Abstract
Background
This study was aimed at exploring the prevalence of somatic symptom disorder (SSD) in patients with chronic cough and comparing SSD comorbid (SSD+) and non-comorbid (SSD−) groups, including sociodemographic, clinical, psychological, and neuroimaging characteristics.
Methods
A total of 463 patients with chronic cough were enrolled. The structured clinical interview from the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders was used for SSD diagnosis. Clinical features, cough-related assessment and psychological assessment were used to compare the SSD+ and SSD− groups, while functional magnetic resonance imaging (fMRI) was performed in 24 patients (12 SSD+ and 12 SSD−) for neuroimaging comparisons.
Results
SSD was diagnosed in 13.8% (64/463) of all enrolled patients. The prevalence of SSD was greater in patients with refractory chronic cough (27.7%) than those with non-refractory chronic cough (7.8%). The SSD+ group had higher levels of capsaicin cough sensitivity (P = 0.016), anxiety (P < 0.001), and depression (P < 0.001), and lower cough-related quality of life scores (P < 0.001), than the SSD− group. Binary logistic stepwise regression indicated that higher anxiety level, female sex, lower cough-related quality of life, and more doctor visits were predictors of SSD diagnosis. Notably, SSD− patients demonstrated enhanced regional neural activity synchronization in the right cerebellum and mid-cingulate cortex, whereas SSD+ patients exhibited diminished spontaneous neural activity in the lingual gyrus (voxel P < 0.001, cluster P < 0.05, FWE corrected).
Conclusion
SSD was identified in 13.8% of chronic cough patients and in approximately 28% of those with refractory chronic cough. Comprehensive evaluation of psychological in chronic cough patients is essential for early identification and management of SSD comorbidity. Interdisciplinary collaboration, including psychosomatic medicine, may enhance diagnostic accuracy and treatment outcomes in this population.
Trial registration
This study was registered in the Chinese Clinical Trials Register (http://www.chictr.org.cn/) (ChiCTR2400079808). Registration date: January 12, 2024.
Graphical Abstract
Supplementary Information
The online version contains supplementary material available at 10.1186/s12890-026-04331-x.
Keywords: Cough, Prevalence, Somatic symptom disorder, Brain imaging
Introduction
Chronic cough, defined as a persistent cough lasting more than 8 weeks in adults, is a prevalent and clinically burdensome condition affecting approximately 10% of adults globally, with regional prevalence reaching 18% [1, 2]. This condition accounts for more than one-third of respiratory clinic consultations and poses a substantial healthcare burden [3]. Studies have indicated higher anxiety, depression, fatigue, and somatic symptoms in patients with chronic cough than in those without a cough [4, 5]. The prevalence of anxiety and depression in patients with chronic cough ranges from 16% to 33% [5]. Psychological distress can contribute to chronic cough, and the condition itself may also increase the risk of mental health issues, thus indicating a two-way relationship [6]. Notably, previous studies have suggested that affective disorders, such as anxiety and depression, in patients with refractory chronic cough are associated with alterations in brain regions involved in emotion regulation and sensory processing, including the anterior cingulate cortex, insula, and prefrontal cortex [7, 8]. These findings underscore the need to address psychological factors in managing chronic cough.
Historically, patients with chronic cough with psychological comorbidities were diagnosed with “psychogenic cough”. This construct has been reconceptualized as “somatic cough syndrome (SCS)” which aligns with the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM5) for somatic symptom disorder (SSD) [9, 10]. SSD is characterized primarily by disproportionate cognitive-affective responses to bodily sensations, such as catastrophic interpretation and health anxiety, alongside genuine somatic symptoms that lack a clear physiological etiology, rather than being defined solely by medically unexplained symptoms [11, 12]. Epidemiological studies have estimated an SSD prevalence of approximately 10% in the general population, according to self-reported questionnaires, whereas structured interviews have suggested lower prevalence rates, such as 5% among adults [13, 14]. The somatic symptoms of SSD are often nonspecific and span across multiple medical disciplines [15]. Cough is a somatic symptom frequently encountered in respiratory departments. To date, no studies have reported the prevalence and characteristics of SSD among patients with chronic cough. The urge-to-cough (UTC) is the subjective sensation or drive to cough that precedes the actual cough reflex and plays a key role in the initiation and perception of chronic cough [8]. Emerging evidence suggests that UTC may share central neural mechanisms with other interoceptive disorders [16, 17]. Similarly, SSD is characterized by the amplified perception of bodily sensations. Whether chronic cough (especially refractory chronic cough) and SSD involve overlapping neural mechanisms remains to be explored.
A cross-sectional study was conducted to establish the prevalence of SSD in patients with chronic cough according to the DSM-5 criteria, and to explore the sociodemographic, clinical, and neuroimaging characteristics of chronic cough in patients with SSD, to provide a basis for exploring the etiology and psychological treatment approaches for such patients in the future.
Methods
Study design and participants
This cross-sectional study enrolled a total of 463 patients with chronic cough from our respiratory clinic between January 2024 and January 2025. A complete medical history, physical examination, and relevant findings from auxiliary examinations were collected. General demographic data, including age, sex, living arrangements, employment, education, number of doctor visits, and smoking and drinking habits, were also collected. All patients completed a cough-related assessment including the cough severity visual analog scale (VAS), capsaicin cough sensitivity testing, the cough symptom score, Leicester Cough Questionnaire (LCQ). Psychosomatic scales including the Patient Health Questionnaire-Somatic Symptom Severity Scale (PHQ‐15), Somatic Symptom Disorder‐B Criteria Scale (SSD‐12), Patient Health Questionnaire‐Depression Scale (PHQ‐9), and General Anxiety Disorder‐7 (GAD‐7) were also estimated. A copyright for the Chinese version of the questionnaires used in this study have been obtained.
