, Marañón- Universidad Complutense, Madrid, Spain Hospital Clínico San Carlos, Universidad Complutense, 3 Madrid, Spain Servicio de Alergia, Hospital Universitario La Paz, IdiPAZ, 9 Madrid, Spain Medical Affairs, MSD Spain, C. de Josefa Valcárcel, 38, 4 28027 Madrid, Spain Servei de Pneumologia, Hospital Clínic de Barcelona, 10 Instituto de Salud Carlos III, CIBERES, IDIBAPS, Corporació Parc Taulí, Universitat Autònoma de Barcelona Universitat de Barcelona, Barcelona, Spain (UAB), Sabadell, Spain 13 Vol.:(0123456789) 276 Lung (2023) 201:275–286 Introduction To obtain current data on the profile of patients with RCC and UCC, and associated health resource consump- Chronic cough, defined as a cough that persists for longer tion (burden to the healthcare system), we undertook a study than eight weeks, has an estimated 12-month period preva- of patients with these conditions who had attended outpa- lence of around 5% according to recent population-based tient clinics at Spanish hospitals. An additional study objec- studies from the United States, Japan, Germany and Spain tive was to explore the impact of RCC and UCC on various [1–4], and is one of the most common reasons for adults aspects of patients’ daily lives (burden to patients); this will to seek medical attention [5, 6]. Chronic cough can cause be reported separately. physical symptoms (e.g., stress urinary incontinence, cough-related syncope, and dysphonia) and may lead to depression, social isolation, and difficulties in personal Methods relationships, with a profoundly negative impact on an individual’s health-related quality of life [7–9]. Study Design Conditions frequently associated with chronic cough include postnasal drip (or upper airway cough syndrome), This retrospective multicenter non-interventional study asthma, eosinophilic bronchitis, and gastroesophageal involved patients with RCC or UCC who attended outpa- reflux disease (GERD). Other associated conditions are tient clinics at representative hospitals from the National recent or active respiratory infection, smoking, and use of Healthcare System of Spain. Patients who were seen at angiotensin-converting enzyme (ACE) inhibitors [5, 10, the clinics between November 2020 and June 2022 were 11]. Troublesome coughing can also be triggered by low invited to participate in the study. The study protocol was levels of innocuous stimuli such as changes in ambient reviewed and approved by the Research Ethic Committees of temperature, taking a deep breath, laughing, talking on all participating hospitals. Enrolled patients provided signed the phone and exposure to aerosols [12]. Although some informed consent before data collection began. individuals with chronic cough may benefit from trigger avoidance and/or usual treatment for cough-associated Patients conditions, in a subset of patients either no underlying disease or etiology can be identified (unexplained chronic Consecutive patients attending outpatient clinics were cough [UCC]), or cough persists despite thorough assess- invited by their treating physician to enroll in the study ment and appropriate treatment of the underlying condi- if they were adults (> 18 years of age); had RCC or UCC tion (refractory chronic cough [RCC]) [10]. according to physicians’ diagnosis; had been seen for The diagnosis and management of RCC and UCC can chronic cough for the first time more than one year before be a prolonged and challenging process for patients and study entry; had cough at the study visit date; and provided doctors. Patients may visit a range of specialists, often signed informed consent. Patients were excluded if they repeatedly, in search of a specific diagnosis or treatment were current smokers or had stopped smoking less than to alleviate the cough. Many patients undergo expensive one year before study entry; were receiving ACE inhibitors; or invasive medical procedures to reach a diagnosis, and had chronic cough related to chronic obstructive pulmonary diagnostic tests are often repeated during follow-up. More- disease, cancer, active infection, bronchiectasis, interstitial over, patients are often treated empirically with various lung disease, cystic fibrosis, or Gilles de la Tourette syn- drugs, with limited effectiveness and associated safety and drome; were participating in interventional studies or had tolerability issues that can lead to treatment discontinua- conditions that, in the judgment of the treating physician, tion [9, 13, 14]. advised against participation (e.g., cognitive impairment, There are limited data specific to Spain regarding the major depression, end-stage disease). consequences and burden of RCC and UCC on patients and the healthcare system. The 2020 population-based Procedures National Health and Wellness Survey conducted across 29 European countries found that Spanish respondents