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Uncommon Causes of Cough : ACCP Evidence-Based Clinical Practice Guidelines FREE TO VIEW

Udaya B.S. Prakash, MD, FCCP
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Correspondence to: Udaya B.S. Prakash, MD, FCCP, Pulmonary and Critical Care East-18, Mayo Building, Mayo Medical Center, Rochester, MN 55905; e-mail: prakash.udaya@mayo.edu



Chest. 2006;129(1_suppl):206S-219S. doi:10.1378/chest.129.1_suppl.206S
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Objectives: To describe the uncommon causes of cough.

Design/methodology: An English language literature search by MEDLINE citations from 1975 through 2004 was used to identify publications on uncommon pulmonary and nonpulmonary disorders in which cough was present as the major or presenting symptom in > 50% of those persons affected by the uncommon diseases.

Results: A substantial number of uncommon or rare pulmonary and nonpulmonary disorders were identified. The uncommon occurrence of these diseases made it difficult to develop a meaningful evidence-based guideline to the diagnosis and therapy of many of the uncommon causes of cough. As cough was the major or presenting symptom, it was usually initially attributed to common respiratory diseases (eg, asthma or bronchitis). As a result, a substantial time lag existed from the onset of cough to the diagnosis of the etiologic entity. Diagnostic tests limited to the respiratory system did not always provide clues to the diagnosis of uncommon causes of cough.

Conclusions: Cough is the major or presenting symptom in many uncommon pulmonary and nonpulmonary disorders. A strong index of suspicion is essential to consider and diagnose the uncommon causes of cough. The diagnosis and management of cough in patients with uncommon causes of cough is dependent on the underlying etiology.

Cough is the most common respiratory symptom encountered by clinicians. Acute cough usually resolves after the diagnosis is established and appropriate therapy is instituted. Chronic cough, defined as cough lasting for > 8 weeks, can interfere with patients’ normal daily activities and can pose a diagnostic and therapeutic dilemma to the clinician. Several publications14 have documented that a cause of chronic cough can be identified in up to 95% of cases, with most causes due to one or more of asthma, gastroesophageal reflux, and rhinitis with postnasal drip. The common etiologies of acute and chronic cough, their mechanisms, diagnostic evaluations, and treatment are discussed in other sections of this guideline.

In up to 20% of patients, the cough remains unexplained even after extensive diagnostic investigations and therapeutic trials.4 In this group of patients, in whom the cough gets labeled as idiopathic chronic cough, the challenge is to find the precise etiology or mechanism responsible for the troublesome symptom so that appropriate therapeutic measures can be initiated to relieve the cough. In patients in whom the cough remains unexplained or unresolved even after extensive diagnostic evaluations and treatment, uncommon causes should be considered. Knowledge of some of the uncommon causes of cough will help to determine the elusive etiology in a significant proportion of patients.

The uncommon occurrence of many of the disorders discussed here precludes a meaningful evidence-based analysis of the literature. For the majority of the disorders discussed below, evidence exists. However, the provision of benefits and recommendations based on the evidence is dependent directly on the ability of the clinician to diagnose the uncommon causes of cough. For inclusion in this section, the author has selected disorders in which cough was reported to be the major or presenting symptom in > 50% of patients.

Cough may present either as one of many respiratory symptoms or as the main symptom of the underlying disorder. Many nonpulmonary disorders, which are relatively common in the West, such as connective tissue diseases, are frequently associated with respiratory complications. The mechanism of cough in these clinical entities is as varied as the disorders themselves (Table 1 ). Depending on the anatomic region of the pulmonary system involved by the underlying pathologic process, the site of stimulations of the neural pathway of cough will vary. Indeed, any disorder that stimulates or irritates the cough reflex can cause cough.

Diagnosis of many of the uncommon pulmonary disorders is difficult not only because of the lack of consideration of the disorder on the part of the clinician but also because many of these entities do not readily exhibit specific or characteristic abnormalities on imaging procedures. For instance, imaging studies such as the chest roentgenogram and CT scan are of limited value in the diagnosis of large airway disorders. Flow-volume curves and direct visualization by bronchoscopy are more helpful in detecting the large airway disorders. A sufficient knowledge of these disorders, an index of suspicion on the clinicians’ part, and appropriate tests are important in confirming the diagnosis.

1. In patients with chronic cough, uncommon causes should be considered when cough persists after evaluation for common causes and when the diagnostic evaluation suggests that an uncommon cause, pulmonary as well as extrapulmonary (see Table 1), may be contributing. Level of evidence, low; benefit, substantial; grade of recommendation, B

2. In patients with chronic cough, until uncommon causes that potentially may be contributing to the patient’s cough have been ruled out, the diagnosis of unexplained cough should not be made. Level of evidence, low; benefit, substantial; grade of recommendation, B

The remaining part of this section provides a review of uncommon causes of cough in both pulmonary and nonpulmonary disorders (Table 1). This arbitrary classification is based on whether pulmonary features are the major manifestation of each discussed disorder.

Tracheomalacia and Bronchomalacia

Tracheomalacia, bronchomalacia, and tracheobronchomalacia denote flaccidity of the airways caused by structural weakness of the airway walls. The pathogenesis is the loss of cartilaginous integrity from various etiologies. Clinically, there is significant narrowing of the coronal diameter during forced expiration or cough. In adults, tracheobronchomalacia can be caused by or associated with pressure necrosis of the cartilage due to endotracheal intubation, thyroid lesions, vascular anomalies, trauma, chronic or recurrent infection of major airways (bronchiectasis), radiation therapy, relapsing polychondritis, tracheobronchomegaly, and collagen disorders, including Ehlers-Danlos syndrome, cutis laxa, and Marfan syndrome. The airway collapse seen in patients with COPD does not represent true tracheobronchomalacia.5

Cough and expiratory wheeze are the two common symptoms observed in almost all patients with airway malacia. Clinical examination, imaging procedures, and pulmonary function tests may provide clues to the presence of excessive airway collapse. During bronchoscopy in conscious patients with tracheobronchomalacia, the coronal narrowing with coughing is > 50%, compared to < 40% coronal narrowing in healthy individuals.67

The treatment options for the palliation of symptoms caused by tracheomalacia include specific therapy aimed at the etiology of tracheomalacia, and, in some instances, the relief of symptoms can be achieved by mechanical means such as surgical resection of the affected airway segment, insertion of an airway prosthesis (stent), or continuous positive-pressure breathing.811

Airway Stenosis/Strictures

The narrowing of airways is caused by both malignant and benign pathologic processes. In the evaluation of chronic cough, particularly in female patients, it is important to consider the possibility of idiopathic laryngotracheal stenosis. This is an uncommon disorder of unknown etiology characterized by slowly progressive stenosis at the level of the cricoid and upper trachea. It occurs almost exclusively in women in their third, fourth, and fifth decades who have no obvious etiology for the stenosis.1214 The main symptoms include persistent cough, dyspnea on exertion, upper airway wheezing, and stridor. Because of the gradual onset of symptoms, asthma is initially diagnosed in many patients. Other uncommon causes of benign airway stenosis include extrinsic compression from mediastinal fibrosis, bronchogenic cysts, fungal and tuberculous infections, and sarcoidosis. Evaluations and therapy should be tailored to each patient.

