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TOPICAL MEDICAL INFORMATION
This interesting article will highlight most of the common causes of a chronic cough not just in childhood but also in
adulthood (see also Paediatric Asthma)
57th Annual Meeting of the American Academy of Allergy, Asthma and Immunology
Day 1 - March 16, 2001
Common Causes and Treatment of Chronic Cough
Mark T. O'Hollaren, MD
Introduction
The diagnosis and effective treatment of chronic cough can often be a vexing problem for the
physician. Both the physician in general practice, as well as specialists in the area of allergy and
pulmonary disease, are commonly faced with the problem of chronic cough. This symposium
explored a number of causes of chronic cough and reviewed the appropriate steps to take in both
diagnosis and treatment of this common disorder.
Cough Due to Gastroesophageal Reflux
Christopher J. Allen, MD,[1] Associate Clinical Professor of Medicine in the Division of Respiratory Medicine at the
Firestone Chest and Allergy Clinic at St. Joseph's Hospital in Hamilton, Ontario, Canada, began by stating that it is now
increasingly apparent that gastroesophageal reflux disease (GERD) is common in patients presenting with a number of
respiratory complaints, including chronic cough. He noted that if patients presenting with
chronic cough are evaluated using a systematic diagnostic protocol, then 21% will have cough either exclusively or in large part due to
GERD.[2] Less than 50% of patients with GERD will have esophagitis visible on upper gastrointestinal (GI) endoscopy. He stated that not
all patients with GERD need to have upper GI endoscopy, but physicians should consider endoscopy when there are
concerns about other possible systemic diseases, complications of GERD, or a failure to respond to therapy. He
suggested consideration for referral of patients with GERD for endoscopy when patients have anemia, dysphagia, when
they fail to respond to therapy, or when there is a need to rule out other pathology, such as Barrett's esophagus,
malignancy, or peptic ulcer disease.
The gold standard for diagnosis of GERD is ambulatory monitoring of esophageal pH.
Esophageal pH values below 4 argue in favor of reflux, and in patients with GERD-associated
cough, there is frequently an association between falls in esophageal pH and episodes of cough.
Of note, GERD is more common in patients with asthma compared with patients without asthma. The incidence of
symptomatic GERD in patients with asthma averages 57%.[3-7] Over 40% of patients with asthma, when objectively
studied, have evidence of esophagitis, and 24-hour esophageal monitoring has been shown to be abnormal in nearly 60%
of asthmatic patients. Furthermore, not all patients with asthma and GERD complain of the typical GERD symptoms of
heartburn or acid regurgitation. In several studies, there was objective evidence of reflux without typical symptoms of
reflux ("silent reflux") in 23% of asthmatics.[5,8] GERD also appears to be more common in a number of other pulmonary
conditions, including chronic bronchitis, idiopathic pulmonary fibrosis, recurrent pneumonia, and cystic fibrosis.
There seems to be very little data looking at the other side of the GERD equation and cough; namely, how many people
presenting with symptoms of GERD also have cough. The incidence may be fairly high. In Dr. Allen's experience at the
Firestone Chest and Allergy Clinic, 62% of patients with proven GERD who were undergoing surgery (referred by
gastroenterologists, internists, or family physicians) complained of cough.
What Is the Mechanism of GERD-Associated Cough?
Dr. Allen reviewed 2 mechanisms to explain the association of cough and GERD: vagally mediated esophagobronchial
reflexes and "micro-aspiration." It is interesting to note that embryologically, both the esophagus and the proximal
airways have a common origin and enervation (vagal), with both structures originating from the foregut. In patients with
chronic cough, instillation of acid into the esophagus (the Bernstein test) induces coughing,
suggesting that the cough may be caused by a vagally mediated reflex.[9] Of note, this acid-induced cough was inhibited by pretreatment in 1
study with topical lidocaine in the esophagus and inhalation of the anticholinergic agent ipratropium.[9]
Cough caused by "micro-aspiration" of gastric contents is sometimes suspected in these patients, but is hard to prove.