who Patients’ clinical records were the primary source of infor- self-reported chronic cough (579 of 7074 respondents in mation; no prospective data collection was performed. After Spain) experienced inferior health status, poorer mental providing consent, patients also completed a printed sur- health, greater healthcare utilization, and lower produc- vey about the impact of chronic cough on their daily life tivity at work and home [4]. However, this study analyzed activities and quality of life; these results will be reported chronic cough patients in general and did not focus on the separately. The predefined period for chart review was up differences between RCC and UCC. to three years before study inclusion. Main items of inter- est were demographics, epidemiological variables, and 13 Lung (2023) 201:275–286 277 comorbidities; cough characteristics; history and manage- Results ment of chronic cough including type of specialist(s) vis- ited and number of visits, type and number of diagnostic Seventeen outpatient clinics across Spain participated in the tests performed, therapies used to treat chronic cough and study. A total of 203 patients were identified for participa- its underlying condition, and antibiotic courses used empir- tion, seven of whom were not enrolled either for failing to ically to treat chronic cough. The differentiation between sign informed consent (n = 5) or current smoking (n = 2). RCC and UCC was based on the diagnosis reflected in the Information was collected for 196 patients. Patients had clinical chart, or according to physicians’ judgment after been recruited in pulmonology (n = 166) or allergy (n = 30) reviewing the clinical history, diagnostic tests performed and departments. The population was 77.6% female, mean age previous therapies used to treat chronic cough. No diagnostic was 58.5 (SD 13.3) years, and most patients (95.4%) were test requirements or protocols were followed to categorize Caucasian. The diagnosis was RCC in 126 patients (64.3%) patients. There were no other specific procedures related to and UCC in 70 patients (35.7%). There were no significant the study. differences between RCC and UCC groups with respect to age, sex distribution, race, smoking status, participation in Statistical Analysis regular exercise, body mass index distribution, or occupa- tional status (Table 1; Supplementary Table 1). The fre- This was an exploratory study with no prespecified hypoth- quency of comorbidities (unrelated to chronic cough) did esis. The sample size was calculated based on a conserva- not differ between RCC and UCC groups (Supplementary tive approach with 95% confidence, 7% precision, and an Table 1). GERD and asthma were the most frequent underly- expected prevalence of 50% of any variable, yielding a sam- ing diseases in patients with RCC (Fig. 1). ple size of 196 patients with RCC or UCC. No stratification The characteristics of cough are described in Table 2. The (i.e., minimum number of each phenotype) was required mean duration of cough was 6.4 (range: 1–21) years. Cough between RCC and UCC. For sample descriptions, quantitative variables are expressed as mean and standard deviation (SD) or median and interquartile range (IQR), and qualitative variables are expressed as frequency and percentage. Results were compared between patients diagnosed with RCC or UCC. The Student t-test or analysis of vari- ance test was used to compare continuous variables, and the chi-squared test or Fisher exact test was used to compare proportions. All analyses were performed using the IBM SPSS 20.0.0 statistical program. Fig. 1  Underlying disease described as the cause of chronic cough in patients with refractory chronic cough (n = 126). Data expressed as number (%) of patients Table 1  Demographic characteristics of the study population Characteristic All patients (N = 196) RCC (N = 126) UCC (N = 70) p-value (RCC vs. UCC) Age, years Mean (SD) 58.5 (13.3) 59.3 (13.0) 57.1 (13.8) 0.263 Sex Men, n (%) 44 (22.4) 29 (23.0) 15 (21.4) 0.799 Women, n (%) 152 (77.6) 97 (77.0) 55 (78.6) Body mass index, kg/m2 Mean (SD) 27.2 (5.0) 27.2 (4.9) 27.3 (5.1) 0.944 Smoking habit Never, n (%) 128 (65.3) 82 (65.1) 46 (65.7) 0.929 Past smoker, n (%) 68 (34.7) 44 (34.9) 24 (34.3) Regular exercise Yes, n (%) 114 (58.2) 74 (58.7) 40 (57.1) See additional information in Supplementary Table 1. RCC​refractory chronic cough; SD standard deviation; UCC​unexplained chronic cough 13 278 Lung (2023) 201:275–286 Table 2  Characteristics of cough Characteristic All patients (N = 196) RCC (N = 126) UCC (N = 70) p-value (RCC vs. UCC) Duration of cough, years Mean (SD) 6.4 (5.0) 7.0 (5.6) 5.3 (3.5) 0.024 Cough frequency* Continuous, n (%) 156 (79.6) 94 (74.6) 62 (88.6) 0.024 Intermittent, but not seasonal, n (%) 34 (17.3) 27 (21.4) 7 (10.0) Intermittent, seasonal, n (%) 6 (3.1) 