The inclusion criteria were as follows: ① age ≥ 18 years; ② diagnosis of chronic cough according to the Chinese Guidelines for the Diagnosis and Treatment of Cough in 2021 [17, 18]; and ③ completion of the cough-related assessment and psychosomatic scale assessment at the first visit. The exclusion criteria were as follows: ① patients with language barriers and limited reading skills; ② lack of completion of the assessments and scales by the patients at the time of the initial diagnosis; and ③ lack of psychosomatic joint diagnosis.
Definition of the somatic symptom disorder
Patients with chronic cough attended one, 40-60-minute diagnostic session at a multi-disciplinary treatment (MDT) clinic performed in the psychosomatic department. Each patient with chronic cough received a psychological assessment on the first visit to the respiratory clinic. If the relevant scale indicated abnormalities (SSD-12 ≥ 16 points, PHQ‐9 ≥ 5 points, or GAD‐7 ≥ 5 points), a psychosomatic combined diagnosis was performed at the MDT clinic. Detailed patient information was collected by the psychiatrists. Patients were interviewed according to the Structured Clinical Interview (SCID) in the DSM‐5 (http://www.scid5.org) and the validated Chinese version (Supplementary 1), which has been confirmed to have good reliability and validity [19]. The interview was conducted by a well‐trained psychiatrist under the supervision of a senior psychiatrist from the Department of Psychosomatic Medicine. The diagnostic criteria for SSD are based on the DSM-5 and require that all three criteria A, B, and C be simultaneously met, followed by a diagnostic interview to confirm the diagnosis (Supplementary 2): SSD criterion A was evaluated according to the PHQ-15 scale. SSD criterion B was evaluated according to the SSD-12 scale (in which ≥ 16 is considered abnormal). SSD criterion C was determined according to whether the cough symptoms persisted for more than 6 months. Symptom severity of SSD was classified according to the total score on the PHQ-15 scale: ≤ 9, mild; 10–14, moderate; and ≥ 15, severe. The final diagnosis of SSD was made according to the three diagnostic criteria and diagnoses by at least two psychiatrists after the interview. Patients with chronic cough combined with SSD were defined as the SSD+ group, and patients with chronic cough without SSD were defined as the SSD− group.
Definition of refractory chronic cough
Refractory chronic cough (RCC) was defined by a duration of cough ≥ 1 year; and meeting one of the following diagnoses: ① presence of positive auxiliary examination results; poor therapeutic efficacy even after the combined use of neuroregulators alongside targeted treatment measures; or ② inability to identify a specific cause despite comprehensive examination, diagnosed as unexplained chronic cough [20].
Cough-related assessment
The cough severity visual analog scale (VAS) is a 100-mm linear scale used to measure patients’ self-perceived cough severity, with 0 mm signifying no cough and 100 mm representing the worst possible cough. In clinical studies, a decrease of 30 mm or more on the VAS is considered a clinically meaningful improvement in chronic cough severity [21, 22].
The capsaicin cough sensitivity test. This test used a modified method originally described by Fujimura et al. [23], recorded as the minimum concentrations of capsaicin required to stimulate two coughs (C2) and five coughs (C5). Capsaicin (MCE, catalog number HY-10448) was dissolved in Tween 80 and absolute ethanol, then diluted in 8 mL of 0.9% NaCl to prepare a 0.01 mol/L stock solution and serially diluted to concentrations from 0.49 to 1000 µmol/L. It was delivered via an air-compressed nebulizer (PARI GmbH, Germany) at 0.5 mL/min. Participants, wearing a nose clip, inhaled each concentration for 15 s, starting with saline and doubling the concentration stepwise. Coughs within 30 s were recorded, and the minimum concentrations eliciting two (C2) and five coughs (C5) were noted. The test ended when C5 was reached, or the concentration reached 1000 µmol/L.
The cough symptom score was assessed with the scale developed by Hsu et al. [24], which consists of two components: daytime and nighttime cough scores. Each score ranges from 0 to 5, where 0 indicates the absence of cough (best), and 5 represents a severe, distressing cough (worst).
Cough-related quality of life was assessed with the Chinese version of the LCQ, which is a 19-item questionnaire assessing the physical, psychological, and social impacts of chronic cough [25, 26].
Psychosomatic-related assessment
The SSD-12 scale is used to quantitatively evaluate patients’ cognition, feelings, and behaviors regarding somatic symptoms. The total score is 48 points, and a higher score indicates a more severe reaction to somatic symptoms. A score ≥ 16 is divided into the threshold value, and the psychometric evaluation has indicated good reliability and validity [27].
The PHQ-15 scale comprises 15 somatic symptoms, each scored from 0 (“not bothered at all”) to 2 (“bothered a lot”), with a total score of 30 points. Studies have indicated that the Chinese version of the PHQ‐15 has satisfactory reliability and provided preliminary evidence of its validity [28].
The PHQ-9 questionnaire is used for evaluating the severity of depressive symptoms over the prior 2 weeks. The total score ranges from 0 to 27; a score ≥ 5 suggests abnormalities [29].
