Cough in adult cystic fibrosis: diagnosis and response to fundoplication

Cystic fibrosis (CF) is a multisystem disease which impacts the digestive system, sweat glands, and the reproductive tract, but progressive pulmonary insufficiency continues to be major cause of morbidity and mortality.[1] The main respiratory manifestations include chronic bacterial colonisation, cough, bronchiectasis, haemoptysis, emphysema, and pneumothorax. As the disease progresses chronic cough becomes a universal symptom, reported by virtually all patients.[2]

Gastroesophageal reflux, which is increasingly recognised as one of the most common causes of chronic cough in general population, occurs frequently in patients with CF.[3] About one in five newly diagnosed infants with cystic fibrosis have pathological reflux,[4] and a higher frequency (25–55%) has been previously reported in children over 1 year old.[5, 6] Similarly, high rates of reflux symptoms, diminished lower oesophageal sphincter pressure and acid reflux are reported in adult CF patients.[7] However, because of the understandable focus on airway disease in CF, reflux as a potential aetiology of chronic cough is often unconsidered. Fortunately, the symptomatology of reflux induced cough allows the clinician to identify cough of gastroesophageal origin.[8]

The medical treatment of oesophageal reflux causing cough is challenging, particularly in the presence of non-acid reflux. In contrast to the treatment of gastroesophageal reflux disease (GORD) causing heart burn, where acid is a vital component, patients with chronic cough frequently fail to respond to full acid suppression with proton pump inhibitors (PPI) and H2 blockers. In the treatment of resistant chronic cough, Nissen fundoplication has been shown to be an effective tool.[9]

Cough is the commonest symptom of medical importance. Chronic cough is a frequent symptom in general population with the incidence of 12%.[13] Whilst airway disease, particularly when characterized by eosinophilic inflammation, can commonly cause cough, gastroesophageal reflux is increasingly recognised as an important precipitant of coughing paroxysms. We have recently described characteristic features in the clinical history which point to reflux as a cause of cough.[8] Associations such as cough on eating, and post-prandially, cough precipitated by a change of posture or on rising in the morning, can be explained by the known physiology of the lower oesophageal sphincter. Extra-oesophageal manifestations such as dysphonia, and an unpleasant taste in the mouth are also important clinical pointers to reflux as a cause of coughing.

Cough is one of the characteristic symptoms of CF, initially presenting as pulmonary exacerbations. In a study of objective cough frequency in 14 CF children with exacerbations, cough rates per hour were reported as 18.2 during the day and 5.8 during the night. [14] Another study of 20 CF adults admitted with exacerbations demonstrated rates of 21.2 during the day and 4.8 at night.[15]

In some patients with CF, cough becomes a persistent chronic symptom. Patients will describe two sorts of cough. One productive and associated with exacerbations and a second dry cough usually characterised by irritation in the throat. We sought the clinical history of reflux cough in our patients with chronic cough and were struck by the high incidence of reflux associated features. As a result, we invited them to undergo oesophageal function studies.

In the normal western population, excessive acid reflux is a common finding with the prevalence of between 10 to 20%.[16] It is well recognised that CF patients have excessive incidence of acid reflux leading to high frequency of the classic symptoms of heart burn and dyspepsia.[17] A recent study has shown that CF patients with demonstrable reflux have a high incidence of increased bile acids in saliva, and they have definitive evidence of gastric aspiration, confirmed by the presence of bile acids in bronchoalveolar lavage fluid.[18] Moreover, significant reductions in FEV1 and FVC,[19] and progression of pulmonary disease due to reflux have been reported previously.[20]

Suggested mechanisms of excessive reflux included abnormalities of pancreatic and duodenal function leading to increased enteroglucagon levels, and hence delayed gastric emptying. Gastric acid secretion may be excessive.[21] Reflux may also be facilitated by oesophageal dysmotility, the head-down position during respiratory treatment or certain respiratory medications (e.g. theophylline).[22] The mechanical disruption of the lower oesophageal sphincter as a result of alterations in the shape of chest wall and flattening of the diaphragm in chronic lung disease can also precipitate reflux.

In all of our studied patients acid reflux was confirmed. The recommended strategy in treatment of reflux cough is therapeutic trials;[23] starting with high dose proton pump inhibitors plus ranitidine[24] (so called full acid suppression), to pro-motility agents (metoclopramide or domperidone) and cough suppressants such as low dose opioid.[25] On therapy, heart burn and dyspepsia were improved, but in contrast there was no or little change in the degree of the cough.

Fundoplication has been reported as extremely effective in the treatment and management of reflux symptoms.[26] It has been shown to be effective in the control of cough in patients with reflux (acid or non-acid), with or with out primary respiratory problems.[27, 28] In our study, the beneficial effects of fundoplication in the form of reduced cough and improvement of voice were reported by the patients and noticed by the physician on the first post operative day. A formal assessment by LCQ of the longer term effects on quality of life showed a consistent benefit of the procedure. The increase in LCQ of 6 points in our patients is the highest clinically significant improvement reported, and nearly was double that seen from the effect of opiates in chronic cough.[25] The changes in spirometrically assessed lung function were small, and while of borderline statistically significance probably do not represent clinically important benefit. What was surprising was the marked reduction in exacerbation rate as defined by the need for antibiotic therapy. This is a non-controlled study and therefore regression to the mean or a placebo effect can not be discounted, however the halving of the incidence may suggest an important affect of fundoplication on pulmonary exacerbations. It is possible that reflux and aspiration maybe a precipitant or even a causal event in the pathogenesis of some pulmonary exacerbations. In support of this hypothesis, pH of exhaled breath condensate has been shown to be markedly lower in the acute phase of the exacerbations.[29]

Whilst the effect of fundoplication in CF has not previously been studied, experiences in the context of lung transplantation have shown improvement in episodes of acute and chronic rejection and the serial lung function.[30, 31] These observations are again consistent with reflux and aspiration as a feature of pulmonary exacerbations, and have an important bearing in the context of CF, since many patients may progress to transplant assessment.

Technically, fundoplication is subtly more difficult in CF patients than in normal subjects with reflux. The tissues are generally more friable and edematous perhaps as a result of previous use of systemic steroids or as part of the systemic disease. In our patients, there were no operative or post-operative complications. Weight loss and dysphagia, recognised operative complications were trivial and short lived.

Our experience in the diagnosis and treatment of chronic cough, led us to the realisation that many patients with CF complain of a similar symptom profile indicative of reflux. In common with other reports, these patients have excessive acid reflux which we found to be unresponsive, in terms of cough, to medical anti-reflux therapy. Fundoplication produced a dramatic symptomatic improvement associated with a halving in the rate of pulmonary exacerbations. If this experience is replicated in larger studies, then reflux and aspiration may be demonstrated to be an important previously unrecognised mechanism of disease progression in CF.