5 (4.0) 1 (1.4) Characteristics of cough Predominantly dry, n (%) 171 (87.2) 108 (85.7) 63 (90.0) 0.389 Predominantly productive, n (%) 25 (12.8) 18 (14.3) 7 (10.0) Cough triggers** Any trigger, n (%) 62 (31.6) 46 (36.5) 16 (22.9) 0.049 Speaking or laughing, n (%) 25 (12.8) 16 (12.7) 9 (12.9) 0.975 Cold air or change in temperature, n (%) 21 (10.7) 14 (11.1) 7 (10.0) 0.810 Dust, pollen, or other air irritants/parti- 22 (11.2) 19 (15.1) 3 (4.3) 0.031 cles like perfumes, n (%) Environmental tobacco smoke, n (%) 13 (6.6) 9 (7.1) 4 (5.7) 0.774 Agents present at work (occupational), 2 (1.0) 2 (1.6) 0 (0.0) 0.538 n (%) Eating or a particular type of food, n 17 (8.7) 11 (8.7) 6 (8.6) 0.970 (%) Exercise or exertion, n (%) 13 (6.6) 9 (7.1) 4 (5.7) 0.774 Other, n (%) 14 (7.1) 10 (7.9) 4 (5.7) 0.774 Atopy*** Yes, n (%) 66 (37.7) 50 (41.0) 16 (30.2) 0.176 Stress urinary incontinence**** Yes, n (%) 36 (18.4) 21 (16.7) 15 (21.4) 0.409 RCC​refractory chronic cough, SD standard deviation, UCC​unexplained chronic cough * Continuous: Patient suffers from cough every day or nearly every day. Intermittent, but not seasonal: patient suffers periods of cough and peri- ods of remission, but the cough is not present at specific periods in the year. Intermittent, seasonal: The patient has a chronic cough at specific times or seasons **Percentages were calculated based on cough triggers identified in patients’ clinical charts. Patients were not interrogated on these or other potential cough triggers ***Atopy, according to local standard tests (positive skin prick test or positive determination of serum-specific IgE to aeroallergens or foods) ****Stress urinary incontinence as reflected in patients’ clinical charts was continuous (i.e., every day or most days) in 79.6% of except for significantly more visits to gastroenterologists by patients and was predominantly dry in 87.2% of patients, patients with RCC than UCC (50.0% vs. 32.9%; p = 0.02). with no notable differences between RCC and UCC groups. Forty patients (20.4%) had visited the hospital emergency A cough trigger was identified in 31.6% of patients, more room (mean 1.5 [0.6] visits) due to cough. frequently in those with RCC than UCC (35.5% vs. 22.9%; Five patients with RCC and one patient with UCC had p < 0.05). As recorded in clinical charts, 37.7% of patients been hospitalized in the previous three years, five due to had atopy, and 18.4% had stress urinary incontinence (9.1% complications related to chronic cough and one for investiga- men and 21.1% women, p = 0.080). tion of chronic cough. During the observation period (up to 3 years before study The main diagnostic tests performed by physicians to entry), patients had visited a range of different physicians investigate chronic cough during the observation period are (Table 3), most frequently pulmonologists (183 patients summarized in Table 4. A complete list is provided in Sup- [93.4%], mean 5.2 [SD 4.6] visits) and primary care physi- plementary Table 2a-d. cians (154 patients [78.6%], mean 5.2 [4.5] visits). Also vis- The 3-year chart review indicated that the most frequent ited frequently were ENT specialists (107 patients [54.6%], diagnostic imaging tests were chest x-radiography in 164 mean 2.0 [1.6] visits), allergists (90 patients [45.9%], mean patients (83.7%), a mean of 2.1 (1.7) times per patient, and 2.7 [3.9] visits), and gastroenterologists (86 patients [43.9%], chest computed tomography (CT) in 100 patients (51.0%), a mean 2.8 [2.1] visits). Twenty-four patients (12.2%) visited mean of 1.3 (1.0) times per patient. Other imaging tests were mental health physicians, and the mean number of visits per performed less frequently (Supplementary Table 2a). There patient was 8.0 [11.9]). Numbers of visits per patient to vari- were no differences in the frequency of use of diagnostic ous specialties did not differ between RCC and UCC groups, imaging tests between patients with RCC or UCC. 13 Lung (2023) 201:275–286 279 Table 3  Physicians visits due to chronic cough in the previous three years Specialty All patients (N = 196) RCC (N = 126) UCC (N = 70) p-value (UCC vs. RCC) Primary care physician Number and percentage of patients visiting, (%) 154 (78.6) 95 (75.4) 59 (84.3) 0.146 Mean (SD) visits per patient visiting* 5.2 (4.5) 4.9 (4.7) 5.7 (4.1) 0.276 Mean (SD) visits per patient, all patients** 4.1 (4.5) 3.8 (4.6) 4.8 (4.3) 0.097 Pulmonologist Number and percentage of patients visiting, (%) 183 (93.4) 114 (90.5) 69 (98.6) 0.035 Mean (SD) visits per patient visiting* 5.2 (4.6) 5.6 (4.7) 4.6 (4.4) 0.167 Mean (SD) visits per patient, all patients** 4.9 (4.7) 5.0 (4.8) 4.5 (4.4) 0.463 Allergist Number and percentage of patients visiting, (%) 90 (45.9) 61 (48.4) 29 (41.4) 0.347 Mean (SD) visits per patient visiting* 2.7 (3.9) 3.1 (4.6) 1.9 (1.7) 0.176 Mean (SD) visits per patient, all