The GAD-7 questionnaire is used to describe the severity of the patient’s anxiety symptoms in the past 2 weeks. The total score is 21 points, and a score ≥ 5 suggests abnormalities [30].
Resting-state functional magnetic resonance imaging and participants
Among participants, functional magnetic resonance imaging (fMRI) was performed on the basis of patient self-selection; 33 patients underwent fMRI scanning (18 in the SSD− group and 15 in the SSD+ group). After exclusion of those with excessive head motion, 12 age-matched patients from each group were ultimately included in the analysis.
All participants were scanned on a 3 T MRI with the following parameters: TR = 2000 ms, TE = 30 ms, FOV = 240 mm, matrix size = 64 × 64, and a 4 mm slice thickness without gaps. During the scan, participants were instructed to breathe normally and avoid consciously focusing on coughing or somatic sensations, aiming to minimize task-related cognitive interference; All participants wore earplugs to reduce noise interference from the scanning process, ensuring comfort and minimizing external distractions; Participants were scanned in the supine position with their heads fixed to reduce motion artifacts; Four patients may have experienced spontaneous coughing during the scan. Due to the impact of coughing on head movement data, these patients’ data were excluded from analysis. The study was designed with participants in a resting state and no additional tasks were performed to minimize the influence of other task-related factors on brain activity. Preprocessing involved discarding the first ten time points, correcting for slice timing differences (by using interpolation with even slices acquired first), and performing head motion correction (excluding subjects with movements greater than 3 mm or 3°). T1 images were registered to Montreal Neurological Institute (MNI) space via the DARTEL algorithm, and functional images were resampled to 3 × 3 × 3 mm³, then smoothed with a 6 mm FWHM Gaussian kernel. Denoising was conducted by regressing out white matter, cerebrospinal fluid signals, and Friston’s 24 motion parameters, and subsequently conducting band-pass filtering (0.01–0.08 Hz). Finally, the fractional amplitude of low-frequency fluctuations (fALFF) was calculated for the whole brain (z-score normalized), and regional homogeneity (ReHo) was derived with Kendall’s coefficient of concordance with subsequent z-score normalization.
Statistical analysis
Normally distributed data are expressed as mean ± standard deviation, whereas data with skewed distributions are expressed as a median (interquartile range). C2 and C5 were log-transformed to normalize the data. Categorical variables were analyzed with the chi-square test. Continuous variables that were normally distributed were evaluated with the t‐test; otherwise, the Mann‐Whitney nonparametric test was used. For the logistic regression, we chose our predictors of interest according to prior research on SSD [14]. Variables were initially selected through single-factor analysis using binary logistic regression, and stepwise regression analysis with the FORWARD method was subsequently performed. The model fit of the stepwise binary regression determined with − 2 log‐likelihood, Cox and Snell R2, and Nagelkerke’s R2 is presented in the results. SPSS 26.0 software (SPSS Inc., Chicago, IL, USA) was used for all statistical analyses. A P-value < 0.05 was accepted as statistically significant. The sample size was calculated based on an anticipated SSD prevalence of 33.8%, derived from a previous multi-center cross-sectional study in China [31]. Using a 95% confidence level (Z = 1.96) and a margin of error of ± 5%, the minimum required sample size was estimated to be approximately 344 participants to ensure adequate precision in prevalence estimation. The fALFF and ReHo indices of the participants were calculated with the DPARSF 5.0 toolbox and DPABI software on the Matlab 2020a platform. Statistical analyses were performed with SPM12 and analyzed with group comparisons conducted via two-sample t-tests (voxel P < 0.001, cluster P < 0.05 FWE-corrected).
Results
Sample characteristics
In total, 510 patients with chronic cough were included. Only the data for 463 patients (64 SSD+ and 399 SSD−) who completed both the questionnaires and interview are presented in this study. The flowchart of patient enrollment is shown in Fig. 1. The etiologies of cough among the 64 SSD+ patients are as follows: 20 were gastroesophageal reflux-induced chronic cough (GERC), 14 were cough variant asthma (CVA), 4 were eosinophilic bronchitis (EB), 3 were atopic cough (AC), 3 were upper airway cough syndrome (UACS), 2 were GERC combined UACS, 3 were GERC combined CVA, and 15 were unexplained cough. The etiologies of cough among the 399 SSD− patients are as follows: 64 were GERC, 80 were CVA, 27 were EB, 35 were AC, 32 were UACS, 158 were combined etiology, and 3 were unexplained cough. Except for cough duration, no significant differences were observed in other general characteristics between groups (Table 1).
Fig. 1.
Flow of patients through the study
Table 1.
