Diagnosis and Treatment of Cough (2021)

Author: Asthma Group, Respiratory Disease Branch of Chinese Medical Association

Corresponding Author: Lai Kefang, Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Guangzhou Medical University, National Respiratory Medicine Center, National Clinical Research Center for Respiratory Diseases, State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Health

Cite this article: Asthma Group of respiratory disease branch of Chinese Medical Association. Guidelines for the Diagnosis and Treatment of Cough (2021) [J] . Chinese Journal of Tuberculosis and Respiratory Disease, 2022, 45(1): 13-46. DOI: 10.3760/cma.j.cn112147-20211101-00759.

summary

In recent years, many new advances have been made in the diagnosis, treatment and pathogenesis of cough. In order to reflect the relevant research results at home and abroad in a timely manner, the Asthma Group of the Respiratory Disease Branch of the Chinese Medical Association organized experts from respiratory medicine, gastroenterology, reflux surgery, otolaryngology, pediatrics, traditional Chinese medicine and other disciplines, and revised the "Guidelines for the Diagnosis and Treatment of Cough (2015)" in China. The original evidence level and recommendation intensity have been reviewed and updated, and some recommendations have been added and deleted. The basic structure of the guidelines remains unchanged, and the main contents include the definition, epidemiology and pathogenesis of cough, the diagnosis, evaluation and examination of cough, the diagnosis and treatment of acute, subacute and chronic cough, and the empiric treatment and symptomatic treatment of cough.

Cough is the most common symptom in respiratory clinics and community clinics. In domestic specialist clinics, chronic cough patients account for more than one-third. Cough etiology is complex and involves a wide range of aspects, diagnosis is not easy to clarify, many patients often repeatedly carry out various examinations or long-term use of antibacterial drugs and antitussive drugs, with little effect and many adverse reactions, which have a serious impact on the patient's work, learning and quality of life, and also bring a serious health economic burden [1- 4].

In order to further standardize the diagnosis and treatment of cough in mainland China and guide the clinical practice and related research of cough, the Asthma Group of the Respiratory Branch of the Chinese Medical Association organized relevant experts, based on the results and clinical practice of domestic cough research, and referred to the American College of Chest Physicians (ACCP), the European Respiratory Society, ERS) and others issued cough guidelines, in 2005 formulated china's "Guidelines for the Diagnosis and Treatment of Cough (Draft)"[5], and revised in 2009 and 2015 [6, 7]. Since the formulation of the guidelines, it has played a good role in guiding clinical practice and significantly improved the level of cough diagnosis and treatment in China. In recent years, many new advances have been made in the study of cough pathogenesis, etiology distribution, diagnosis and treatment at home and abroad. In order to further improve the guidelines and timely reflect the relevant research results at home and abroad, the Asthma Group of the Respiratory Disease Branch of the Chinese Medical Association launched the revision of the new version of the "Guidelines for the Diagnosis and Treatment of Cough" in March 2021.

Based on the original guidelines, all the literature as of April 13, 2021 was searched, the original evidence level and recommendation intensity were reviewed and updated, and some recommendations were added and deleted. The new version of the guidelines mainly adds and revises the following aspects: (1) Adds epidemiological aspects, including risk factors and economic burdens. (2) The history and laboratory examination parts have been streamlined. (3) The cough assessment section removed the cough symptom score that lacked evidence-based medical evidence, and added a new simplified cough degree score. (4) The rare cause of chronic cough is increased, and the concept of refractory chronic cough is introduced on the basis of the original unexplained chronic cough and cough hypersensitivity syndrome. For psychological cough, a new diagnostic term was introduced: somatic cough syndrome. (5) Appropriately expand the etiology and treatment of chronic cough in children. (6) The recommended intensity was changed from the original 3 levels to 2 levels: strong recommendation and weak recommendation, and the intermediate level was abolished. (7) The overall recommendations have been streamlined, and some diagnostic and therapeutic principles that have been widely accepted in clinical practice have been changed to descriptive content and no longer appear in the form of recommendations. Based on the latest findings, the strength of minority recommendations and the level of evidence were adjusted. A few recommendations with similar content have been consolidated. (8) The contents of cough diagnosis process, induced sputum cytology, esophageal reflux monitoring, cough provocation test, cough degree assessment, etc. are uniformly placed in Annex 1, 2, 3, 4, 5, 6, 7.

The guide has a cross-reference table of proper nouns in English and English for the reader to read, as detailed in Table 1.

First, the methodology of the development of the guide

1. Guidelines Target population: cough patients.

2. Guidelines for users: respiratory specialists, physicians, TCM practitioners, general practitioners, pediatricians and other relevant department personnel.

3. Guideline Development Working Group: This guideline development working group is composed of experts from respiratory medicine, gastroenterology, reflux surgery, otolaryngology, pediatrics, traditional Chinese medicine and other disciplines, evidence-based medical experts, clinical epidemiology experts, and graduate students majoring in respiratory diseases, and establishes a guideline revision expert group, a guideline methodology group, a secretarial group and a senior expert review group, and the specific list is shown below.

4. Literature search: This guide systematically searches Pubmed/Medline, Embase, Cochrane Library, China Biomedical Literature Database, Wanfang Database, CNKI and Chinese full-text databases of scientific and technological journals until April 13, 2021. The Guide Methodology Group conducts methodological training for teams of experts after the kick-off meeting of the Guide, including the development of literature search strategies, literature screening, evidence extraction and evaluation. If the team of experts encounters questions during the process of evidence retrieval, evaluation, etc., the members of the Methodology Group and the Secretariat will provide methodological support to assist the team in solving and quality control.

5. Quality of evidence and strength of recommendations: The quality of evidence and recommended strength grading criteria recommended in this guideline are based on the grading criteria [8, 9] and GRADE (grading of recommendations assessment, development and evaluation) methods used in conjunction with the ACCP's 2014 "Guidelines for Evidence-Based Practice in The Diagnosis and Management of Cough" [10], as detailed in Table 2. The quality of the evidence was divided into four grades: "high, medium, low, and very low", which were expressed in A, B, C, and D, respectively, and the recommendation was divided into two levels: "strong recommendation and weak recommendation", which were expressed in 1 and 2 respectively.

Recommendation strength is determined based on factors such as the quality of the evidence, a balance of pros and cons, patient values and willingness, and resource costs [10]. The Guideline Development Working Group held several consensus meetings where each specific clinical issue and intervention was fully discussed. In the end, all recommendations were voted on by delphi law. Voting is subject to the following rules[11]: First, for areas where there is persistent disagreement, recommending or opposing an intervention requires at least 50% of the participants to approve, and the proportion of participants who hold opposing opinions needs to be less than 20%, and failure to meet this criterion will not produce recommendations. Second, a recommendation that is listed as a strong recommendation rather than a weak recommendation needs to be approved by at least 70% of the participants.

6. Statement of Conflict of Interest: During the development of this guide, all experts and members of the guide working group who participated in the expert workshop of this guide have signed a written statement of interest, and there is no conflict of interest related to the guide for pharmaceutical companies.

7. Estimated favorable factors and unfavorable factors in the implementation of the guidelines: (1) Favorable factors: (1) With the popularization and deepening of the idea of evidence-based medicine among Chinese respiratory doctors, the objective demand for high-quality evidence-based guidelines is increasing; (2) cough is the most common symptom of clinical patients seeking diagnosis, and a large number of patients are not effectively diagnosed and treated, which seriously affects the quality of life of patients and causes a heavy economic burden, and the cough evidence-based diagnosis and treatment guidelines have a good clinical application need ;(3) The promotion and application of the previous versions of the cough guidelines have laid a good foundation for the implementation of this guideline. (2) Unfavorable factors: (1) In view of the importance of different levels of clinicians to the guidelines and the differences in the understanding of the recommendations, it will take time to fully promote, publicize and implement this guidelines; (2) some units have not yet carried out bronchial provocation tests, induced sputum cytology examinations, esophageal reflux monitoring, exhaled nitric oxide (FeNO) and other examinations, and the restrictions of these conditions may have a certain impact on the promotion and application of this guideline.

8. Publication, dissemination and update of the guidelines: The guidelines will be published in academic journals, and after the release, they will be disseminated nationwide in the form of academic conferences, study classes, etc., so as to promote the widespread use of the guidelines in the clinic and make them better guide clinical practice. The Guideline Development Working Group will conduct regular literature searches, evidence updates and evaluations, and plans to update the guidelines every 3 to 5 years.

2. Definition, classification and epidemiology of cough

Cough is a defensive nerve reflex in the body that helps to clear respiratory secretions and harmful factors. Cough in adults is usually divided into three categories by time: acute cough (<3 weeks), subacute cough (3 to 8 weeks), and chronic cough (>8 weeks) [5]. Cough according to the nature can be divided into dry cough and wet cough, it is recommended to take the daily sputum amount of > 10 ml as the standard for wet cough. Different types of cough have different etiological distribution characteristics. Different epidemiological and clinical studies have adopted different definitions of chronic cough, usually with cough as the only or main symptom, the duration of the disease > 8 weeks, and the X-ray chest x-ray without obvious abnormalities is called chronic cough. With the in-depth study of chronic cough and the popularization of guidelines, the level of diagnosis and treatment of common causes of chronic cough by specialists has been continuously improved, and some coughs with chest imaging abnormalities, such as chronic obstructive pulmonary disease (referred to as COPD), typical bronchial asthma (referred to as asthma), lung cancer, and cough of interstitial pneumonia, have also been included in the scope of chronic cough research [12, 13, 14, 15]. Thus, chronic cough in a broad sense includes patients with both normal and abnormal imaging. The pathogenesis and treatment of refractory chronic cough and rare cause chronic cough have become a research hotspot of widespread concern at home and abroad in recent years.

Due to differences in environmental and genetic factors, the prevalence of chronic cough varies from country to country. A systematic review showed a global prevalence of chronic cough in adults of 9.6 percent (95 percent CI: 7.6 percent to 11.7 percent), with a higher prevalence in Europe and the United States than in Asia [16]. There are no national epidemiological survey data in China, and the prevalence of chronic cough is 2.0% to 28.3% according to studies from various parts of the country [4,17, 18, 19, 20]. The largest number of chronic cough patients in China is in the 30-40 age group, with a similar proportion of men and women, while European and American countries have the largest number in the 50-60 age group [21], and the proportion of women is significantly higher than that of men. Chronic cough and air pollution are closely related [22, 23, 24]. Air pollution, seasonal factors, dietary factors, occupational factors, allergens, smoking, women, advanced age, obesity, and gastroesophageal reflux disease (GERD)/bronchiectasis are all risk factors for chronic cough [25, 26, 27]. However, the majority of patients in respiratory clinics are non-smokers [26].

Frequent and severe coughs, especially chronic coughs, have a serious impact on the patient's work, life and social activities. Chronic cough can cause complications of cardiovascular, digestive, neurological, urinary, musculoskeletal, and other systems, such as increased blood pressure, arrhythmias, rupture of blood vessels, pneumothorax, urinary incontinence, syncope, insomnia, depression, and anxiety [2,27]. Cough-induced urinary incontinence in up to 50 percent of women with chronic cough seriously affects the quality of life [2,28].

Coughing places a heavy financial burden on patients and society. Frequent medical treatment, various examinations, and the extensive use of antitussive drugs and antibacterial drugs are the most important reasons for cough patients to spend, and cough is also the hardest hit area of antibacterial drug abuse. In the United States, the average annual economic loss due to acute cough is as high as US$9 billion; in the United Kingdom, the average annual economic loss due to acute cough is £979 million,[29] and in mainland China, the annual sales volume of cold and cough medicines ranks first in retail pharmacies, with sales of 51.6 billion yuan in 2016.[4] However, there have been no reports of the economic burden and long-term prognosis of chronic cough alone, possibly due to the lack of a harmonized International Classification of Diseases (ICD) code for chronic cough, which is only considered a clinical manifestation or concomitant symptom of other respiratory diseases.

3. Pathogenesis

The involuntary cough reflex is completed by the intact cough reflex arc, which consists of cough peripheral receptors, vagus afferent nerves, cough advanced centers, efferent nerves, and effectors (diaphragm, larynx, chest, and abdominal muscle groups, etc.). Stimulation of the C fibers that innervate the trachea, lungs, and myelated mechanical receptors (Aδ fibers) that are sensitive to machinery and acids can directly induce coughing. In addition, irritation of the vagus nerve or its branches distributed in the upper airway, throat, esophagus, and external auditory canal may also lead to coughing [30, 31]. Cough is controlled by the bulbar cough center, which is regulated by the cerebral cortex. Cough hypersensitivity is an important clinical and pathophysiological feature of chronic cough, and its mechanisms are related to transient receptor potential (TRP) pathways such as transient receptor potential vanilloid 1 (TRPV1) and transient receptor potential anchor protein subtype 1 (transient receptor). Potential ankyrin 1, TRPA1) activation, airway inflammation, and susceptibility of nerve pathways and cough centers [32, 33, 34, 35, 36, 37]. Increased cough sensitivity includes increased peripheral cough sensitivity and central cough sensitivity. Increased central cough sensitivity is an important mechanism for chronic cough, particularly refractory chronic cough and cough hypersensitivity syndrome [34].