Dr. Allen notes that the patient may give a history of coughing and/or choking episodes, a "globus" sensation, or
frequent laryngitis symptoms in this setting.
Dr. Allen and colleagues have performed studies to see if increased respiratory efforts resulting in a wider swing in
intrathoracic pressures might explain the increased incidence of GERD seen in patients with lower airway disease (such
as patients with asthma). Healthy subjects inspired against progressively increasing external resistance while lower
esophageal pH was measured. They noted no increase in GERD with increasing transdiaphragmatic pressures, arguing
against this hypothesis.[10]
An area requiring further investigation is the role that eosinophils may play in the etiology of these esophageal
symptoms in some patients. Fifty percent of patients with GERD have eosinophils in biopsy specimens of the esophagus,
which Dr. Allen termed "eosinophilic esophagitis." The clinical significance of this finding is unclear at this time. There
is animal research currently being done in this area in an attempt to elucidate any connection between allergic airway
disease and the findings of eosinophils in the esophagus. For example, in mice, introduction of allergen into the airway
results in an increase in the concentration of eosinophils in the esophagus. We await further studies to investigate any
similar associations between eosinophil responses in the airway and eosinophilic infiltration of the esophagus in
humans.
Assessment of GERD in Patients With Chronic Cough
If a patient presents with a history of chronic cough, is a nonsmoker, has a normal chest x-ray, and is not taking an
angiotensin-converting enzyme inhibitor, the cough is commonly due to either GERD, asthma, or postnasal drip (PND). A
negative history of reflux does not rule out reflux as a cause of cough, since a significant percentage of patients with
GERD-associated cough will deny any symptoms of heartburn.
The preferred treatment for GERD includes treatment with a proton pump inhibitor (PPI), as well as the other usual
measures for GERD management. These include avoidance of foods and beverages known to loosen the lower
esophageal sphincter, such as caffeine-containing beverages, alcohol, chocolate, cigarette smoking, etc. The head of
the bed should be elevated 4 to 6 inches on blocks, and the patients should not eat or drink liquids for 2 to 3 hours
before going to bed at night.
It should be noted, however, that not all patients with chronic cough due to GERD will respond to PPIs such as omeprazole.
In some patients, chronic GERD may need fiberoptic laparoscopic fundoplication, and experience at McMaster University in
Hamilton, Ontario, Canada, shows persistence of relief after 5 years. What percent of patients improve with chronic cough
following surgical intervention? In the experience at McMaster, they note approximately 79% of patients have improvement
in cough. Who should you send to surgery for GERD? They need documentation of GERD by ambulatory monitoring, maximal
medical treatment failure of double-dose PPI therapy (given twice daily), or persistent severe evidence of aspiration. A
positive Bernstein test would also be helpful. In general, patients with the most severe cough will get the best response to
surgery. Those with a positive Bernstein test (ie, more cough during acid infusion -- done on a double-blind basis) are
more likely to have benefit from a surgical procedure in the McMaster experience. In general,
approximately 70% to 75% of patients will have prolonged relief from cough with surgical therapy. As with all new endoscopic surgical treatments, the
experience of the surgeon may have a profound effect on the success rates of this procedure.
Chronic Cough Due to Upper Airway Causes
William W. Busse, MD,[11] Professor of Medicine and Head of Allergy/Clinical Immunology at University of Wisconsin
Hospital and Clinics in Madison, Wisconsin, addressed the role of the upper airway in producing chronic cough. He
stated that PND syndromes are second only to asthma as a cause of chronic cough in children, and are most likely 1 of
the principal causes of chronic cough in adults. Patients may point to the upper laryngeal area as the
source of their chronic cough when it is due to upper airway causes. They may note a sensation of PND, nasal discharge, throat
clearing, snoring, hoarseness, nasal congestion, and/or increased nasal secretions. Physical exam may vary in patients
with cough due to upper airway causes. If sinusitis is responsible, there may be reddened nasal mucosa, as well as
purulent nasal discharge or cloudy PND. Exam of the oropharynx may show posterior pharyngeal cobblestoning.