Clinical characteristics, cough and psychological related evaluations of enrolled patients with chronic cough
| Variables | SSD− (N = 399) |
SSD+ (N = 64) |
Test results |
|---|---|---|---|
| Age (y) | 48.52 ± 15.37 | 49.69 ± 14.57 | t=-0.610, P = 0.542 |
| Sex (F/M) | 257/142 | 40/24 | χ2 = 0.088, P = 0.780 |
| Body mass index (kg/m2) | 24.73 ± 6.26 | 24.07 ± 3.81 | t = 0.816, P = 0.415 |
| Duration (m) | 12.00(44.00) | 18.00(31.00) * | Z=-2.847, P = 0.004 |
| Lung function | |||
| FEV1 predicted (%) | 101.32 ± 12.01 | 102.15 ± 14.02 | t=-0.216, P = 0.829 |
| FVC predicted (%) | 101.61 ± 13.52 | 100.15 ± 12.63 | t = 0.347, P = 0.729 |
| FEV1/FVC% | 83.29 ± 7.71 | 85.79 ± 8.00 | t=-1.030, P = 0.305 |
| VAS | 65.44 ± 16.17 | 68.75 ± 17.77 | t=-1.499, P = 0.134 |
| Cough symptom score | |||
| Daytime | 3.00(2.00) | 3.00(2.00) | Z=-0.955, P = 0.339 |
| Nighttime | 1.00(2.00) | 2.00(2.00) | Z=-1.518, P = 0.129 |
| Capsaicin cough sensitivity | |||
| C2 | 0.98 ± 0.45 | 0.80 ± 0.18* | t = 3.120, P = 0.002 |
| C5 | 1.18 ± 0.99 | 1.01 ± 0.40* | t = 2.420, P = 0.016 |
| LCQ score | |||
| Total score | 14.16(3.52) | 10.91(3.47) ** | Z=-8.827, P < 0.001 |
| Physical domain | 5.35(1.01) | 4.33(1.18) ** | Z=-4.656, P < 0.001 |
| Psychological domain | 4.61(1.27) | 2.54(0.43) ** | Z=-10.923, P < 0.001 |
| Social domain | 5.20(0.75) | 3.50(1.25) ** | Z=-8.258, P < 0.001 |
| Psychological domain | |||
| SSD − 12 score | 0.0(5.0) | 21.0(6.8) ** | Z=-11.334, P < 0.001 |
| PHQ-15 score | 0.0(3.0) | 6.5(6.0) ** | Z=-8.948, P < 0.001 |
| GAD-7 score | 0.0(3.0) | 6.0(7.0) ** | Z=-8.359, P < 0.001 |
| PHQ-9 score | 0.0(2.0) | 7.0(6.8) ** | Z=-9.241, P < 0.001 |
Data are presented as mean ±standard deviation., median (interquartile range), or No. (%) unless otherwise indicated
SSD somatic symptom disorder, FEV1 forced expiratory volume in 1 s, FVC forced vital capacity, VAS cough severity visual analog scale, C2 capsaicin solution concentration with ≥ 2 coughs, C5 capsaicin solution concentration with ≥ 5 coughs, SSD-12 somatic symptom disorder-B criteria scale, LCQ Leicester cough questionnaire, PHQ-15 patient health questionnaire-15, PHQ-9 patient health questionnaire-9, GAD-7 general anxiety disorder-7
* Compared with SSD− group, P < 0.05; ** compared with SSD− group, P < 0.001
In the neuroimaging analysis subsample, the two groups of patients were well-matched in baseline characteristics such as age, sex, and body mass index with no statistically significant differences observed (all P > 0.05). This subsample was comparable to the overall study sample in key sociodemographic and clinical features. Detailed data are provided in supplementary table in Supplementary 6.
Sociodemographic characteristics of enrolled patients
No differences were found in health insurance, marital status, family income, and smoking and drinking habits between groups. The proportions of life situation, employment, education, and doctor visits within a year differed between groups (Table 2).
Table 2.
Sociodemographic characteristics of enrolled patients
| Total | SSD− | SSD+ | Test results | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| N | % | N | % | N | % | χ2 | df | P | ||
| Health insurance | Yes | 335 | 72.4 | 294 | 73.7 | 41 | 64.1 | 2.553 | 1 | 0.110 |
| No | 128 | 27.6 | 105 | 26.3 | 23 | 35.9 | ||||
| Marital status | Single | 57 | 12.3 | 45 | 11.3 | 12 | 18.8 | 6.808 | 4 | 0.146 |
| Married | 377 | 81.4 | 327 | 82.0 | 50 | 78.1 | ||||
| Divorced | 11 | 2.4 | 11 | 2.8 | 0 | 0 | ||||
| Widowed | 8 | 1.7 | 6 | 1.5 | 2 | 3.1 | ||||
| Married but separated | 10 | 2.2 | 10 | 2.5 | 0 | 0 | ||||
| Life situation | Alone | 39 | 8.4 | 26a | 6.5 | 13b | 20.3 | 25.511 | 6 | <0.001 |
| With partner | 177 | 38.2 | 163a | 40.9 | 14b | 21.9 | ||||
| Alone with children | 23 | 5.0 | 21a | 5.3 | 2a | 3.1 | ||||
| With partner and children | 144 | 31.1 | 121a | 30.3 | 23a | 35.9 | ||||
| With parents | 22 | 4.8 | 22a | 5.5 | 0a | 0 | ||||
| With parents, partner, and children | 44 | 9.5 | 36a | 9.0 | 8a | 12.5 | ||||
| Other | 14 | 3.0 | 10a | 2.5 | 4a | 6.3 | ||||
| Family income (monthly) | Low (under 4000 RMB) | 48 | 10.4 | 42 | 10.5 | 6 | 9.4 | 0.813 | 2 | 0.666 |
| Middle (4000–8000 RMB) | 179 | 38.7 | 151 | 37.8 | 28 | 43.8 | ||||
| High (above 8000 RMB) | 236 | 51.0 | 206 | 51.6 | 30 | 46.9 | ||||
| Employment | Employed | 189 | 40.8 | 149a | 37.3 | 40b | 62.5 | 24.784 | 3 | <0.001 |
| Unemployed | 28 | 6.0 | 20a | 5.0 | 8b | 12.5 | ||||
| Retired | 225 | 48.6 | 210a | 52.6 | 15b | 23.4 | ||||
| Student | 21 | 4.5 | 20a | 5.0 | 1a | 1.6 | ||||
| Education | Elementary school | 36 | 7.8 | 36a | 9.0 | 0b | 0 | 14.457 | 3 | 0.002 |
| Middle school | 125 | 27.0 | 111a | 27.8 | 14a | 21.9 | ||||