4. Medical history and laboratory tests

A careful history and physical examination can narrow the diagnosis of cough, provide clues to the diagnosis of the cause, and even draw initial diagnosis and empirical treatment, or select the relevant tests based on the clues provided by the history, so that the diagnosis of the cause can be determined more quickly [38].

1. Ask the medical history: asking about the duration, duration, nature, timbre of the cough, as well as the precipitating or aggravating factors, postural effects, concomitant symptoms, etc., and the history of sputum volume, color, and traits, as well as whether there is a history of smoking, occupational or environmental exposure, and the history of taking angiotensin converting enzyme inhibitors (ACEI) drugs is of great diagnostic value [7]. A history of special occupational exposure should be noted for the possibility of occupational cough.

2. Physical examination: including body shape, nose, pharynx, larynx, trachea, lungs, etc. In addition to auscultation of the lungs, attention is paid to both lung breath sounds and the presence or absence of wheezing, crackles, and bursting sounds, and it is also necessary to pay attention to the presence of abnormal signs in various parts of the upper airway, such as pharyngeal mucosal hyperemia, posterior pharyngeal lymphatic follicle hyperplasia (pebbled changes), sticky secretion attachment, pallor edema or congestion of the nasal mucosa, nasal secretions, etc., indicating the presence of pharyngitis, rhinitis and other underlying diseases. Obese people should be aware of obstructive sleep apnea (OSA) or gastroesophageal reflux with chronic cough.

3. Diagnostic examination: mainly including imaging examination, induced sputum cytology examination, lung ventilation function and airway reactivity examination, FeNO detection, esophageal reflux monitoring, allergen detection, etc.

(1) Imaging examination: chest x-ray is a routine examination of chronic cough, if obvious lesions are found, further relevant examinations are selected according to the characteristics of the lesion. Chest x-ray without obvious lesions is examined according to the chronic cough diagnostic procedure. Chest CT is not recommended as the preferred test in patients with chronic cough at the first diagnosis [39, 40, 41] (2C). Chest CT is recommended for patients with chronic cough whose cause has not been identified on previous examination, or who have not responded to treatment for common causes, or who suspect a rare cause such as bronchiectasis, lung cancer, or foreign bodies [42] (2C). Chest CT examination helps to find tracheal wall thickening, tracheal wall calcification, tracheal stenosis, bronchiectasis, etc., for some rare chronic cough causes, such as bronchial stones, recurrent polychondritis, bronchial foreign bodies, early qualitative lung disease, etc., X-ray chest x-ray chest x-ray is not easy to find such lesions, high-resolution CT is helpful in diagnosis. When sinusitis is suspected, SINUS CT is preferred [43]. Patients with chronic cough should avoid repeated chest x-rays or CT scans for short periods of time.

(2) Pulmonary function test: pulmonary ventilation function test and bronchial provocation test are of great value for the diagnosis of the etiology of chronic cough, and those who have the condition should be used as the preferred test for the diagnosis and treatment of chronic cough. A positive bronchial provocation test is an important criterion for diagnosing cough variant asthma (CVA), and hospitals that perform an unconditional bronchoscopic test can also monitor the peak expiratory flow (PEF) variability, with an average diurnal variation of PEF > 10% (13% in children >) supporting the diagnosis of CVA [44].

(3) Induced sputum cytology: Induced sputum cytology is an important non-invasive examination method for the diagnosis of chronic cough etiology and airway inflammation assessment, and its safety and tolerability are relatively good [45, 46]. Induced sputum cytology is helpful in diagnosing the etiology of chronic cough and guiding hormone therapy in patients with chronic cough, and induction sputum cytology is recommended as a first-line examination for chronic cough [45] (1C). Sputum eosinophilia is a necessary indicator for the diagnosis of eosinophilic bronchitis (EB) and can also be used to aid in the diagnosis of CVA [46]. Ultrasonic nebulization-induced sputum cytology with hypertonic saline is recommended, but repeated hypertonic saline nebulization induction should be avoided within 48 h [47, 48, 49] (see Annex 4 for specific methods). In patients who can cough up sputum spontaneously, spontaneous sputum cytology has similar diagnostic value as induced sputum cytology.

(4) FeNO detection: It is a non-invasive airway inflammation detection technology widely used in clinical practice, which can be used as a preliminary screening method for airway inflammation detection. Elevated FeNO levels suggest eosinophilic airway inflammation and can be used to predict response to hormone therapy in patients with chronic cough [50, 51] (2B). ATS recommends eosinophilic airway inflammation at 25 to 50 ppb and eosinophilic airway inflammation at >50 ppb [52], but domestic studies of adult patients with chronic cough have shown that FeNO ≥ 32 ppb suggest eosinophilic airway inflammation or hormone-sensitive cough [51]. It is important to note that FeNO screening for chronic cough-associated eosinophilic airway inflammation is not sensitive, and feno levels are normal in approximately 40 percent of patients with elevated sputum eosinophils [51,53]. At present, there are many brands of FeNO detection instruments on the market, but the reference values for healthy people have not been completely unified, and the threshold value for diagnosing eosinophilic airway inflammation has not yet been determined.

(5) Allergic skin test and serum IgE test: used to detect the presence of atopy and determine the type of allergen in patients, which is helpful in the diagnosis of allergic diseases [such as allergic rhinitis and allergic cough (AC)]. Atopics are present in 60 to 70 percent of CVA and 30 percent of EB patients [54].

(6) Esophageal reflux monitoring: This is currently the most commonly used and effective method to determine whether a patient has gastroesophageal reflux. By the parameters of acid exposure time (AET), esophageal pH value <4, total reflux times, and maximum reflux time, AET, DeMeester integral and total reflux (acid, non-acid) frequency are the main indicators of abnormal reflux. During the examination, the symptoms related to cough and reflux are recorded in real time to obtain the correlation probability (SAP) between reflux and cough symptoms, and to determine the relationship between reflux and cough (see Annex 5 for methods). AET >6% and SAP ≥ 95% are recommended to determine the presence of pathological acid exposure in the esophagus and the association of acid exposure with cough symptoms [55, 56, 57, 58, 59] (1C). A symptom index of >75 percent or an elevated DeMeester score (≥14.7) can help determine the presence of gastroesophageal reflux [60]. However, it should be noted that the AET ≤ 6% can not exclude GERC, this standard may cause non-acid, weak acid reflux patients missed diagnosis, some patients did not meet this standard, but anti-gastroesophageal reflux treatment is effective, especially AET in 4% to 6%, can be used with esophageal manometry and other tests to assist in GERC diagnosis.

(7) Bronchoscopy: Bronchoscopy can be used to exclude cough caused by airway lesions, such as bronchial lung cancer, foreign bodies, tuberculosis, and recurrent polychondritis, but it is not recommended to take bronchoscopy as a routine examination for patients with chronic cough [61, 62] (2C).

(8) Other tests: elevated peripheral blood eosinophils suggest allergic disease and are also helpful in determining whether eosinophilic airway inflammation is present [63]. Salivary pepsin testing has been used to diagnose GERD, but the optimal sample type, sampling time, and diagnostic thresholds need to be further investigated [64, 65, 66]. In addition, nasopharyngoscopy can be used to detect some occult upper airway lesions, and laryngeal reflux monitoring can help diagnose reflux laryngitis and GERD.

V. Principles and procedures for cough diagnosis

The diagnostic procedures for acute cough, subacute cough, and chronic cough are shown in Annexes 1, 2, and 3, respectively.

The etiology of chronic cough should be diagnosed in accordance with the following principles [67] :(1) Pay attention to the medical history, including history of entolaryngological and digestive diseases, occupational and environmental exposure, smoking history, and medication history. (2) Select the relevant examination according to the medical history, from simple to complex. EB and CVA are the most common causes of chronic cough, accounting for about 50% of the causes of chronic cough in China [68], so lung ventilation function test, bronchial provocative test, and induced sputum cytology are recommended as the first-line examination of chronic cough [7,46,69]. FeNO testing is recommended as an initial screening for airway inflammation testing [53,70, 71, 72, 73]. Examinations such as esophageal reflux monitoring, bronchoscopy, and nasopharyngeal microscopy are recommended as second-line examinations. (3) Consider common diseases first, and then consider rare diseases. Patients with chronic cough should first consider the possibility of common causes such as upper airway cough syndrome (UACS), CVA, EB, GERC, and AC [68,74, 75]. (4) Diagnosis and treatment should be carried out simultaneously or sequentially. If the test conditions are not available, diagnostic treatment can be performed according to the clinical features, and the cause of cough can be determined according to the response to treatment [38], and the relevant test is selected when treatment is ineffective. Typical rhinitis, sinusitis symptoms, or signs and symptoms of retronasal instillation can be treated with UACS first. If there are typical symptoms associated with gastroesophageal reflux or cough after eating, treatment is started with GERC. (5) Effective treatment is the premise of clarifying the cause. Treatment is partially effective but not completely relieved, and the factors influencing efficacy and the presence of other compound causes of chronic cough, such as UACS with GERC, CVA, or EB, GERC with EB or CVA, etc. should be evaluated. (6) When treatment is ineffective, it should be assessed whether the diagnosis is wrong, whether the intensity and time of treatment are sufficient, and whether there are factors that affect the efficacy, such as occupational or environmental exposure factors.

6. Assessment of cough

The assessment of cough mainly includes visual analogue scale (VAS), cough symptom score, quality of life assessment, cough frequency monitoring, and cough sensitivity detection, which are helpful for disease assessment and efficacy observation [27,76].

1. VAS: The patient marks the corresponding scale on the line marked 0 to 10 cm or 0 to 100 mm according to their own feelings to indicate the severity of cough. VaS is more finely graded than the cough symptom score, which facilitates longitudinal comparisons before and after treatment [76, 77].

2. The simple cough evaluation test (CET) includes five items (see Annex 7) on the degree of daytime cough, the impact of nocturnal cough on sleep, the severity of cough, and the impact of cough on daily life and psychology (see Annex 7 for details), and the study confirmed that CET has a good retest reliability and response validity, and has a good correlation with VAS score and cough quality of life questionnaire. CET is recommended for a simple assessment of cough severity and its health effects [78] (2B). Pre-existing cough symptom scores are not recommended in this guideline due to the lack of evidence-based medical evidence.

3. Cough quality of life assessment: The special scale for cough mainly includes the cough-specific quality of life questionnaire (CQLQ), the Leicester cough questionnaire (LCQ) and the chronic cough impact questionnaire (LCQ). CCIQ), each questionnaire showed good reliability, validity, and responsiveness, and gradually showed its important role in systematically evaluating the degree and efficacy of cough [77,79,80,81, 82], and the Chinese version of LCQ is recommended to assess cough-related quality of life [80,83] (1B), as detailed in Annex 8.

4. Cough frequency monitoring: It is an objective record and analysis of the frequency, intensity and characteristics of coughs that occur in patients within a certain period of time, which is an ideal method for objectively assessing cough condition and observation of efficacy [84, 85, 86]. Due to the effects of the patient's subjective tolerance, the frequency of cough is not necessarily proportional to the patient's self-perceived cough severity. There is no such instrument in China, and clinical application is limited.

5. Cough sensitivity test: can be used to judge the efficacy and study the cough mechanism. By atomizing the subject to inhale a quantitative irritant aerosol, stimulate the corresponding cough receptors to induce cough, and stimulate the concentration of irritant (C5) that stimulates cough ≥ 5 times as an indicator of cough sensitivity. Cough provocation test is commonly performed by inhalation of capsaicin (TRPV1 agonist) (see Annex 6 for methods). The reference value of capsaicin provocation test C5 in healthy people in China ≥ 125 μmol/L [87]. In addition to capsaicin, excitants such as citric acid and allyl isothiocyanate (TRPA1 agonist) can be used for cough provocation tests [33]. Increased cough sensitivity is an important feature of chronic cough, and cough sensitivity may be increased in UACS, CVA, EB, AC, and GERC, which are more pronounced with GERC and AC [35]. In addition, cough sensitivity for viral postinfectious cough (PIC) tends to increase [88]. Cough sensitivity is higher in women than in men [89 to 90]. The use of cough provocation tests to assess the safety, tolerability, and reproducibility of cough sensitivity is helpful in identifying patients with high cough sensitivity and can be used as an objective indicator of quantitative assessment of cough, but is not a substitute for subjective measures to assess cough frequency and severity [29,91,92,93,94,95].

7. Diagnosis and treatment of acute cough

Common diseases of acute cough are the common cold and acute tracheo-bronchitis. Attention should be paid to distinguishing between acute myocardial infarction, left-sided insufficiency, pneumonia, pneumothorax, pulmonary embolism, and foreign body aspiration that may present as acute cough [96, 97, 98, 99, 100, 101]. Some acute infectious respiratory diseases, such as influenza (flu), severe acute respiratory syndrome (SARS), novel coronavirus infection, etc., cough is also the main symptom, the incidence rate is usually up to 70% or higher [102, 103], clinical attention should be paid to the distinction. In addition to cough symptoms, these acute infectious respiratory diseases are often accompanied by obvious systemic symptoms such as fever, fatigue, muscle pain, etc., and some people who progress may have symptoms such as shortness of breath and dyspnea. Because coughing can lead to an increased risk of virus transmission through droplets or aerosols, hygiene measures such as cough etiquette, mask wearing, and social distancing are particularly needed during a pandemic. Exacerbations of pre-existing conditions such as asthma, chronic bronchitis, and bronchiectasis can also lead to worsening cough or acute coughing. In addition, exposure to environmental factors or occupational factors is increasingly the cause of acute cough.

