*Centre for Digestive Diseases, Blizard Institute of Cell & Molecular Science, Barts, and the London School of Medicine and Dentistry, Queen Mary University of London
†Department of Respiratory Medicine, the London Chest Hospital, London, UK
Declaration of funding source: Daniel Sifrim receives a Research Grant from Sandhill Scientific, Denver, USA.
Reprints: Daniel Sifrim, MD, PhD, The Wingate Institute of Neurogastroenterology, 26 Ashfield Street, London E1 2AJ, UK (e-mail: firstname.lastname@example.org).
Conflict of interest disclosure: Authors have no conflict of interest related to this editorial.
The reflux-cough syndrome is now considered as one of the extraesophageal GERD manifestations.1 Population-based surveys have shown an increased risk of chronic cough among patients with reflux symptoms or esophagitis, a high prevalences of objective signs of GERD in chronic cough patients, and reports of response to GERD treatment.2–4
GER is the third most common cause of chronic cough,5 and according to Jaspersen et al,6 cough is common either in erosive (30.5%) and nonerosive (34.9%) reflux disease. Patients with chronic cough and suspected GER often receive long-term treatment with high doses of PPI but do not respond and heartburn patients to these regimens. Better understanding of the causal relationship between reflux and cough is important, because it will allow to identify subsets of patients most likely to benefit from aggressive antireflux therapy7.
In this number of Journal of Clinical Gastroenterology, Hersh et al8 described a diagnostic algorithm to better predict treatment outcomes in patients with GERD-related cough. In a retrospective analysis, the authors assessed the clinical value of ambulatory pH monitoring in predicting long-term symptomatic outcome in 53 patients with chronic cough. They conducted quantitative analysis (acid exposure time, AET) and symptom association analysis [Symptom Index (SI) and Symptom Association Probability (SAP)]. Hierarchical use of AET, SAP, and SI had the best value. When all the 3 were positive, the best long-term symptomatic response could be predicted in 85.7% of the patients.
If increased GER can provoke chronic cough, treatment of GER should reduce the cough. However, results of antireflux therapy in patients with cough are somewhat disappointing. A Cochrane meta-analysis of the outcome of acid suppressive therapy in chronic cough failed to find a significant difference between PPI treatment and placebo in total resolution of cough.9 The authors concluded that there is presently insufficient evidence that PPI treatment is beneficial for chronic cough presumed to be associated with GERD in adults. Clinicians should be aware of the lack of evidence for PPI treatment and the possibility of a natural resolution of cough with time.
The place of antireflux surgery in the management of suspected GERD-related chronic cough is at least as controversial. Ranson et al10 reported the outcomes of a prospective study of 91 patients who underwent antireflux surgery at a community hospital for typical or atypical GERD symptoms. Typical GERD symptoms responded better to surgery than did the atypical symptoms. The cough present in 80% of the patients was the atypical GERD symptom with the largest improvement after antireflux surgery. In patients with a clearly shown association between reflux and cough but no response to agressive treatment with PPI's, antireflux surgery has been proposed. The rationale is the persistence of nonacid reflux despite PPI's. So far, uncontrolled studies are encouraging11,12; however, there is a need for new outcome controlled studies with objective cough measurements before and after surgery to consolidate the recommendation for antireflux surgery in patients with confirmed reflux-related chronic cough not responding to PPI's.
Why do patients with GER-related cough not respond to PPI therapy?
The reasons are probably related to incomplete understanding of the pathophysiology of the association of the refluxcough leading to poor phenotyping and selection of patients for treatment.
Reflux of gastric contents into the pharynx with microaspiration into the airways is considered one of the mechanisms underlying reflux-related cough. Patients with GER and chronic cough have higher laryngitis scores and decreased upper esophageal sphincter pressure compared with patients with GER without cough.13
A second important mechanism consists of vagally mediated reflexes elicited from the distal esophagus through reflux-related esophageal distention or acid-related esophageal sensory stimulation. Acid perfusion of the distal esophagus can induce or increase cough.14 Such an esophageal-bronchial reflex is sensitized in patients with GERD and chronic cough.15,16 These patients have a hypersensitive cough reflux to both capsaicin and citric acid inhalation. Whether central or peripheral mechanisms are responsible for sensitization of this reflex is unknown.