patients** 1.2 (2.9) 1.5 (3.5) 0.8 (1.2) 0.107 ENT specialist Number and percentage of patients visiting, (%) 107 (54.6) 64 (50.8) 43 (61.4) 0.152 Mean (SD) visits per patient visiting* 2.0 (1.6) 1.8 (1.4) 2.2 (1.8) 0.261 Mean (SD) visits per patient, all patients** 1.1 (1.5) 0.9 (1.4) 1.3 (1.8) 0.071 Gastroenterologist Number and percentage of patients visiting, (%) 86 (43.9) 63 (50.0) 23 (32.9) 0.020 Mean (SD) visits per patient visiting* 2.8 (2.1) 3.0 (2.2) 2.7 (1.7) 0.151 Mean (SD) visits per patient, all patients** 1.2 (2.0) 1.5 (2.2) 0.7 (1.4) 0.010 Mental health (psy- Number and percentage of patients visiting, (%) 24 (12.2) 16 (12.7) 8 (11.4) 0.795 chiatrist or psycholo- Mean (SD) visits per patient visiting* 8.0 (11.9) 5.9 (4.7) 12.1 (20.0) 0.232 gist) Mean (SD) visits per patient, all patients** 1.0 (4.8) 0.8 (3.5) 1.4 (7.4) 0.377 Physiotherapist Number and percentage of patients visiting, (%) 8 (4.1) 5 (4.0) 3 (4.3) 1.000 Mean (SD) visits per patient visiting* 5.0 (6.4) 4.8 (7.4) 5.3 (5.9) 0.920 Mean (SD) visits per patient, all patients** 0.2 (1.6) 0.2 (1.6) 0.2 (1.5) 0.871 Emergency room*** Number and percentage of patients visiting, (%) 40 (20.4) 20 (15.9) 20 (28.6) 0.035 Mean (SD) visits per patient visiting* 1.5 (0.6) 1.6 (0.6) 1.4 (0.6) 0.295 Mean (SD) visits per patient, all patients** 0.3 (0.6) 0.3 (0.6) 0.4 (0.7) 0.146 ENT ear, nose, and throat, RCC​refractory chronic cough, SD standard deviation, UCC​unexplained chronic cough * Mean and SD were calculated on patients who had visited the specialist listed **The number of visits per patient in the previous three years was calculated with the overall population as the denominator, including patients who had no visits ***In Spain, patients can attend an emergency room by their own decision, without need for referral by a physician The most common diagnostic lung function study was patients with RCC than UCC (69.0% vs. 45.7%; p = 0.001) spirometry with bronchodilator test, performed in 151 underwent serum total IgE concentration measurement. patients (77.0%), a mean of 1.9 (1.2) times per patient, with Tests/cultures to detect infectious diseases, Ziehl–Neelsen no difference between the RCC and UCC groups. Simple stained microscopy, Mantoux tests, and nasal cytology were spirometry was performed in 111 patients (56.6%), more performed infrequently, with no differences between the often in those with RCC versus UCC (61.9% vs. 47.1%; RCC and UCC groups (Supplementary Table 2c). p = 0.046). The exhaled nitric oxide (FeNO) test was used There were no differences in the proportion of patients in 48.0% of patients, the methacholine test in 29.1% of with RCC or UCC who, during the three years before study patients, and the Diffusing Capacity of Lung for Carbon inclusion, had undergone diagnostic rhinoscopy (overall Monoxide (DLCO) test in 15.8% of patients, with no dif- percentage: 33.7%), bronchoscopy (14.8%), laryngoscopy ferences between the RCC and UCC groups. All other lung (20.9%), or esophageal manometry (23.5%). Diagnostic function tests were performed infrequently (Supplementary upper digestive endoscopy was performed in a significantly Table 2b). greater proportion of patients with RCC than UCC (32.5% Skin prick testing was performed in 103 patients (52.6%). vs. 18.6%, p = 0.036) (Table 4; Supplementary Table 2d). The most frequent laboratory determinations were serum During the 3-year chart review period, the main treat- total IgE concentration (119 patients [60.7%]) and spe- ments used to manage chronic cough were medications for cific IgE against aeroallergens (78 patients [39.8%]). More respiratory diseases (antihistamines, inhaled corticosteroids, 13 280 Lung (2023) 201:275–286 Table 4  Diagnostic tests performed due to chronic cough in the previous three years Diagnostic test All patients (N = 196) RCC (N = 126) UCC (N = 70) p-value (RCC vs. UCC) a. Image Chest x-radiography Number of patients (%) 164 (83.7) 108 (85.7) 56 (80.0) 0.300 Mean (SD) tests per patient per- 2.1 (1.7) 2.1 (1.8) 2.0 (1.3) 0.612 formed* Mean (SD) tests per patient, all 1.8 (1.7) 1.8 (1.9) 1.6 (1.4) 0.359 patients** X-radiography of other locations Number of patients (%) 44 (22.4) 31 (24.6) 13 (18.6) 0.332 Mean (SD) tests per patient per- 2.0 (1.7) 2.0 (1.9) 2.2 (1.2) 0.745 formed* Mean (SD) tests per patient, all 0.5 (1.2) 0.5 (1.3) 0.4 (1.0) 0.629 patients** Chest CT scan Number of patients (%) 100 (51.0) 69 (54.8) 31 (44.3) 0.160 Mean (SD) tests per patient per- 1.3 (1.0) 1.4 (1.2) 1.2 (0.5) 0.312 formed* Mean (SD) tests per patient, all 0.7 (1.0) 0.8 (1.1) 0.5 (0.7) 0.094 patients** b. Lung function and other lung tests Simple spirometry Number of patients (%) 111 (56.6) 78 (61.9) 33 (47.1) 0.046 Mean (SD) tests per patient per- 1.9 (1.2) 2.0 (1.4) 1.4 (0.7) 0.017 formed* Mean (SD) tests per patient, all 1.1 (1.3) 1.3 (1.5) 0.7 (0.9) 0.002 patients** Spirometry with bronchodilation Number of patients (%) 151 (77.0) 97 (77.0) 54 (77.1) 0.980 test Mean (SD) tests per patient per- 1.4 (0.8) 1.5 (1.0) 1.2 (0.5) 0.048 formed* Mean (SD) tests per patient, all 1.1 (1.0) 1.1 (1.1) 0.9 (0.6) 0.126 patients** Methacholine test Number of patients (%) 57 (29.1) 36 (28.6) 21 (30.0) 0.833 Mean (SD) tests per patient per- 1.1 (0.2) 1.1 (0.3) 1.0 (0.0) 0.180 formed* Mean (SD) tests per patient, all 0.3 (0.5) 0.3 (0.5) 0.3 (0.5) 0.898 patients** Exhaled nitric oxide test (FeNO) Number of patients (%) 94 (48.0) 63 (50.0) 31 (44.3) 0.443 Mean (SD) tests per patient per- 1.6 (1.1) 1.8 (1.2) 1.3 (0.8) 0.045 formed* Mean (SD) tests per patient, all 0.8 (1.1) 0.9 (1.2) 0.6 (0.8) 0.055 patients** c. Other laboratory determinations Total IgE Determination Number of patients (%) 119 (60.7) 87 (69.0) 32 (45.7) 0.001 Mean (SD) tests per patient per- 1.4 (2.2) 1.5 (2.5) 1.1 (0.2) 0.366 formed* Mean (SD) tests per patient, all 0.8 (1.8) 1.0 (2.2) 0.5 (0.6) 0.051 patients** Determination of specific IgE Number of patients (%) 78 (39.8) 54 (42.9) 24 (34.3) 0.240 against aeroallergens Mean (SD) tests per patient per- 1.6 (2.5) 1.3 (1.1) 2.3 (4.2) 0.116 formed* Mean (SD) tests per patient, all 0.6 (1.8) 0.6 (0.9) 0.8 (2.7) 0.395 patients** 13 Lung (2023) 201:275–286 281 Table 4  (continued) Diagnostic test All patients (N = 196) RCC (N = 126) UCC (N = 70) p-value (RCC vs. UCC) Skin prick testing Number of patients (%) 103 (52.6) 64 (50.8) 39 (55.7) 0.509 Mean (SD) tests per patient per- 1.1 (0.4) 1.1 (0.4) 1.1 (0.2) 0.234 formed* Mean (SD) tests per patient, all 0.6 (0.6) 0.6 (0.6) 0.6 (0.6) 0.945 patients** d. Invasive diagnosis Rhinoscopy Number of patients (%) 66 (33.7) 39 (31.0) 27 (38.6) 0.279 Mean (SD) tests per patient per- 1.2 (0.5) 1.3 (0.6) 1.1 (0.3) 0.209 formed* Mean (SD) tests per patient, all 0.4 (0.7) 0.4 (0.7) 0.4 (0.6) 0.746 patients** Bronchoscopy Number of patients (%) 29 (14.8) 19 (15.1) 10 (14.3) 0.881 Mean (SD) tests per patient per- 1.0 (0.0) 1.0 (0.0) 1.0 (0.0) (*) formed* Mean (SD) tests per patient, all 0.1 (0.4) 0.1 (0.4) 0.1 (0.4) 0.882 patients** Laryngoscopy Number of patients (%) 41 (20.9) 26 (20.6) 15 (21.4) 0.896 Mean (SD) tests per patient per- 1.2 (0.8) 1.3 (1.1) 1.0 (0.0) 0.266 formed* Mean (SD) tests per patient, all 0.3 (0.6) 0.3 (0.7) 0.2 (0.4) 0.549 patients** Upper gastrointestinal endoscopy Number of patients (%) 54 (27.6) 41 (32.5) 13 (18.6) 0.036 Mean (SD) tests per patient per- 1.1 (0.4) 1.1 (4.0) 1.1 (0.3) 0.708 formed* Mean (SD) tests per patient, all 0.3 (0.5) 0.4 (0.6) 0.2 (0.4) 0.038 patients** Esophageal manometry/pH moni- Number of patients (%) 46 (23.5) 33 (26.2) 13 (18.6) 0.228 toring Mean (SD) tests per patient per- 1.1 (0.5) 1.2 (0.6) 1.0 (0.0) 0.290 formed* Mean (SD) tests per patient, all 0.3 (0.5) 0.3 (0.6) 0.2 (0.4) 0.083 patients** The table shows diagnostic tests performed on more than 25% of patients and invasive tests. See Supplementary Table 2 for information about additional tests, including other image and lung function tests and other laboratory and microbiological determinations. *Mean and SD were calculated on patients who had received the diagnostic test listed. **Mean number of tests per patient in the previous three years calculated with the overall population as the denominator, including patients who had not received such diagnostic test. (*) All patients underwent one bron- choscopy; the p-value cannot be calculated. CT computed tomography; RCC​refractory chronic cough; SD standard deviation; UCC​unexplained chronic cough oral corticosteroids, inhaled bronchodilators) and proton Opioid-derivate cough suppressants were prescribed to 83 pump inhibitors, prescribed to 87.8% and 79.5% of patients, patients (42.3%), of whom 22 received > 8 weeks of treat- respectively, with no differences between the RCC and ment. Use of anticonvulsants or other nervous system drugs UCC groups (Table 5). For most therapeutic drug classes (gabapentin, pregabalin) and muscle relaxants (baclofen) prescribed to patients with RCC, the primary reason was was infrequent (14.3% and 6.6%, respectively) although ‘empirical treatment of cough’, although respiratory disease about half of patients prescribed these medications (51.9% medications and proton pump inhibitors were also prescribed and 53.8%, respectively) had a cumulative treatment dura- ‘to treat underlying disease’ or for both reasons (Sup- tion of > 8 weeks. plementary Table 3). Most patients who were prescribed Over the previous three years, 56 patients (28.6%) had respiratory disease medications or proton pump inhibitors been prescribed antibiotics for empirical treatment of chronic (84.6% and 84.0%, respectively) had a cumulative treatment cough (i.e., without evidence of underlying infectious disease). duration of > 