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Achalasia is a rare esophageal motility disorder for which the etiology is not fully understood. Evidence suggests that autoimmune inflammatory infiltrates, possibly triggered by a viral infection, may lead to a degeneration of neurons within the myenteric plexus. While the infection is eventually resolved, genetically susceptible individuals may still be at risk of developing achalasia. This study aimed to determine whether immunological and physiological networks differ between male and female patients with achalasia. This cross-sectional study included 189 preoperative achalasia patients and 500 healthy blood donor volunteers. Demographic, clinical, laboratory, immunological, and tissue biomarkers were collected. Male and female participants were evaluated separately to determine the role of sex. Correlation matrices were constructed using bivariate relationships to generate complex inferential networks. These matrices were filtered based on their statistical significance to identify the most relevant relationships between variables. Network topology and node centrality were calculated using tools available in the R programming language. Previous occurrences of chickenpox, measles, and mumps infections have been proposed as potential risk factors for achalasia, with a stronger association observed in females. Principal component analysis (PCA) identified IL-22, Th2, and regulatory B lymphocytes as key variables contributing to the disease. The physiological network topology has the potential to inform whether a localized injury or illness is likely to produce systemic consequences and the resulting clinical presentation. Here we show that immunological involvement in achalasia appears localized in men because of their highly modular physiological network. In contrast, in women the disease becomes systemic because of their robust network with a larger number of inter-cluster linkages., (© 2024. The Author(s).)

Background: Achalasia is an autoimmune disease whose probable causal agent is a neurotropic virus that chronically infects the myenteric plexus of the esophagus and induces the disease in a genetically susceptible host. The association between achalasia and coronaviruses has not been reported., Aims: To evaluate the presence of the SARS-CoV-2 virus, the ACE2 expression, the tissue architecture, and immune response in the lower esophageal sphincter muscle (LESm) of achalasia patients who posteriorly had SARS-CoV-2 (achalasia-COVID-19) infection before laparoscopic Heller myotomy (LHM) and compare the findings with type II achalasia patients and transplant donors (controls) without COVID-19., Methods: The LESm of 7 achalasia-COVID-19 patients (diagnosed by PCR), ten achalasia patients, and ten controls without COVID-19 were included. The presence of the virus was evaluated by in situ PCR and immunohistochemistry. ACE2 receptor expression and effector CD4 T cell and regulatory subsets were determined by immunohistochemistry., Key Results: Coronavirus was detected in 6/7 patients-COVID-19. The SARS-CoV-2 was undetectable in the LESm of the achalasia patients and controls. ACE2 receptor was expressed in all the patients and controls. One patient developed achalasia type II post-COVID-19. The percentage of Th22/Th17/Th1/pDCreg was higher in achalasia and achalasia-COVID-19 pre-HLM vs. controls. The Th2/Treg/Breg cell percentages were higher only in achalasia vs. controls., Conclusion & Inferences: SARS-CoV2 and its receptor expression in the LESm of achalasia patients who posteriorly had COVID-19 but not in the controls suggests that it could affect the myenteric plexus. Unlike achalasia, patients-COVID-19 have an imbalance between effector CD4 T cells and the regulatory mechanisms., (© 2022 John Wiley & Sons Ltd.)

Background: Serum anti-myenteric autoantibodies define autoimmune achalasia and tissue MMP-9 activity may locally process autoantigenic proteins in the muscle of the lower esophageal sphincter (LES) of achalasia patients., Methods: Biopsies of the LES muscle from 36 achalasia patients, 6 esophagogastric junction outflow obstruction (EGJOO) patients, and 16 transplant donors (TD) were compared in a blind cross-sectional study. Histological characteristics such as inflammation, fibrosis, presence of ganglion cells, cells of Cajal, GAD65, PNMA2, S-100, P substance, and MMP-9 proteoforms in tissue were assessed by H&E and Picrosirius Red staining and immunohistochemistry analysis. Anti-neuronal antibodies, onconeural antigens, recoverin, SOX-1, titin, zic4, GAD65, and Tr were evaluated by immunoblot/line assay., Key Results: Tissue of achalasia patients had heterogeneous inflammatory infiltrates with fibrosis and contrasting higher levels of activated MMP-9, as compared with EGJOO and TD. Moreover, lower ganglion cell percentages and cell of Cajal percentages were determined in esophageal tissues of achalasia patients versus TD. The tissues of achalasia versus EGJOO patients had higher GAD65 and PNMA2 protein expression. Unexpectedly, these proteins were absent in TD tissue. S-100 and P substance had similar expression levels in tissues of achalasia patients versus TD and EGJOO. Most of the achalasia sera had anti-GAD65 (83%) and anti-PNMA2 (90%) autoantibodies versus EGJOO (17% and 33%, respectively) and healthy volunteers (10% and 0%, respectively)., Conclusions and Inferences: Tissue-specific ectopic expression of GAD65 and PNMA/Ta2 and active MMP-9, associated with the presence of specific autoantibodies directed against these proteins, might participate in the pathophysiology of achalasia triggering and/or perpetuating autoimmune disease., (© 2022 John Wiley & Sons Ltd.)