Tracheobronchopathia Osteochondroplastica

Tracheobronchopathia osteochondroplastica, also known as tracheopathia osteoplastica, is an uncommon benign disease of unknown etiology that is characterized by multiple cartilaginous or bony submucosal nodules that protrude into the tracheobronchial lumen and cause various respiratory symptoms.1518 The submucosal excrescences originate in the airway cartilage, sparing the posterior membranous wall. Tracheopathia osteoplastica occurs more commonly than has been reported. It is usually labeled as asthma because of chronic cough and associated wheezing. The incidence of tracheopathia osteoplastica has ranged from 1 in 125 to 1 in 6,000 patients as judged by in vivo bronchoscopies. At the Mayo Clinic, the incidence of tracheopathia osteoplastica in patients undergoing bronchoscopy has been 1 in 772 patients.,15

In one report16on 41 patients with tracheopathia osteoplastica, 54% had chronic cough and 34% exhibited sputum production. The diagnosis is usually established after lack of response to medical therapies and a diagnostic bronchoscopy is performed. The CT imaging may show multiple sessile submucosal nodules with or without calcification along the cartilaginous portion of the trachea. However, CT imaging is not sensitive in detecting milder forms of the disease. In patients with tracheopathia osteoplastica, bronchoscopic appearance alone is diagnostic of the disease. A biopsy of the airway nodules is not necessary. When performed, biopsy samples have shown histologic confirmation of heterotopic bone formation in 60% of patients.17

The severity of cough will depend on the size and number of intraluminal nodules that compromise the airway. Besides cough, other symptoms include wheezing, hoarseness, dyspnea, and hemoptysis. There is no definitive therapy for tracheopathia osteoplastica, and treatment is palliative.

Tracheobronchomegaly (Mounier-Kuhn Syndrome)

Tracheobronchomegaly is an uncommon disorder that is characterized by dilatation of the tracheobronchial tree and by recurrent bouts of bronchitis and lung infections. The etiology is unknown, although tracheobronchomegaly has been observed in patients with Ehlers-Danlos syndrome, generalized elastolysis, Marfanoid condition, or ankylosing spondylitis.

Both the airway cartilage and membranous portions of the major airways are affected. Many patients with tracheobronchomegaly, particularly men in their third and fourth decades of life, present with symptoms of obstructive airway disease. End-stage bronchiectasis is the result in those with recurrent infections. Chronic cough is the major symptom in this disorder. Cough may be associated with sputum production if the disorder is complicated by an acute infection or chronic bronchiectasis.

Chest radiographs may reveal the diagnosis by demonstrating significantly widened tracheal air bronchograms.19 Tracheobronchial diverticula occur in some patients and can be demonstrated by CT scan or MRI. Bronchoscopy can reveal the easy collapsibility, large airways, and diverticula.

Tracheobronchial Amyloidosis

Tracheobronchial amyloidosis is an idiopathic localized disorder that is characterized by the deposition of fibrillar proteins in the tracheobronchial tree.2021 This form of amyloidosis is considered to be a separate entity compared to the more common form of systemic amyloidosis known as primary idiopathic amyloidosis or amyloid light-chain amyloidosis. Primary amyloid may manifest diversely with heart failure, renal failure, or neuropathy. In contrast, tracheobronchial amyloidosis is limited to the airways. There are sporadic case descriptions of tracheobronchial amyloidosis associated with amyloid deposition in other organs.

The deposition of amyloid in the airway submucosa is slow and gradual. The average age of the patients at the time diagnosis is 55 years, with slight male predominance. The main symptom is cough, and when it is associated with wheezing, asthma is diagnosed in most patients. Hemoptysis is present in almost all patients, and this is the symptom that eventually warrants bronchoscopy and biopsy for the diagnosis of amyloidosis.2022

Bronchoscopic visualization usually reveals a diffuse submucosal infiltrative process in the trachea and bronchi. The appearance can be mistaken for diffuse neoplastic process because of nodular, tumor-like, or polypoid appearance. A biopsy of airway lesions is diagnostic.20

Tracheobronchial amyloidosis has been treated by local therapy (eg, bronchoscopic debulking and laser ablation) and systemic chemotherapy, and even by radiation therapy. However, the recurrence of disease is the rule. Bronchoscopic debulking resections have been successful in some patients, and repeat treatments are often required.23

Airway Foreign Bodies

Cough is usually the first symptom and has abrupt onset in almost all subjects who aspirate foreign bodies into their airways.24A witnessed aspiration of a foreign body is usually handled emergently by the patient or relatives (if the patient is a child) and physicians. In this situation, prompt removal of the foreign body results in the abatement of cough. In contrast, an unwitnessed or unsuspected aspiration may lead to chronic persistent cough as a result of prolonged retention of a foreign body in the airways. Cough is usually persistent and harsh. Other symptoms such as wheezing, fever, postobstructive atelectasis and infection, and hemoptysis may follow if complications develop at the site of foreign body impaction. A radiopaque foreign body should be readily detectable on the chest roentgenogram. The chest roentgenogram findings are normal in up to 30% of patients with acute foreign body aspirations.25

In pediatric patients, any acute or persistent cough should raise the index of suspicion regarding the possibility of an airway foreign body.26Unless an obvious cause for the cough is readily discernible, bronchoscopic examination is recommended. In adults who develop cough because of chronic foreign body retention, the diagnosis is seldom considered. Obtaining historical details of cough, appropriate imaging procedures, and ultimately a bronchoscopic examination will lead to the correct diagnosis and treatment.27

Broncholithiasis

Broncholiths are calcified peribronchial lymph nodes that encroach on adjacent airways and cause clinical and roentgenographic abnormalities.28 Most broncholiths are a sequelae of fungal or mycobacterial granulomatous lymphadenitis. Calcified hilar and mediastinal lymph nodes are common findings on chest imaging. However, these normally do not produce respiratory symptoms. Respiratory symptoms develop when the calcified lymph node impinges on or erodes into the airway lumen. Cough, sometimes abrupt in onset and usually harsh, is present in almost all patients. This may be associated with hemoptysis, expectoration of a broncholith (lithoptysis), recurrent pneumonia, and fistulas between the bronchi and adjacent mediastinal structures.