| High school | 89 | 19.2 | 81a | 20.3 | 8a | 12.5 | ||||
| University degree | 213 | 46.0 | 171a | 42.9 | 42b | 65.6 | ||||
| Smoking history | Never | 378 | 81.6 | 320 | 80.2 | 58 | 90.6 | 4.044 | 2 | 0.132 |
| Currently | 24 | 5.2 | 22 | 5.5 | 2 | 3.1 | ||||
| In the past | 61 | 13.2 | 57 | 14.3 | 4 | 6.3 | ||||
| Alcohol consumption | Never | 265 | 57.2 | 228 | 57.1 | 37 | 57.8 | 3.874 | 3 | 0.275 |
| Social drinking | 176 | 38.0 | 149 | 37.3 | 27 | 42.2 | ||||
| Drink in the past, but quit now | 16 | 3.5 | 16 | 4.0 | 0 | 0 | ||||
| Almost drink every day (≥ 3 days/week) | 6 | 1.3 | 6 | 1.5 | 0 | 0 | ||||
| Number of doctor visits in the past 12 months | 0–2 | 48 | 10.4 | 47a | 11.8 | 1b | 1.6 | 152.060 | 3 | <0.001 |
| 3–10 | 309 | 66.7 | 291a | 72.9 | 18b | 28.1 | ||||
| 11–20 | 81 | 17.5 | 58a | 35.9 | 23b | 14.5 | ||||
| 20+ | 25 | 5.4 | 3a | 0.8 | 22b | 34.4 | ||||
Percentages are normally column percentages. RMB: the renminbi is the currency of the People’s Republic of China; 1000 RMB is equivalent to approximately 125 Euro
a, b: Each subscript letter denotes a subset of the SSD− and SSD+ groups whose column proportions do not differ significantly from each other at the 0.05 level
Prevalence of SSD in chronic cough patients
The prevalence of SSD in the whole sample was 13.8% (64/463). Among the 64 patients diagnosed with SSD, the ratio of mild, moderate, and severe SSD was 64.1% (41/64), 28.1% (18/64), and 7.8% (5/64), respectively. The prevalence of SSD in patients with RCC was 27.7% (39/141), much higher than that in patients with non-refractory chronic cough (7.8%; 25/322), among the 39 RCC patients diagnosed with SSD, the ratio of mild, moderate, and severe SSD was 56.4% (22/39), 17.4% (7/39), and 25.6% (10/39), respectively (Fig. 2A). Furthermore, the proportion of patients with moderate or severe SSD was higher among those with refractory chronic cough than non-refractory chronic cough. Among the 463 patients included in the final analysis, 98 patients had anxiety (51 SSD+ and 47 SSD−) and 118 patients had depression (41 SSD+ and 77 SSD−). Among the 64 patients with SSD, 22.2% (35/64) had concurrent anxiety and depression, whereas 7% (11/64) did not have comorbid anxiety or depression (Fig. 2B).
Fig. 2.
Prevalence, psychological comorbidities, and neuroimaging characteristics of SSD in patients with chronic cough (Neuroimaging data are based on the subsample of 24 patients). A Prevalence of SSD in patients with refractory chronic cough and non-refractory chronic cough; B Comorbidity of anxiety and depression in patients with chronic cough with SSD; C Differential regions of ReHo values between the SSD − and SSD+ groups; D Differential regions of fALFF values between the SSD − and SSD+ groups; E Group distribution of significant fMRI metrics: significant differences in ReHo in the rMCC (Right, MNI: 3, -21, 42), ReHo in the R lobule VIII (Middle, MNI: 18, -72, -39), and fALFF in the R-LG (Left, MNI: 6, -81, -3). SSD, somatic symptom disorder; PHQ-15, patient health questionnaire-15; PHQ-9, patient health questionnaire-9; GAD-7, general anxiety disorder-7; rMCC, right middle cingulate cortex; R lobule VIII, right cerebellar lobule VIII, R-LG, right lingual gyrus. **** Compared with SSD− group, P<0.0001
Cough-related and psychosocial-related assessment in the two groups
No significant differences were observed in cough symptom scores between groups. The capsaicin cough sensitivity of C2 and C5 were both significantly higher in the SSD+ group than in the SSD− group. Furthermore, the SSD+ group reported lower LCQ scores, and higher SSD-12, PHQ-15, PHQ-9, and GAD-7 scores, than the SSD− group (Table 1).
Predictor variables of SSD in patients with chronic cough
In a binary logistic regression analysis, single-factor analysis demonstrated that indicators such as the GAD-7 score (exp(B) = 1.253, P < 0.001), LCQ score (exp(B) = 0.646, P < 0.001), cough course (exp(B) = 0.983, P = 0.008), male sex (exp(B) = 0.336, P = 0.026), non-refractory chronic cough (exp(B) = 0.212, P = 0.004), and number of doctor visits (exp(B) = 1.277, P < 0.001) were significant factors associated with SSD. These variables were included in the stepwise regression analysis to establish the model (Supplementary 3). Stepwise regression indicated that GAD-7, LCQ, doctor visits, and sex were predictor variables of SSD diagnosis (Supplementary 4). The explained variance was Nagelkerke R2 = 0.654. In the final model, 97.2% of the patients without SSD and 60.9% of the patients with SSD were identified correctly. The sensitivity and specificity of this model were good (correct and incorrect predictions of the four models in Supplementary 5).
