The spectrum,clinical features and diagnosis of chronic cough due to rare causes

BackgroundChronic cough has many diverse causes, including common and uncommon causes. There are few comprehensive reports on rare causes of chronic cough. The purpose of this study is to determine the etiological distribution, clinical features, and diagnostic value of special examinations in patients with rare causes of chronic cough.MethodsA retrospective analysis of patients with chronic cough who underwent medical history taking, full examination, and etiological treatment over a 13-year period was conducted. Causes of chronic cough with a prevalence of less than 3% were defined as rare causes.ResultsA total of 1,554 patients were enrolled, and 39 causes of chronic cough were identified. Among them, 1,055 cases were due to common causes, whereas 235 cases were due to rare causes; the causes involved 7 bodily systems. The top five rare causes were protracted bacterial bronchitis, somatic cough syndrome, diffuse panbronchiolitis, obstructive sleep apnea syndrome (OSAS), and interstitial lung disease, accounting for 67.2% of all rare causes. Among 235 patients with rare causes, causes in 90 (38.3%) patients were detected by chest high-resolution computed tomography (HRCT), in 44 (18.7%) patients by bronchoscopy/nasopharyngoscopy, and in 21 (8.9%) patients by pulmonary spirometry and diffusing capacity testing.ConclusionsAmong the 31 rare causes of chronic cough in this cohort, the top five were protracted bacterial bronchitis, somatic cough syndrome, diffuse panbronchiolitis, OSAS, and interstitial lung disease. Special examinations, such as chest HRCT and bronchoscopy, should be considered after excluding common causes of chronic cough.     

Chronic cough in adults

Cough, a defense mechanism for clearing the airways of secretions, exudate, or foreign bodies, may become a troublesome symptom. Chronic cough, one of the most frequent symptoms requiring medical attention, is often not due to identifiable causes in adults. Chronic productive cough defines chronic bronchitis, and thus is present in 100% of these patients, and frequently in patients with bronchiectasis, cystic fibrosis, and chronic infectious respiratory diseases. However, chronic cough is most frequently dry. Thus, chronic cough in adults is a difficult syndrome requiring multidisciplinary approaches, particularly to diagnose and treat the most frequent identifiable causes, but also to decide which patients may benefit by treating the central cough hypersensitivity by neuromodulatory therapy and/or non-pharmacologic treatment (speech pathology therapy). Recent guidelines provide algorithms for diagnosis and assessment of cough severity; particularly chronic cough in adults. After excluding life-threatening diseases, chronic cough due to identifiable causes (triggers and/or diseases), particularly smoking and/or the most frequent diseases (asthma, chronic bronchitis, chronic obstructive pulmonary disease, eosinophilic bronchitis, and adverse reactions to drugs [angiotensin-converting enzyme inhibitors and sitagliptin]) should be treated by avoiding triggers and/or according to guidelines for each underlying disease. In patients with troublesome chronic cough due to unknown causes or persisting even after adequate avoidance of triggers, and/or treatment of the underlying disease(s), a symptomatic approach with neuromodulators and/or speech pathology therapy should be considered. Additional novel promising neuromodulatory agents in clinical development (e.g., P2X3 inhibitors) will hopefully become available in the near future.     

Does idiopathic cough exist?

Despite a meticulous protocol involving diagnostic testing and trials of empirical therapy, there may be no obvious cause for a chronic cough in up to 42% of cases referred for specialist evaluation. In some cases, failure to consider causes that include the asthma/eosinophilic airway syndromes such as eosinophilic bronchitis and atopic cough, or nonacid gastroesophageal reflux disease may explain diagnostic failure. However, a distinct group of patients may be considered to have true idiopathic cough. Current published evidence suggests a certain patient phenotype, namely, middle-aged females with prolonged nonproductive cough and cough reflex hypersensitivity. Almost nothing else is known about this clinical entity and currently no specific therapy exists.     

Does Idiopathic Cough Exist?

Despite a meticulous protocol involving diagnostic testing and trials of empirical therapy, there may be no obvious cause for a chronic cough in up to 42% of cases referred for specialist evaluation. In some cases, failure to consider causes that include the asthma/eosinophilic airway syndromes such as eosinophilic bronchitis and atopic cough, or nonacid gastroesophageal reflux disease may explain diagnostic failure. However, a distinct group of patients may be considered to have true idiopathic cough. Current published evidence suggests a certain patient phenotype, namely, middle-aged females with prolonged nonproductive cough and cough reflex hypersensitivity. Almost nothing else is known about this clinical entity and currently no specific therapy exists.     