Broncholithiasis is rarely considered in patients with chronic cough. The presence of calcified structures in perihilar areas or in the vicinity of bronchi as seen in images obtained with various techniques is an indication of broncholithiasis as the potential etiology of cough. In the absence of confirmed lithoptysis, bronchoscopy is the most definitive diagnostic test to identify broncholithiasis. Bronchoscopy is also useful in the treatment of broncholithiasis. One study28 of 127 broncholiths in 95 patients documented that 48% of the partially eroding broncholiths and all free broncholiths were successfully removed bronchoscopically. Complications of bronchoscopic extraction in two patients with partially eroded broncholiths included hemorrhage in one patient, requiring thoracotomy, and transient dyspnea in another patient due to a loose broncholith that was lodged in the trachea.28

3. If cough persists after consideration of the most common causes, perform a CT scan and, if necessary, a bronchoscopic evaluation. Level of evidence, low; benefit, substantial; grade of recommendation, B

4. In patients who present with abrupt onset of cough, consider the possibility of an airway foreign body. Level of evidence, low; benefit, substantial; grade of recommendation, B

Lymphangioleiomyomatosis

Lymphangioleiomyomatosis is an uncommon disease of unknown etiology that usually affects women of reproductive age. The pulmonary pathology consists of the proliferation of immature-appearing smooth muscle cells in the lungs and lymphatics in the thorax, and the development of thin-walled pulmonary cysts. The clinical respiratory manifestations are caused by the compression of the smaller airways, blood vessels, and lymphatics by the proliferating smooth muscle cells. Airway obstruction leads to the progressive obstruction of airflow, air-trapping, alveolar disruption, and the formation of pulmonary cysts.2931 Similar pathologic changes also occur in patients with tuberous sclerosis. A literature review32 of 183 articles citing a total of 445 cases of lymphangioleiomyomatosis observed that 83 had tuberous sclerosis, 69 did not, and in 293 patients it was not clear whether tuberous sclerosis was present or excluded.

The clinical characteristics of lymphangioleiomyomatosis include slowly progressive dyspnea, cough, hemoptysis, chylothorax, and spontaneous pneumothorax. Frequent cough was reported in 66% of 35 patients.31A literature review32 of a subgroup of 152 patients with lymphangioleiomyomatosis observed cough in 30% of patients. Hemoptysis occurs in 20% of patients. Diagnosis is based on clinical features, imaging procedure findings, and lung biopsy.

The management of lymphangioleiomyomatosis has included treatment of pneumothorax, chylothorax, and hormonal manipulation. In most patients, however, the response to medical therapy is less than satisfactory. A successful lung transplantation is the more definitive therapy in advanced or progressive cases.

Pulmonary Langerhans Cell Histiocytosis

Pulmonary Langerhans cell histiocytosis is an uncommon interstitial lung disease (ILD) that is part of the spectrum of disorders called Langerhans cell histiocytoses. The hallmark of the disease is the proliferation of specific histiocytic cells, known as Langerhans cells, and their infiltration of pulmonary and other organ systems.3335 An association between the disorder and tobacco smoking has been observed.

In patients with both single-organ or multisystem Langerhans cell histiocytosis, the most common affected site is the lung.36Cough is the most common and major symptom in pulmonary Langerhans cell histiocytosis. Cough and dyspnea develop in over two thirds of patients.37In one report38on 102 patients with the disorder, cough was noted in 50%, dyspnea was noted in 38%, and no symptoms were noted in 15%. The cough is usually dry, and hemoptysis is rare. Spontaneous pneumothorax is a well-known complication of pulmonary Langerhans cell histiocytosis.39

The accumulation of Langerhans cells in the pulmonary parenchyma leads to chest roentgenographic abnormalities including micronodular or reticulonodular and interstitial infiltration, with a predominance of middle-lobe and upper-lobe involvement bilaterally. Cystic changes occur in later stages, with some cysts coalescing and producing a cavitated appearance. CT scans exhibit characteristic peribronchiolar nodular infiltrates combined with irregularly shaped cystic spaces.33

Pulmonary Langerhans cell histiocytosis can be diagnosed on the basis of clinical features and typical radiographic features. In doubtful cases, the results of BAL can be diagnostic if the proportion of CD1a-stained cells is > 5%. Bronchoscopic or surgical lung biopsy are definitive.38,40

Treatments have included systemic corticosteroids, chemotherapeutic drugs, and lung transplantation. The cessation of tobacco smoking is important. The course of pulmonary Langerhans cell histiocytosis in adults is variable and unpredictable, ranging from an asymptomatic radiographic presentation to progressive respiratory failure. If the disease responds to the treatment, the cough may also decrease or subside.38,40

Pulmonary Alveolar Proteinosis

Pulmonary alveolar phospholipoproteinosis is an uncommon diffuse lung disease that is characterized by the accumulation of excessive amounts of a phospholipoproteinaceous material in the alveoli.4143 Primary and secondary forms of the disorder exist, but clinically they are difficult to differentiate. Many patients with the disorder are active smokers. Deficiency of granulocyte-macrophage colony-stimulating factor is thought to be responsible for the pathogenesis. This leads to excessive production of surfactant and/or diminished clearance of surfactant by alveolar macrophages. Histology of the affected lung reveals alveolar filling by a granular lipoproteinaceous substance that stains a deep pink with periodic acid-Schiff stain.

Over 80% of cases are encountered in patients who are in the third or fourth decade of life. Clinically, nearly one third are asymptomatic or minimally symptomatic. In others, the illness is characterized by an initial febrile episode, followed by cough and progressive dyspnea. Dyspnea is the most common presenting symptom. Cough that is minimally productive of sputum is also common. Hemoptysis is rare.

The chest roentgenogram reveals bilateral, usually asymmetric, patchy airspace consolidation, more pronounced in the lower two thirds of the lungs. In advanced cases, a dense alveolar pattern is seen (known as bat’s wing pattern or reverse pulmonary edema pattern). A high-resolution CT (HRCT) scan of the chest may show a “crazy paving” pattern caused by airspace consolidation and thickened interlobular septae. Pulmonary function test results normally reveal a restrictive dysfunction with reduced carbon monoxide diffusion capacity. BAL effluent yields sandy-colored or light-brown fluid from an affected segment. A bronchoscopic or surgical lung biopsy is diagnostic.

