Patients presenting with GERD symptoms and alarm features should undergo initial diagnostic endoscopy to evaluate their symptoms. Alarm symptoms include dysphagia, odynophagia, gastrointestinal bleeding, anorexia, weight loss, and persistent vomiting; their presence may indicate more serious underlying conditions that require immediate and thorough investigation (Table 1). This management approach is important to rule out malignancies, strictures, or other significant esophageal mucosal pathologies that could cause these symptoms. Both the American Gastroenterological Association (AGA) and the American College of Gastroenterology (ACG) support this recommendation, emphasizing the need for endoscopic testing in patients with alarm symptoms [12,13]. In a retrospective analysis of approximately 30000 patients with dysphagia who underwent endoscopy, more than 50% had important clinical findings, including esophageal strictures (the most common finding, 40.8%), followed by ulcers, Schatzki’s ring, esophageal food impaction, and suspected malignancies [14]. Therefore, endoscopy is prioritized over empirical PPI therapy for these patients.

Patients with an increased risk for BE also require upfront testing. BE is the only known precursor of esophageal adenocarcinoma, a cancer that has exhibited a rapidly increasing incidence over recent decades [15]. The risk group is comprised of individuals with chronic (≥5 years) GERD symptoms and three or more of the following risk factors: male sex, age over 50 years, White race, tobacco smoking, obesity, or a family history of BE or esophageal adenocarcinoma [16]. A systematic review and meta-analysis demonstrated that the prevalence of BE in individuals with GERD and one or more of the aforementioned risk factors is as high as 12.2%. Furthermore, a positive linear relationship was observed, with each additional risk factor increasing BE prevalence by 1.2%, supporting the rationale for targeted BE screening in high-risk populations [17]. Moreover, a recent retrospective analysis of over 350000 patients from two national databases evaluated the prevalence of BE after a negative initial endoscopy. The prevalence of BE on repeat endoscopy was 1.7%–3.4%, which was higher in patients with multiple risk factors, suggesting that most cases were likely missed initially. The authors emphasized the importance of high-quality initial endoscopic examinations [18]. In summary, patients with GERD symptoms and BE risk factors should undergo endoscopy rather than empirical PPI therapy. This approach ensures an accurate diagnosis and appropriate management of BE [12,13].

The presence of underlying comorbidities, such as morbid obesity or a suspected hiatal hernia, requires therapeutic interventions such as bariatric surgery or hernia repair with anti-reflux surgery, respectively. 13 In both clinical scenarios, pre-surgical endoscopic evaluation and, if unremarkable, reflux testing and esophageal manometry are recommended. Roux-en-Y gastric bypass is increasingly regarded as the anti-reflux surgery of choice for obese patients (body mass index >35 kg/m2), serving both as a primary anti-reflux procedure and as an effective weight reduction intervention [19].

Other comorbidities, including mixed connective tissue disorder and scleroderma, warrant consideration for upfront testing because of the potential for significant esophageal mucosal abnormality and esophageal motility disorders. Testing includes endoscopy and esophageal manometry. These patients commonly present with moderate to severe EE or BE [20].

When twice daily empirical PPI treatment results in a partial or non response in patients with GERD and typical reflux symptoms after at least 8 weeks of treatment, further testing may be necessary. Ultimately, there are several reasons justifying the decision for testing: to establish a GERD diagnosis if one was not previously made, evaluate for complications, assess treatment response, and determine the underlying mechanism(s) for the lack of treatment response [21]. A recent study involving 366 patients referred to gastrointestinal clinics for heartburn unresponsive to PPIs found that, after extensive evaluation, only 78 patients (21%) had heartburn that was truly refractory to PPIs and related to reflux [22].

The initial test should be an upper endoscopy, if not recently performed. If negative, the next test should be reflux testing, followed by esophageal manometry.

Special consideration is required when managing GERD in individuals of advanced age. Concomitant comorbidities, such as diabetes mellitus, neurological disorders, and polypharmacy, may lead to advanced EE and GERD complications [23]. Although the diagnostic approach for older patients largely mirrors that for younger individuals, atypical symptoms, such as dysphagia, respiratory complaints, and vomiting, are more prevalent than typical symptoms, particularly in patients with severe EE [24]. Endoscopy plays a pivotal role in older patients, as this population is more likely to present with GERD-related mucosal abnormalities [23]. The diagnostic yield of upper endoscopy is significantly higher in this demographic than it is in younger patients, with an estimated 50% of older patients showing clinically significant findings [25]. Therefore, empirical treatment should not be automatically initiated in this patient population; instead, an individualized approach should be considered, often including additional diagnostic evaluations prior to therapy initiation.

The diagnostic accuracy of PPI testing in patients with atypical/extraesophageal symptoms and signs, such as chronic cough, wheezing, hoarseness, sinusitis, laryngitis, globus, nausea, and epigastric pain, has not been well studied. Empirical PPI trials, on the other hand, show no or minimal superiority over placebo in patients with suspected extraesophageal reflux-related symptoms, largely because 50%–60% of these patients do not have underlying GERD and, thus, do not respond to anti-reflux therapy [26]. A prospective, double-blind study used dual-probe pH monitoring to compare the diagnostic accuracy of empirical PPI therapy with pantoprazole (40 mg, twice daily) for four months in patients with laryngopharyngeal reflux (LPR); the authors reported a 92.5% sensitivity and a 14% specificity [27]. Again, this finding corresponded with the fact that acid is an uncommon cause of LPR in the absence of typical reflux symptoms or endoscopic features of reflux esophagitis. De Bortoli et al. [28] found that only 12.2% of patients with LPR symptoms had abnormal esophageal acid exposure times, and these patients predominantly exhibited classic GERD and LPR symptoms. Moreover, cost-effectiveness studies have shown a preference for early reflux monitoring over empirical PPI trials when evaluating extra-esophageal reflux-related symptoms, indicating cost savings with upfront testing [29,30]. For example, the initial physiological evaluation of pH impedance in patients with LPR is estimated to cost an average of $1897, compared with $3033 for empirical twice-daily PPI therapy [29].

Chronic cough has also been linked to GERD, but recent studies and systematic reviews indicate that PPIs are generally ineffective for treating chronic cough in most patients, reflecting a significantly lower likelihood of acid reflux being a direct cause [10,31,32]. A randomized controlled trial involving 40 individuals with chronic cough but without heartburn demonstrated no improvement in cough-related quality of life or symptoms following PPI treatment [32]. However, the role of PPIs in asthma treatment remains unclear. Although one study showed improved nocturnal asthma symptoms in patients receiving twice-daily PPI treatment, others failed to demonstrate any effectiveness [33-35].

Given the aforementioned findings, the current guidelines of the AGA, ACG, and recent Lyon Consensus recommend upfront endoscopy and, if negative reflux testing (e.g., pH impedance monitoring), over relying solely on empirical PPI therapy for diagnosing GERD in patients presenting with only extraesophageal manifestations and lacking typical GERD symptoms (e.g., heartburn and regurgitation) [2,5].

For extra-esophageal symptoms having a low likelihood of reflux as the underlying cause, such as cough or asthma, an initial evaluation by a pulmonologist may be warranted. In contrast, patients with symptoms such as globus or hoarseness may require an initial laryngoscopy. Conditions such as supragastric belching and rumination should ideally be identified using pH impedance testing and esophageal manometry, respectively, and managed with behavioral therapy [10].