Diagnostic evaluation of chronic cough may show that chronic sinusitis may be an insidious cause of chronic cough.
Sinus imaging is frequently helpful when the diagnosis is in question. Sinus computed tomography (CT) screening
examinations are most commonly used in this setting.
Treatment of PND syndromes includes antihistamines, decongestants, intranasal
corticosteroids, intranasal anticholinergics, and antibiotics for treatment of chronic sinusitis. It should be noted that prolonged antibiotic treatment
for 6 to 8 weeks may be needed for resistant cases before the patient is labeled a "treatment failure." Some clinicians
have used nebulized lidocaine (2 ccs to 3 ccs of a 1% solution) in an attempt to "break the cycle" of chronic cough as
well.
Tanaka and colleagues[12] noted that patients with chronic cough due to upper airway
causes may have a lowered "cough threshold" and that this may be due to increased
sensitivity to any stimuli. This study showed that oral loratadine improved cough in these patients.
Asthma as a Cause of Chronic Cough: "Cough Variant Asthma"
Frederick E. Hargreave, MD,[13] Professor in the Department of Medicine and Faculty of Health Sciences at McMaster
University in Hamilton, Ontario, Canada, mentioned the term "eosinophilic bronchitis" in association with asthma, but
also noted that there is a form of eosinophilic bronchitis without asthma. He noted that patients with this condition have
also been referred to as having "cough-variant asthma." Asthma is an inflammatory disease, in which there is variable
narrowing of the bronchial tubes of the lungs. One of the hallmarks of asthma is the presence of bronchial
hyperresponsiveness (BHR), and it has been shown that more severe asthma is accompanied by increasing BHR.[14]
What is it that makes a patient with asthma present with chronic cough? It may be most commonly due to the presence
of airway inflammation from eosinophils in the airways. In previous years, it was necessary to do bronchial alveolar
lavage to assess BHR in patients with asthma. Now, Dr. Hargreave uses a protocol with premedication with beta
agonists, rinsing the mouth with water and swallowing, blowing the nose, and inhaling hypertonic
saline. The sputum obtained is then processed using a cytospin technique and cell staining, etc. This sputum is then analyzed for the
presence of mediators of inflammation.
Eosinophilic bronchitis without asthma may produce cough. Expired nitric oxide (NO) may be
a useful marker for inflammation in asthma, but it is not known if it will be helpful in patients with chronic cough due to eosinophilic
bronchitis without asthma (ie, cough-variant asthma). When performing such studies, one needs to be careful regarding
factors that may interfere with measurement of NO. For example, simultaneous treatment with inhaled corticosteroids
(ICS) may alter measurements of NO in expired air.
Treatment of "Cough-Variant Asthma"
Brightling and colleagues[15] showed some improvement in inflammatory cells (eosinophilia) with treatment of this
disorder with inhaled budesonide. They also showed that there may be some loss of lung function in patients with
eosinophilic bronchitis without asthma (as noted by a fall in forced expiratory volume in 1 second [FEV1]), when patients
are followed over several years.[16]
Chronic cough may be associated both with asthma and with cough-variant asthma (also referred to by Dr. Hargreave as
"eosinophilic bronchitis without asthma"). [Author's note: The diagnosis and management of asthma is well documented
in many sources, including the 1997 NIH "Guidelines for the diagnosis and treatment of asthma," as well as "The Allergy
Report," a consensus document of 21 national organizations in the United States, including medical specialty, primary
care, governmental, and lay organizations. It can be accessed online at:
www.theallergyreport.org]
When treating suspected cough-variant asthma, a trial of ICS may be used, or if there is no response to ICS then a trial
of oral prednisone may be tried. Dr. Hargreave reviewed a case of Dr. Brightling noted immediately above, who
experienced a progressive fall in FEV1 over several years. Interestingly, this patient showed no evidence of BHR when
tested, and also had no response to inhaled bronchodilators, arguing that the patient did not have classic asthma, but
nonetheless had a fall in pulmonary function over time. This would argue that patients with cough-variant asthma may
have falls in FEV1 over time, while not meeting the typical diagnostic criteria for asthma.