The Japanese respiratory society guidelines for the management of cough and sputum (digest edition)

Cough and sputum are common complaints at outpatient visits. In this digest version, we provide a general overview of these two symptoms and discuss the management of acute (up to three weeks) and prolonged/chronic cough (longer than three weeks). Flowcharts are provided, along with a step-by-step explanation of their diagnosis and management. Most cases of acute cough are due to an infection. In chronic respiratory illness, a cough could be a symptom of a respiratory infection such as pulmonary tuberculosis, malignancy such as a pulmonary tumor, asthma, chronic obstructive pulmonary disease, chronic bronchitis, bronchiectasis, drug-induced lung injury, heart failure, nasal sinus disease, sinobronchial syndrome, eosinophilic sinusitis, cough variant asthma (CVA), atopic cough, chronic laryngeal allergy, gastroesophageal reflux (GER), and post-infectious cough. Antibiotics should not be prescribed for over-peak cough but can be considered for atypical infections. The exploration of a single/major cause is recommended for persistent/chronic cough. When sputum is present, a sputum smear/culture (general bacteria, mycobacteria), cytology, cell differentiation, chest computed tomography (CT), and sinus X-ray or CT should be performed. There are two types of rhinosinusitis. Conventional sinusitis and eosinophilic rhinosinusitis present primarily with neutrophilic inflammation and eosinophilic inflammation, respectively. The most common causes of dry cough include CVA, atopic cough/laryngeal allergy (chronic), GER, and post-infectious cough. In the last chapter, future challenges and perspectives are discussed. We hope that the clarification of the pathology of cough hypersensitivity syndrome will lead to further development of “pathology-specific non-specific therapeutic drugs” and provide benefits to patients with chronic refractory cough.     

112例误诊为支气管炎的老年慢性咳嗽病因分析

目的探讨老年患者慢性咳嗽的误诊及病因分布。方法基层医院误诊为支气管炎的112例老年慢性咳嗽患者,采用咳嗽诊治指南制定的诊断程序,判断病因并予针对性治疗。结果最终病因明确107例(95.54%),其中单一病因为89例(79.46%),复合病因为18例(16.07%)。老年患者病因诊断前三位为胃食管返流性咳嗽、咳嗽变异型哮喘、上气道咳嗽综合征,在女性患者和男性患者中分别占26.39%,20.83%,18.06%和29.31%,22.41%,18.97%。三者占慢性咳嗽病因的67.69%,其次是ACEI诱发的咳嗽。经特异性治疗后咳嗽明显减轻或消失为103例,有效率为91.96%,其余均为部分缓解。结论老年慢性咳嗽病因复杂常被误诊,规范慢性咳嗽病因诊断程序对提高老年慢性咳嗽诊治水平有重要意义。     

Acute and chronic cough

Individuals are generally content to self-medicate for acute cough. It is only when the cough becomes persistent that they seek medical assistance. It is not known why patients cough in association with an acute upper respiratory tract infection (URTI), although interest has focused on how viruses may influence airway sensory nerve function and contribute to heightened cough reflex sensitivity. Why some patients develop a persistent cough following a viral URTI is also unclear. Much more is known about the causes and aggravants of chronic cough although there is no broad agreement as to the best way to manage such patients. Asthma, upper gastrointestinal dysfunction and rhinitis are frequently associated with chronic cough, although the impact of cough in suppurative lung disease and interstitial lung fibrosis is rarely considered. The development of effective treatments for cough remains a challenge and will require co-operation between clinicians, scientists and the pharmaceutical industry.     

Does Idiopathic Cough Exist?

Despite a meticulous protocol involving diagnostic testing and trials of empirical therapy, there may be no obvious cause for a chronic cough in up to 42% of cases referred for specialist evaluation. In some cases, failure to consider causes that include the asthma/eosinophilic airway syndromes such as eosinophilic bronchitis and atopic cough, or nonacid gastroesophageal reflux disease may explain diagnostic failure. However, a distinct group of patients may be considered to have true idiopathic cough. Current published evidence suggests a certain patient phenotype, namely, middle-aged females with prolonged nonproductive cough and cough reflex hypersensitivity. Almost nothing else is known about this clinical entity and currently no specific therapy exists.