Treatment is not indicated in all patients because spontaneous improvement is observed in 30% of cases. The cessation of smoking may help to hasten resolution of the cough. Currently, the treatment of choice is a whole-lung lavage using a normal saline solution. Some patients require repeated lavages at intervals of several weeks to months. The administration of granulocyte-macrophage colony-stimulating factor has been reported to be effective, and this therapy remains experimental. Lung transplantation has been performed in patients with progressive respiratory failure.

Pulmonary Alveolar Microlithiasis

Pulmonary alveolar microlithiasis is a rare, often familial (autosomal-recessive) disorder of unknown etiology, which is characterized by a roentgenographic appearance of very fine, sand-like mottling uniformly distributed through both lungs that is caused by extensive intraalveolar deposition of microliths (calcispherites) that measure 0.01 to 3.0 mm in diameter.4445 Microliths are made up of calcium phosphate. In late stages, fibrosis and apical blebs/bullae and cysts are seen.

Among the approximately 400 cases described in the literature,44 the mean age at diagnosis has been 35 years. Many patients are asymptomatic. Dyspnea is a major complaint in advanced cases. Mild-to-moderate cough is present in 40 to 50% of patients. Occasionally, patients cough up sand-like particles. Cor pulmonale may be seen in progressive cases. The diagnosis is considered when an incidental chest roentgenogram reveals the distinct sand-like diffuse microndularity. An HRCT scan of the chest will confirm dense calcification of the lung parenchyma. A radionuclide scan of the lungs using 99mTc diphosphonate will demonstrate significant uptake of the radionuclide into the lungs. There is no known therapy.

Miscellaneous

Upper airway disorders including supraglottic pathology should be excluded in the evaluation of otherwise unexplained chronic cough. A study46of eight consecutive patients with unexplained chronic cough and enlarged tonsils observed that cough and cough reflex sensitivity improved after tonsillectomy. Tonsillar hypertrophy and an unusually long uvula are among the uncommon causes of chronic cough in children.47 In children with cough, it is essential to exclude congenital anomalies including tracheal cartilaginous sleeve, “hourglass trachea,” Williams-Campbell syndrome (ie, the deficiency of airway cartilage), tracheoesophageal fistula, and other abnormalities.

Connective Tissue Disorders

Connective tissue disorders include rheumatoid arthritis, systemic lupus erythematosus (SLE), scleroderma, Sjögren syndrome, mixed connective tissue disease, relapsing polychondritis, and ankylosing spondylitis. Any anatomic location of the respiratory system can be affected by these diseases. Alveolar and/or interstitial inflammation and ILD is a major manifestation of several of these diseases. Scleroderma and rheumatoid arthritis are two of the disorders in which ILD is more commonly observed. SLE is an uncommon cause of ILD. The pathogenesis of pulmonary parenchymal involvement is secondary to lymphocytic alveolitis. Bronchoalveolar lymphocytosis has been demonstrated in patients with lung diseases caused by rheumatoid arthritis, Sjögren syndrome, and scleroderma.4849

Chronic cough is a frequent respiratory manifestation in many autoimmune and collagen disorders. This can be the result of any of the several intrathoracic complications of these diseases. However, it is important to recognize that the only indication of the thoracic manifestation being the cause of cough is when cough resolves with the disappearance of pulmonary complications of these disorders. The following paragraphs provide brief descriptions of the more important collagenoses.

Relapsing Polychondritis

Relapsing polychondritis is an uncommon autoimmune disorder that is caused by recurrent inflammation and the widespread destruction of cartilage and other connective tissues. Pathologic findings in patients with relapsing polychondritis include perichondral inflammation, and cartilaginous fragmentation and destruction with replacement by fibrosis.10 The disease exhibits an equal male/female ratio, and the mean age at diagnosis is 51 years. The most common symptoms include swelling and erythema of the ears (88%) and arthralgias (81%).50A relapsing course is seen in 86% of patients, and continuous symptoms are seen in 14%.51

Airway involvement is among the most serious manifestations of relapsing polychondritis. Chondritis of the respiratory tract is responsible for many of the pulmonary complications. All locations of respiratory cartilage can be involved, including those in the external nares, nasal septal turbinates, eustachian tubes, epiglottis, larynx, thyroid, cricoid, arytenoid, trachea, and bronchi. The respiratory system is affected in > 50% of patients with relapsing polychondritis, and pulmonary symptoms are the presenting features in up to 25% of patients.10,5051 Persistent or chronic cough is one of the first and important symptoms, and may signify respiratory involvement. Other pulmonary symptoms and signs include wheezing, stridor, dyspnea, hoarseness or aphonia, and tenderness over the laryngotracheal cartilage.

Patients who are suspected to have relapsing polychondritis should undergo pulmonary function tests, including the determination of inspiratory and expiratory flow-volume curves, to identify clinically subtle airway involvement. A chest radiograph is usually unhelpful in the diagnosis. CT scanning may reveal thickening and stenosis of the tracheobronchial wall. CT scanning may also show collapse and calcification of the cartilage, and bronchiectasis. The pulmonary parenchyma is uninvolved. In the late stages of the disease, bronchiectasis can be seen. While bronchoscopy is not always required in patients with relapsing polychondritis, bronchoscopic findings may include inflammation, collapse and stenosis of the larynx, trachea, and/or bronchi. Bronchoscopy is not required for the diagnosis because the findings are not diagnostic of the disease.5254

Therapy for relapsing polychondritis has consisted of salicylates, nonsteroidal antiinflammatory drugs, corticosteroids, and cytotoxic agents. Patients with acute cases exhibit a good response to therapy. Respiratory involvement usually requires the long-term use of systemic corticosteroids and other immunosuppressants. Mortality is frequently related to respiratory complications.5253

Scleroderma

Scleroderma or systemic sclerosis is complicated by respiratory involvement in up to 85% of patients.5557 The major pulmonary manifestations of scleroderma include ILD, pulmonary hypertension, and aspiration caused by esophageal involvement by scleroderma. Nonproductive cough of varying severity is a frequent symptom in those patients with ILD and aspiration. Increased sensitivity of the cough reflex has been reported in patients with scleroderma and ILD. One study58 examined the cough reflex in patients with scleroderma, with and without associated ILD, by subjecting patients to inhaled chloride-deficient solutions and capsaicin. Patients with scleroderma-associated ILD reported a significantly higher cough score than scleroderma patients without ILD.58 Diagnostic and therapeutic approaches to pulmonary problems are dictated by the severity of respiratory symptoms.