Finally, recent studies have shown that not only acid but also weakly acidic reflux events with pH between 5 to 7 can be associated with cough17,18 suggesting that the acidity of the refluxate may be less important when stimulating an already sensitized esophageal bronchial reflex. Persistence of weakly acidic reflux is very common in patients “on” PPI, and this becomes relevant, when evaluating patients not responding to PPI treatment. It is possible that cough and reflux may precipitate each other resulting in a self-perpetuating cycle.17 The existence of this phenomenon is suggested by studies showing that the antitussive effect of antireflux therapy is prolonged far beyond the duration of antireflux therapy itself.
Each of these pathophysiologic mechanisms might predominate in individual patients and may explain in part the lack of efficacy of acid suppressing drugs in some patients, and why antireflux surgery has been shown to be beneficial in some studies.
On the basis of good clinical suspicion criteria, both from the pneumology and gastroenterology sides, and state of the art physiology measurements, it might be possible to better phenotype patients with reflux-related cough.
Ambulatory pHmetry is useful to identify patients with increased esophageal acid exposure. Adding an objective cough monitoring (manometry or microphone-based), makes possible to accurately assess the time association between individual reflux and cough episodes. Adding impedance to reflux monitoring allows for identification of cough associated with weakly acidic reflux or simply to reflux (of any acidity as detected by impedance).
It is still controversial whether a total esophageal burden exposure to reflux or a one-to-one association is relevant for diagnosis and treatment. In pooled data analysis, the majority of cough episodes of these patients is not associated to reflux.17 However, using statistical algorithms that exclude a chance association (ie, SAP) can help to identify those patients with a higher likelihood to respond to PPI therapy. This is the case in patients with reflux-related heartburn.19 So far, studies analyzing the association reflux-cough (including the study by Hersh et al) used SI and SAP algorithms with reflux-cough time windows of 5 minutes and 2 minutes, respectively. These time windows were initially chosen to assess associations between reflux-heartburn or chest pain. It is possible that assessment of reflux-cough association requires another symptom association analysis. In a recent study, we tried to identify the symptom association analysis that could best predict the response to PPI in a group of 30 patients with suspicion of reflux-related cough. Using combined ambulatory impedance-pH-manometry, we found that patients are less likely to respond to PPI, if they have a negative SAP for total reflux (acid+non-acid) using a 4-minute time window and an objective technique for cough recording. This new algorithm should be tested in a larger population, and its clinical relevance evaluated in terms of prediction of therapeutic response.20
Measuring cough-reflex sensitivity with capsaicin or citric acid inhalation allows identification of patients with reflux-related chronic cough owing to hypersensitive esophago-bronchial reflex. Esophageal acid perfusion increases the cough reflex sensitivity in patients with GORD and cough but has no effect in patients with GERD without cough.16
The retrospective analysis by Hersh et al has some limitations. More than 50% of the cohort was lost. Furthermore, from a respiratory point of view, there was an insufficient characterization of the patients, concerning lung function, presence of asthma, and smoking status. This is particularly important, because studies of chronic cough consistently show that many patients have multiple potential causes of their cough that quite frequently all need to be treated. Most of the patients included had reflux monitoring because of earlier failure of PPI treatment. It would have been important to characterize the reflux pattern and reflux-cough association in patients with initial response to PPI. In any case, Hersh et al should be congratulated for their attempt to identify the patients who would better respond to antireflux therapy. Using pHmetry and a hierarchical analysis of esophageal acid exposure and symptom association algorithms, they found that the stronger the evidence for GERD, the more likely it is that cough will respond to GERD management.
1. Vakil N, Van Zanten SV, Kahrilas P, et al. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am J Gastroenterol. 2006;101:1900–1920.