     

胃食管反流性咳嗽的发病机制及诊疗

胃食管反流性咳嗽为胃食管反流病的一种特殊类型,是慢性咳嗽常见病因之一.与典型胃食管反流病相比,胃食管反流性咳嗽在发病机制、诊疗方面有其特点.胃食管反流性咳嗽的发病机制可能是高位反流、低位反流和气道高敏感性等多因素共同作用的结果,诊断需结合临床表现和辅助检查建立,多通道食管腔内阻抗联合pH监测可以区分酸与非酸性反流,是有前景的诊断技术,抗反流药物治疗是目前胃食管反流性咳嗽的主要治疗方法.     

Chronic cough in adults with interstitial lung disease

PURPOSE OF REVIEW: Although dyspnea is the most common and distressing symptom in patients with chronic interstitial lung disease, chronic cough, a potentially debilitating symptom that impairs health-related quality of life, has been described as another common symptom in these patients. RECENT FINDINGS: Many patients with interstitial lung disease have their chronic cough mistakenly attributed to that condition when, in fact, the cough is due to more common disorders such as asthma, upper airway cough syndrome (previously referred to as postnasal drip syndrome), or gastroesophageal reflux disease. This article presents new data on a select group of patients and shows that more than 50% of patients with interstitial lung disease who are referred to a cough clinic for evaluation can have cough caused by these other more common causes of chronic cough. It is also clear, however, that chronic interstitial lung disease, by itself, can cause chronic cough, perhaps related to an increased cough reflex sensitivity. SUMMARY: Clinicians should be cautious when ascribing chronic cough to interstitial lung disease without first completely evaluating for other possible causes of cough. When cough is attributed to interstitial lung disease, therapy, when available, should be directed at the specific underlying diagnosis. Corticosteroids may be helpful in alleviating chronic cough in some cases of interstitial lung disease, but, because of the potential side effects of corticosteroids and lack of proven efficacy for some types of interstitial lung disease (e.g. idiopathic pulmonary fibrosis), treatment should weigh the risks and benefits for each patient individually. Nonspecific antitussive therapies shown to be clinically effective for chronic cough in general are codeine and dextromethorphan, but these have not been studied specifically in interstitial lung disease.     

Management of chronic refractory cough in adults

Cough is a common respiratory symptom that is considered to be chronic when it lasts more than eight weeks. When severe, chronic cough may significantly impact an individual's quality of life, and such patients are frequently referred for specialist evaluation. Current international guidelines provide algorithms for the management of chronic cough: in most cases, treatment of the underlying disease is sufficient to improve or resolve cough symptoms. Severe chronic cough may significantly affect patients' quality of life and necessitate frequent referral for specialist evaluations. In this narrative review, we summarize non-pharmacologic and pharmacologic management of adult patients with chronic cough of known cause that persists after proper treatment (chronic refractory cough, CRC) or chronic cough of unknown cause in adult patients. If chronic cough persists even after treatment of the underlying disease, or if the chronic cough is not attributable to any cause, then a symptomatic approach with neuromodulators may be considered, with gabapentin as the first choice, and opioids or macrolides as alternatives. Speech pathology treatment and/or neuromodulators should be discussed with patients and alternative options carefully considered, taking into account risk/benefit. Novel promising drugs are under investigation (e.g. P2×3 inhibitors), but additional studies are needed in this field. Speech pathology can be combined with a neuromodulator to give an enhanced treatment response of longer duration suggesting that non-pharmacologic treatment may play a key role in the management of CRC.     

Controversies in the evaluation and management of chronic cough

Chronic cough that cannot be explained after basic evaluation is a common reason for patients to be referred to respiratory outpatient clinics. Asthma, gastroesophageal reflux, and upper airway disorders frequently coexist with chronic cough. There is some controversy as to whether these conditions are causes or aggravants of cough. Heightened cough reflex sensitivity is an important feature in most patients. There is good evidence that it is reversible when associated with upper respiratory tract infection, angiotensin-converting enzyme inhibitor medications, and chronic cough associated with eosinophilic airway inflammation. In many patients, heightened cough reflex sensitivity is persistent and their cough is unexplained. There are few therapeutic options for patients with unexplained chronic cough. There is a pressing need to understand the genetic, molecular, and physiological basis of unexplained chronic cough and to develop novel antitussive drugs that down-regulate cough reflex sensitivity.     