Background: Laparoscopic Heller myotomy fails in approximately 3.5% to 15% of patients. Evidence of successful laparoscopic reoperation is limited to a few studies., Methods: This case-control study was conducted in patients who underwent laparoscopic Heller myotomy reoperation (LHM-R) from 2008 to 2016. The operative outcomes, preoperative and last follow-up manometric parameters, and symptom questionnaire results, including the Eckardt, Gastroesophageal Reflux Disease-Health Related Quality of Life (GERD-HRQL) and eating assessment tool (EAT-10) scores, were obtained. The data were compared with those of patients who underwent primary laparoscopic Heller myotomy (LHM-1)., Results: Thirty-five patients who underwent LHM-R and 35 patients who underwent LHM-1 were included. The reasons for failure in the LHM-R patient group included incomplete myotomy (71.4%), myotomy fibrosis (25.7%) and structural alterations in fundoplication (2.9%). The follow-up duration was 34 months for the LHM-R group and 24 months for the LHM-1 group (p = 0.557). The procedure was performed by laparoscopy in 100% of the patients in the two groups. No differences were found regarding surgical morbidity (11.4% LHM-R vs. 2.9% LHM-1, p = 0.164). The symptomatic outcomes were equivalent between groups (Eckardt p = 0.063, EAT-10 p = 0.166, GERD-HRQL p = 0.075). An IRP < 15 mmHg was achieved in 100% of the LHM-R and LHM-1 patients. At the last follow-up, 82.1% of the LHM-R patients and 91.4% of the LHM-1 patients were in symptomatic remission (p = 0.271)., Conclusion: The results achieved with LHM-R are similar to those achieved with LHM-1. Laparoscopic reoperation should be considered an effective and safe treatment after a failed Heller myotomy., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

Background: It is unknown whether surgically treated achalasia cases regain or surpass their usual weight into obesity or overweight in the long-term post-operative period. Here, we aimed to assess the incidence of overweight/obesity (Ob/Ow) and the risk for reoccurrence up to 48 months post-laparoscopic Heller myotomy (LHM)., Methods: We performed a cohort of 114 achalasia cases undergoing LHM. All patients had a confirmed diagnosis of achalasia and had no added comorbidities. We followed up the body mass index (BMI) at the immediate post-operative period, and at one-, six-, 12-, 24-, and 48 months after LHM. We measured the incidence of Ob/Ow and its reoccurrence risk with Cox regression., Key Results and Conclusions: In the immediate post-operative period, the incidence of Ob/Ow was significantly less than the usual BMI (before the onset of symptoms) (28.2% vs 66.3%). From the sixth to the 48th month, there was a progressive increase in the incidence of Ob/Ow and at this timepoint the percent of Ob/Ow was not statistically different from the usual BMI. The most significant hazard for Ob/Ow reoccurrence in the long term following LHM is a usual BMI with obesity grade I or III and males lacking pre-surgical weight loss., Inferences: Achalasia cases undergoing surgical treatment should be monitored closely in the post-operative period for weight regain, regardless of their pre-operative BMI. Notably, males who before the onset of symptoms were obese or overweight are at significantly increased risk of regaining or surpassing their weight, despite most having lost weight pre-surgically., (© 2020 John Wiley & Sons Ltd.)

Objective: To determine the differences between clinical, manometric, and neuroimmunological profile of esophagogastric junction outflow obstruction (EGJOO) and achalasia patients., Methods: Seven EGJOO and 27 achalasia patients were enrolled in a blind cross-sectional study. Peripheral blood (PB) of 10 healthy donors and 10 lower esophageal sphincter (LES) muscle biopsies from organ transplant donors were included as controls. The presence of ganglion cells, cells of Cajal, Th22/Th7/Th2/Th1/Tregs/Bregs/pDCregs in tissue, and PB was assessed by immunohistochemistry and flow cytometry. Serum concentration of IL-22/IL-17A/IL-17F/IL-4/IFN-γ/IL-1β/IL-6/IL-23/IL-33/TNF-α/IL-10 was determined using bioplex plates. ANAs and antineuronal antibodies were evaluated by immunofluorescence and Western blot., Key Results: EGJOO and achalasia patients had lower ganglion cells and cells of Cajal percentage vs. controls, while fibrosis was present only in achalasia patients. EGJOO and controls had lower cell percentage of Th22/Th17/Th2 vs. achalasia. EGJOO tissue had lower Th1/Treg cell number vs. achalasia, but higher levels vs. control group. Bregs and pDCregs percentage was higher in EGJOO vs. control group. Percentage of PB subpopulations in EGJOO was not significantly different from control group. Serum cytokine levels were higher for IL-1β/IL-6/TNF-α, while IL-17A levels were lower in EGJOO vs. achalasia and control group. EGJOO group was negative for ANAs, while in achalasia group, 54% were positive. GAD65 and PNMa/Ta2 antibodies were present in achalasia, whereas Yo and recoverin were positive in EGJOO group., Conclusions and Inferences: Although EGJOO shares some clinical characteristics with achalasia, the neuroimmunological profile is completely different, suggesting that EGJOO might be a different entity., (© 2020 John Wiley & Sons Ltd.)