Neuroimaging characteristics between SSD+ and SSD− patients with chronic cough
Compared with the SSD− group, SSD+ patients exhibited decreased ReHo in cerebellar lobule VIII (R lobule VIII)(MNI: 18, -72, -39; T = 5.65, cluster size = 58 voxels) and the mid-cingulate cortex (rMCC) (MNI: 3, -21, 42; T = 4.64, cluster size = 50 voxels) (voxel P < 0.001, cluster P < 0.05 FWE-corrected) (Fig. 2C), as well as decreased fALFF in the right lingual gyrus (R-LG) (MNI coordinates: 6, -81, 3; T = 4.86, cluster size = 30 voxels; voxel P < 0.001, cluster P < 0.05 FWE-corrected) (Fig. 2D). Besides, a correlation analysis between the ReHo values of the rMCC and SSD severity as measured by the PHQ-15 scale. The results showed a strong and highly significant negative correlation between rMCC ReHo values and SSD severity (r = − 0.843, P < 0.001), indicating that lower ReHo values in the rMCC are associated with more severe SSD symptoms. However, no significant correlations were observed between SSD symptom severity and ReHo in the R lobule VIII (r = − 0.56, P = 0.059) or fALFF in the R-LG (r = − 0.406, P = 0.19). Detailed fMRI data between the SSD− and SSD+ patients with chronic cough can be found in the supplementary file (Supplementary 6).
Discussion
We conducted this prospective cross-sectional study to perform the first investigation of the prevalence of combined SSD in adults with chronic cough and its association with social, clinical, psychological, and neuroimaging characteristics. The prevalence of SSD in patients with chronic cough was 13.8% and was higher in patients with refractory cough, approximately 28%. According to the socio-demographic statistics, SSD+ patients were more likely to live alone, be employed, and have higher education levels, whereas SSD− patients were more likely to live only with a partner and to be retired. Moreover, patients with chronic cough with SSD had higher cough sensitivity, worse cough-related quality of life and more serious psychological problems. Higher anxiety level, female sex, lower cough-related quality of life, and more doctor visits were predictive risk factors for SSD in patients with chronic cough. In addition, neuroimaging findings indicated that SSD− patients showed compensatory cerebellar-cingulate hyperactivity, whereas SSD+ patients displayed hypoactivity in visuolimbic regions implicated in somatic symptom processing.
Both the previously recognized psychogenic cough and the newly proposed SCS lack sufficient evidence supporting their definitions, yet both are emphasized as exclusive diagnoses that can only be made after ruling out other common causes of chronic cough. In contrast, SSD is symptom-focused and may coexist with conditions of various etiologies, including different causes of cough, highlighting its broader applicability in clinical practice. The prevalence of SSD in patients with chronic cough has not been reported to date. Previous studies have estimated that the prevalence of psychogenic cough among patients with chronic cough in China is approximately 2.1% [32], whereas the prevalence of SCS is approximately 4.23% [33]. a value much lower than the prevalence of chronic cough combined with SSD reported in this study. We speculate that the prevalence in a prior SCS study might be associated with the exclusion of other cough etiologies. In this study, in 15 of 64 SSD+ patients, the cause of cough could not be identified; these patients accounted for approximately 3.2% of all patients, a value similar to the prevalence of psychological cough and SCS in adults reported in previous studies. In addition, we observed patients with different etiologies of chronic cough combined with SSD. Therefore, SSD present across all etiologies of chronic cough, rather than only in patients with an unclear cough etiology.
Studies have found that the prevalence of SSD is 4.5%–17.4% in the general population [9, 34] and 3.5%–45.5% in general hospitals [34, 35]. Differences exist among studies, possibly because of regional differences and diagnoses by different medical specialties. In addition, in most studies, the prevalence estimates of SSD were derived primarily from clinical assessments and self-reported questionnaires rather than being based on standard diagnostic interviews, thus potentially leading to an overestimation of the prevalence. A multi-center cross-sectional study in China has found a 33.8% prevalence of SSD among general hospital outpatients. The rates were 40.2% in neurology, 19.0% in gastroenterology, and 42.1% in traditional Chinese and psychosomatic medicine [31]. In our study, the prevalence of SSD was relatively lower. This discrepancy might have been because our study focused specifically on cough as a single symptom, whereas previous studies have assessed the overall prevalence of SSD across specialties, considering multiple symptoms rather than only one symptom.
We also found that the prevalence of SSD in patients with refractory chronic cough was higher and more severe than that among patients with non-refractory chronic cough. This finding might have been due to multifactorial interactions: neurobiological sensitization, such as central hyperexcitability in brainstem cough centers and cortical regions leading to lowered reflex thresholds and amplified symptom perception [36, 37]; dysregulated autonomic nervous activity, such as vagal dysfunction linking laryngeal hypersensitivity and anxiety-related comorbidities; and psychobehavioral mechanisms, such as illness-related anxiety reinforced by diagnostic uncertainty and ineffective therapies. Concurrent maladaptive cognitive patterns, such as catastrophizing and hypervigilance, may further cause somatosensory amplification and exacerbate cough severity.