(1) Common cold

Viral infections are the main cause of colds [104, 105]. Diagnosis of a cold is based primarily on history and physical examination, and usually does not require etiology or imaging [97,106]. In addition to cough, clinical manifestations are accompanied by other upper respiratory tract-related symptoms such as runny nose, sneezing, nasal congestion and postnasal drip influenza, throat irritation or discomfort, and may be accompanied by fever with fewer systemic symptoms [104, 105, 106, 107, 108, 109]. Coughs from the common cold are often associated with drips behind the nose. In addition to cough symptoms, influenza often has systemic symptoms such as fever and myalgia [107].

The common cold is mainly symptomatic treatment. (1) Antibacterial drugs: antibacterial drugs cannot shorten the course of cold disease or alleviate symptoms, and adverse reactions may occur, and it is not recommended that cold patients routinely use antibacterial drugs [110, 111, 112, 113, 114] (1A). (2) Decongestants and antihistamines: the combination of decongestants and first-generation antihistamines can significantly alleviate cough and improve symptoms such as sneezing and nasal congestion [115, 116, 117, 118, 119, 120] (1A). However, it is necessary to pay attention to adverse reactions, and children should be cautious in taking drugs. There is no clear clinical benefit from treatment with first-generation antihistamines alone [118,121]. (3) Antipyretic analgesics: Antipyretic analgesics are mainly aimed at symptoms such as fever, sore throat and general aches in common cold patients, and are recommended for short-term application, and the risk of stroke should be noted [119,122, 123]. Acetaminophen is one of the most widely used NSAIDs in clinical practice. Treatment with NSAIDs is not recommended for patients with a common cold whose predominant manifestations of respiratory symptoms such as cough do not have fever, headache, or myalgia [119,122,124] (1A). (4) Antitussive drugs: If the cough is severe, central or peripheral antitussive drugs can be used when necessary. The routine use of central cough medications (eg, dextromethorphan, codeine) is not recommended for patients with cough caused by the common cold [118,125, 126, 127] (2C). A combination of first-generation antihistamines, decongestants, and antitussives is recommended for the treatment of the common cold with cough [128, 129] (1A). Traditional Chinese medicine has a certain effect on the treatment of colds, but there is a lack of high-quality clinical research data [130, 131].

(2) Acute tracheo-bronchitis

Acute tracheo-bronchitis is an acute inflammation of the tracheo-bronchial mucosa caused by biological or abiotic factors. Viral infections are the most common cause, rhinoviruses and influenza viruses are common, and a small proportion can be caused by bacteria [105,132, 133, 134, 135, 136]. Cold air, dust and irritating gases can also cause the disease. Most patients are self-limiting. Infants and the elderly and infirm may develop prolonged bronchitis.

1. Clinical manifestations: symptoms of upper respiratory tract infection are often present at the beginning of the disease. Cough may then be exacerbated with or without sputum production, and people with bacterial infections often cough up yellow pus sputum. Acute tracheo-bronchitis is usually self-limiting, and systemic symptoms can disappear within a few days, but cough and sputum production generally last for 2 to 3 weeks. Chest x-ray with no significant abnormalities or only increased lung texture. On physical examination, both lungs have thick breath sounds, and sometimes wet or dry rales may be heard.

Diagnosis and differential diagnosis: diagnosis is based primarily on clinical presentation and usually does not require etiological examination [97,132,137]. Cough lasting less than three weeks, with or without sputum production, should be considered after clinical symptoms and/or imaging tests rule out acute exacerbations of colds, pneumonia, asthma, and COPD [97,138]. Patients considering acute bronchitis are less likely to develop pneumonia if their heart rate ≤ 100 bpm, respiratory rate ≤ 24 bpm, body temperature ≤ 38 °C, and no abnormal signs of chest [139, 140, 141].

3. Treatment: The treatment principle is based on symptomatic treatment. Antitussive drugs may be appropriately used in patients with severe dry cough, and expectorants or muscous sputrines are recommended for those who have sputum but are not easily coughed up [142, 143, 144] (1B). Extended-release guaifenesin relieves symptoms of acute respiratory infections [145, 146] (2B). Foreign evidence suggests that antimicrobial therapy has no significant effect on cough relief and course of disease in patients with acute tracheo-bronchitis [97,112,147, 148], but there is still a lack of research evidence in China. Routine use of antibacterial drugs for the treatment of acute tracheo-bronchitis (1A) is not recommended. In patients with acute tracheo-bronchitis who cough up yellow purulent sputum, antibacterial therapy (2D) is recommended. If there is a bacterial infection, such as coughing up purulent sputum or elevated peripheral blood white blood cells, antibacterial drugs may be selected based on the pathogen of infection and drug susceptibility tests. Before obtaining a positive result for pathogens, oral antimicrobials such as β-lactams and quinolones are available [7, 8]. In adults with acute tracheo-bronchitis with cough and wheezing, beta2 agonists are recommended [149, 150] (2A). There is no high-quality evidence of the efficacy and safety of Chinese herbal medicine in the treatment of acute tracheo-bronchitis [131,151].

8. Diagnosis and treatment of subacute cough

The most common cause of subacute cough is PIC, followed by CVA, EB, UACS, etc. [152, 153]. In the management of subacute cough, it is first necessary to determine whether the cough is secondary to a previous respiratory infection and to perform empiric treatment. If treatment is ineffective, consider other causes and refer to the chronic cough diagnosis procedure for diagnosis and treatment. It is important to note that sometimes diagnosing PICs solely on the basis of a history of colds or upper respiratory tract infections and cough symptoms may result in missed EB and CVA diagnoses, and some so-called "refractory PICs" may actually be EB, CVA, and GERC [152]. For subacute cough that does not respond to conventional PIC treatment, it is recommended that bronchial provocation tests, induced sputum cytology, etc., or empiric therapy of other etiologies should be performed when conditions permit.

When the symptoms of the acute phase of the respiratory infection disappear, the cough still persists for 3 to 8 weeks, and those who have no obvious abnormalities on chest x-ray are called PICs [153, 154], of which cough caused by viral colds is the most common, also known as "cough after a cold". Patients with a previous history of PIC and increased cough sensitivity are more likely to develop PIC [152,154]. PICs are often self-limited and can relieve on their own, but some patients have a stubborn cough and even develop a chronic cough. Viral PICs do not have to be treated with antibacterial drugs. For some patients with obvious cough symptoms, it is recommended to use short-term antitussive drugs, antihistamines plus or minus decongestants. Combined methoxamine has some effect on the treatment of PICs [155] (2C). Inhaled corticosteroids (ICS) and montelukast sodium for PIC [156, 157, 158, 159] are not recommended(2B). Chinese medicine believes that PIC is caused by the lung and lung qi loss of wind and evil, and it is advisable to treat the lungs and cough and pharynx, and the use of Suhuang cough capsules to treat PIC has a certain effect [160, 161] (2C).

Due to low resistance, poor sputum discharge, bacterial resistance or poor anti-infection efficacy, bacteria can not be removed in the bronchi in a timely and effective manner, and some patients with bacterial acute bronchitis may have a course of more than 3 weeks, known as protracted bacterial bronchitis (PBB). PBB is more common in infants and young children, but may sometimes be seen in adults [162, 163, 164]. Pathogenic bacteria are haemophilus influenzae and Streptococcus pneumoniae. In addition to bacteria, infection with the trachea-bronchus such as Mycoplasma pneumoniae and Chlamydia pneumoniae can also cause a prolonged infectious cough, but the etiological diagnosis is often not readily available clinically, and this guideline recommends that it be called protracted infectious bronchitis (PIB). For PIB, anti-infective therapy is recommended for 1 to 2 weeks or more.

Serological antibody testing is the most effective means of diagnosing Mycoplasma/chlamydia infection and is recommended as a routine adjunctive test [165, 166] (1C). The ≥ of hethrombin is 1:64, and the titer of the serum mycoplasma IgM antibody in the acute and convalescent phases is increased fourfold, indicating a recent mycoplasma infection [166, 167] (2D). Chlamydia serum antibody titer ≥4 times or a single antibody titer of IgM≥1:16 or IgG ≥ 1:512 are diagnostic of chlamydia infection. PIB caused by Mycoplasma pneumoniae and Chlamydia pneumoniae is recommended with macrolides or quinolone antimicrobials [167] (2C). Prolonged infectious cough caused by Gram-positive cocci can be treated with amoxicillin or cephalosporins for 2 to 3 weeks [168, 169, 170] (2B).

The possibility of pertussis infection should be considered when the titer of the pertussis serum antibody IgG is high in adolescent and adult cough patients [171, 172, 173] (2C). In adults with acute or subacute cough, the possibility of pertussis should be considered if vomiting after cough and inhalation phase stridor are present [174, 175] (2C). Polymerase chain reaction (PCR), and bacterial culture confirm the diagnosis of whooping cough [176, 177, 178] (2C). Once whooping cough is diagnosed, it is recommended to start macrolide therapy as early as possible (1 to 2 weeks after onset of illness), which, although it does not change the course of the disease, can reduce the infectivity of the disease [179, 180] (1B). Antimicrobial therapy is not recommended for patients with non-catarrhal stage (deferred) pertussis [181, 182] (1A). Corticosteroids, beta2-adrenoceptor agonists, pertussis-specific immunoglobulins, and antihistamines are not recommended for the treatment of pertussis [183, 184] (1A).

9. Diagnosis and treatment of common chronic cough causes

Common causes such as CVA, UACS, EB, AC, and GERC, which account for 70 to 95 percent of chronic cough causes, should be considered first in the diagnosis of chronic cough [68,75,185, 186]. Most chronic coughs are not associated with infection, so misuse of antimicrobial therapy should be avoided.

(i) UACS [postnasal drip syndrome (PNDS)]

Due to nasal diseases, secretions are reversed to the back of the nose and throat, directly or indirectly irritating cough receptors, resulting in a clinical syndrome called PNDS with cough as the main manifestation. Since it is not possible to determine whether upper respiratory tract-related cough is caused by direct stimulation by retronasal drip or inflammation that irritates the upper respiratory tract cough receptors, the 2006 U.S. Cough Guidelines recommend replacing PNDS with UACS [187]. There are still objections about the concept of PNDS, and whether upper airway diseases should be used as an alternative to PNDS and its association with cough .[188] In some patients with typical signs and symptoms of retronasal instillation, the diagnosis with PNDS is more intuitive and visual. Therefore, this guide retains the term PNDS.

UACS/PNDS is one of the most common causes of chronic cough, and its underlying disorders are rhinitis and sinusitis, which need to be confirmed after targeted or empiric therapy is effective [68,189]. In addition to nasal disorders, UACS/PNDS may also be associated with diseases of the throat, such as chronic laryngitis and chronic tonsillitis [6, 7,189]. Chronic cough due to diseases of the throat may be associated with high sensitivity to the larynx [190, 191].

1. Clinical manifestations: (1) Symptoms: In addition to cough and sputum production, nasal congestion, increased nasal secretions, frequent throat clearance, postpharyngeal mucus attachment and postnasal drip influenza can be seen. Allergic rhinitis also manifests as itchy nose, sneezing, watery nose, and itchy eyes. Rhino-sinusitis often has symptoms such as nasal congestion and purulent discharge, and may also be accompanied by facial pain/swelling and abnormal sense of smell [192]. (2) Signs: The nasal mucosa of allergic rhinitis is mainly pale or edematous, and clear or sticky nasal discharge can be seen in the nasal passage and the bottom of the nasal cavity. The nasal mucosa of non-allergic rhinitis is often hypertrophic or hyperemic, and the mucous membrane of the oropharynx may be cobbled or muscular discharge attached to the posterior pharyngeal wall in some patients. (3) Auxiliary examination: imaging signs of chronic sinusitis are thickening of the sinus mucosa and the level of intrasinal fluid in the sinuses. Cough has seasonal prompts associated with exposure to inhaled allergens (eg, grass pollen, dust mites), and allergen testing is helpful in diagnosis. Chronic sinusitis involves multiple types, such as viral, bacterial, fungal, and allergic sinusitis, partially concomitant with nasal polyps. When sinusitis is suspected, CT is preferred, followed by nasal endoscopy, allergens, and immunology if necessary.

2. Diagnosis: UACS/PNDS involves a variety of basic diseases such as nose, sinuses, pharynx, and larynx, and the symptoms and signs are quite different and non-specific, so it is necessary to make a comprehensive judgment of the medical history, signs, related examinations and treatment response. The following criteria are recommended for diagnosis of UACS/PNDS: (1) chronic cough, predominantly during the day or after postural changes, with less after falling asleep; (2) clinical manifestations and history of nasal and/or throat disorders; (3) adjunctive examinations to support the diagnosis of nasal and/or throat disorders; and (4) cough relief after treatment of the underlying disease.