Rheumatoid Arthritis

Rheumatoid arthritis is associated with several pulmonary complications, among which the more common are bronchiolitis, ILD, alveolitis, fibrosis, lung nodules, and pleural effusion.48,5961 Cough can be caused by any of the respiratory complications. However, diffuse lung diseases are more commonly manifested by cough. As in patients with scleroderma, diagnostic and therapeutic approaches to cough associated with rheumatoid arthritis are dependent on the underlying lung diseases.

SLE

SLE is also associated with many respiratory complications including pleural effusion, pleuritis, plate-like atelectasis, alveolar hemorrhage, nonspecific ILD, diaphragmatic weakness, “shrinking lung syndrome,” and the rare “lupus lung.”6263 Diffuse ILD is uncommon in patients with lupus. Cough is usually experienced by most patients in whom respiratory complications develop from lupus. The diagnostic and treatment approaches are similar to those noted above in patients with scleroderma and rheumatoid arthritis.

Sjögren Syndrome

Sjögren syndrome is a chronic inflammatory and autoimmune disorder that is characterized by decreased lacrimal and salivary gland secretion (sicca complex), resulting in keratoconjunctivitis sicca and xerostomia.6465 The sicca complex frequently develops in patients with other connective tissue diseases (eg, rheumatoid arthritis, SLE, scleroderma, and polymyositis). Sjögren syndrome also exists as a primary clinical entity with no associated disorder. The main symptoms include xerophthalmia and xerostomia.

Pulmonary complications are seen in both primary and secondary forms of Sjögren syndrome and are reported to occur in approximately 10% of patients. Pulmonary manifestations include diffuse interstitial pneumonitis, desiccation of the upper respiratory tract (xerotrachea), obstructive process involving both large and small airways, localized infiltrates, discoid atelectasis, recurrent tracheobronchitis, and bronchiectasis.

Cough is observed in > 50% of patients with Sjögren syndrome and is the most common pulmonary symptom.66The pathogenesis of cough is partly related to the drying of the mucosa in the upper airways, including the trachea (xerotrachea).67One mechanism of cough in patients with Sjögren syndrome is the presence of bronchial hyperreactivity. A prospective study68of 21 patients with Sjögren syndrome demonstrated slight-to-severe bronchial hyperreactivity to methacholine challenge in 60% of patients, and 83% in this group had a nonproductive cough. The bronchial hyperreactivity is theorized to be the result of lymphocytic inflammation leading to bronchial gland dysfunction.69 If other respiratory manifestations are present, there may be more than one pathogenic mechanism for the harsh cough observed in these patients. A majority of patients with cough and Sjögren syndrome have normal chest roentgenogram findings.6667 Treatment is symptomatic in patients with primary Sjögren syndrome and is disease-specific in those with secondary Sjögren syndrome. The role of long-term steroid therapy to treat cough in this group of patients is unclear.

Other Autoimmune Disorders

Studies7071 have reported the association of “idiopathic chronic cough” with organ-specific autoimmune diseases. A case-control study71 reported that patients with idiopathic chronic cough are predominantly female (77%) and are eight times more likely to have an organ-specific autoimmune disease, particularly hypothyroidism. These studies70have also suggested that idiopathic chronic cough is associated with lymphocytic airway inflammation. These authors71have suggested that the idiopathic chronic cough might be caused by lymphocyte homing from the primary site of autoimmune inflammation or the result of an autoimmune process in the respiratory system itself. Similar mechanisms may be responsible for the lymphocytic airway inflammation and bronchoalveolar lymphocytosis seen in some patients with inflammatory bowel disease (see below).7273 It is of interest to note that patients who have been treated for hypothyroidism and inflammatory bowel disease have increased prevalence of respiratory symptoms compared with control subjects, and that the profile of symptoms reported is remarkably similar.

It is important to recognize that chronic cough can be the result of bronchoalveolar lymphocytosis without physiologic and radiologic changes. Successful therapy of the underlying primary disorder usually resolves the unexplained chronic cough associated with BAL fluid lymphocytosis. Systemic corticosteroid therapy alone may not resolve chronic cough secondary to bronchoalveolar lymphocytosis unless the primary causative disorder is successfully treated.

Whether lymphocytic bronchitis is a distinct entity is also debatable. The prevailing literature suggests that lymphocytic infiltration of airways is seen in many well-defined and unclassified autoimmune disorders, as discussed above. Indeed, isolated aggregations of lymphoid cells have been found in the distal airways of nonsmokers, smokers, and asthmatic patients.74 It is unclear whether such aggregations of lymphocytes contribute to or result from persistent airway inflammation.

Chronic cough has been reported as a presenting feature of thyroiditis in two patients.75In both patients, the cough improved following treatment of the inflammatory thyroid disorder, and the cough was thought to be due to a local irritative effect of the inflamed thyroid. Thyroid-related upper airway obstruction due to tracheomalacia, extrinsic compression by goiter, and/or tracheal ingrowth by thyroid malignancy may also cause cough.76

Vasculitides

This group of systemic disorders, in which the respiratory system is frequently affected, includes giant cell arteritis, Wegener granulomatosis, Churg-Strauss syndrome, Behçet disease, hypocomplementemic urticarial vasculitis, microscopic polyangiitis, pulmonary capillaritis, and Takayasu arteritis. Among these, giant cell arteritis and Wegener granulomatosis are important entities for consideration in the uncommon etiologies of chronic cough.

Giant Cell Arteritis

Giant cell arteritis, also known as temporal arteritis, cranial arteritis, and granulomatous arteritis, is the most common systemic vasculitis in North America. Giant cell arteritis usually develops in persons > 50 years of age, and usually involves the arteries supplying the extracranial structures of the head, neck, and upper extremities.77The illness manifests gradually, with nonspecific systemic symptoms such as low-grade fever, malaise, and weight loss. Headache, often severe, is the most common symptom. Other symptoms include amaurosis fugax in 20% and visual loss in 10%. Moderate elevation of the erythrocyte sedimentation rate is common. The diagnosis of giant cell arteritis is established by biopsy of the temporal artery. However, the diagnostic sensitivity of biopsy varies from 67 to 97%, and the performance of bilateral biopsies increases the yield by an additional 5 to 10%.78

Respiratory involvement in patients with giant cell arteritis occurs in < 10% of cases and may precede the diagnosis of giant cell arteritis.7980 Chronic cough is the most frequent respiratory symptom of giant cell arteritis, is typically harsh and nonproductive, and may be associated with sore throat, hoarseness, and tenderness of the cervical structures.7980 The mechanism of cough in patients with giant cell arteritis is unknown. Other observed respiratory complications such as isolated small airways disease, lung nodules, interstitial infiltrates, vasculitis of pulmonary artery, and ill-defined granulomas within the bronchial wall and alveolar interstitium may contribute to the origin of cough. However, the majority of patients with giant cell arteritis presenting with cough do not exhibit other pulmonary manifestations. Troublesome cough of “unknown etiology” and headaches in persons > 50 years of age should raise the possibility of giant cell arteritis.