In clinical comparisons, the SSD+ patients exhibited significantly longer cough duration than SSD− patients, in agreement with prior reports on SCS [33]. Notably, conventional cough symptom scores did not differentiate the groups, thus suggesting a need for multidimensional assessment protocols incorporating cough reflex sensitivity and psychobehavioral profiles. Additionally, our study indicated partial comorbidity of anxiety and depression in patients with chronic cough with SSD; however, the comorbidities were not entirely matched (some patients exhibited only a single psychological issue, either anxiety or depression, and consequently did not meet the criteria for SSD diagnosis). Thus, the concept of SCS might not fully encompass this subset of patients with chronic cough with combined psychological issues.
Sociodemographic statistics indicated that patients with chronic cough and SSD were more likely to live alone, to be employed, and to have a higher education level, whereas patients without SSD were more likely to live only with a partner or to be retired. These findings may be associated with the pathogenesis of SSD being affected by multiple biological, psychological, and social factors. Previous studies have suggested that psychosocial stress, such as acute physical illness, a stressful work environment, negative life events, and how family members treat their illness may be important factors inducing physical discomfort [35].
According to our multivariate analysis, SSD should be considered more frequently in female patients with chronic cough who have high GAD-7 scores and low LCQ scores. Female sex was found to be a risk factor for SSD with chronic cough. On the one hand, women might be more sensitive to stress and emotion than men. This sex difference in response to stress might make women more prone to internalizing problems, possibly because women might be less able to adapt to the high levels of neuropeptides involved in physiological and psychological stress responses [38]. On the other hand, women with chronic cough might have relatively painful complications, such as urinary incontinence, thus increasing the incidence of psychological problems [39]. Studies from other disciplines suggest that patients with comorbid SSD indeed experience elevated anxiety [40, 41]. The persistent state of anxiety leads to frequent medical visits for these patients, and ineffective treatment exacerbates their psychological issues, thus decreasing quality of life [41].
Our neuroimaging findings delineated distinct neural signatures between SSD− and SSD+ patients. The increased ReHo in the right cerebellar lobule VIII (R lobule VIII region in the SSD− group was implicated in sensorimotor-emotional integration. The cerebellum is a key region involved in regulating body balance, muscle tone, and the coordination of voluntary movements, recent studies have also suggested that the cerebellum plays a key role in the pathology of SSD [42]. Specifically, R lobule VIII participates primarily in motor integration and receives projections from the motor cortex [43]. In recent years, functional imaging studies have demonstrated that the cerebellum is also involved in sensory processing, cognition, emotion, social behavior, and language regulation [44]. Additionally, the cerebellum may be closely associated with fiber projections to the brainstem cough center [45].
The mid-cingulate cortex (rMCC) plays a pivotal role in emotional awareness through the integration of cognitive, affective, and visceromotor functions, and is part of a cortical-subcortical midline system that mediates self-referential processing and is critical for experiential feelings of self [46]. Our findings revealed significantly lower ReHo in the rMCC in SSD+ than SSD− patients and correlates with SSD severity, thus suggesting that impaired self-monitoring might drive excessive somatic symptom fixation. These findings contrast with prior studies reporting greater ReHo in the rMCC in general SSD populations than healthy controls [47]; this difference might be attributable to pre-existing abnormalities in the rMCC in patients with chronic cough, thus implicating dysfunctional rMCC activity as a potential neurobiological substrate shared between chronic cough and SSD.
Notably, in SSD+ patients, the diminished fALFF in the lingual gyrus, a region traditionally considered a visual area, is consistent with emerging evidence of its involvement in cross-modal visceral representation [48]. However, this region was not associated with SSD symptom severity, and the voluntary recruitment of patients for fMRI examinations limited the sample size and consequently the generalizability of the findings, because of potential biases. Future large-scale studies with prospective designs and including matched control groups are warranted to validate these preliminary findings.
In this study, although SSD+ patients exhibited more severe cough and somatic symptoms, the SSD– group demonstrated stronger resting-state neural activity, particularly in the cerebellum and mid-cingulate cortex. This pattern may reflect distinct underlying neural mechanisms between the two groups. The stronger activation in the SSD– group suggests a greater reliance on reflexive cough pathways, with the cerebellum and mid-cingulate cortex playing key roles in involuntary motor control and sensory feedback integration. In contrast, despite having a higher symptom burden, the SSD+ group showed relatively weaker activation in these reflex-related regions, which may indicate that their cough is more influenced by abnormal central sensory processing and higher-order cognitive modulation, accompanied by behavioral reinforcement or habit formation, thereby reorganizing or attenuating the function of traditional reflex pathways, consistent with previous research [8]. These findings may support the interpretation that cough in SSD– patients is more closely aligned with reflexive responses, whereas cough in SSD+ patients is more likely to be influenced by consciously or cognitively mediated processes.
Current studies have reported that timely psychological interventions, including both pharmacological and non-pharmacological treatments, are effective in alleviating symptoms in patients with SSD [49, 50]. Among non-pharmacological approaches, behavioral cough suppression therapy (BCST), which incorporates speech-language therapy and cognitive-behavioral strategies, has demonstrated significant efficacy in patients with refractory chronic cough and can ameliorate cough symptoms in these individuals [51, 52]. In recent years, cognitive behavioral therapy has been found to improve symptoms in patients with chronic airway diseases, such as chronic obstructive pulmonary disease and asthma [53, 54]. Therefore, for patients with chronic cough and other symptom-predominant respiratory disorders, early collaborations among psychosomatic medicine teams might potentially result in better outcomes. More high-quality studies remain needed to confirm this possibility.