3. Treatment: depends on the underlying disorder that causes UACS/PNDS.

(1) Etiological treatment: (1) non-allergic rhinitis and the common cold: the first choice of oral first-generation antihistamines and decongestants is recommended [193, 194, 195] (1B). Most patients respond within a few days to 2 weeks after initial treatment. (2) Allergic rhinitis: the first choice of nasal inhalation of nasal glucocorticoids and oral second-generation antihistamines is recommended [196, 197, 198, 199, 200, 201] (1A). Nasal glucocorticoids include mometasone furoate, fludecarsone propionate, and budesonide nasal sprays. Second-generation antihistamines are commonly used in loratadine, cetirizine and the like. If there is no second-generation antihistamine, the first generation of antihistamines has the same effect, but adverse reactions such as drowsiness are more obvious. Leukotriene receptor antagonists are effective in the treatment of allergic rhinitis [197, 202, 203] (1A). For allergic rhinitis with severe symptoms and poor response to conventional pharmacotherapy, specific allergen immunotherapy may be effective but has a longer onset of action [204, 205, 206, 207] (2B). Avoiding or reducing exposure to allergens can help reduce the symptoms of allergic rhinitis. (3) Chronic sinusitis: A. Sinus secretion bacteria cultures in patients with chronic sinusitis are dominated by Staphylococcus aureus or Staphylococcus epidermidis and pneumococcus, but it should be noted that in most cases, colonizing bacteria may be associated with acute attacks, and the cultured flora may have bacterial biofilm formation [208, 209]. Bacterial sinusitis is mostly a co-infection, and anti-infection is an important treatment measure. It is recommended that the antibacterial spectrum should cover gram-positive, negative and anaerobic bacteria, and the acute pathogenesis should be applied for ≥ 2 weeks, and the chronic patients should be extended for use as appropriate (2B). Commonly used drugs are amoxicillin/clavulanate, cephalosporins, or quinolones [67,210, 211, 212, 213]. B. There is limited evidence of long-term, low-dose macrolides in the treatment of chronic sinusitis and is not recommended as routine therapy [214, 215, 216, 217, 218, 219, 220, 221, 222] (2B). C. Combined with nasal inhalation of nasal corticosteroids, the course of treatment is more than 3 months. Treatment of chronic sinusitis with nasal polyps with nasal corticosteroids is recommended to avoid unnecessary surgery [223, 224, 225, 226] (1A). In patients with chronic sinusitis with nasal polyps, oral hormone sequential topical inhaled hormones are more effective than nasal inhaled hormones alone [227, 228] (2A). D. The better effect of drug treatment or surgery is currently inconclusive. When medical treatment is ineffective, consultation with an otolaryngologist and, if necessary, nasal endoscopic surgery [229, 230, 231] (2B).

(2) Symptomatic treatment: (1) Nasal decongestants can reduce nasal mucosal congestion and edema, facilitate the drainage of secretions, alleviate nasal congestion symptoms, but should not be used for a long time, and need to be vigilant against adverse reactions that lead to drug-induced rhinitis. The course of treatment with nasal decongestants is generally < 1 week [232, 233, 234] (1B). A combination of first-generation oral antihistamines and nasal decongestants is recommended for a course of 2 to 3 weeks [235, 236, 237] (2D). (2) Patients may benefit from mucolytic agents (carboxylsteine/erdostam) in the treatment of chronic sinusitis [238, 239, 240] (2B). (3) Saline nasal irrigation is effective in the treatment of chronic sinusitis [241, 242] (2B).

(ii) CVA

CVA is a special type of asthma, cough is its only or main clinical manifestation, there is no obvious wheezing, shortness of breath and other symptoms, but there is a high airway response. CVA is the most common cause of chronic cough [68,75,243], and domestic multicenter survey results show that it accounts for about one-third of the causes of chronic cough [68]. Some asthmatic patients have significantly reduced lung function, but cough is still the only symptom or main symptom; there are also some typical asthma patients who have transient wheezing symptoms, but persistent cough is the main symptom [244], these two conditions are also called cough predominate asthma (CPA), which has become an important issue of clinical concern in recent years. The 2020 new version of the ACCP cough guidelines refers to CVA and CPA as "chronic cough due to asthma" and "asthmatic cough" in the new 2020 ERS cough guidelines. This guideline recommends that CVA and CPA be collectively referred to as cough-type asthma.

1. Clinical manifestations: the main manifestations are irritating dry cough, usually cough is more intense, and cough at night and in the early morning is an important feature [245]. Colds, cold air, dust, and oil smoke can easily induce or worsen cough, but these triggers are also present in chronic coughs of other causes [245].

2. Diagnosis: Diagnosis is based on a history of chronic cough, bronchial provocative tests, and effective comprehensive analysis of anti-asthma therapy. Effective bronchodilator therapy is an important clinical feature of CVA, but some (30% to 40%) patients with CVA do not respond well to bronchodilator-alone therapy [246, 247], so effective bronchodilator therapy is no longer considered a diagnostic criterion. However, the average variability of PEF can be used as a reference criterion .[248] Induced sputum eosinophilia and FeNO elevation contribute to the diagnosis of CVA [46,72,73,249] Elevated FeNO levels combined with decreased small airway function suggest airway hyperreactivity [250]. Some units in China have not yet carried out bronchial provocative tests, and the diagnosis of CVA based solely on medical history requires caution to prevent overdiagnosis.

CVA is confirmed by meeting all of the following criteria: (1) Chronic cough, often accompanied by a pronounced nocturnal irritating cough. (2) Positive bronchial excitation test, or PEF average diurnal variability > 10%, or positive bronchodilation test. (3) Anti-asthma treatment is effective.

Treatment: (1) Inhaled ICS plus bronchodilators such as long-acting beta-agonists (LABA) or ICS alone are recommended [251, 252, 253] (1B). Combination therapy provides faster and more effective cough relief than ICS or bronchodilator therapy alone, but more clinical evidence is needed [252, 253]. The duration of treatment is more than 8 weeks, and some patients may require long-term treatment or intermittent treatment as needed, and it is recommended to refer to the asthma treatment model, evaluate the patient's response to treatment during treatment, and adjust the treatment plan [44] (2D). (2) If the patient has severe symptoms or airway inflammation, or does not respond well to ICS treatment, short-term oral glucocorticoid therapy (10 to 20 mg/day, 3 to 5 days) or inhaled preparations using ultrafine particles can be used. Long-term oral corticosteroid therapy for CVA [254, 255] (2C) is not recommended. (3) Leukotriene receptor antagonists are effective in treating CVA, which can alleviate cough symptoms, improve quality of life, and slow down airway inflammation [256, 257, 258] (2B). In a small number of patients who do not respond to ICS therapy, leukotriene receptor antagonist therapy may be effective. The course of treatment and the inhibitory effect on airway inflammation need to be further studied. (4) Chinese medicine believes that CVA is related to the lung and lung qi loss of wind and evil, and the treatment should be to relieve the wind and promote the lungs, cough and pharynx, and the treatment with Suhuang cough capsules has a certain effect [259, 260] (2B).

If ICS treatment is ineffective for more than 4 weeks, it should be re-evaluated, paying close attention to whether there is a diagnostic error, a false positive bronchial challenge test or other disease, or some factors that affect efficacy.

4. Prognosis: some patients with CVA develop typical asthma, and long course of illness, high airway responsiveness, and induced sputum eosinophils are risk factors for developing typical asthma. Long-term inhalation of hormones may help prevent the development of typical asthma [261, 262, 263].

(iii) EB

EB is a common cause of chronic cough, accounting for 13 to 22 percent of chronic cough causes [68,74,243]. EB is characterized by airway eosinophil infiltration, sputum eosinophils are elevated, but the range of airway inflammation is more limited, the density of intra-smooth muscle mast cell infiltration is lower than that of asthmatic patients, and the degree of inflammation and oxidative stress level are differently lower than in CVA patients [264, 265, 266, 267]. About one third of patients have allergic rhinitis [54,74].

1. Clinical manifestations: mainly chronic irritating cough, often the only clinical symptom, dry cough or cough a little white mucus sputum, mostly daytime cough, a few with nocturnal cough. Patients are sensitive to fumes, dust, odors, or cold air and are often predisposing factors for cough. Patients do not have symptoms associated with airflow limitation, such as wheezing and dyspnea. Pulmonary ventilation function and PEF variability are normal, and there is no airway hyperreaction.

2. Diagnosis: EB clinical manifestations lack specificity, clinical manifestations are similar to CVA, there are no abnormalities on physical examination, and sputum eosinophils are the necessary diagnostic basis. FeNO testing has a low sensitivity to diagnose EB, and elevated (FeNO≥32 ppb) suggests eosinophilic-associated chronic cough (e.g., EB or CVA) [51,53,71,73]. Exposure to flour, isocyanic acid, and chlorine has been reported to have caused EB [268, 269, 270, 271, 272, 273], so occupational factors should be considered in the diagnosis of EB. Diagnosis of EB must be based on a combination of history, eosinophil count induced sputum (or bronchial lavage fluid), airway reactivity measurement, and effectiveness of hormone therapy. EB is confirmed by meeting all of the following criteria: (1) Chronic cough, presenting as an irritating dry cough or with a small amount of sticky sputum. (2) The lung ventilation function is normal, there is no airway hyperresponsiveness, and the PEF variability is normal. (3) Sputum cytology check the proportion of eosinophils ≥ 2.5%. (4) Exclude other eosinophilic diseases. (5) Oral or inhaled glucocorticoids are effective.

3. Treatment: EB responds well to glucocorticoids, and the cough disappears quickly or decreases significantly after treatment. ICS therapy is recommended for more than 8 weeks [39,251,274] (2C). Initial treatment can be combined with oral prednisone 10 to 20 mg/day for 3 to 5 days [275]. If ineffective, attention should be paid to the presence of systemic disorders related to eosinophilia, such as eosinophilic hypertrophic syndrome and eosinophilic granulomatous polyangiitis.

4. Prognosis: more than half of EB patients relapse after remission, with rhinitis and persistent eosinophilia as risk factors for recurrence [54]. A small number of patients with EB have been reported to develop chronic airflow obstructive disease (asthma or COPD) [276, 277, 278]. Long-term follow-up studies of patients with EB in China show that their lung function remains stable, suggesting that EB is not a pre-stage stage of chronic airway obstructive disease, but an independent disease [54].

(4) GERC

A clinical syndrome in which cough is prominently manifested by the regurgitation of gastric acid and other gastric contents into the esophagus is a special type of GERD and is a common cause of chronic cough [68,74, 75]. The pathogenesis involves micropitting, esophageal-bronchial reflex, esophageal motor dysfunction, autonomic dysfunction, and airway neurogenic inflammation, and airway neurogenic inflammation and central cough hypersensitivity caused by esophageal-bronchial reflex play a major role [279, 280, 281, 282]. In addition to acid reflux, some patients are associated with abnormal non-acid reflux such as weak acids or weak bases (e.g., bile reflux).

1. Clinical manifestations: in addition to cough, 40% to 68% of PATIENTS with GERC can have typical reflux symptoms such as acid reflux, retrosternal burning sensation, and belching, but many patients also have cough as the only symptom [279,283]. Coughs mostly occur during the day, in the upright position, and during postural changes, with a dry cough or coughing up a small amount of white sticky sputum. Eating acidic, greasy foods can easily induce or worsen cough [279,284].

2. Diagnostic criteria: (1) Chronic cough, which is common during the day, may have a nocturnal cough in a small number of patients. (2) Esophageal reflux monitoring AET >6% and SAP ≥ 95% [57, 58, 59]. (3) Cough is significantly reduced or disappeared after anti-reflux therapy.

Esophageal reflux monitoring is the most important and effective method for diagnosing GERC, but normal monitoring does not exclude GERC because patients may have non-acidic or weak acid reflux, or intermittent reflux. Patients with AET between 4% and 6% and suspected GERC can be judged in conjunction with other tests or empiric therapy. DeMeester integrals and throat reflux integrals also have certain diagnostic value. Other tests for gastroesophageal reflux include gastroscopy, nasopharyngeal mirror, barium meals in the digestive tract, and esophageal manometry. For example, endoscopic intercodigoedema, false vocal cord groove suggests throat reflux, esophageal mucosal hyperemia, fragile damage, erosive ulceration and other changes suggest reflux esophagitis; barium upper gastrointestinal meal and esophageal manometry abnormalities can be used to assist in the diagnosis of GERD, but the sensitivity of diagnosing GERC is not high, and most patients with GERD are examined normally. For patients with chronic cough who are not eligible for esophageal reflux monitoring, patients who: (1) have a significant eating-related cough, such as postprandial cough, eating cough, etc.; (2) with typical retrosternal burning sensation, reflux symptoms such as acid reflux, or gastroesophageal reflus disease questionnaire (GerdQ) ≥ 8 points; (3) exclude common causes of chronic cough such as CVA, UACS, EB , or in terms of characteristics such as poor treatment for these diseases, the possibility of GERC should be considered and diagnostic treatment recommended [38,55,245,285,286] (2C). Proton pump inhibitor (PPI) test [287, 288] (2C): oral standard dose PPI (e.g., omeprazole 20 to 40 mg/day, 2 times/day) is recommended, and the diagnostic treatment time is not less than 2 weeks. Cough disappears or resolves significantly after anti-reflux therapy, and GERC can be clinically diagnosed. These diagnostic strategies are more economical and simple than tests such as esophageal reflux monitoring [287], but have low specificity. In addition, the Hull airway reflux questionnaire (HARQ) and the GerdQ questionnaire (HARQ≥24, GerdQ≥8.0) help in the diagnosis of GERC in the absence of esophageal reflux monitoring conditions or when patients are reluctant to test [289, 290].