Chronic cough: future directions in chronic cough: mechanisms and antitussives

Cough is an important defensive reflex of the respiratory tract needed to clear and protect the upper airways; however, it may become exaggerated and interfere with quality of life. Although chronic cough may be successfully treated when associated with the common causes such as asthma and eosinophilic bronchitis, gastrooesophageal reflux disease and post-nasal drip syndrome or rhinosinusitis, increasingly, idiopathic cough or cough with no associated cause is recognised. Chronic cough is often associated with an increased response to tussive agents such as capsaicin, used as an index of the cough reflex. Some airway receptors mediate or influence cough through activation of vagal afferent pathways which converge on brain stem respiratory networks and of supramedullary centres. Plastic changes in intrinsic and synaptic excitability at the brain stem, spinal or ganglionic level may be the mechanism by which the cough reflex is enhanced in chronic cough. Subjective and objective measurements of cough in the clinic are now available but a major unmet need in chronic cough is the availability of effective antitussives. Future directions in chronic cough include the pathophysiological mechanisms of the enhanced cough reflex, and the discovery of effective antitussives that can successfully alleviate chronic cough.     

小儿慢性咳嗽的诊断体会

目的探讨小儿慢性咳嗽的诊断方法。方法对146例慢性咳嗽患儿临床资料按年龄分婴幼儿、学龄前、学龄儿童三组进行回顾性分析。结果咳嗽变异性哮喘、反复呼吸道感染、上气道咳嗽综合征是小儿慢性咳嗽主要病因,其次为结核感染、上感后慢性咳嗽、支原体感染。不同年龄慢性咳嗽病因不尽相同,年龄越小,反复呼吸道感染所占比率越高,年龄越大,咳嗽变异型哮喘比率越高。结论小儿慢性咳嗽的病因复杂多样,除病史、体检以外,患儿年龄、针对性的辅助检查及试验性治疗的反应都能提供诊断线索。     

Eosinophilic bronchitis as a cause of chronic cough

Eosinophilic bronchitis is a recently described condition in patients with chronic cough, sputum eosinophilia, normal spirometry and no evidence of bronchial hyperreactivity. The aim of the study was to assess the causes of chronic cough and to identify the prevalence of eosinophilic bronchitis as a cause of chronic cough. Thirty-six patients [mean age 45.4 +/- 14.3 years (range 16-69 years), M/F: 4/32] with an isolated chronic cough lasting for more than 4 weeks were recruited from the outpatient clinic. In all patients, after a full history and physical examination, blood eosinophil count, eosinophilic cationic protein (ECP), serum total and specific IgE levels were measured. Spirometry, methacholine provocation test, skin prick tests, ear, nose and throat examination, induction of sputum and esophageal pH testing were performed. The mean duration of cough was 31.3 +/- 52.3 months. Sputum eosinophilia greater than 3% was present in 12 (33.3%) patients and they were diagnosed as eosinophilic bronchitis. Their induced sputum had a mean eosinophil count of 8.3% and a mean ECP level of 98.5 mg x l(-1), which were higher than the others (P=0.003, both). The diagnosis of the remaining patients were postnasal drip syndrome in eight, gastroesophageal reflux disease in eight, post-infectious cough in two and cough-variant asthma in one patient. In conclusion, eosinophilic bronchitis is an important cause of chronic cough and should be considered in the assessment of patients before regarding them as having idiopathic chronic cough.     

Eosinophilic airway disorders associated with chronic cough

Chronic cough is a major clinical problem. The causes of chronic cough can be categorized into eosinophilic and noneosinophilic disorders, the former being comprised of asthma, cough variant asthma (CVA), atopic cough (AC) and non-asthmatic eosinophilic bronchitis (NAEB).Cough is one of the major symptoms of asthma. Cough in asthma can be classified into three categories; 1) CVA: asthma presenting solely with coughing, 2) cough-predominant asthma: asthma predominantly presenting with coughing but also with dyspnea and/or wheezing, and 3) cough remaining after treatment with inhaled corticosteroid (ICS) and β2-agonists in patients with classical asthma, despite control of other symptoms. There may be two subtypes in the last category; one is cough responsive to anti-mediator drugs such as leukotriene receptor antagonists and histamine H1 receptor antagonists, and the other is cough due to co-morbid conditions such as gastroesophageal reflux.CVA is one of the commonest causes of chronic isolated cough. It shares a number of pathophysiological features with classical asthma with wheezing such as atopy, airway hyperresponsiveness (AHR), eosinophilic airway inflammation and various features of airway remodeling. One third of adult patients may develop wheezing and progress to classical asthma. As established in classical asthma, ICS is considered the first-line treatment, which improves cough and may also reduce the risk of progression to classical asthma.AC proposed by Fujimura et al. presents with bronchodilator-resistant dry cough associated with an atopic constitution. It involves eosinophilic tracheobronchitis and cough hypersensitivity and responds to ICS treatment, while lacking in AHR and variable airflow obstruction. These features are shared by non-asthmatic eosinophilic bronchitis (NAEB). However, atopic cough does not involve bronchoalveolar eosinophilia, has no evidence of airway remodeling, and rarely progresses to classical asthma, unlike CVA and NAEB. Histamine H1 antagonists are effective in atopic cough, but their efficacy in NAEB is unknown. AHR of NAEB may improve with ICS within the normal range. Taken together, NAEB significantly overlaps with atopic cough, but might also include milder cases of CVA with very modest AHR. The similarity and difference of these related entities presenting with chronic cough and characterized by airway eosinophilia will be discussed.     