8 weeks (Table 5; Supplementary Table 4). The proportion was numerically but not significantly higher 13 282 Lung (2023) 201:275–286 Table 5  Treatments prescribed for chronic cough in the previous three years Treatment All patients (N = 196) RCC (N = 126) UCC (N = 70) p-value (RCC vs. UCC)* Opioid-derivate cough suppressant Number of patients (%) who were 83 (42.3) 54 (42.9) 29 (41.4) 0.846 drugs: codeine, dextromethorphan, prescribed dimemorfan, noscapine Number of patients (%) who 22 (27.2) 14 (25.9) 8 (29.6) received > 8 weeks of treatment* Other cough suppressant drugs: Number of patients (%) who were 24 (12.2) 10 (7.9) 14 (20.0) 0.014 levodropropizine, cloperastine prescribed Number of patients (%) who 10 (16.1) 9 (22.5) 1 (4.5) received > 8 weeks of treatment* Expectorants: guaifenesin or others Number of patients (%) who were 12 (6.1) 8 (6.3) 4 (5.7) 1.000 prescribed Number of patients (%) who 2 (16.7) 1 (12.5) 1 (25.0) received > 8 weeks of treatment* Mucolytics: acetylcysteine, Number of patients (%) who were 65 (33.2) 42 (33.3) 23 (32.9) 0.946 ambroxol, bromhexine, carbo- prescribed cisteine, or others Number of patients (%) who 10 (16.1) 9 (22.5) 1 (4.5) received > 8 weeks of treatment* Anticonvulsants or other nerv- Number of patients (%) who were 28 (14.3) 15 (11.9) 13 (18.6) 0.201 ous system drugs: gabapentin, prescribed pregabalin Number of patients (%) who 14 (51.9) 8 (53.3) 6 (50.0) received > 8 weeks of treatment* Muscle relaxants (baclofen) Number of patients (%) who were 13 (6.6) 7 (5.6) 6 (8.6) 0.416 prescribed Number of patients (%) who 7 (53.8) 2 (28.6) 5 (83.3) received > 8 weeks of treatment* Proton pump inhibitors Number of patients (%) who were 156 (79.6) 104 (82.5) 52 (74.3) 0.169 prescribed Number of patients (%) who 126 (84.0) 90 (88.2) 36 (75.0) received > 8 weeks of treatment* Therapies used to treat other res- Number of patients (%) who were 172 (87.8) 110 (87.3) 62 (88.6) 0.795 piratory diseases: antihistamines, prescribed inhaled corticosteroids, oral corti- Number of patients (%) who 143 (84.6) 95 (87.2) 48 (80.0) costeroids, inhaled bronchodilators received > 8 weeks of treatment* (beta-agonists, anticholinergics) Therapeutic families were classified according to the classification of the Ministry of Health of Spain. Reasons for prescribing therapies in patients with RCC are provided in Supplementary Table 3 RCC​refractory chronic cough; UCC​unexplained chronic cough *See Supplementary Table 4 for more details about the cumulative duration of therapy and p-values in the UCC than RCC group (34.5% vs. 25.4%; p = 0.187). Discussion Macrolides were the antibiotic family prescribed most often. Among 18 patients (9.2%) who were prescribed non-cephalo- This retrospective study aimed to evaluate the charac- sporin beta-lactams (e.g., amoxicillin and others), the number teristics and management approach to RCC and UCC in of courses per patient was higher in the RCC versus UCC Spanish outpatient clinics to better understand the con- group (3.6 vs. 1.5 courses; p = 0.040). This pattern was not sequences and burden of these conditions to patients and observed with other antibiotic classes (Fig. 2). 13 Lung (2023) 201:275–286 283 More than 90% of patients had visited a pulmonologist, and approximately 80% of patients had visited a primary care physician, for a cough-related reason an average of five times per specialist during the previous three years. One in five patients (more with UCC than RCC) had visited an emergency department due to cough. Although only 12% of patients had sought mental health services (psychiatrist, psychologist), the mean (SD) number of visits per patient (8.0 [11.9]) over the 3-year observation period was the high- est among specialties. An expert panel has advocated for clinicians treating chronic cough to practice ‘intervention fidelity’, which is described as adhering closely to best practice diagnostic and treatment guidelines [13]. The high observed usage of Fig. 2  Percentage of patients receiving antibiotic therapies for empiri- chest X-rays and spirometry as diagnostic tests aligns with cal treatment of chronic cough and number of antibiotic cycles. Num- bers in the bars represent the mean (standard deviation) number of guideline recommendations for a diagnostic work-up of cycles received per patient who received a specific antibiotic from chronic cough [10, 11]. Likewise, frequent use of chest CT each class. Percentages reflect the percentage of patients who had scans, IgE determination, and skin prick testing suggested received such an antibiotic at least once to treat chronic cough with- that physicians were attempting to identify cough-associated out evidence of underlying infection. RCC​ refractory chronic cough, UCC​unexplained chronic cough conditions or treatable traits as per European guideline rec- ommendations [10]. More frequent use of total IgE deter- mination and upper gastrointestinal endoscopy in RCC than the healthcare system. The study provides quantitative UCC patients was likely due to the presence of asthma and/ data about health resource utilization associated with the or GERD in most of the RCC group. diagnosis and management of RCC and UCC, as recorded Medications prescribed to RCC and UCC patients in patients’ medical records. Data reported by Spanish reflected the treatment repertoire for chronic cough at the patients who participated in the cross-sectional European time of the study and aligned broadly with management rec- National Health and Wellness Survey applied to chronic ommendations [10, 11]. Consistent with GERD and asthma cough in general [4], whereas our study is specific to the as common cough-associated conditions [10, 11], the most difficult-to-manage subsets of patients with RCC or UCC. frequently prescribed therapeutic classes to treat an underly- It is important to emphasize that the results derive from ing disease or for empirical reasons (or both) were proton patients who were being followed for their RCC or UCC pump inhibitors and respiratory medications. A cumulative in outpatient hospital clinics. Population-based studies of treatment duration of > 8 weeks in most patients who were health-seeking behavior due to cough found that a substan- prescribed these medications suggests a reasonable trial tial proportion (60%) of individuals with chronic cough of therapy. In contrast, the prescribing of opioid-derivate do not seek medical treatment for their condition [15–17]. cough suppressants to 42% of patients, and a cumulative In Spain, there are no cough clinics per se that can con- treatment duration of > 8 weeks in 27% of this group, may tribute a large number of patients to investigation. Thus, be of concern given the risks and adverse events associated a relatively large number of centers participated in the with extended use of opioids, although this is unclear in present study. The inclusion period had to be extended to the absence of any detail about the quantity and frequency 19 months due to restrictions imposed by the COVID 19 of administration. The use of nonspecific therapies (e.g., pandemic. anticonvulsants, muscle relaxants), mainly for empiri- Our cohort was similar with respect to gender distribution cal purposes, was low, which is not unexpected given that and mean age as other chronic cough populations partici- their effectiveness in alleviating chronic cough is unclear pating in noninterventional studies [18, 19] or randomized and tolerability can be poor [11]. Interestingly, despite controlled trials [20, 21]. The main difference between RCC the wide range of medications prescribed to treat chronic and UCC groups was that, by definition, RCC patients had cough, patients still presented cough at study enrolment (as a known cough-associated condition (e.g., GERD, asthma), per inclusion criteria), which was described as continuous which was ultimately reflected by between-group variation (i.e., every day or nearly every day) in 80% of subjects, high- in both the type and number of physician visits and diag- lighting the need for more effective therapies to treat RCC nostic tests. or UCC. Our study confirmed that RCC and UCC are responsi- Chronic cough appears to be a driver for inappropri- ble for substantial health resource consumption in Spain. ate use of antibiotics. Antibiotics were used empirically 13 284 Lung (2023) 201:275–286 in more than one-quarter of patients, despite being indi- of P2X3 receptor antagonists with potential efficacy for cated only to treat an underlying infectious disease such as treating RCC and UCC and alleviating patients from the sinusitis or chronic bronchitis refractory to other therapy burden of excessive cough [26]. [10, 11]. As such, there is a continued need to improve antibiotic stewardship in the outpatient setting to avoid unnecessary or inappropriate use that can favor the devel- opment of antimicrobial resistance [22, 23]. Conclusion Study limitations include those inherent to observa- tional studies, such as selection bias, lack of a control This retrospective study, which aimed to profile patients group, and incomplete or missing data. Patients who seek with RCC and UCC and determine their health resource and subsequently maintain medical treatment for chronic utilization, confirms that these conditions pose a substan- cough represent a minority of the chronic cough popula- tial burden to healthcare systems in Spain. Despite broad tion. There were no established criteria other than phy- alignment between European guideline recommendations sicians’ clinical judgment (based on patients’ history, for treating chronic cough and the management approaches diagnostic test results and therapies