3. Treatment: (1) Lifestyle adjustment: For patients with suspected GERC, controlling diet, weight loss, raising the head of the bed, and avoiding eating before going to bed is conducive to relieving symptoms (2D). In addition, avoid over-fullness, avoid eating acidic, spicy, and greasy foods, avoid coffee, acidic beverages, and smoking, and avoid strenuous exercise [285,291]. (2) Acid suppressive drugs: Acid suppressive drugs, including PPIs and potassium ion-competitive acid blockers, are recommended as the preferred treatment for GERC [292, 293, 294] (1A). PPI has a good acid-suppressing effect and symptomatic relief, but should be taken half an hour or one hour before meals [295]. H2 receptor antagonists can also be used without PPIs. (3) Gastric motility drugs: gastric motility drugs may be effective in relieving GERD-related symptoms, it is recommended that for patients with GERC, gastric motility drugs can be combined with gastric motility drugs on the basis of acid suppression [296, 297, 298] (1D). Anti-reflux therapy is given for at least 8 weeks, with a gradual tapering.

Patients with chronic cough with objective evidence of abnormal reflux should consider whether the dose and duration of treatment are adequate, and whether there is chronic cough due to non-acid reflux, non-reflux, or other compound causes when treated with standard anti-reflux drugs is ineffective or ineffective [57,59] (2C). Patients with GERC who do not respond to acid suppressor therapy are recommended for esophageal reflux monitoring to determine the cause of their ineffectiveness [299, 300]. Gabapentin has a similar therapeutic effect with baclofen for refractory GERC that does not respond to acid suppressor therapy, but adverse effects need to be noted [301, 302, 303] (2C). There is clear evidence of reflux, but increasing the dose of PPI may be effective when haplotype PPI therapy is ineffective [304, 305] (2A), and switching to another PPI may be effective when treatment with one PPI is ineffective [306, 307] (2C). For patients with GERC who have failed or recurrent drug therapy, choose anti-reflux surgery (laparoscopic fundoplication or endoscopic anti-reflux surgery) with caution, consulting an relevant specialist if necessary to jointly study treatment options [308, 309, 310, 311, 312, 313, 314] (1A). Due to postoperative complications and recurrence, the indications for surgery should be strictly grasped. Surgical treatment may be considered if the following surgical indications are met: (1) GERC diagnosis is clear, anti-reflux therapy is effective, but the patient has poor long-term medication compliance and has a willingness to operate; (2) antirelux drug therapy is ineffective, but multiple objective examination methods determine the presence of reflux, or the presence of anatomical abnormalities, and symptoms are related to reflux.

(5) AC

Clinically, some patients with chronic cough have atopics, normal sputum eosinophils, no airway hyperreactivity, and are effective in glucocorticoids and antihistamines, defining such coughs as AC. Domestic studies have shown that AC is a common cause of chronic cough [68,185,243,315]. If a patient with chronic cough has a negative bronchial provocation test and sputum eosinophils are not high, the possibility of AC should be considered. Its pathogenesis needs to be further clarified. Chronic cough caused by fungi (basidiomycetes) as allergens has been reported in Japan, and antifungal therapy is effective [316].

1. Clinical manifestations: irritating dry cough, mostly paroxysmal, cough during the day or at night, oil smoke, dust, cold air, speech, etc. are easy to induce cough, often accompanied by itchy throat. Ventilation function is normal, there is no airway hyperreactivity, and the proportion of eosinophils is normal when inducing sputum cytology.

2. Compliance with one of the following criteria (1), (2), (3), (5) and (4) confirms the diagnosis of AC: (1) Chronic cough, mostly irritating dry cough. (2) The lung ventilation function is normal, and the bronchial excitation test is negative. (3) Induction of sputum eosinophils does not increase. (4) Have one of the following indications: (1) a history of allergic diseases or allergen exposure; (2) a positive allergen skin test; (3) an increase in serum total IgE or specific IgE. (5) Glucocorticoids or antihistamines are effective in treatment.

Treatment: inhaled ICS and/or oral antihistamines for more than 4 weeks, with short-term oral low-dose glucocorticoids (3 to 5 days) at the beginning [68,275] (2C).

10. Diagnosis and treatment of other causes of chronic cough

(i) Chronic bronchitis

Definition: Cough, sputum production for more than 2 consecutive years, accumulated or persisted for at least 3 months per year, and other causes of chronic cough are excluded. Cough and sputum production are generally obvious in the morning, coughing up white foamy sputum or mucus sputum, and there is also a night cough during aggravation. Often associated with smoking and environmental exposures.

Chronic bronchitis is a common disease in community epidemiological investigations, however chronic bronchitis is only a minority of patients with chronic cough treated in specialist clinics. The reason for this discrepancy may be related to the lack of objective criteria for the diagnosis of chronic bronchitis at present, and the tendency to misdiagnose patients with chronic cough caused by many other etiologies as chronic bronchitis during epidemiological investigations. Chronic bronchitis-type COPD is a special phenotype of COPD, and the presence of chronic cough with sputum production is associated with an increase in the rate of acute exacerbations and mortality [317, 318].

Smoking cessation or elimination of exposure to environmental risk factors is an important management method for patients with chronic bronchitis. The results of two Asian studies showed that patients with acute exacerbations of chronic bronchitis were mostly infected with Haemophilus influenzae, Moraxella catarrhalis, Pneumococcus pneumoniae, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter aeruginosa, and should conduct epidemiological investigations of local bacterial resistance and guide antimicrobial selection [319, 320] (1B). Due to broad-spectrum antimicrobial activity and low drug-related adverse events, moxifloxacin is recommended as the mainstay of treatment in acute exacerbations of chronic bronchitis [321, 322, 323, 324] (2B).

(ii) Bronchiectasis (bronchiectasis)

Due to chronic inflammation causing disruption of the airway wall, resulting in irreversible bronchiectasis and lumen deformation, the main lesion site of bronchiectasis is the subsegment bronchi. Typical clinical manifestations are chronic cough, massive coughing up of purulent sputum, and intermittent haemoptysis, often with chronic sinusitis. Diagnosis is not difficult in people with a typical history, and mild bronchiectasis without a typical history is easily misdiagnosed. Chest x-ray changes (e.g., curl-like signs) are suggestive of diagnosis, and the best diagnosis is high-resolution ct of the chest when bronchiectasis is suspected [325].

Routine inhalation of ICS is not recommended in patients with stable bronchiectasis, but a combination of inhalation of ICS+LABA is recommended for patients with stable-stage bronchiectasis with chronic airflow obstruction or airway hyperreactivity [326, 327, 328] (2B). Postural drainage has a role in bronchiectasis patients [329, 330] (2C). In patients with severe bronchiectasis, intravenous infusion of antimicrobial therapy may help reduce cough symptoms and avoid acute exacerbations, and is recommended when the patient is generally poor and requires hospitalization, or when the infected pathogen does not respond to oral antimicrobial therapy, or when oral antimicrobial therapy fails [331, 332, 333, 334] (2B). Macrolides can help improve symptoms and reduce the risk of acute exacerbations in patients with stable bronchiectasis, but should pay attention to bacterial resistance and adverse drug reactions caused by long-term use [335, 336, 337] (2B). Inhaled antimicrobial therapy for bronchiectasis is effective in reducing sputum bacterial load and the risk of acute onset, delaying the progression of the disease, and is well tolerated [338, 339] (1B). Inhaled airway mucolytic agents are not recommended for routine use [340] (1A). Statins [341, 342] and mannitol inhalation may also be helpful in the treatment of bronchiectasis, but routine clinical use is not recommended [343, 344] (2B). Hypertonic saline atomization helps relieve clinical symptoms in patients with bronchiectasis and reduces bacterial colonization [345, 346] (2B).

(iii) Bronchial tuberculosis

Domestic tracheo-bronchial tuberculosis is not uncommon in chronic cough, most of which are concomitant with tuberculosis, and many patients only present with simple bronchial tuberculosis. Its main symptoms are chronic cough, which can be accompanied by symptoms of tuberculosis poisoning such as low-grade fever, night sweats, and anti-tuberculosis, and cough in some patients is the only clinical manifestation, and the dry rales of the localized inhalation period can sometimes be heard on physical examination, and there is no obvious abnormal change in chest x-ray, which is easily misdiagnosed and missed clinically [347, 348, 349].

Patients with suspected tracheo-bronchial TB should first have a sputum smear for acid-fast bacilli. Some patients may have positive cultures of Mycobacterium tuberculosis. There are few direct signs of chest x-ray, and lesions such as thickening of the walls of the trachea, main bronchi, lumen stenosis, or obstruction may be found. Chest CT (particularly high-resolution CT) shows signs of bronchial lesions more sensitive than chest x-ray, and can show lesions of the subverse bronchi in particular, which can indirectly suggest a diagnosis. Bronchoscopy is the main means of diagnosing tracheo-bronchial tuberculosis, and the positive rate of routine microscopic brushing and tissue biopsy is high [350]. The principles of treatment are carried out in accordance with the guidelines related to tuberculosis.

(d) Cough induced by ACE Inhibitor and other drugs

Cough is a common adverse effect of ACEI antihypertensives, occurring in 5 to 25 percent, and in chronic cough 1.7 percent to 12.0 percent [351]. Independent risk factors for cough caused by ACEI include a history of smoking, a history of cough caused by ACEI [352], and a Chinese [353], independent of age, sex, and ACEI dose.

Cough relief after discontinuation of ACE Inhibitor is confirmed. Cough usually disappears or resolves significantly after 1 to 4 weeks of discontinuation [354]. For patients who have had a previous or are likely to be an ACEI-associated cough, alternative antihypertensive agents may be used to treat the primary disease with ACEI drugs.

In addition to ACEI, there have also been case studies of mofetilate, nitrofurantoin, propofol, β-receptor blockers, leflunomide, simvastatin, γ-interferon, and omeprazole that can also cause cough [355, 356, 357].

Bronchogenic carcinoma

Cough is often an early and common symptom of central lung cancer, occurring in 25 to 86 percent of the area [13,358]. Early chest x-ray examination is often abnormal, so it is easy to miss and misdiagnose. Therefore, after a detailed history, patients with a long history of smoking, irritating dry cough, blood in sputum, chest pain and weight loss, or changes in the nature of the original cough should be highly suspected of lung cancer, and further imaging and bronchoscopy should be conducted. The key to the treatment of lung cancer cough lies in the treatment of the primary lesion, and radiation therapy, chemotherapy, radiofrequency ablation, and surgical removal of lung tumors can alleviate cough symptoms in lung cancer patients [359, 360, 361]. Cough after lung surgery is a common clinical problem, the mechanism is unclear, and may involve anesthesia, surgical resection, lymphatic dissection, postoperative bronchial twisting, etc. Antitustric drugs such as dextromethorphan and mesyldlust ( a novel selective Th2 cytokine inhibitor ) may have a role in coughing after lung cancer surgery [362, 363, 364]. Intractable cough can be treated with central or peripheral antitussive drugs.

(6) Psychologic cough/somatic cough syndrome

The pathogenesis of psychotic cough may not be a single psychological factor, but is associated with psychiatric factors such as central regulatory disorders, anxiety, or depression [365]. The 2015 ACCP Cough Guidelines recommend replacing psychological cough with the term somatic cough syndrome [366]. Psychotic cough is typically presented as a daytime cough, focusing on one thing and disappearing at nighttime rest, often accompanied by symptoms of anxiety. A variety of factors, such as feelings, behaviors, mood, learning, and lifestyle, can cause cough and should be taken clinically .[367]

At present, the diagnosis of psychological cough is an exclusive diagnosis, there is a lack of specific diagnostic criteria, and this diagnosis can only be considered after the common and rare causes of chronic cough have been ruled out. Psychotropic drugs such as anti-anxiety or antidepressants can be appropriately used, supplemented by psychological interventions.

(7) Other rare and rare causes of chronic cough

The proportion of rare and rare chronic cough causes is not high, but there are many causes involved, and Table 3 lists some rare and rare causes of chronic cough reported in the domestic and foreign literature [6,368, 369].

Unexplained chronic cough, chronic refractory cough, chronic cough hypersensitivity syndrome

Most patients with chronic cough can obtain a clear diagnosis of the cause, and cough can be relieved with targeted treatment. However, there are some patients with chronic cough who, after a comprehensive examination, the cause of which is still not clear, called unexplained chronic cough, which is also known as idiopathic cough in the past. Diagnostic principles of unexplained chronic cough: A systematic examination of the cause of chronic cough must be done to rule out a known cause of chronic cough, and unexplained chronic cough can only be considered if treatment for the cause of chronic cough is ineffective. In addition to unexplained chronic cough, there are some patients with potential chronic cough causes clinically, but for these causes of treatment, cough symptoms have no significant relief, called refractory chronic cough. According to the newly published Expert Consensus on the Diagnosis and Treatment of Refractory Chronic Cough in China [370], refractory chronic cough also includes unexplained chronic cough. Due to the prevalence of cough hypersensitivity in chronic patients, a new diagnostic term "cough hypersensitivity syndrome" has been proposed in recent years to describe patients with such chronic cough [371].