Background: Idiopathic achalasia is an uncommon esophageal motor disorder. The disease involves interaction between inflammatory and autoimmune responses. However, the antigens related to the disease are still unknown., Aim: To identify the possible antigen targets in muscle biopsies from lower esophageal sphincter (LES) of achalasia patients., Methods: Esophageal biopsies of patients with type I and type II achalasia and esophagogastric junction outflow obstruction (EGJOO) were analyzed. Lower esophageal sphincter muscle biopsy from a Healthy organ Donor (HD) was included as control for two-dimensional gel electrophoresis. Immunoblotting of muscle from LES lysate with sera of type I, type II achalasia, or type III achalasia, sera of EGJOO and sera of healthy subjects (HS) was performed. The target proteins of the serum were identified by mass spectrometry Matrix-assited laser desorption/ionization time-of-flight (MALDI-TOF)., Key Results: The proteomic map of muscle from LES tissue lysates of type I, and type II achalasia, EGJOO, and HD were analyzed and divided into three important regions. We found a difference in the concentration of certain spots. Further, we observed the serum reactivity of type I achalasia and type II achalasia against 45 and 25 kDa bands of type I achalasia tissue. Serum of type III achalasia and EGJOO mainly recognized 25 kDa band. Bands correspond to triosephosphate isomerase (TPI) (25 kDa), carbonic anhydrase (CA) (25 kDa) and creatinine kinase-brain (CKB) isoform (45 kDa)., Conclusions and Inferences: We identify three antigen targets, TPI, CA, and CKB isoform, which are recognized by sera from patients with achalasia., (© 2020 John Wiley & Sons Ltd.)

Complete blood count (CBC)-derived parameters such as neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), eosinophil-to-lymphocyte (ELR) ratio, and platelet-to-lymphocyte ratio (PLR) are sensitive markers of occult inflammation and disease activity for systemic lupus erythematosus, rheumatoid arthritis, psoriasis, esophageal cancer, etc. We assessed NLR, PLR, MLR, and ELR as indicators of inflammation in achalasia patients.This cross-sectional study included 103 achalasia patients and 500 healthy blood donor volunteers (HD). Demographic, clinical and laboratory information was collected. NLR, MLR, ELR and PLR were calculated. Peripheral Th22, Th17, Th2 and Th1 subsets were determined by flow cytometry. Correlation between hematologic indices and clinical questionnaires scores, HRM parameters and CD4+ T-cells were assessed. Hematologic parameters associated with the different achalasia subtypes were evaluated by logistic regression analysis.Hemoglobin, leukocytes, lymphocytes, monocytes, and platelets counts were significantly lower in achalasia patients vs controls. NLR (P = .006) and ELR (P < .05) were higher in achalasia patients vs controls. NLR was significantly associated with achalasia in multivariate analysis (P < .001). Compared to HD, the achalasia group was 1.804 times more likely to have higher NLR (95% CI 1.287-2.59; P < .001). GERD-HRQL score had statistically significant correlations with PLR (Pearson's rho:0.318, P = .003), and ELR (Pearson's rho:0.216; P = .044). No correlation between CD4+ T-cells and hematologic indices were determined. NLR with a cut-off value of ≥2.20 and area under the curve of 0.581 yielded a specificity of 80% and sensitivity of 40%, for the diagnosis of achalasia.NLR is increased in achalasia patients vs HD. Sensitivity and specificity achieved by NLR may contribute to a clinical and manometric evaluation. We suggest these indices as potential indicators of silent inflammation and disease activity.