Dr. Hargreave stated that the level of eosinophilia in patients with eosinophilic bronchitis may be higher than that seen
in patients with asthma. Sensitizers in patients with eosinophilic bronchitis without asthma appear to be the same as
those in patients with asthma, in Dr. Hargreave's experience, such as isocyanates and other well known inhaled
allergens.
In summary, the appropriate and thorough evaluation of patients with chronic cough requires a complete history;
physical examination; and, often, diagnostic tests including sinus imaging, ambulatory pH monitoring, and/or trials of
treatment for GERD and PND syndrome. If cough-variant asthma is suspected, then an empiric trial of inhaled and/or oral
corticosteroids may be needed.
References
1. Allen CJ. Didactic Workshop: Mechanisms and management of chronic cough. Program and
abstracts of the 57th Annual Meeting of the American Academy of Allergy, Asthma and Immunology;
March 16-21, 2001; New Orleans, Louisiana.
2. Irwin RS, Curley FJ, French CL. Chronic cough. The spectrum and frequency of causes, key components of the diagnostic evaluation, and outcome of specific therapy. Am Rev Respir Dis.
1990;141:640-647.
3. Perrin Fayolle M. Gastroesophageal reflux and chronic respiratory disease in adults.
Influence and results of surgical therapy. Clin Rev Allergy. 1990;8:457-469.
4. Perrin Fayolle M, Bel A, Kofman J. Asthma and gastroesophageal reflux. Results of a survey over 150 cases. Pouman Coeur. 1980;36:225-230.
5. Mays EE. Intrinsic asthma in adults. Association with gastroesophageal reflux. JAMA.
1976;236:2626-2628.
6. Clemencon GH, Ihre B, Plengier LH. Hiatal hernia in bronchial asthma. Gastroenterologia.
1960:93:337-356.
7. Kjellen B, Brundin A, Tibbling L, Wranne B. Oesophageal function in asthmatics. Eur J Respir Dis.
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8. Irwin RS, Curley FJ, French CL. Difficult to control asthma. Contributing factors and outcome of a
systematic management protocol. Chest. 1993;103:1662-1669.
9. Ing AJ, Ngu MC, Breslin AB. Pathogenesis of chronic persistent cough associated with
gastroesophageal reflux. Am J Respir Crit Care Med. 1994;149:160-167.
10. Sllrn CJ, Waterfall WE. The effect of respiratory loading on the lower esophageal sphincter in normal
subjects. Dig Dis Sci. 1984;29:567.
11. Busse WW. Didactic Workshop: Mechanisms and management of chronic cough. Program and
abstracts of the 57th Annual Meeting of the American Academy of Allergy, Asthma and Immunology;
March 16-21, 2001; New Orleans, Louisiana.
12. Tanaka S, Hirata K, Kurihara N, Yoshikawa J, Takeda T. Effect of loratadine, an H1 antihistamine,
on induced cough in non-asthmatic patients with chronic cough. Thorax. 1996;51:810-814.
13. Hargreave FE. Didactic Workshop: Mechanisms and management of chronic cough.
Program and abstracts of the 57th Annual Meeting of the American Academy of Allergy, Asthma and Immunology; March 16-21, 2001; New Orleans, Louisiana.
14. Sterk PJ. Virus-induced airway hyperresponsiveness in man. Eur Respir J.
1993;6:894-902.
15. Brightling CE, Ward R, Wardlaw AJ, Pavord ID. Airway inflammation, airway responsiveness and cough before and after inhaled budesonide in patients with eosinophilic bronchitis. Eur Respir J.
2000;15:682-686.
16. Brightling CE, Woltmann G, Wardlaw AJ, Pavord ID. Development of irreversible airflow obstruction in a patient with eosinophilic bronchitis without asthma. Eur Respir J. 1999;14:1228-1230.
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