Treatment options for refractory chronic cough or cough hypersensitivity syndrome are limited, including both pharmacological and non-pharmacological treatments. Clinical studies have shown that neuromodulatory agents plus barbapentine are effective [301,372,373] (2B), and other drugs such as amitriptyline, baclofen, carbamazepine, pregabalin, etc. can also be used [301,373, 374, 375, 376] (2B). Inhaled lidocaine nebulized has some effect on the temporary relief of refractory chronic cough [377, 378, 379] (2B). Non-pharmacological treatments include speech-language pathotherapy and cough-suppressing physiotherapy, collectively referred to as cough-suppressing therapy. Cough suppressive therapy has shown some effect in improving cough-related quality of life and reducing cough sensitivity and frequency [380, 381, 382, 383] (2B). There have also been case studies of surgically blocking afferent nerves to treat cough [384].

XII. Etiological distribution characteristics and treatment principles of chronic cough in children

Definition of chronic cough in children: For children, the cough time is usually > 4 weeks, and cough is the main or only symptom, and chest x-ray is normally called chronic cough. The distribution of chronic cough causes in children differs from that in adults, and the distribution of chronic cough causes in children of different ages also varies. Neonatal and infants should be aware of congenital diseases, such as tracheomalacia, abnormal tracheal openings, macrovascular malformations, primary ciliary immobility syndrome, bronchiectasis, etc. [385, 386, 387, 388, 389]; < 3-year-olds should first consider respiratory infectious-related diseases. Bacterial culture of bronchoalveolar lavage fluid is important for diagnosis. The prevalence of PBB in infants and young children is high, and nearly half of the children have tracheomalacia, and Streptococcus pneumoniae and Haemophilus influenzae are the main pathogens. PBB is recommended with amoxicillin clavulanate potassium or second and third-generation cephalosporins and plus enzyme inhibitors for 2 weeks [390, 391, 392, 393, 394] (2C). Retronasal drip syndrome and CVA, which are common in adults, are not common causes of chronic cough in infants and young children. Foreign bodies in the airways are more likely to occur in children aged 1 to 3 years, and for long-term coughs and poor treatment results, pay attention to asking about the history of foreign body inhalation, and do chest X-ray or CT examination to rule out the possibility of foreign body inhalation [395, 396, 397, 398]. Cough from allergic diseases, including asthma, gradually becomes a common cause after the age of 3. Chronic cough in school-age children should first be considered as possible CVA [399, 400, 401] (2C). Allergic rhinitis, sinusitis, and adenoidal hypertrophy can all cause UACS and are effective for treatment [402, 403, 404, 405]. EB is one of the important causes of chronic cough in adults, but it seems rare in children. Some chronic cough causes are relatively rare in adults and more common in children, such as chronic cough caused by atypical pathogens (mycoplasma, chlamydia) infection and whooping cough, cough caused by foreign body inhalation, psychological cough and cough caused by congenital diseases. Due to physiological reasons, gastroesophageal reflux is a common phenomenon in young children, and the incidence of gastroesophageal reflux in healthy infants is 40% to 65%, but there are still different opinions on whether it is the common cough cause in young children. Children with psychotic cough (now called "somatic cough syndrome") should be distinguished from Tourette's syndrome and are recommended with non-pharmacological interventions such as hypnosis, suggestive therapy, counseling, or psychological counseling [406, 407] (2B); for children with habitual cough (now called "twitch cough"), treatment is recommended with reference to tic disorder if symptoms do not affect life, learning, and social activities, and if so, it is recommended to refer to tic disorder [407, 408] (2C). In children with acute cough, the possibility of whooping cough (2C) should be considered if vomiting after cough is present.

The principle of treatment of chronic cough in children is to identify the cause and treat it according to the cause. If the cause is unknown, or if the child is too young to be tested, empiric or symptomatic therapy may be given. If the cough symptoms do not resolve after treatment, they should be re-evaluated. Antitussive drugs should not be used in infants.

13. Empiric treatment of chronic cough

Etiological diagnosis is the basis for the success of chronic cough diagnosis and treatment, but etiological diagnosis requires certain equipment and technical conditions, which is difficult to implement for patients with limited economic conditions in primary hospitals or economic conditions. Thus, when objective conditions are limited, empiric therapy can be used as an alternative measure [38,409, 410].

Empiric treatment of chronic cough refers to the diagnosis of the cause is uncertain, the corresponding therapeutic measures are given according to the condition and the possible diagnosis, and the diagnosis is established or excluded by the response to treatment. Empiric treatment should follow the following principles.

1. Treatment is recommended for common causes of chronic cough, CVA, UACS/PNDS, EB, AC, and GERC [68,74, 75]. For patients with no obvious clinical features suggestive of an underlying cause, a stepwise, sequential treatment strategy based on common causes is recommended [411] (2C).

2. Speculate on a possible cause of chronic cough based on history and treat accordingly [38,409,412]. Understanding the patient's cough phase and accompanying symptoms has certain reference value in the diagnosis of chronic cough etiology [286] (2B). If the patient's main manifestation is a nocturnal or early morning irritating cough, it can be treated according to CVA first; if the cough is accompanied by significant acid reflux, belching, and retrosternal burning, gerc treatment is considered; if the cough after a cold does not heal, it can be treated according to PIC. Cough with runny nose, nasal congestion, nasal itching, frequent throat clearing and postnasal flu drops are treated with UACS/PNDS first.

3. It is recommended that chronic cough be divided into hormone-sensitive cough (including CVA, EB and AC), UACS, and GERC for empiric therapy according to clinical characteristics [38] (2C), which is conducive to reducing the blindness of empiric therapy and improving the success rate of empiric therapy [38]. Mesmin pseudohemp solution and compound methoxamine are recommended for empiric treatments such as UACS/PNDS, AC, and PIC [411,413, 414] (2C). In patients with suspected hormonally sensitive cough, oral low-dose hormone therapy is recommended for 5 to 7 days or inhaled ICS for 4 weeks, and maintenance therapy with inhaled ICS for more than 8 weeks after symptom resolution [38, 39] (2C).

4. Patients with cough with coughing up pus sputum or purulent nasal discharge with chronic cough, it is recommended to use antibacterial drug therapy (2D). Most chronic cough causes are not infection-related [25,68,415], and antimicrobial abuse should be avoided with empiric treatment.

5. Empirical treatment has a certain degree of blindness, and care should be taken to exclude tracheal malignancy, tuberculosis and other lung diseases. For those who are ineffective for 4 weeks of empiric treatment for the underlying cause, it is recommended to go to a hospital with the condition to conduct a relevant examination to determine the cause [275].

14. Symptomatic treatment

Mild cough does not require antitussive therapy. Cough can be caused by a variety of causes, the key to treatment lies in the treatment of the cause, and antitussive drugs can only play a role in temporary relief of symptoms. However, severe cough, such as severe dry cough or frequent coughing that affects rest and sleep, may be given appropriate antitussive therapy. Patients with sputum should be treated with expectorant drugs.

(1) Antitussive drugs

Generally, according to its pharmacological mechanism of action, antitussive drugs are divided into two categories: central and peripheral. Central cough suppressants are drugs that act on one or more sites of the bulbar cough center to have an antitussive effect; peripheral cough suppressants are drugs that combine with cough receptors, afferent nerves, efferent nerves, and receptors at the effector site on the cough reflex arc to produce a cough suppressant effect [3,27,127].

1. Central antitussive drugs: These drugs have an inhibitory effect on the brain center, and can be divided into dependent and non-dependent antitussive drugs according to whether they have addictive and anesthetic effects. The former is a morphine alkaloid and its derivatives, which have a very obvious antitussive effect and are only used briefly when other treatments are ineffective due to their addictive nature. The latter are mostly synthetic antitussive drugs, such as dextromethorphan and pentovirin, which are widely used in clinical practice. Common central antitussives are as follows: (1) dependent antitussives: (1) codeine (codeine)[3]: direct inhibition of the brain center, strong and rapid cough effect, but also has analgesic and sedative effects, can be used for unknown etiology, poor treatment and severe dry cough and irritating cough, especially with chest pain. (2) Pholcodine: the effect is similar to that of codeine, but the addictiveness is weaker. (2) Non-dependent antitussive drugs: (1) dextromethorphan: the most widely used cough drug in clinical practice, the effect is similar to that of codeine, but there is no analgesic and hypnotic effect, and the therapeutic dose has no inhibitory effect on the respiratory center and is not addictive [416]. (2) Pentoxyverine: the intensity of action is one-third of that of codeine, and it has an anticonvulsant and antispasmodic effect. Glaucoma and cardiac insufficiency should be used with caution. (3) Dextrophan: a metabolite of dextromethorphan, the patient's tolerance is better, and it may replace dextromethorphan for clinical treatment in the future.

2. Peripheral cough suppressants: also known as peripheral cough suppressants, which play an antitussive role by inhibiting a certain link in the cough reflex arc. Such drugs include local anesthetics and mucosal protectors. Common peripheral cough suppressants are as follows: (1) Narcodine: The isowalin alkaloids contained in opioids, acting on a comparable basis to codeine, are independent, have no inhibitory effect on the respiratory center, and are suitable for coughs caused by different causes. (2) Benproperine: non-narcotic antitussive drug, the effect is 2 to 4 times that of codeine. It can inhibit peripheral afferent nerves and can also suppress the cough center. (3) Moguisteine :peripheral non-narcotic antitussive drug with strong effect.

(2) Expectorant drugs

Expectorant drugs improve cough efficiency in clearing airway secretions. The mechanism of action of expectorant drugs includes: increasing the discharge of secretions, reducing the viscosity of secretions, and enhancing the clearance function of cilia. Expectorant drugs are widely available, and more evidence-based medical evidence is needed for their effectiveness in addition to individual drugs. Common expectorants are as follows.

1. Guaifenesin: The only expectorant drug approved by the U.S. Food and Drug Administration (FDA). It can stimulate the gastric mucosa, reflexively cause increased airway secretions, reduce sputum viscosity, and have a certain bronchodilation effect to achieve the effect of enhancing mucus discharge. It is often used in combination with antihistamines, antitussives, and decongestants [417, 418, 419].

2. Myrtol: An extract of the leaves of the myrtle family, which is a volatile vegetable oil, the main ingredients of which include eucalyptin, limonene and α-pinene, which can promote the movement of cilia of the airway and sinus mucosa, and can be used for acute bronchitis, chronic bronchitis and sinusitis [420, 421].

3. Ambroxol (ambroxol) and bromhexine (bromhexine): both belong to the mucus dissolving agent, ambroxol is a metabolite of bromoxen in the body, destroying the acidic mucopolysaccharide structure of mucinoids, reducing the viscosity of secretions, and also promoting ciliary movement and enhancing the concentration of antibacterial drugs in the respiratory tract. For use in patients with symptoms of sputum production.

4. Acetylcysteine (N-acetylcysteine): it can break the sulfur bonds of the mucus glycoprotein polypeptide chain, reduce the viscosity of sputum, and also has antioxidant effects for chronic cough patients with high mucus secretion of sputum.

5. Carbocistein: it can break the disulfide bonds of mucin and reduce the viscosity of secretions. Erdosteine is its precursor drug, which is orally metabolized to produce 3 metabolites containing free thiol groups and exert pharmacological effects.

6. Others: Hypertonic saline and mannitol inhalation can improve the hydration of airway mucus secretion, improve the biorheology of mucus, and thus promote mucus clearance. Combined bronchodilators improve cough clearance in some patients [343,422].

15. Traditional Chinese medicine treatment

Traditional Chinese medicine believes that cough is both a symptom of lung disease and an independent disease. Chronic cough belongs to the category of "long cough" and "stubborn cough" in Traditional Chinese medicine.

The name of cough disease first appeared in the Yellow Emperor's Inner Classic, and in the understanding of the cause of cough, he put forward the view that "all the internal organs and intestines are coughing, not only the lungs" [423]. The ancients originally classified cough by naming the internal organs, which coincided with the anatomical distribution of chronic cough in modern medicine. There are many dialectical types of cough, and the Ming Dynasty's "Jingyue Quanshu" [424] adheres to simplicity and complexity, and divides cough into two categories: external cough and internal injury cough, which have been used to this day. In short, it is the lung loss and the lung qi is coughing.

Traditional Chinese medicine has a long history and rich experience in the treatment of cough, and some examples of unexplained refractory chronic cough can be relieved after treatment with traditional Chinese medicine. The advantages of traditional Chinese medicine in the treatment of chronic cough are first of all characterized by the three-cause condition, reflecting a high degree of individualization and precision dialectical treatment; secondly, through the multi-link, multi-target compound effect; the third is to follow the principle of "urgent treatment of its symptoms, slow treatment of its root causes", which is a comprehensive management model of both symptoms and root causes. There are many kinds of traditional Chinese medicines and proprietary medicines used to treat cough [425, 426, 427]. The types of cough syndromes include wind and cold attack lung certificate, wind fever offender lung certificate, wind evil volt lung certificate, gastric gas reversal evidence, damp and hot depressed lung certificate, lung spleen yang deficiency certificate, lung yin deficiency certificate, etc., among which the common types of chronic cough syndrome are wind evil volt lung certificate, damp and hot depressed lung certificate, lung spleen and yang deficiency certificate, cold drink volt lung certificate, etc. The following are several commonly used clinical cough patterns and prescription drugs [426,428, 429].