Currently available cough suppressants for chronic cough

Chronic cough is a common symptom but only a fraction of patients seek medical attention. Addressing the causes of chronic cough may lead to control of cough; however, this approach is not always successful since there is a certain degree of failure even when the cause(s) of cough are adequately treated; in idiopathic cough, there is no cause to treat. Persistent cough may be associated with deterioration of quality of life, and treatment with cough suppressants is indicated. Currently available cough suppressants include the centrally acting opioids such as morphine, codeine, and dextromethorphan. Peripherally acting antitussives include moguisteine and levodropropizine. Early studies report success in reducing cough in patients with chronic bronchitis or COPD; however, a carefully conducted study showed no effect of codeine on cough of COPD. Success with these cough suppressants can be achieved at high doses that are associated with side effects. Slow-release morphine has been reported to be useful in controlling intractable cough with good tolerance to constipation and drowsiness. There have been case reports of the success of centrally acting drugs such as amitryptiline, paroxetine, gabapentin, and carbamezepine in chronic cough. New opioids such as nociceptin or antagonists of TRPV1 may turn out to be more effective. Efficacy of cough suppressants must be tested in double-blind randomised trials using validated measures of cough in patients with chronic cough not responding to specific treatments. Patients with chronic cough are in desperate need of effective antitussives that can be used either on demand or on a long-term basis.     

Currently Available Cough Suppressants for Chronic Cough

Chronic cough is a common symptom but only a fraction of patients seek medical attention. Addressing the causes of chronic cough may lead to control of cough; however, this approach is not always successful since there is a certain degree of failure even when the cause(s) of cough are adequately treated; in idiopathic cough, there is no cause to treat. Persistent cough may be associated with deterioration of quality of life, and treatment with cough suppressants is indicated. Currently available cough suppressants include the centrally acting opioids such as morphine, codeine, and dextromethorphan. Peripherally acting antitussives include moguisteine and levodropropizine. Early studies report success in reducing cough in patients with chronic bronchitis or COPD; however, a carefully conducted study showed no effect of codeine on cough of COPD. Success with these cough suppressants can be achieved at high doses that are associated with side effects. Slow-release morphine has been reported to be useful in controlling intractable cough with good tolerance to constipation and drowsiness. There have been case reports of the success of centrally acting drugs such as amitryptiline, paroxetine, gabapentin, and carbamezepine in chronic cough. New opioids such as nociceptin or antagonists of TRPV1 may turn out to be more effective. Efficacy of cough suppressants must be tested in double-blind randomised trials using validated measures of cough in patients with chronic cough not responding to specific treatments. Patients with chronic cough are in desperate need of effective antitussives that can be used either on demand or on a long-term basis.     

不同年龄慢性咳嗽患者病因分析和疗效观察

目的 探讨不同年龄慢性咳嗽患者的病因和针对性治疗的疗效.方法 258例慢性咳嗽患者分为青年组145例和中老年组113例,采用中华医学会《咳嗽的诊断与治疗指南》对其病因进行分析,根据临床表现、辅助检查和特异性治疗效果综合判断,针对慢性咳嗽的病因给予特异性治疗,停药4周后判断疗效.结果 青年组和中老年组患者中,最终病因明确...     

The current state of cough research: the clinician's perspective

Cough is one of the most common reasons for medical consultation and it is responsible for a large human and socioeconomic burden. Current guidelines provide a useful framework for cough management and summarize current knowledge of causes and optimal testing sequences and treatments of cough. However, research is needed on the role of noninvasive airway inflammation measurement in assessing etiology; optimal treatment of postinfectious cough or cough due to gastroesophageal reflux disease; protussive treatment; causes of chronic cough in immunocompromised hosts; and characteristics and management of psychogenic cough. The effects of the use or nonuse of evidence-based guidelines should be documented. An empiric, integrative approach to management of chronic cough also needs further validation.