2. El-Serag HB, Sonnenberg A. Comorbid occurrence of laryngeal or pulmonary disease with esophagitis in United States military veterans. Gastroenterology. 1997;113:755–760.
3. Gislason T, Janson C, Vermeire P, et al. Respiratory symptoms and nocturnal gastro-esophageal reflux: a population based study of young adults in three European countries. Chest. 2002;121:158–163.
4. Poelmans J, Tack J. Extraoesophageal manifestations of gastro-oesophageal reflux.Gut.
5. 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 Dis. 1981;123:413–417.
6. Jaspersen D, Kulig M, Labenz J, et al. Prevalence of extra-oesophageal manifestations in gastro-oesophageal reflux disease: an analysis based on the ProGERD Study. Aliment Pharmacol Ther. 2003;17:1515–1520.
7. Richter JE. Review article: extraoesophageal manifestations of gastro-oesophageal reflux disease. Aliment Pharmacol Ther. 2005;22(suppl 1):70–80.
8. Hersh MJ, Sayuk GS, Gyawali CP. Long-term therapeutic outcome of patients undergoing ambulatory pH monitoring for chronic unexplained cough. J Clin Gastroenterol. 2010;44:254–260.
9. Chang AB, Lasserson TJ, Kiljander TO, et al. Systematic review and meta-analysis of randomised controlled trials of gastro-oesophageal reflux interventions for chronic cough associated with gastro-oesophageal reflux. BMJ. 2006;332:1–7.
10. Ranson ME, Danielson A, Maxwell GJ, et al. Prospective study of laparoscopic nissen fundoplication in a community hospital and its effect on typical, atypical, and nonspecific gastrointestinal symptoms. Journal of the Society of Laparoendoscopic Surgeons. 2007;11:66–71.
11. Mainie I, Tutuian R, Agrawal A, et al. Fundoplication eliminates chronic cough due to non-acid reflux identified by impedance pH monitoring. Thorax. 2005;60:521–523.
12. Mainie I, Tutuian R, Agrawal A, et al. Combined multichannel intraluminal impedance-pH monitoring to select patients with persistent gastro-oesophageal reflux for laparoscopic Nissen fundoplication. Br J Surg. 2006;93:1483–1487.
13. Rolla G, Colagrande P, Magnano M, et al. Extrathoracic airway dysfunction in cough associated with gastroesophageal reflux. J Allergy Clin Immunol. 1998;102:204–209.
14. Ing AJ, Ngu MC, Breslin AB. Pathogenesis of chronic persistent cough associated with gastro-oesophageal reflux. Am J Respir Crit Care Med. 1994;149:160–167.
15. Benini L, Ferrari M, Sembenini C, et al. Cough threshold in reflux oesophagitis: influence of acid and of laryngeal and oesophageal damage. Gut. 2000;46:762–767.
16. Javorkova N, Varechova S, Pecova R, et al. Acidification of the oesophagus acutely increases the cough sensitivity in patients with gastro-oesophageal reflux and chronic cough. Neurogastroenterol Motil. 2008;20:119–124.
17. Sifrim D, Dupont L, Blondeau K, et al. Weakly acidic reflux in patients with chronic unexplained cough during 24 hour pressure, pH, and impedance monitoring. Gut. 2005;54:449–454.
18. Blondeau K, Dupont LJ, Mertens V, et al. Improved diagnosis of gastro-oesophageal reflux in patients with unexplained chronic cough. Aliment Pharmacol Ther. 2007;25:723–732.
19. Aanen MC, Weusten BL, Numans M, et al. Effect of proton-pump inhibitor treatment on symptoms and quality of life in GERD patients depends on the symptom-reflux association. J Clin Gastroenterol. 2008;42:441–447.
20. Blondeau K, Mertens V, Dupont L, et al. Improved reflux-symptom association analysis to predict PPI treatment outcome in patients with chronic cough. Gastrenterology. 2009; 136(Suppl 1):A-735.(abstract).