Prednisone therapy dramatically diminishes the symptoms of giant cell arteritis, including the resolution of the harsh cough and other respiratory manifestations. The usual initial dosage of prednisone is 40 to 60 mg/d. The duration of therapy will depend on the response of ocular and other symptoms.81

Wegener Granulomatosis

Wegener granulomatosis is a distinct systemic vasculitis that is characterized by necrotizing granulomatous vasculitis of the upper and lower respiratory tract, glomerulonephritis, and variable degrees of small-vessel vasculitis involving arteries and veins.8283 The Wegener triad consists of necrotizing granulomas of the upper and/or lower respiratory tract, generalized focal necrotizing vasculitis of arteries and veins in the lungs, and glomerulonephritis.

The lower respiratory tract is involved in > 90% of patients. Cough and hemoptysis (in > 95% of patients) are the major symptoms.82,84 The clinical presentation varies from subacute nonspecific respiratory illness to rapidly progressive respiratory insufficiency. Respiratory symptoms are usually associated with chest radiographic abnormalities, which include unilateral or bilateral infiltrates, nodules, and cavitation. Diffuse alveolar infiltrates may indicate alveolar hemorrhage.

Tracheobronchial stenosis occurs in 15% of patients. Subglottic stenosis has been described in 5 to 23% of treated patients. Benign-appearing stenoses are more likely in patients with chronic cases and in patients with the disease whose conditions are stable. The symptoms are insidious in patients in whom airway stenosis develops.8485 Persistent cough, followed by wheezing and dyspnea, may be initially diagnosed as asthma. Abnormal inspiratory and expiratory flow-volume loops may lead to further diagnostic tests, eventually culminating in the diagnosis.

Wegener granulomatosis is initially treated with a combination of systemic corticosteroids and cyclophosphamide. Complete remission is achieved in > 90% of patients; the median time to achieve remission is 12 months. Stenoses of large airways may require bronchoscopic interventions, including dilation by rigid bronchoscope, flexible bronchoscopic balloon dilatation, YAG laser treatment, placement of silicone airway stents, and surgical intervention.8687

Tracheoesophageal Fistula

Tracheoesophageal and bronchoesophageal fistulas usually produce cough immediately following the swallowing of liquids. This symptom along with a history of esophageal surgery, esophageal cancer, or radiation therapy involving the esophagus should raise the possibility of fistula between the airways and the esophagus.8889

Inflammatory Bowel Diseases

Pulmonary complications of inflammatory bowel disease have been well-described. One report90in 2003 summarized the published experience of > 400 cases of pulmonary manifestations of inflammatory bowel disease. Ulcerative colitis is more likely than Crohn disease to cause respiratory complications. Ulcerative colitis is well-known to be associated with pulmonary complications including bronchitis, bronchiectasis, bronchiolitis, nodular lung lesions, and pulmonary vasculitis.9194 These pathologic features are separate from ILD due to sulfasalazine or mesalamine that has been used to treat the primary disease.91 The data from an ongoing registry containing 33 patients with cases of ulcerative colitis or, less often, Crohn disease reported that in several cases, the correct diagnosis and the relation of pulmonary disease to inflammatory bowel disease had not been established for many years.91 In the majority of the patients (28 of 33 patients), pulmonary features followed the onset of inflammatory bowel disease and in the remainder, pulmonary manifestations preceded those of inflammatory bowel disease. Respiratory complications included subglottic stenosis, chronic bronchitis, bronchiectasis, and chronic bronchiolitis. Histologic analysis revealed varied patterns of ILD, mainly bronchiolitis obliterans with organizing pneumonia, pulmonary infiltrates and eosinophilia, and neutrophilic necrotic parenchymal nodules. Systemic corticosteroid therapy resulted in marked improvement in patients with ILD and necrotic nodules, but was not as effective in the resolution of severe airway inflammation or chronic bronchiolitis.91 An interesting finding in this study was that respiratory problems developed postcolectomy in 8 of the 28 patients. This observation stresses the importance of considering the relationship between an unexplained cough and a “treated” nonpulmonary disorder.

Crohn disease is a less well-known cause of respiratory pathology. In a series of 11 patients with Crohn disease, cough was among the presenting symptoms in six patients. Radiologic studies showed bilateral diffuse infiltrates, lung nodules, and “ground-glass” infiltrates. Lung biopsy specimens in these 11 patients revealed chronic bronchiolitis with nonnecrotizing granulomatous inflammation, acute bronchiolitis associated with a neutrophil-rich bronchopneumonia and vague granulomatous features, cellular interstitial pneumonia with rare giant cells, and organizing pneumonia with focal granulomatous features. Four of the patients were receiving therapy with mesalamine, a known cause of pulmonary toxicity.95This publication also identified descriptions in the literature of another 14 patients with similar pulmonary findings. The variable histologic appearances in these 25 patients were similar to those encountered in patients with ulcerative colitis. A prospective, controlled study of 23 patients with ulcerative colitis, 13 patients with Crohn disease, and 14 control subjects observed pulmonary function abnormality in 21 of 36 patients, whereas HRCT scanning demonstrated air-trapping, fibrosis, emphysema, bronchiectasis, and alveolitis in 19 patients. Even though nearly 80% of the patients with respiratory involvement had active bowel disease, one third of the patients with pulmonary function abnormality and 42% of the patients with radiologic abnormalities had no respiratory symptoms.96 Many of the drugs used to treat inflammatory bowel diseases are known to cause cough by affecting the respiratory system.90,95 In addition to inflammatory bowel disease, chronic cough has also been reported as the presenting manifestation of celiac disease.67

Miscellaneous

Drug-induced cough is an important cause to consider in patients with chronic unexplained cough.97 In the absence of abnormalities seen on diagnostic imaging procedures, many cases of drug-induced or iatrogenic lung diseases are misdiagnosed or are not considered in the differential diagnosis when clinicians encounter patients with chronic cough. Chronic dry cough in the absence of chest-imaging abnormalities is typical of the following drugs: angiotensin-converting enzyme inhibitors; inhaled medications; mycophenolate mofetil; nitrofurantoin; propofol; and beta-blockers. Along with the dry cough, bronchospasm is sometimes observed in patients who receive therapy with these drugs. Bronchospasm with or without cough is also caused by aspirin, nonsteroidal antiinflammatory drugs, beta-blockers, antibiotics (eg, amphotericin, erythromycin, sulfonamides, and aminoglycosides), chemotherapeutic agents, and others.,97The mechanism of cough associated with drug-induced infiltrative pulmonary disease is most likely the infiltrative disorder itself.98100 The management of drug-induced cough includes the consideration of other causes and the cessation of therapy with the alleged drug to see whether the cough resolves.