used) to classify undertaken by Spanish physicians, the findings highlight patients as RCC or UCC in this study. Although unlikely, the shortcomings of available treatments, which mainly do we cannot rule out some misclassification. Selection bias not address the underlying pathology of cough. Recogniz- was mitigated to some extent by enrolling consecutive ing cough reflex hypersensitivity as a clinical feature may patients, although patients with serious conditions are help identify patients with potential to benefit from new more frequent attendees at outpatient clinics and thus have therapies that target specific receptors in the cough path- a greater chance of being enrolled. There may be inac- way. These newer therapies offer opportunities for more curacies in the data as the primary source was patients’ effective management of RCC and UCC to the benefit of medical records without prospective confirmation. Visits patients and healthcare systems. to primary care physicians in particular may be underes- Supplementary Information The online version contains supplemen- timated as several outpatient hospital clinics had no easy tary material available at https://​doi.​org/​10.​1007/​s00408-​023-​00620-y. access to this information. Moreover, because we studied only the three years prior to enrollment, the frequency Acknowledgements This study was funded by MSD Spain. Profes- of specialist visits, diagnostic tests, and prescribed treat- sional medical writing assistance was provided by Kerry Dechant, ISMPP CMPP™, on behalf of Content Ed Net (Madrid, Spain) with ments reflects this time period, not the entire patient his- funding from MSD Spain. tory, and may also be underestimated. For the same reason, the study reflects only 83.7% of patients having undergone Author Contributions ID, LP, SQ, CD-R, LC-C, and MS-J designed the chest radiography; the remainder are assumed to have had study in its objectives and methodology, and reviewed and interpreted the outcomes. The manuscript was drafted by these same authors. The this essential test performed before the study observation remaining authors participated in data acquisition and made substantial period. The mean 6.4 (5.0) year duration of chronic cough contributions to the current manuscript. in the cohort suggests that, in some patients, the bulk of the diagnostic work-up and associated health resource uti- Funding This study was funded by MSD Spain. Medical writing sup- port was funded by MSD Spain. lization had taken place before our three-year chart review period. Declarations In recent years, chronic cough has become increas- ingly recognized as a condition of neural dysregulation Competing Interest Ignacio Dávila: Consulting fees from Allergy [7]. Most patients with chronic cough have cough reflex Therapeutics, AstraZeneca, GSK, MSD, Novartis, and Sanofi. Lectures for Allergy Therapeutics, AstraZeneca, Chiesi, Diater, GSK, LETI, hypersensitivity, which is characterized by a heightened Novartis, and Sanofi. Grants to institution from ISCIII, Junta de Cas- neural responsivity to various stimuli affecting the air- tilla de León, and Thermofisher. Luis Puente: No conflict of interest way and lungs [11]. The shift in perception from cough declared. Santiago Quirce has received speaking, lecture and consulting as a consequence of underlying disease to cough as a dis- fees from Allergy Therapeutics, AstraZeneca, GSK, Mundipharma, Novartis, Sanofi, and Teva. Ebymar Arismendi: No conflict of interest tinct clinical entity has paved the way for development of declared. Miguel Díaz-Palacios: No conflict of interest declared. Anto- novel antitussives that act on specific cough pathways [24]. nio Pereira-Vega: No conflict of interest declared. Alfredo de Diego: No Pathophysiological underlying mechanisms such as ATP conflict of interest declared. Juan Luis Rodríguez-Hermosa: Consulting release, which may stimulate vagal C-fiber afferent sensory fees from Bial and Grifols; payments for lectures including service on speakers’ bureaus from Boehringer, Grifols, GSK, and Zambon. neurons upon binding to purinergic receptors, including Christian Domingo-Ribas: No conflict of interest declared. Luis Cea- the P2X3 receptor, have been identified as contributors Calvo, Marta Sánchez-Jareño and Pilar López-Cotarelo are full-time to chronic cough [25]. This has led to the development employees at MSD, Spain. 13 Lung (2023) 201:275–286 285 Ethical Approval The study was performed in accordance with Good McGarvey L, Rigau D, Satia I, Smith J, Song WJ, Tonia T, van Pharmacoepidemiology Practice standards and the principles of the den Berg JWK, van Manen MJG, Zacharasiewicz A (2020) ERS Declaration of Helsinki. guidelines on the diagnosis and treatment of chronic cough in adults and children. 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