refluxandchroniccough

1、GI Motility online (2006) doi:10.1038/gimo77Published 16 May 2006Gastroesophageal reflux and chronic coughSusan M. Harding, M.D., F.C.C.P., F.A.G.A.Key Points Chronic cough has more than 20 causes, and in up to 62% of cases more than one cause can be involved Specific therapy for the cause of chroni

2、c cough leads to cough resolution in up to 98% of cases Gastroesophageal reflux (GER)-related chronic cough is the second most common cause of chronic cough and is defined as a cough that improves or is eliminated with GER-specific therapy Although GER is a cause of chronic cough in 40% of chronic c

3、ough patients, it can be clinically silent in up to 75% of patients with GER-related chronic cough Pathophysiologic mechanisms of GER-related chronic cough include an esophagotracheobronchial cough reflex and niicroaspiration. In addition, nonacid gastric refluxate and esophageal dysmotility may als

4、o play a role in GER-related cough. The American College of Chest Physicians in January 2006 published evidence-based guidelines for the diagnosis and management of chronic cough These guidelines suggest initiating empiric GER therapy using lifestyle modification therapy and proton pump inhibition i

5、n order to identify and treat GER-related chronic cough Cough resolution often occurs within 2 weeks of proton pump inhibitor therapy, but it may take more than 50 days in some patients. Tests such as esophageal pH testing and impedance monitoring are reserved for nonresponders Fundoplication is use

6、d in selected patients and in patients with nonacid GER.DefinitionGastroesophageal reflux (GER) can impact the lung and is a cause of subacute and chronic cough The esophagus and the lung share common embiyonic foregut origins and vagal innenrationIn 199& the American College of Chest Physicians

7、 (ACCP) published their first evidenced-based guideline concerning the diagnosis and management of chronic cough that included a systematic, diagnostic protocol.- These guidelines were updated in January 2006 and include an empiric integrative approach that can be easily implemented for individual p

8、atientsThese new guidelines define subacute cough as a cough lasting 3 to 8 weeks and chronic cough as a cough lasting more than 8 weeks in a nonsmoking, immunocompetent host. It also states that the subject should have a normal or stable chest radiograph and not be on medications that could cause c

9、hronic cough, including angiotensin-converting enzyme (ACE) inhibitors. Utilizing this systematic anatomic protocol allows the cause of chronic cough to be determined in 88% to 100% of cases Specific therapy toward the cause of chronic cough leads to cough resolution in up to 98% of cases.丄 Subacute

10、 and chronic cough has more than 20 etiologies? 2 3 4 5 Gastroesophageal reflux-related chronic cough is defined as a chronic cough that is improved or eliminated with GER-specific therapy1"- (Table 1). Even though GER is a cause of subacute cough, this review focuses on chronic coughTable 1: C

11、ommon causes of chronic cough" (Excluding ACE inhibitors)% Full size tableHistory of DiseaseRichard Irwin and colleagues- initially noted that GER caused chronic cough in 1981. These investigators evaluated the spectrum and frequency of chronic cough causes In 1981, GER was the fourth most comm

12、on cause of chronic cough with a prevalence of 10%.-With the advent of more sophisticated diagnostic and therapeutic options to identify subjects with GER, GER was found to be 什le cause of chronic cough in 36% to 41 % of cases and is currently considered the second most common cause of chronic cough

13、.- Also, during the past 25 years researchers have elucidated physiologic mechanisms explaining how GER causes cough Cough can also be elicited by nonacid GER/EpidemiologyWhen the diagnosis of GER-related cough is based on a favorable response to GER therapy, prospective before and after interventio

14、n studies show that GER is one of the most common causes of chronic cough in adults.- In subjects with chronic cough, prevalence of GER-related chronic cough ranges from 5% to 41%, depending on how GER isUm i二门 Establishing a prevalence rate for GER-related coughis complicated by the fact that in ma

15、ny patients, cough can have more than one underlying cause For instance, recent investigations reveal that chronic cough is caused by more than one condition in up to 62% of cases.- In combining reports, a single cause of chronic cough was found in 38% to 82%, two causes of cough were found in 18% t