【Wind and cold attack lung evidence】Symptoms see heavy cough, shortness of breath and itchy throat, cough sputum thin and white, nasal congestion, runny nose, headache, thin white tongue, floating or tight pulse.

Treatment: loosen the wind and cold, promote the lungs and relieve cough.

Examples of prescription medicines: San'ao Tang (Taiping Huimin and Pharmacy Bureau Fang) + Anti-Cough Dispersion ("Medical Enlightenment") Addition and Subtraction: Ephedra, Almond, Aster, Hundred Parts, Platycodon, White Front, Wattle Mustard, Tangerine Peel, Burning Licorice.

【Lung evidence of wind and fever offenders】Symptoms are frequent cough, dry throat and sore throat, unpleasant sputum, sticky or thick yellow sputum, yellow nose, thirst, headache, red tongue, thin yellow tongue, floating or slippery pulse.

Treatment: ventilation and heat removal, lung and cough.

Prescription example: Mulberry drink ("Wen Disease Article Identification") Plus and minus: mulberry leaves, chrysanthemums, almonds, forsythia, mint, platycodon, raw licorice, reed root.

【Wind evil volt lung evidence】Symptoms see cough formations, cough with itchy throat, dry cough or less phlegm, poor phlegm, often induced by hot and cold air, peculiar smell, laughter, and no obvious cold and heat. External sensations often induce worsening or recurrence of cough. The tongue is reddish, the moss is thin and white, and the veins are stringy or slippery.

Treatment: loosen the wind and promote the lungs, cough and phlegm.

Examples of prescription medicines: ephedra, perilla leaf, ground dragon, loquat leaf, perilla seed, cicada molt, front beard, burdock seed, schisandra. Or stop coughing ("Medical Enlightenment") plus and minus: aster, hundred parts, platycodon, white front, wattle mustard, tangerine peel, burning licorice.

【Gastric reversal】 Paroxysmal choking cough, cough even vomiting bitter water, symptoms worsen after lying flat or full, may be accompanied by putrefaction, noisy or burning pain, reddish tongue, yellowish moss, smooth or fine pulse. This certificate is similar to GERC.

Treatment: lowers turbidity and sputum, and stomach cough.

Examples of prescription medicines: Ochre soup ("On Typhoid Fever") Combined with Half Summer Laxative Heart Soup ("On Typhoid Fever") Plus and minus: Spiral Compound Flower, Substitute Ochre, Ginseng, Half Summer, Ginger, Jujube, Huanglian, Skullcap, Licorice.

【Damp and hot lung evidence】Symptoms of cough, itchy throat, and unfavorable sputum can be accompanied by bloating, dry mouth and no desire to drink or thirst, bitter mouth, sticky stool, cold back, red tongue and yellow moss, and slippery pulse.

Treatment: promote lung cough, clear heat and dampness.

Examples of prescription medicines: Sanren Tang ("Wen Sick Article Identification") Combined To Stop Cough Dispersion ("Medical Enlightenment") Addition and Subtraction: Almond, White Cocoa Kernel, Raw Coix Kernel, Half Summer, Magnolia, Talc, Tongcao, Bamboo Leaf, Aster, Hundred Parts, Wattle Mustard.

【Lung and spleen yang deficiency evidence】Symptoms see cough, throat itching, aggravation in cold, sputum saliva is thin and white or foamy, cold as palms, can be accompanied by chest tightness, stomach cold, loose stool, wind intolerance, self-sweating, fat tongue, light tongue, pale moss, smooth pulse.

Treatment: loose wind and lungs, warm yang healthy spleen.

Examples of prescription medicines: Xiaoqinglong Tang ("On Typhoid Fever") Heling Guishu Gantang ("Golden Essentials") Plus and minus: ephedra, peony, fine spices, dried ginger, guizhi, schisandra, half summer, licorice, poria and baishu.

[Lung yin deficiency evidence] symptoms see dry cough, less sticky sputum, or gradual hoarseness, dry mouth and throat, slow onset, red tongue, less moss, fine pulses.

Treatment: nourish the yin and clear the heat, moisturize the lungs and relieve cough.

Prescription example: Sand ginseng wheat winter soup ("Wen Disease Bar Identification") plus and minus: sand ginseng, wheat winter, jade bamboo, smallpox pollen, white lentils, mulberry leaves, raw licorice.

At present, the treatment of cough in traditional Chinese medicine is mostly concentrated in one party or expert experience, and there is a lack of rigorous evidence-based medical research data, and the level of evidence is generally low [430]. There are many kinds of proprietary Chinese medicines in China, but most of them stay at the level of symptomatic treatment, and the effective components, treatment indications and adverse reactions need to be further clarified to facilitate the effective use of proprietary Chinese medicines. In the future, it is necessary to adopt modern medical methods combined with the concept of traditional Chinese medicine to excavate more Chinese medicine preparations with clear indications and positive efficacy. External treatment of TCM includes acupuncture point patches, acupuncture, moxibustion, cupping, gua sha, etc., and more evidence of high-quality evidence-based medical research is needed for TCM identification and efficacy evaluation of cough.

16. Outlook

Cough as a common problem in the clinic, the domestic systematic research in this field has also been more than 20 years, in its diagnosis, treatment and pathogenesis has achieved a series of results, and based on the formulation of Chinese cough guidelines, and participated in the European ERS, the United States ACCP cough guidelines. After the guidelines were formulated, they were publicized and promoted through various academic conferences, especially since 2017, the China Cough Guidelines Promotion Activity held by the China Cough Alliance has significantly improved the awareness and diagnosis and treatment level of domestic clinicians on cough. Some units in China have also established cough laboratories, carried out induced sputum cytology examination, esophageal reflux monitoring, etc., and set up chronic cough subspecialties and cough clinics. Although we have made great progress in the field of cough, we are also facing many new challenges. First, although the chronic cough guidelines have been well promoted in major urban hospitals, the popularization of primary and community hospitals is still a difficult task. Secondly, the diagnosis and treatment of common causes of chronic cough has been better solved, but refractory chronic cough and chronic cough of related underlying diseases have increasingly become a concern of clinicians, but there are not many units studying chronic cough in China, and more colleagues are urgently needed to participate in the research ranks of chronic cough. In addition, the diagnosis and treatment of some chronic cough and the mechanism still need to be further studied, such as the pathogenesis and treatment of cough-type asthma, the relationship between air pollution and chronic cough, the mechanism and treatment of chronic cough with high sensitivity and refractory chronic cough, etc. We still lack data on the national epidemiological survey of chronic cough, including the prevalence and risk factors of chronic cough, and it is necessary to conduct epidemiological investigation and registration studies of chronic cough to provide a basis for the prevention and control of chronic cough. Looking forward to the future, there is still a long way to go, and it is expected that the whole country will work together to study the clinical diagnosis and treatment of the above cough, provide more high-quality evidence for the revision of the guidelines, further strengthen the promotion of The Chinese Cough Guidelines, especially at the grass-roots level, and continuously push the diagnosis and treatment level and research level of chronic cough in China to a new level.

Annex 1 Diagnostic procedures for the etiology of acute cough

Annex 2 Diagnostic procedures for the etiology of subacute cough

Annex 3 Procedures for diagnosing the causes of chronic cough

Annex 4 Methods of sputum cytology induced by atomization of hypertonic saline

Patients are induced to cough up sputum by inhaling hypertonic saline by nebulization to detect the total number of inflammatory cells and cell classification results of sputum, to clarify the type and extent of airway inflammation in patients, and to assist in diagnosis and treatment and prognosis observation.

Hypertonic saline atomization method can be used single concentration method (NaCl solution concentration: 3.0% or 4.5%) or gradient concentration method (NaCl solution concentration: 3%, 4%, 5%), and physiological saline atomization can be used in severe asthma or children to reduce adverse reactions. Ultrasound nebulization is recommended for clinical use using a single concentration method.

Reagents: hypertonic saline, 0.1% dithiothreitol (DTT) and hematoxylin-efan or Diff-Quik staining solution.

Detection instruments: ultrasonic nebulizer or compression nebulizer, water bath box, vortex or horizontal oscillator, low-speed centrifuge, cell centrifugal smear machine and upright optical microscope.

How to do this:

1. Hypertonic saline atomization: (1) Single concentration method: (1) Let the patient inhale 400 μg of salbutamol 10 minutes before induction, and inform the patient of the precautions and coordination methods for examination. (2) Rinse your mouth and blow your nose after 10 minutes. (3) Hypertonic saline (3.0% or 4.5%) is inhaled as aerosolized for 10 minutes, and after gargling and blowing the nose, actively cough up sputum to a Petri dish. (4) If the patient has no sputum or insufficient sputum, repeat step (3) until a sufficient amount of qualified sputum specimens is coughed up or the total time of atomization reaches 30 min to stop atomization. (2) Gradient concentration method: (1) Let the patient inhale 400 μg of salbutamol 10 minutes before induction, and inform the patient of the precautions for examination and the method of cooperation. (2) Rinse your mouth and blow your nose after 10 minutes. (3) 3% hypertonic saline is inhaled for 15 minutes, rinse mouth, blow nose and actively cough up sputum to a Petri dish. (4) If the patient has no sputum or insufficient sputum, switch to 4% hypertonic saline and continue to atomize for 8 min. (5) If the patient has no sputum or insufficient sputum, the induction procedure is terminated after switching to 5% hypertonic saline and continuing to atomize for 7 min. (6) During the atomization period, if the patient coughs up a sufficient amount of qualified sputum specimens or the total time of atomization reaches 30 min, the atomization is terminated. Teaching patients to take the initiative to cough hard and examiners to give percussion to expel sputum can effectively improve the success rate of induction.

2. Sputum treatment and detection: after the sputum is coughed up, the inspector should immediately use the sharp-beaked forceps to pick out the qualified sputum specimens, and when picking the specimens, it is recommended to select the sputum specimens with white blood cells gathered under the microscope and the squamous epithelial cells, and when the conditions are not available, the sputum plug with high density and opaque under the eyes can be picked, and the transparent and clear saliva can be removed. Specimens should be treated promptly and stored at 4 °C for no more than 3 h. Depending on the viscosity of the sputum specimen, add 2 to 4 volumes of DTT to fully mix room temperature for 15 min, liquefy sputum, 37 °C water bath and horizontal gentle oscillation can improve the liquefaction effect, after liquefaction, the sputum is filtered with a 48 μm filter membrane/300 mesh nylon strainer, the filtrate centrifuged at room temperature for 10 min (1 200 × g), the supernatant is discarded after the phosphate buffer (PBS) resuspends the precipitated cells, and the hemocyt count plate counts the total number of sputum cells. The cell suspension can be manually smeared or made by using a cell centrifugal smear machine, the cell smear is naturally air-dried, and the formaldehyde and other fixative solutions are fixed. HE staining or Diff-Quik staining after fixation, a triage count of more than 400 inflammatory cells (neutrophils, eosinophils, macrophages, lymphocytes) and airway epithelial cells under light microscopy, the results are shown as a percentage of various cells.

Precautions: (1) If the patient can cough up a qualified sputum specimen on his own (the proportion of squamous epithelial cells / total sputum cells <30%), hypertonic saline atomization is not required. (2) Patients with severe asthma, asthmatic exacerbations or acute attacks of COPD need to be combined with lung function and clinical symptoms to determine whether hypertonic saline atomization is appropriate. When the patient's first-second forced expiratory volume (FEV1) accounts for 60% of the expected value < or the percutaneous oxygen saturation (SpO2) < 90% or wheezing symptoms and dyspnea are obvious, it is recommended that the patient cough up sputum naturally or undergo saline atomization induction. (3) The laboratory must be equipped with rescue guidelines, equipment and drugs for adverse reactions such as asthma exacerbations, closely observe the patient's performance during the atomization process, and monitor the patient's blood oxygen saturation and lung function. (4) Hormones, antiallergic drugs, theophylline and other drugs may affect the examination results, and it is necessary to stop the drug for more than 3 days, but when observing the effect of treatment follow-up, the drug can not be discontinued during the examination.

Quality control requirements: Meeting the following requirements is the key point to test whether the induced sputum cytology examination is qualified. (1) There are differences in the success rate of active sputum coughing in patients with different diseases, but the success rate of inducing sputum specimens after hypertonic saline atomization should be > 80%. (2) Sputum cell viability should be > 75%. (3) Sputum cells in the microscopic cell smear should be evenly distributed, not aggregated, and the morphology and integrity of the cells are good. (4) The proportion of squamous epithelial cells in the cell smear should be < 30% of the total cells.

Contraindications: (1) Patients with recent active hemoptysis. (2) Pneumothorax or mediastinal emphysema. (3) A large number of pleural effusions or pericardial effusions caused by various reasons. (4) Severe cardiac insufficiency. (5) Respiratory infectious diseases.

Annex 5 Methods for monitoring esophageal reflux

Esophageal reflux monitoring, as the gold standard for GERD detection, has an irreplaceable role in the clinic.

