This article explores the diagnosis and treatment of extra-esophageal reflux (EER), a particularly challenging issue for clinicians. It adopts a multidisciplinary approach, integrating perspectives from otolaryngology, lung transplantation medicine, and gastroenterology, with a focus on the potential of pepsin as a novel therapeutic target. The research methodology involves a comparative analysis of diagnostic tools, including pH-impedance testing, salivary pepsin detection, and endoscopy, while also proposing innovative treatment strategies for non-acid reflux. The results indicate that targeted therapy using HIV protease inhibitors shows promise in treating EER cases unresponsive to PPIs and highlights the potential impact of EER on lung transplant patients. Key features of this article include its multidisciplinary approach, innovative therapeutic strategies, and the citation of a large number of high-quality references.

General Comments:

1. Given the challenges in both diagnosis and the treatment, the supporting evidence linked to treatment outcome is encouraged. The authors are encouraged to provide more convincing data, including large-scale controlled trials or well-designed longitudinal studies published in high-impact journals, to substantiate their statements.
2. Considering the heterogeneity of the patient population for LPR "symptoms and signs" and the absence of a diagnostic gold standard, the authors are advised to clarify how they define LPR itself rather than solely focusing on LPR symptoms.
3. Given the limited sensitivity and specificity of the pepsin test in clinical practice, the authors are invited to share their views on the reflexogenic mechanism responsible for LPR symptom generation and its implications for diagnosis and treatment.
4. The authors highlight the significance of non-acid reflux detected by impedance-pH monitoring in PPI-refractory LPR patients. However, non-acid reflux episodes are often over-diagnosed. The authors are encouraged to provide data supporting the diagnostic criteria, along with evidence of their validity, reliability, and relevance to patient outcomes.
5. If possible, it would be beneficial for the authors to present a diagnostic and treatment algorithm to offer a more structured approach to clinical practice.
   Specific Comment:
6. Could the authors clarify the meaning of the sentence, “…acidic reflux exposure in the hypopharynx is abnormal in this patient population, although perhaps not causative of pathology,” and provide the relevant references to support this statement?

Thank you for the opportunity to review this high-quality manuscript.