16、o 62%, and three causes of cough were found in up to 42% of cases.丄 The three most common causes of chronic cough are upper aii-way cough syndrome (formerly referred to as postnasal drip), GER, and cough-variant asthma. In general studies show that GER is a cause of chronic cough in approximately 25

17、% of adults. These data depend partly on how the GER diagnosis is made For instance, if GER is diagnosed by history, endoscopy, or barium esophagram, 10% of chronic cough patients have GER.- However, if 24-hour esophageal testing is employed, GER is the cause of cough in 40% of patients. Esophageal

18、GER symptoms are present in 6% to 10% of chronic cough patients; however, GER may be clinically silent from an esophageal standpoint. Irwin and colleagues- found that 43% of patients with cough (that improved or was eliminated with GER therapy) denied heartburn and/or a sour taste in their mouth, wh

19、ich are common indicators of silent reflux. Kiljander and colleagues noted that 28% of patients with chronic cough that improved with GER therapy did not have typical GER symptoms. In another prospective study population, Irwin and colleagues noted that GER was clinically silent in 75% of GER-relate

20、d chronic cough patients. In conclusion, GER is a cause of chronic cough in up to 41% of cases and is the second most common cause of chronic cough Furthermore, GER is clinically silent in up to 75% of patients with GER-related chronic cough (cough improved with GER therapy).PathophysiologyTwo major

21、 pathophysiologic mechanisms play a role in GER-related chronic cough including an esophagotracheobronchial cough reflex and microaspiration Furthermore, nonacid gastric refluxate may contribute to cough Cough can also induce GER episodes, causing a cough/GER self-perpetuated cycle that may further

22、potentiate chronic cough Esophageal dysmotility may also play a roleMany investigators note the presence of an esophagotracheobronchial cough reflex Irwin and colleagues, using dual probe esophageal pH testing, noted that cough occurred simultaneously with acid instillation in the distal esophagus 2

23、8% of the time compared to 6% of the time with acid in the proximal esophagus. Ing and colleagues noted that distal esophageal acid occurred simultaneously with coughing in 78% of cough episodes, without evidence of aspiration on chest radiographs or laryngeal examinations. In a randomized controlle

24、d study, Ing and colleagues also examined the afferent pathway of the cough reflex, showing an increase in cough frequency with esophageal acid compared to esophageal infusions of normal saline Blocking the afferent limb of the cough reflex with esophageal lidocaine inhibited acid-induced cough. Blo

25、cking the efferent limb of the cough reflex with inhaled ipratropium (an anticholinergic agent) also inhibited cough, but esophageal ipratropium did not inhibit the cough reflex This supports the presence of a vagally mediated cough reflex.With this neural reflex mechanism, refluxate into the esopha

26、gus is thought to be a sufficient stimulus to cause cough.There are also local axonal reflexes between the esophagus and the trachea that can impact cough二 For instance, Ferrari and colleagues noted that the capsaicin inhalation cough threshold is lower in subjects with GER but without cough, compar

27、ed to controls, irrespective of the presence of esophagitis, suggesting that GER may decrease the cough threshold. Capsaicin polarizes C-fibers in the afferent neurons, so neuroinflammatory mediators may also come into play.So why does GER cause cough in some individuals but not in otllers? Potentia

28、l theories abound, including different response characteristics of esophageal receptors and primary afferents, altered responsiveness of the cough center in the central nervous system, local release of protussive neurotransmitters, and niicroaspiration. Further research is needed to investigate thes

29、e possibilities.Furthermore, GER can stimulate the afferent limb of the cough reflex by irritating the upper respiratory tract (as in the laiynx) without aspiration, or by irritating the lower airway respiratory tract by macroaspiration or microaspiration into the lung, or GER may irritate the lower

30、 airway respiratory tract by macroaspiration or niicroaspiration.Rolla and colleagues examined seven subjects with GER and chronic cough, and seven subjects with GER but without cough They noted that those with chronic cough had higher laryngitis scores, decreased lower esophageal sphincter (LES) pr