5. In patients with unexplained cough, evaluate the possibility of drug-induced cough. Level of evidence, low; benefit, substantial; grade of recommendation, B

6. In patients with unexplained cough, consider a therapeutic trial of withdrawing the drug that is suspected to cause the cough. Level of evidence, low; benefit, substantial; grade of recommendation, B

Cough developing in patients with previous lung surgery has many common and uncommon etiologic possibilities. Among the very uncommon causes is the presence of endobronchial sutures that irritate the airway mucosa and cause cough. The sutures can be metallic or nonmetallic. Normally, the exposed loose sutures lead to cough. Associated granulation tissue also contributes to the cough. Bronchoscopy is the most important diagnostic test to exclude not only recurrent disease but also to rule out the possibility of loose sutures as the cause of cough. Bronchoscopic removal of exposed loose sutures almost always alleviates the cough.101104

Mediastinal lesions may impinge on the adjacent airways and lead to chronic cough. Indeed, cough is among the prominent symptoms in patients with mediastinal masses. However, cough as the main or sole manifestation of a mediastinal lesion is unusual. The mediastinal lesions that led to cough as the sole or main manifestation of the underlying disorder have included esophageal cysts and tumors, Hodgkin lymphoma, and mediastinal lipomatosis.105108 Neuromas and neurilemmomas of the vagus nerve and internal laryngeal nerve have been described as the primary causes of severe or significant cough.109110

Vocal cord dysfunction, whether primary or secondary, can be the cause of chronic cough. Paradoxic adduction, vocal cord palsy, paradoxic vocal fold motion, and vocal cord dysfunction caused by external irritants have been described111114 as the major etiologic factors of chronic cough.

Ear problems, especially when the underlying pathology affects anatomic regions supplied by Arnold nerve, a branch of the vagus, can lead to chronic irritating cough.115117 A clinicoanatomic study118 of the auricular branch of the vagus nerve and the Arnold ear-cough reflex in 514 patients reported that the frequency of the ear-cough reflex was 2.3%, and it was bilateral in 0.6%.

Pulmonary edema, whether cardiogenic or noncardiogenic, has the potential to cause cough. Occasionally, cough can be the sole presenting manifestation of congestive heart failure.119

Among the uncommon causes of cough is the common clinical problem of pulmonary embolism. It is not often appreciated that cough develops in nearly half of the patients with documented pulmonary embolism and that can cough occasionally be the presenting complaint.120

High-altitude exposure is a well-known cause of paroxysmal cough in climbers. Dry cough is experienced by 40 to 60% of mountaineers.121122 A well-known cause of cough in these subjects is high-altitude pulmonary edema.123A less recognized mechanism is the increase in cough and cough-receptor sensitivity at altitude. A study124 that monitored cough frequency in 10 subjects observed that the cough frequency increased from no cough at sea level to a median of 5 coughs at 5,000 m and to > 60 coughs in subjects ascending to 7,000 m. Additionally, in 42 subjects, the cough-receptor sensitivity to inhaled citric acid also increased at 5,300 m compared with that at sea level. The cough threshold was unrelated to acute mountain sickness, oxygen saturation, carbon dioxide tension, or lung function.124A similar study125 of eight subjects at a simulated altitude of 8,848 m observed increased frequency of coughing and cough-receptor sensitivity with increasing altitude. Because the temperature and humidity were controlled in the simulation chamber, the thesis that cold dry air may be responsible for the cough was refuted.125 While the precise mechanism of increased cough and cough-receptor sensitivity at altitude is unclear, the potential causes include subclinical pulmonary edema, high-altitude pharyngitis/bronchitis, postnasal drainage from altitude-induced vasomotor rhinitis, coryza, infections, or other as-yet-unknown mechanisms.121,126Severe altitude-induced cough has resulted in multiple cough-induced stress fractures, prompting addition of the term high altitude cough syndrome to the medical syntax.127

Tourette syndrome is a relatively common, biological, genetic neurobehavioral disorder with clinical manifestations that wax and wane. Tics, the clinical hallmark of this disorder, consist of brief, intermittent, involuntary or semivoluntary movements or sounds. Chronic repetitive coughing encountered in these patients is a form of simple phonic tic.128Chronic cough as the presenting manifestation of Tourette syndrome has been described in a patient.129

High cervical ossification of the ligamentum flavum following a traffic accident and leading to an intractable cough has been described in a patient.130 The cough subsided immediately after decompressive laminectomy was performed for the removal of the ossified lesion.130

The importance of gastroesophageal aspiration in the etiology of cough is discussed elsewhere in this guideline. Neoplastic lesions of the esophagus can cause extrinsic compression on the airways and can lead to persistent cough.

1. In patients with chronic cough, uncommon causes should be considered when cough persists after evaluation for common causes and when the diagnostic evaluation suggests that an uncommon cause, pulmonary as well as extrapulmonary (see Table 1), may be contributing. Level of evidence, low; benefit, substantial; grade of recommendation, B

2. In patients with chronic cough, until uncommon causes that potentially may be contributing to the patient’s cough have been ruled out, the diagnosis of unexplained cough should not be made. Level of evidence, low; benefit, substantial; grade of recommendation, B

3. If cough persists after consideration of the most common causes, perform a CT scan and, if necessary, a bronchoscopic evaluation. Level of evidence, low; benefit, substantial; grade of recommendation, B

4. In patients who present with abrupt onset of cough, consider the possibility of an airway foreign body. Level of evidence, low; benefit, substantial; grade of recommendation, B

5. In patients with unexplained cough, evaluate the possibility of drug-induced cough. Level of evidence, low; benefit, substantial; grade of recommendation, B

6. In patients with unexplained cough, consider a therapeutic trial of withdrawing the drug that is suspected to cause the cough. Level of evidence, low; benefit, substantial; grade of recommendation, B

Abbreviations: HRCT = high-resolution CT; ILD = interstitial lung disease; SLE = systemic lupus erythematosus

Table Graphic Jump Location
Table 1. Uncommon Causes of Cough*
* 

WG = Wegener granulomatosis; GCA = giant cell arteritis (temporal arteritis); RPC = relapsing polychondritis.

