Different clinical symptom patterns in patients with reflux micro-aspiration

Discussion

Aspiration of gastric refluxate has been long recognised as a less common form of GORD [12–15]. It can lead to pulmonary complications including adult-onset asthma, chronic cough and pulmonary fibrosis [16–20].

Reflux micro-aspiration has been suspected in adults and children with chronic unexplained respiratory symptoms. However, no current recommendations exist in whom possibility of GORD should be interrogated early for fear of pulmonary disease [21–25].

The diagnosis of atypical or extra-oesophageal manifestations of GORD can be challenging. For example, patients presenting with laryngo-pharyngeal reflux (LRP) to this service tend to be 8 years older than those presenting with typical GORD, many of whom spent years between subspeciality medical services without diagnosis [10].

The aim of this study was to examine common clinical symptom patterns amongst patients with proven reflux aspiration. We have discovered that commonly patients with reflux aspiration would present with a combination of typical GORD symptoms (most commonly regurgitation and heartburn) and respiratory symptoms such as cough or throat clearing.

Cluster analysis revealed two distinct patterns of symptoms clustering. The first cluster included aspiration associated with laryngospasm, voice change and atypical chest pain, most suggestive of volume proximal reflux and possibly impaired pharyngeal guarding and/or clearance. The second cluster included symptoms of nausea, vomiting, early satiety, bloating, flatus, pneumonia, asthma, diarrhoea, dyspepsia and lethargy suggestive of motility-related irritable bowel syndrome-like symptoms which were associated with pulmonary complications of the reflux aspiration. This raises the question of reflux aspiration being associated with IBS in a group of patients. Global gut dysmotility has been proposed as one of the pathophysiological explanations for IBS [26]. Furthermore, bloating and constipation has been associated with refractory GORD and laryngopharyngeal reflux (LPR) [27]. Can two of the diseases (IBS and reflux aspiration) be related? We have previously demonstrated a link between dysmotility and aspiration [10] and in this study have demonstrated clustering of IBS symptoms in patients with proven reflux aspiration. The connection seems plausible; however, specific studies in patients with confirmed IBS are needed to test for a possible relationship.

Typical GORD symptoms such as regurgitation can be overlooked by clinicians and not presented by patients as both concentrate on heartburn. The results of this study demonstrated this to be the most common symptom in patients with reflux aspiration and made apparent by experienced questioning. We therefore suggest taking focused GORD symptom history in patients presenting with chronic cough unexplained by most common causes such as smoking, angiotensin-converting enzyme (ACE) inhibitor use and post-nasal drip. The use of validated questionnaires such as Hull Airways Reflux Questionnaire can be helpful to further select patients requiring a confirmatory test to demonstrate aspiration or proximal pharyngeal reflux.

Patients with reflux micro-aspiration can present with isolated respiratory complaints, usually cough, with little-to-no typical symptoms of GORD such as heartburn or retrosternal chest pain. Multiple hypotheses have been proposed to explain this including aerosolised refluxate (airway reflux) producing little irritation to the digestive system [12]. Amongst these patients eliciting symptoms related to the oesophageal dysmotility (such as slow transit dysphagia, globus, bloating and early satiety) can increase the index of suspicion of airway reflux as ineffective oesophageal motility is strongly associated with reflux micro-aspiration [10].

Proton pump inhibitors (PPIs), which were prescribed in close to 70% of patients in this study, can mask some of the typical GORD symptoms by reducing the acidity of the refluxate. Whilst reducing the acidity of the refluxate, PPIs have not been shown to reduce the rate of reflux events, and possibly increase aspiration risk as the rates of community-acquired pneumonia are increased amongst PPI users [28, 29].

Conventional GORD investigations such as endoscopy, impedance and pH monitoring have limited sensitivity in detecting proximal reflux and are unable to demonstrate reflux aspiration. Use of invasive tests such as salivary or bronchial lavage testing for pepsin has had conflicting evidence [5, 6, 30]. Patients with suspected reflux aspiration should therefore proceed on to confirmatory tests such as the modern precise reflux scintigraphy, which is inexpensive and noninvasive with excellent specificity [1, 11].

Multiple hypotheses of causative relationships between cough and reflux have been proposed including oesophago-bronchial reflex hypersensitivity, laryngeal irritation by LPR and micro-aspiration [9, 31]. The results of our study where participants were confirmed to have pulmonary reflux micro-aspiration and proximal (LPR) reflux would support both above-mentioned hypotheses.

A limitation of this study was in significant pre-selection bias as the decision to refer patients for RASP was based on the clinical judgement of a senior treating clinician. Generally, patients with a combination of typical GORD symptoms and presence of extra-oesophageal symptoms or discordant findings of clinical history and impedance or manometry would prompt RASP study. Since RASP is not used to investigate all patients referred to this service, selection bias was introduced when patients were referred for scintigraphy. It was therefore difficult to perform comparison with patients in whom RASP study was negative for micro-aspiration, as the pre-test probability was very high by the virtue of referral to a tertiary reflux institution and further pre-test selection by clinical suspicion based on history. Therefore, results cannot be generalised to all patients with typical or atypical GORD. A further limitation was lack of a control group to assess the specificity of the symptom patterns. Another limitation of this study is a lack of use of validated questionnaires limiting ability to assess the sensitivity of such questionnaires.

Possible bias may have been introduced by modification of the RASP technique, most significantly by addition of SPECT/CT in 2017. This is thought to increase sensitivity and specificity of the study; however, to date this has not been shown to increase micro-aspiration detection rates.

The strength of this study is robust symptom recording and the use of the validated RASP study to confirm reflux micro-aspiration and pharyngeal contamination.