To our knowledge, this is the largest study of the effect of acid suppression on cough in patients with chronic cough. Our findings indicate that heartburn is the only significant predictor of success of acid suppression therapy when treating chronic cough in a ‘real-life’ setting. However, it must be acknowledged that only just over a third of those with heartburn gained benefit. (8,10,11)
Evidence that acid suppression improves cough in chronic cough patients is limited to studies with a small number of patients. Kahrilas et al. carried out a retrospective review and found nine RCTs on the effect of acid suppressive therapy (either PPIs or the H2 antagonist ranitidine) on chronic cough symptoms (8). Six of these studies did not report a significant improvement in cough, but two of these negative studies excluded patients with heartburn (11, 12). It is also worth noting that the 3 of the negative studies included patients without pathological evidence of oesophageal acid exposure. Kahrilas et al., report that the therapeutic gain of treating chronic cough patients with acid suppressive treatment was low and variable (between 8.6%-35.8%) but is increased by selecting patients who report heartburn as a symptom. This is in keeping with the findings of our larger study. A more recent study of 312 patients with acute and sub-acute cough found that 46% had GORD symptoms such as heartburn, which is significantly higher than in our study (13). However, this may be due to the inclusion of a population with shorter duration of cough. The same group went on to investigate the effects of acid suppression treatment in patients with chronic cough in a smaller study (n=37), selecting patients with both heartburn and cough, and treating them with a PPI and prokinetic agent. Again, patients with GERD symptoms and cough improved significantly with acid suppression, consistent with our findings.
The most important finding of this study is the low response rate of chronic cough to acid suppression, even in the context of heartburn. Only 17% of the patients in this dataset reported a response of their cough to acid suppression which reflects the treatment refractory nature of chronic cough patients seen in specialist clinics (14). Despite this low response rate, heartburn was a highly significant predictor of the likelihood of success of acid suppression therapy (p=0.007) and resulted in a near three-fold increase in the success of treatment. It is worth noting however, that the vast proportion of patients with chronic cough with concomitant heartburn that respond to acid suppression are probably managed in the community and thus are far less likely to present to specialist clinics. A large epidemiological study looking at 14,669 individuals in a population-based cohort found that reported gastroesophageal reflux disease was a significant risk factor for chronic cough, especially in never and former smokers (17). Another possible explanation for the low numbers of responders to acid suppression is that these therapies only suppress the acidity of the refluxate and have no effect on non-acid reflux or the number of reflux events. Decalmer et al 2010 found that approximately 2/3 of reflux events in chronic cough patients were non-acid (5). Other studies also report that chronic cough patients have an increased incidence of weak peristalsis with large breaks leading to poor oesophageal clearance of reflux (4, 5). Thus, acid suppression alone may be ineffective at treating the commonest types of reflux in this patient group. In order to explore this further trials in chronic cough patients using therapies that target lower oesophageal sphincter relaxations, reducing non-acid and acid reflux and/or poor oesophageal clearance are needed.
Our data set was typical of patients attending specialists cough clinics with the majority of patients being females between the ages of 50-60 years old, with normal spirometry and non- smokers. The patients in the responder vs non-responder group were well matched, with no significant differences between them (apart from reporting of heartburn). There were some statistically significant differences between the patients attending the US clinic and those attending the UK one (Table 2). The US group was older, had a lower FVC and reported shorter duration of their cough than the UK group. However, none of these differences impacted our results. Although the US group was older they are still within the typical age group of chronic cough patients (14, 15). The US clinic was based in Florida which is a popular retirement destination, and although we do not have data on where the patients attending the clinic came from, we speculate that the increased age may simply reflect the local population. The FVC percent predicted was slightly lower in the US patients however this did not reflect a clinically relevant difference. It is possible that there was a difference in body mass index between the patients attending the two clinics that can account for the difference in FVC, however, we do not have data on BMI for the UK patients. Subjects in the US group had a shorter duration of cough, but this is not clinically significant as these patients would still be classed as chronic cough patients. Furthermore, the duration of cough was not a significant factor between the responders and non-responders. One explanation for the difference in cough duration is that the US clinic accepts direct GP/primary care/ self-referrals, whereas the UK clinic only accepts patients from secondary care. Thus, there is a delay from presentation to specialist clinic review (in the UK) which might account for the difference in cough duration. Twice as many patients in the UK group complained of heartburn compared to the US group (32.8% vs. 16%), although on the whole the numbers were small in both groups. The wider availability of over-the-counter acid suppression medication in the US and therefore the possibility of self-management of reflux compared to the UK could account this difference with patients successfully treating acid reflux related chronic cough and avoiding the need for referral to specialist clinics. In general, UK patients need to be seen by a doctor prior to being prescribed acid suppression (at least for significant periods and at treatment doses) whereas in the US patients self-medication with these drugs is common, with treatment level doses being readily available over the counter. Despite the difference in the number of patients with heartburn in each group, this did not translate to a significant difference in the PPI response rate when the data were modelled.
At the time of collecting the data for this study, guidelines recommended treatment trials of acid suppression therapy as routine for all patients with chronic cough even in the absence of GORD symptoms such as heartburn (16). Our study data does not support this practice and suggested that acid suppression is unlikely to be successful in the majority of patients with chronic cough, which led to a change in practice in our centre. Since then, the guidelines have been updated and now discouraged routine empirical acid suppression use in these patients (17, 18).
Due to the observational and retrospective nature of this study the findings should be interpreted with some caution. As with all observational studies, misclassification of data or information bias when collecting the data may have occurred. We endeavoured to ensure that the classification of patients was as accurate as possible and excluded all patients were incomplete/misclassification of information was present. The dosage of acid suppression therapy used was at the discretion of the prescribing clinician. However, both centres followed the current chronic cough guidelines (19, 20) on the management of GORD related cough. Thus, although the dosing regimen may have differed between patients the treatment was in line with current guidelines and reflective of what happens in a real life setting.
As this was a retrospective review, there were no validated endpoints. We used the reporting of heartburn and cough response as the main variables, which were both subjectively measured. There was no formal standardised way of measuring heartburn and thus this could vary between patients and clinicians and the degree of response was not recorded in a standard manner and therefore cannot be reported.