This study investigated the potential association between EMDs and VZV using salivary VZV DNA detection and serological antibody analysis. Our findings revealed no significant differences in either parameter between patients with EMDs and those with normal esophageal motility. Thus, we concluded that any relationship between EMDs and VZV was weak, negligible, or absent. However, given the complexity of EMD pathogenesis and previous reports indicating potential viral involvement, further investigation is warranted.

Esophageal achalasia is a primary motility disorder characterized by the degeneration of enteric neurons in the esophageal body and LES, the etiology of which is unclear. Previous studies have examined the possible role of viral infections, including VZV, in the pathogenesis of achalasia. Birgisson et al. employed PCR to detect viral DNA sequences in esophageal myotomy specimens from patients with achalasia, but found no viral DNA, including VZV, in either their experimental or control patients [14]. Similarly, Moradi et al. utilized PCR and reverse transcription PCR to amplify the DNA sequences of various viruses, including VZV, in esophageal biopsy tissue and blood specimens of patients with achalasia and controls. Again, both groups tested negative for VZV DNA [15]. These findings are consistent with our results.

Several studies have suggested a potential link between VZV and achalasia. In 1993, Robertson et al. reported a higher prevalence of VZV DNA in the esophageal myenteric plexus of patients with achalasia compared to controls, along with significantly elevated serum VZV antibody titers [16]. More recently, Naik et al. identified VZV DNA, transcripts, and proteins in esophageal muscularis specimens from achalasia patients and detected salivary VZV DNA in 12 of 15 achalasia patients [7]. Gaber et al. conducted a large case–control study using medical insurance claims data and found a significant association between VZV and achalasia [17]. However, salivary VZV DNA has been reported in individuals experiencing physiological stress, such as astronauts during or after space flight and medical residents on night calls [18, 19]. Maria et al. detected salivary VZV DNA in individuals up to 144 months post-herpes zoster infection, as well as some with no history of herpes zoster [20]. This suggests that salivary VZV DNA detection can be influenced by various physiological and environmental conditions. This is a considerable obstacle to attempts to evaluate the association between EMDs and viral infections. Future studies could provide further insights into the potential role of VZV in EMDs by approaching the musculature and nerves of the esophagus.

Aside from VZV, other viral pathogens, including herpes simplex virus 1 and SARS-CoV-2, have been implicated in esophageal neurodegeneration and achalasia pathogenesis [21]. Furuzawa-Carballeda et al. identified SARS-CoV-2 and its receptors in the LES muscle tissue of patients with type II achalasia following COVID-19 infection, but not in controls type II achalasia patients or transplant donors [22]. This suggests that viral infections may affect the integrity of the mesenteric plexus. However, achalasia is increasingly recognized as a multifactorial disorder, likely resulting from a complex interplay of genetic susceptibility, environmental triggers, allergy-mediated processes, and autoimmune-mediated neuronal degeneration [23, 24].

To the best of our knowledge, this is the first study to investigate salivary VZV DNA not only in achalasia but also in other EMD subtypes. EGJOO is regarded as a precursor or variant of achalasia [25], while absent contractility can be difficult to distinguish from type I achalasia [4]. However, our findings suggest that VZV is not strongly implicated in the pathogenesis of these disorders, further challenging the hypothesis that EMDs have direct viral etiologies.

Nevertheless, our study had some limitations. First, the sample size was relatively small. A larger cohort would provide more robust statistical results. Second, we utilized the primers suggested by the National Institute of Infectious Diseases for detecting Japanese wild-type VZV strains. However, prior studies investigating salivary VZV DNA have used PCR to target different ORFs [10, 26]. Although we validated our primer selection, alternative PCR conditions may yield additional results. Third, for patients in the normal group, endoscopic findings and multichannel intraluminal impedance-pH test results were not considered. Their HRM results were normal, but the final diagnosis may be some other disease. Finally, in patients with non-achalasia EMDs, associated symptoms and additional supportive testing (such as timed barium esophagram or EndoFLIP) were not considered in the analysis. Therefore, the clinical significance of non-achalasia EMDs remains unclear.

In conclusion, this study found no significant differences in the rates of salivary VZV DNA or VZV antibody titers between EMD patients and controls. Given the complex, multifactorial nature of EMDs, further research is warranted to explore alternative mechanisms that may underlie this group of disorders.