31、essures and upper esophageal sphincter (UES) pressures, higher esophageal acid contact times, and more prolonged esophageal acid clearance times, compared to subjects with GER but without cough Laryngitis scores were inversely proportional to the provocative dose of histamine required to produce fiv

32、e coughs Furthermore, laryngitis scores and the provocative dose findings improved with GER therapy. Benini and colleagues performed bronchial biopsies in six subjects with GER-related chronic cough showing evidence of airway inflammation with epithelial desquamation, with inflammatory cells, includ

33、ing monocytes.Paterson and Murat observed microaspiration into the hypopharynx in nine of 15 chronic cough patients. Notably, many GER-related chronic cough patients had evidence of laryngeal injury. This is further evidenced by Phu a and colleagues, who examined laryngopharyngeal sensitivity testin

34、g in 15 GER-related chronic cough patients and 10 normal controls Laryngopharyngeal sensitivity threshold was higher in the GER-related chronic cough patients (9.5 niniHg) compared to control subjects (3.7 mmHg). Thus, the sensory integrity of the laryngopharynx is impaired in GER-related chronic co

35、ugh patients, which could predispose to aspirationEsophageal dysmotility may also be important. Kastelik and colleagues noted that esophageal dysmotility is common in patients with GER-related chronic cough They noted that 67% of chronic cough patients had abnormal esophageal manometryFurthermore, e

36、sophageal dysmotility was 什ie only esophageal abnormality found in one-third of patients These patients had normal esophageal acid contact times. At this point it is not known whether esophageal dysmotility is an adverse occurrence due to GER, or whether it contributes to GER in these patients.Nonac

37、id GER may also impact chronic cough Irwin and colleagues noted that esophageal acid and saline caused cough at the same frequency, so acid may not be the sole cough mediator. Furthermore, GER-related cough does not always resolve despite control of esophageal acid with aggressive medical therapy an

38、d may require fundoplication for resolution.Sifrim and colleagues- verified that nonacid GER events do occur in chronic cough patients They examined 28 chronic cough patients with combined esophageal pH and impedance and examined the temporal association between cough and acid events (pH <4), wea

39、kly acidic events (pH v7), and alkaline events (pH I 应).Of 98 GER-cough episodes, 65% involved acid GER, 29% involved weakly acidic GER, and 6% involved alkaline GER, verifying that both weakly acidic and nonacid GER are temporally associated with coughThere may also be a self-perpetuating positive

40、feedback cycle between cough and GER, where cough actually precipitates GER. For instance, cough can cause a pressure gradient differential between the abdomen and the thorax leading to a functional decrease in LES pressure Furthermore, cough can potentially trigger transient LES relaxations. Swallo

41、wing- related LES relaxations may also predispose to GER in the distal esophagus The GER then initiates the distal esophagotracheobronchial reflex, leading to coughing episodes and potentially a cough-GER cycle. Although cough-induced GER episodes are observed in 24-hour esophageal pH tracings, the

42、mechanism by which GER episodes are triggered by coughing is still not fully elucidated.Clinical FeaturesClinical features of a cough that is at least partially caused by GER include a chronic cough associated with symptoms of GER such as heartburn or regurgitation Worsening of cough may be noted wh

43、en eating foods that decrease LES pressure (peppermint, chocolate, alcohol). Using a prospective study design, Mello and colleagues found that detailed questions about cough characteristics, sputum production, and timing were not useful in determining the underlying cause of cough.Many patients with

44、 cough that is at least partially caused by GER do not have esophageal GER symptoms. Irwin and Madison- describe the clinical profile of patients with chronic cough owing to "silent" reflux. This clinical profile is based on post hoc analysis of four prospective intervention studies.s： 30

45、This clinical profile includes individuals with chest radiographs that are normal or that have stable nonsignificant findings, individuals who are not exposed to environmental irritants, and individuals who are nonsmokers who do not take ACE inhibitors or othermedications that can cause chronic coug