To our knowledge, this study is the first to provide a comprehensive and detailed clinical characterization of SSD in adults with chronic cough, including prevalence, symptom profiles, and associated risk factors. By systematically diagnosing SSD using the SCID-5, we generated a rich dataset that offers substantial value for improving diagnostic accuracy and informing clinical management strategies in this patient population. This detailed clinical profiling constitutes the principal contribution of our work.
In addition to the clinical findings, our exploratory neuroimaging analysis revealed differences in brain regions between SSD+ and SSD− patients. However, these results should be interpreted with caution, as they represent preliminary observations derived from a relatively small voluntary subsample and in the absence of a matched healthy control group. Further validation in larger, more diverse cohorts using multimodal neuroimaging approaches will be essential to confirm and extend these findings.
This study has several limitations. Its cross-sectional design precludes assessment of disease progression or treatment outcomes. As a single-center study conducted in Shanghai, regional differences in healthcare resources, education, and social pressures may limit the generalizability of the results. Furthermore, the lack of systematic comorbidity data represents another constraint. Moreover, the neuroimaging component has specific constraints: the fMRI findings are derived from a small, self-selected subsample, resulting in a substantial disparity in sample size compared to the main study cohort. This may introduce selection bias and limit the statistical power to detect subtle neural effects. Consequently, these neuroimaging findings should be regarded as preliminary and exploratory. Future studies should adopt multicenter longitudinal designs, recruiting larger and geographically diverse cohorts, including matched control groups, and employing various neuroimaging analysis methods to validate and extend these preliminary findings, thereby better elucidating the characteristics and potential neural mechanisms underlying somatic symptom disorder and comorbid chronic cough.
Conclusion
The prevalence of SSD in chronic cough patients was 13.8%, while it was notably higher at approximately 28% in patients with refractory chronic cough. Respiratory clinicians should pay attention to patients’ psychological and behavioral features; conduct thorough assessments of biological, psychological, and social factors; remain attentive to the co-occurrence of chronic cough with somatic illnesses; and carry out timely screening, evaluation, and diagnosis of SSD. When necessary, collaboration with psychosomatic medicine should be pursued for interdisciplinary diagnosis and treatment.
Supplementary Information
Acknowledgements
The authors are grateful to all the members of Dept. of Pulmonary and Critical Care Medicine and Dept. of Psychosomatic Medicine, Tongji Hospital, Tongji University School of Medicine for the fruitful discussions and their contributions.
Abbreviations
- SSD
Somatic symptom disorder
- SCS
Somatic cough syndrome
- DSM-5
The diagnostic and statistical manual of mental disorders, fifth edition
- LCQ
Leicester Cough Questionnaire
- PHQ‐15
The patient health questionnaire‐somatic symptom severity scale
- SSD‐12
Somatic Symptom Disorder‐B Criteria Scale
- PHQ‐9
Patient Health Questionnaire‐Depression Scale
- GAD‐7
General Anxiety Disorder‐7
- fMRI
Functional magnetic resonance imaging
- MDT
Multi-disciplinary treatment
- SCID
The structured clinical interview
- SSD+
Patients with Chronic Cough Combined with SSD
- SSD−
Patients with chronic cough without SSD
- VAS
The cough severity visual analog scale
- C2
The lowest concentration of inhaled capsaicin that provokes ≥2 coughs
- C5
The lowest concentration of inhaled capsaicin that provokes ≥5 coughs
- fALFF
Fractional amplitude of low-frequency fluctuations
- ReHo
Regional homogeneity
- GERC
Gastroesophageal reflux‐induced chronic cough
- CVA
Cough variant asthma
- UACS
Upper airway cough syndrome
- R Lobule VIII
Right cerebellar lobule VIII
- rMCC
The mid-cingulate cortex
Authors’ contributions
TYZZ: Conceptualization, Methodology, Formal analysis, Writing – Original Draft; HW: Data Curation, Investigation, Validation; HDB: Writing– original draft; XHX and LY: Supervision, Project administration, Funding acquisition; YXZ, YQZ and WZL: Software, Formal analysis; SYW, JSY and NW: Writing – review & editing.
Funding
This study was supported by the National Natural Science Foundation of China (No. 82270114), the Key Supported Discipline of Health System in Shanghai (2023ZDFC0302), the Program of Shanghai Municipal Health Commission Clinical Research (No. 20244Y0147), the Program of Shanghai Academic Research Leader (No. 22XD1422700).
Data availability
Some or all datasets generated during and/or analyzed during the current study are not publicly available but are available from the author (TYZZ) on reasonable request.
Declarations
Ethics approval and consent to participate
This study was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki. The study was approved by the Ethics Committee of Tongji Hospital (The ethics approval number is K-2023-027). The protocol was registered in the Chinese Clinical Trials Register (http://www.chictr.org.cn/) (ChiCTR2400079808). Written informed consent was obtained from all participants before enrollment.
Consent for publication
Written informed consent for publication was obtained from all participants.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Tongyangzi Zhang, Heng Wu and Haodong Bai contributed equally to this work.
Contributor Information
Xianghuai Xu, Email: 05849@tongji.edu.cn.
Li Yu, Email: 96778@tongji.edu.cn.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Some or all datasets generated during and/or analyzed during the current study are not publicly available but are available from the author (TYZZ) on reasonable request.