 

Conditions in which cough is a major symptom (present in > 50% of patients) or a presenting symptom.

 

These include rheumatoid arthritis, systemic lupus erythematosus, scleroderma, Sjögren syndrome, mixed connective tissue disease, relapsing polychondritis.

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Newman, KB, Mason, UG, 3rd, Schmaling, KB Clinical features of vocal cord dysfunction.Am J Respir Crit Care Med1995;152,1382-1386
 
Perkner, JJ, Fennelly, KP, Balkissoon, R, et al Irritant-associated vocal cord dysfunction.J Occup Environ Med1998;40,136-143
 
Feldman, JI, Woodworth, WF Cause for intractable chronic cough: Arnold’s nerve [letter].Arch Otolaryngol Head Neck Surg1993;119,1042
 
Smith, FM, Jr Arnold’s nerve reflex; a little known cause of cough in pediatric patients.J La State Med Soc1963;115,17-18
 
Irwin, RS, Madison, JM Persistent troublesome cough.Am J Respir Crit Care Med2003;167,1151-1152
 
Tekdemir, I, Aslan, A, Elhan, A A clinico-anatomic study of the auricular branch of the vagus nerve and Arnold’s ear-cough reflex.Surg Radiol Anat1998;20,253-257
 
Irwin, RS, Corrao, WM, Pratter, MR Chronic persistent cough in the adult: the spectrum and frequency of causes and successful outcome of specific therapy.Am Rev Respir Dis1981;123,413-417
 
Moser, KM Pulmonary embolism.Am Rev Respir Dis1977;115,829-852
 
Murdoch, DR Symptoms of infection and altitude illness among hikers in the Mount Everest region of Nepal.Aviat Space Environ Med1995;66,148-151
 
Rupwate, RU, Chitaley, M, Kamat, SR Cardiopulmonary functional changes in acute acclimatisation to high altitude in mountaineers.Eur J Epidemiol1990;6,266-272
 
Hultgren, HN, Honigman, B, Theis, K, et al High-altitude pulmonary edema at a ski resort.West J Med1996;164,222-227
 
Barry, PW, Mason, NP, Riordan, M, et al Cough frequency and cough-receptor sensitivity are increased in man at altitude.Clin Sci (Lond)1997;93,181-186
 
Mason, NP, Barry, PW, Despiau, G, et al Cough frequency and cough receptor sensitivity to citric acid challenge during a simulated ascent to extreme altitude.Eur Respir J1999;13,508-513
 
Basnyat, B, Litch, JA Medical problems of porters and trekkers in the Nepal Himalaya.Wilderness Environ Med1997;8,78-81
 
Litch, JA, Tuggy, M Cough induced stress fracture and arthropathy of the ribs at extreme altitude.Int J Sports Med1998;19,220-222
 
Jankovic, J Tourette’s syndrome.N Engl J Med2001;345,1184-1192
 
Duncan, KL, Faust, RA Tourette syndrome manifest as chronic cough.Int J Pediatr Otorhinolaryngol2002;65,65-68
 
Chou, YC, Lee, CC, Yen, PS, et al Cough induced by ossification of the ligamentum flavum in the high cervical spine: case report.J Neurosurg Spine2004;100,364-366
 

Figures

Tables

Table Graphic Jump Location
Table 1. Uncommon Causes of Cough*
* 

WG = Wegener granulomatosis; GCA = giant cell arteritis (temporal arteritis); RPC = relapsing polychondritis.

 

Conditions in which cough is a major symptom (present in > 50% of patients) or a presenting symptom.

 

These include rheumatoid arthritis, systemic lupus erythematosus, scleroderma, Sjögren syndrome, mixed connective tissue disease, relapsing polychondritis.

References

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Perkner, JJ, Fennelly, KP, Balkissoon, R, et al Irritant-associated vocal cord dysfunction.J Occup Environ Med1998;40,136-143
 
Feldman, JI, Woodworth, WF Cause for intractable chronic cough: Arnold’s nerve [letter].Arch Otolaryngol Head Neck Surg1993;119,1042
 
Smith, FM, Jr Arnold’s nerve reflex; a little known cause of cough in pediatric patients.J La State Med Soc1963;115,17-18
 
Irwin, RS, Madison, JM Persistent troublesome cough.Am J Respir Crit Care Med2003;167,1151-1152
 
Tekdemir, I, Aslan, A, Elhan, A A clinico-anatomic study of the auricular branch of the vagus nerve and Arnold’s ear-cough reflex.Surg Radiol Anat1998;20,253-257
 
Irwin, RS, Corrao, WM, Pratter, MR Chronic persistent cough in the adult: the spectrum and frequency of causes and successful outcome of specific therapy.Am Rev Respir Dis1981;123,413-417
 
Moser, KM Pulmonary embolism.Am Rev Respir Dis1977;115,829-852
 
Murdoch, DR Symptoms of infection and altitude illness among hikers in the Mount Everest region of Nepal.Aviat Space Environ Med1995;66,148-151
 
Rupwate, RU, Chitaley, M, Kamat, SR Cardiopulmonary functional changes in acute acclimatisation to high altitude in mountaineers.Eur J Epidemiol1990;6,266-272
 
Hultgren, HN, Honigman, B, Theis, K, et al High-altitude pulmonary edema at a ski resort.West J Med1996;164,222-227
 
Barry, PW, Mason, NP, Riordan, M, et al Cough frequency and cough-receptor sensitivity are increased in man at altitude.Clin Sci (Lond)1997;93,181-186
 
Mason, NP, Barry, PW, Despiau, G, et al Cough frequency and cough receptor sensitivity to citric acid challenge during a simulated ascent to extreme altitude.Eur Respir J1999;13,508-513
 
Basnyat, B, Litch, JA Medical problems of porters and trekkers in the Nepal Himalaya.Wilderness Environ Med1997;8,78-81
 
Litch, JA, Tuggy, M Cough induced stress fracture and arthropathy of the ribs at extreme altitude.Int J Sports Med1998;19,220-222
 
Jankovic, J Tourette’s syndrome.N Engl J Med2001;345,1184-1192
 
Duncan, KL, Faust, RA Tourette syndrome manifest as chronic cough.Int J Pediatr Otorhinolaryngol2002;65,65-68
 
Chou, YC, Lee, CC, Yen, PS, et al Cough induced by ossification of the ligamentum flavum in the high cervical spine: case report.J Neurosurg Spine2004;100,364-366
 
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