46、h Furthermore, symptomatic asthma has been ruled out either by the cough not being improved with aggressive therapy or negative methacholine inhalation challenge test. Upper airway cough syndrome (postnasal drip syndrome) has been ruled out, with the cough failing to improve with first-generation Hr

47、 antagonist therapy and a sinus computed tomography (CT) scan showing no evidence of sinusitis. Furthermore, nonasthmatic eosinophilic bronchitis has been ruled out either by the cough not being improved on inhaled or systemic corticosteroids, or absence of eosinophils in sputum cytology These indiv

48、iduals fit the clinical profile for patients having silent GER. Table 2 illustrates these points.Table 2: Pntient profile for patients with cliniodly silent past】 oesophageal l dlux (GERLirlated chronic cou父h1"'0 Full size tableHistoryIn patients with chronic cough, the characteristic and t

49、iming of the cough are not helpful in the clinical evaluation of cough that is at least partially caused by GER.- All patients with chronic cough should be asked about the presence of typical esophageal GER symptoms including regurgitation, heartburn, and dysphagia Other extraesophageal manifestatio

50、ns of GER may be present including hoarseness, globus, sore throat, and dysphonia Some patients note hoarseness and cough after eating More commonly, patients present with a daytime cough that is nonproductive and is long-standingup to 58 months in duration. Patients may notice that their cough isin

51、haledexacerbated by certain asthma medications that promote GER including theophylline, R -adrenergic agonists, oral corticosteroids, progesterone, calcium channel blockers, anticholinergic agents, morphine, and meperidine." “ "匸 Many patients have asymptomatic GER.Physical Examination Fin

52、dingsIn patients with GER-related chronic cough, physical examination findings are commonly normal. Pulmonary examination does not reveal wheezing, rales, or findings consistent with other pulmonary diseases that can cause cough Patients may cough during examination, especially with continued respir

53、atory effort Evidence of laryngeal inflammation may be found on upper airway endoscopy Patients with GER-related chronic cough do not have findings of postnasal drip in their upper airwa y.Laboratory FindingsThere are two potential reasons for performing laboratory evaluations in patients with chron

54、ic cough caused by GER. One is to rule out other causes of chronic cough and the other is to evaluate for Hie presence of GER.As part of the workup for chronic cough, the following evaluations are helpful1 2 4Chest radiograph to ensure that no underlying pulmonary parenchymal disease is present such

55、 as interstitial lung disease.High-resolution CT chest scan to delineate other pulmonary parenchymal causes of chronic cough (including bronchiectasis)Spirometry before and after bronchodilator therapy with an inhaled 2-agonist, methacholine challenge test, or peak expiratory flow rate monitoring to

56、 evaluate for asthmaSinus CT scan to evaluate for sinusitis and upper airway cough syndrome (postnasal drip syndrome).Upper airway examination with nasal endoscopy for evaluation of sinusitis and lipper airway syndrome (postnasal drip syndrome).Caidiac evaluation for the possibility of pulmonary ede

57、maSputum cytology for eosinophils to evaluate for nonasthmatic eosinophilic bronchitis Bronchoscopy when there is an indication for bronchoscopy (such as a suspicion of an endobronchial anatomical abnormality), a suspicion of a secondary underlying pulmonary process, or to evaluate the source of hem

58、optysis.Pertussis evaluation is useful in selected patients: nasopharyngeal aspirate for Bordetella pertussis culture, noting a fourfold increase in immunoglobulin G (IgG) or IgA, and antibodies to Bordetella pertussisThe American College of Chest Physicians evidence-based cough guidelines can guide

59、 physicians through this complicated workup.- From a gastroenterologists point of view, most of this workup is performed by a pulmonologist, allergist, or a primary care physician. Often a gastroenterologist evaluates chronic cough patients who have failed aggressive GER medical therapy or those in whom there is a question of whether GER is adequately controlled Gastroenterologists may also see patients with complicated GER, and chronic cough