Monitoring equipment: including monitoring catheter (pH monitoring catheter, impedance-pH monitoring catheter), portable monitoring recorder and data processing system 3 parts.

1. Prepare before inspection

(1) Patient preparation

1. Before the examination, the antacid should be discontinued for > 1 day, the gastric motility agent and the H2 receptor antagonist should be stopped for ≥ 3 days, and the acid suppressant drug (PPI, potassium ion competitive acid blocker) should be stopped for ≥ 7 days. If the patient has not previously definitively diagnosed GERD, it is recommended to discontinue acid-suppressing drugs and perform esophageal reflux monitoring, and if the patient has confirmed GERD, esophageal reflux monitoring can be performed while taking antacid suppressants to determine the reason for the failure of acid suppressant therapy.

2. Fast for 6 to 8 h before examination.

3. Before the examination, it is necessary to understand the relevant medical history from the patient, review the upper gastrointestinal angiography and gastroscopy before the examination, understand whether there are anatomical abnormalities, and exclude contraindications. The patient is then fully explained to the patient the steps of the examination, the significance and safety of the examination, the patient's fear is eliminated, the patient's cooperation is obtained and the informed consent form is signed.

(2) Instrument preparation

Before the inspection, the electrode catheter and the portable recorder are connected and the recorder is turned on to correct the catheter electrode. After the correction is completed, enter the patient information on the recorder and define the patient's main symptoms for the recorder button, generally recording the onset of episodic symptoms (such as heartburn, acid reflux, chest pain, belching, cough, etc.).

Second, the inspection process and operation methods

(1) The subject takes a sitting position, selects the nasal cavity with good ventilation for catheterization, and uses a surface anesthetic to anesthetize the nasal mucosa of the nostrils on the inspected side before the catheterization. (2) With the cooperation of the patient, the catheter is sent to the esophagus through the nose, and the pH electrode is placed 5 cm from the orifice side of the upper edge of the inferior esophageal sphincter. The positioning method of the electrode recommends the use of esophageal manometry, if conditions are not available, the pH gradient method or X-ray fluoroscopy method can be used. (3) After determining the placement of the pH electrode, fix the catheter on the patient's cheek with tape, and instruct the subject to wear a recorder. (4) It is recommended to start monitoring 30 minutes after catheterization, and the monitoring time should be as long as possible to 24 h, the shortest should not be < 16 h, of which the daytime monitoring time should not be < 10 h. During monitoring, patients maintain daily activities and meals, but do not bathe, fast acid or alkaline foods and irritating foods, and abstain from drinking acidic, fruit juice, and irritating drinks. Patients need to correctly press the signal button of the recorder and record the time of eating and sleeping and the accurate time of cough, chest tightness, nausea and other related symptoms. (5) After completing the monitoring, the patient returns to the hospital for extubation, uploads the data in the recorder to the computer, and analyzes it through special analysis software.

Analysis of test results: The analysis content includes the measurement and calculation of the properties of the reflux (liquid, gas or mixture), pH (acidic, weakly acidic or non-acidic), the number of times, the time of food mass clearance, the exposure time of the food mass and the time of esophageal acid clearance, and the evaluation of symptom-reflux correlation. AET ≥4% or a DeMeester score≥ of 14.72 indicate pathological acid exposure in the esophagus. The 2018 Lyon Consensus on GASTROES proposes [431] that the total number of reflux < 40 times can rule out THE POSSIBILITy of GERD, and the total number of reflux > 80 times is an adjunctive diagnostic evidence to support GERD, but it is not recommended to rely solely on this indicator to diagnose GERD. SAP ≥ positive in 95%, suggesting that symptoms are more likely to be associated with reflux.

Indications: (1) It is necessary to clarify whether symptoms or esophageal mucosal injury are related to reflux. (2) Have symptoms related to reflux, but the treatment effect of acid suppressants is not good. (3) Assess the severity of reflux to guide patients in medication and predict efficacy. (4) Evaluation related to gastroesophageal surgery. (5) Differentiation of functional gastrointestinal diseases.

Contraindications: (1) Patients with obvious anatomical abnormalities in the nasopharynx or esophagus. (2) Patients who cannot tolerate catheters, such patients may consider switching to wireless pH monitoring. (3) Patients with mental illness or unconsciousness and inability to cooperate, as well as patients who do not cooperate with self-extubation. (4) Severe coagulation dysfunction, severe esophageal varicose veins, cardiopulmonary insufficiency should be carefully examined.

Annex 6 Cough provocative test method

Cough provocation tests use physical or chemical stimulation to act on the cough receptors of the airways, causing nerve impulses and inducing coughing in the body. The level of cough sensitivity is assessed by comparing the intensity of the stimulus (concentration, dose, etc.) or the cough response (frequency, time of appearance, etc.).

The cough provocation test commonly used in clinical practice is to induce the subject to inhale a quantitative cough stimulant aerosol particles by atomization, inducing it to produce cough, and the minimum excitation concentration (C5) of the patient's cough ≥ 5 times after inhalation indicates the sensitivity of cough. Commonly used stimulants include capsaicin, citric acid, cinnamaldehyde, etc., and the following is illustrated by capsaicin as an example.

Preparation of the excitator: Capsaicin was dissolved in Tween 80 liquid and absolute ethanol, then dissolved in 8 ml of 0.9% NaCl solution to form a 0.01 mol/L stock solution. Before use, dilute with normal saline at concentrations of 1.95, 3.9, 7.8, 15.6, 31.2, 62.5, 125, 250, 500, 1 000 μmol/L.

Measuring instrument: A dosing device using an inspiratory trigger. The compressed air flow rate is 0.11 L/s, the total output is about 160 mg/min (standard with normal saline), and the single inhalation time is 0.5 s. Subjects are instructed to inhale slowly from the residual gas level to the total lung position, and inhale the capsaicin atomization solution in the upper half of the inhalation.

Operation method: (1) First inhale the nebulized saline as the basic control. (2) Subsequently inhaled by the minimum concentration (1.95 μmol/L) the nebulized capsaicin solution and the number of coughs within 30 s was recorded. If the C5 standard cannot be reached, the inhalation of the next concentration is carried out, and the concentration is increased by 1 times each time. (3) Terminate the test when the C5 standard is reached, and this concentration is the threshold of its cough. If the concentration reaches 1 000 μmol/L and the subject has not yet developed C5, the test should be terminated with a threshold concentration of >1 000 μmol/L. If the patient experiences significant discomfort (eg, severe retrosternal burning, shortness of breath, dyspnea, etc.), the test should also be terminated immediately.

Precautions: (1) The excitant solution used in the test must be freshly prepared. (2) Patients with the following conditions should not be tested: pregnant women, asthma exacerbations, pneumothorax, recent hemoptysis and severe heart disease. (3) Subjects should be in a calm state throughout the process. Behaviors such as not talking after inhaling irritants may affect coughing.

Annex 7 Cough Degree Scoring Table (CET)

Please read the following questions and √ in the appropriate place based on your current cough situation

Annex 8 Leicester Cough Quality of Life Questionnaire (LCQ) Chinese edition

1. Have you experienced chest or abdominal pain from coughing in the last 2 weeks? (1) Always (2) Most of the time (3) Often (4) Sometimes (5) Occasionally ( 6) Hardly (7) Never

2. Have you been plagued by sputum production in the last 2 weeks? (1) Always (2) Most of the time (3) Often (4) Sometimes (5) Occasionally ( 6) Hardly (7) Never

3. Have you ever felt tired and tired from coughing in the last 2 weeks? (1) Always (2) Most of the time (3) Often (4) Sometimes (5) Occasionally ( 6) Hardly (7) Never

4. Have you been able to control your cough in the last 2 weeks? (1) Never (2) Almost not (3) Occasionally can (4) Sometimes can ,5) Can often (6) Most of the time can (7) Always

5. Have you ever felt embarrassed by a cough in the last 2 weeks? (1) Always (2) Most of the time (3) Often (4) Sometimes (5) Occasionally ( 6) Hardly (7) Never

6. Have you felt anxious about coughing in the last 2 weeks? (1) Always (2) Most of the time (3) Often (4) Sometimes (5) Occasionally ( 6) Hardly (7) Never

7. Have you been affected by coughing in the last 2 weeks? (1) Always (2) Most of the time (3) Often (4) Sometimes (5) Occasionally ( 6) Hardly (7) Never

8. Have your leisure or recreation been affected by cough in the last 2 weeks? (1) Always (2) Most of the time (3) Often (4) Sometimes (5) Occasionally ( 6) Hardly (7) Never

9. In the last 2 weeks, have you ever coughed from smelling irritating smells such as paint, dust, smoke, etc.? (1) Always (2) Most of the time (3) Often (4) Sometimes (5) Occasionally ( 6) Hardly (7) Never

10. Have you had a cough in your sleep in the last 2 weeks? (1) Always (2) Most of the time (3) Often (4) Sometimes (5) Occasionally ( 6) Hardly (7) Never

11. Have you had a paroxysmal cough every day in the last 2 weeks? (1) Always (2) Most of the time (3) Often (4) Sometimes (5) Occasionally ( 6) Hardly (7) Never

12. Have you felt lost or depressed by coughing in the last 2 weeks? (1) Always (2) Most of the time (3) Often (4) Sometimes (5) Occasionally ( 6) Hardly (7) Never

13. Have you been bored with coughing in the last 2 weeks? (1) Always (2) Most of the time (3) Often (4) Sometimes (5) Occasionally ( 6) Hardly (7) Never

14. In the last 2 weeks, have you become hoarse due to coughing? (1) Always (2) Most of the time (3) Often (4) Sometimes (5) Occasionally ( 6) Hardly (7) Never

15. Have you felt energetic in the last 2 weeks? (1) Never (2) Almost never (3) Occasionally (4) Sometimes (5) Often (6) Most of the time (7) Always

16. In the last 2 weeks, have you been concerned that coughing suggests something serious? (1) Always (2) Most of the time will be (3) often (4) Sometimes (5) Occasionally (6) Almost not (7) Never

17. In the last 2 weeks, have you worried about being thought you are sick? (1) Always (2) Most of the time (3) Often (4) Sometimes (5) Occasionally ( 6) Hardly (7) Never

18. Have you interrupted your conversation or phone conversation due to cough in the last 2 weeks? (1) Always (2) Most of the time (3) Often (4) Sometimes (5) Occasionally ( 6) Hardly (7) Never

19. In the last 2 weeks, have you felt that your cough has interfered with your classmates, friends or family? (1) Always (2) Most of the time (3) Often (4) Sometimes (5) Occasionally ( 6) Hardly (7) Never

Members of the Guideline Revision Expert Group (in alphabetical order by last name):

Hao Chuangli (Children's Hospital Affiliated to Soochow University), Huang Kewu (Beijing Chaoyang Hospital Affiliated to Capital Medical University), Jiang Mei (First Affiliated Hospital of Guangzhou Medical University), Lai Kefang (First Affiliated Hospital of Guangzhou Medical University), Liu Enmei (Children's Hospital Affiliated to Chongqing Medical University), Liu Huiguo (Tongji Hospital of Huazhong University of Science and Technology), Luo Wei (First Affiliated Hospital of Guangzhou Medical University), Qiu Zhongmin (Tongji Hospital Affiliated to Tongji University), Shen Huahao (Second Affiliated Hospital of Zhejiang University School of Medicine), Shi Liqing (Oriental Hospital of Beijing University of Chinese Medicine), Sun Tieying (Beijing Hospital), Wang Gang (West China Hospital of Sichuan University), Wu Jimin (Rocket Force Special Medical Center), Xiao Yinglian (First Affiliated Hospital of Sun Yat-sen University), Xu Rui (First Affiliated Hospital of Sun Yat-sen University), Min Zhang (First People's Hospital Affiliated to Shanghai Jiao Tong University), Zhang Jiannan (China-Japan Friendship Hospital), Zhong Nanshan (First Affiliated Hospital of Guangzhou Medical University)

Guide Methodology Group: Jiang Mei, Luo Wei, Yi Fang

Secretarial team: Yi Fang, Hua Wen, Chen Ruchong

Senior Expert Review Group (in alphabetical order by last name):

Chen Ping (General Hospital of the Northern Theater of the People's Liberation Army), Lin Jiangtao (China-Japan Friendship Hospital), Wang Changzheng (Second Affiliated Hospital of Army Military Medical University), Zhang Luo (Beijing Tongren Hospital Affiliated to Capital Medical University), Zhong Nanshan (First Affiliated Hospital of Guangzhou Medical University), Zhou Xin (First People's Hospital Affiliated to Shanghai Jiao Tong University)

Literature searchers (in alphabetical order by last name):

Bai Yichen, Bao Wuping, Chen Dehua, Chen Songfeng, Dang Xiangyang, Feng Xiaokai, Feng Zien, Li Zhouyang, Lin Mingtong, Liu Jiannan, Liu Meishan, Liu Wei, Ma Jianling, Pan Yilin, Tang Yuyi, Tian Shurui, Wang Changyong, Wang Ji, Weng Jianzhen, Wu Yanping, Xiang Keheng, Xiao Zhengyao, Xu Zhihuai, Xu Tingting, Ye Haohan, Yu Li, Yu Xingmei, Yu Yang, Zhang Li, Zhang Mengyu, Zhang Weiyi, Zhou Ling

References (abbreviated)