Objectives: Achalasia is a primary esophageal motility disorder resulting from selective loss of inhibitory neurons in the esophageal myenteric plexus, likely due to an autoimmune response with involvement of the adaptive immune system. Innate immune processes of the host constitute the bridge between environmental etiological factors and the adaptive immune system. Although these remain poorly investigated, they might be of diagnostic and therapeutic relevance. In view of the role of extracellular proteolysis in organ-specific autoimmunity, we studied gelatinases of the matrix metalloproteinase (MMP) family in achalasia patients., Methods: The presence of MMP-2 and MMP-9 proteoforms was analyzed in sera of two cohorts of achalasia patients. Additionally, with the use of immunohistopathological analysis, in situ MMP-2 and MMP-9 expression was investigated. Finally, we tested the paradigm of remnant epitopes generating autoimmunity (REGA) for achalasia-associated autoantigens by evaluating whether autoantigenic proteins are cleaved by MMP-9 into remnant epitopes., Results: We showed significantly increased ratios of MMP-9/MMP-2 and activated MMP-9/proMMP-9 in sera of achalasia patients (n = 88) versus controls (n = 60). MMP-9-positive and MMP-2-positive cells were more abundant in achalasia (n = 49) versus control biopsies from transplant donors (n = 10). Furthermore, extensive damage within the plexus was found in the tissues with more MMP-9-positive cells. Additionally, we documented achalasia-associated autoantigens PNMA2, Ri, GAD65, and VIP as novel MMP-9 substrates., Conclusions: We provide new biomarkers and insights into innate immune mechanisms in the autoimmune pathology of achalasia. Our results imply that extracellular protease inhibition is worthwhile to test as therapeutic intervention in achalasia.

Idiopathic achalasia is a relatively infrequent esophageal motor disorder for which major histocompatibility complex (MHC) genes are well-identified risk factors. However, no information about HLA-achalasia susceptibility in Mexicans has previously been reported. We studied a group of 91 patients diagnosed with achalasia and 234 healthy controls with Mexican admixed ancestry. HLA alleles and conserved extended haplotypes were analyzed using high-resolution HLA typing based on Sanger and next-generation sequencing technologies. Admixture estimates were determined using HLA-B and short tandem repeats. Results were analyzed by non-parametric statistical analysis and Bonferroni correction. P-values < 0.05 were considered significant. Patients with achalasia had 56.7% Native American genes, 24.7% European genes, 16.5% African genes and 2.0% Asian genes, which was comparable with the estimates in the controls. Significant increases in the frequencies of alleles DRB1*14:54 and DQB1*05:03 and the extended haplotypes DRB1*14:54-DQB1*05:03 and DRB1*11:01-DQB1*03:01, even after Bonferroni correction (pC<0.05), were found in the achalasia group compared to those in the controls. Concluding, the HLA class II alleles HLA-DRB1*14:54:01 and DQB1*05:03:01 and the extended haplotype are risk factors for achalasia in mixed-ancestry Mexican individuals. These results also suggest that the HLA-DRB1*14:54-DQB1*05:03 haplotype was introduced by admixture with European and/or Asian populations., Competing Interests: The authors have declared that no competing interests exist.

Background: Laparoscopic Heller myotomy (LHM) with partial fundoplication is an effective treatment for achalasia. However, the type of fundoplication is still a subject of debate., Aim: The aim of the study is to identify which partial fundoplication leads to better control of acid exposure, manometric parameters, and symptoms scores., Methods: A randomized controlled trial was performed to compare Dor vs Toupet fundoplication after LHM. The preoperative diagnosis was made by high-resolution manometry (HRM), upper endoscopy, and barium esophagogram. Preoperative and postoperative symptoms were evaluated with Eckardt, GERD-HRQL, and EAT-10 questionnaires., Results: Seventy-three patients were randomized, 38 underwent Dor and 35 Toupet. Baseline characteristics were similar between groups. Postoperative HRM showed that the integrated relaxation pressure (IRP) and basal lower esophageal sphincter (LES) pressure were similar at 6 and 24 months. The number of patients with abnormal acid exposure was significantly lower for Dor (6.9%) than that of Toupet (34.0%) at 6 months, but it was not different at 12 or 24 months. No differences were found in postoperative symptom scores at 1, 6, or 24 months., Conclusion: There were no differences in symptom scores or HRM between fundoplications in the long term. A higher percentage of abnormal 24-h pH test were found for the Toupet group, with no difference in the long term.

Background and Aim: Idiopathic achalasia is a rare esophageal motor disorder. The disease state manifests local and systemic inflammation, and it appears that an autoimmune component and specific autoantibodies participate in the pathogenesis. The study aims to determine the prevalence of autoimmune and chronic inflammatory diseases in patients with achalasia and compare the results with those from patients with gastroesophageal reflux disease (GERD)., Methods: It was a cross-sectional and included 114 patients with idiopathic achalasia and 114 age-matched and sex-matched control patients with GERD. Data on the presence of autoimmune and inflammatory diseases, the time of presentation, and any family history of autoimmune disease were obtained from the hospital's medical records., Results: Seventy three (64%) were female patients (mean age: 42.3 ± 15.5; median disease duration: 12 months). We identified the presence of autoimmune disease in 19 patients with achalasia (16.7%), hypothyroidism was the main diagnosis, and it was present in 52.6% of patients compared with 4.2% in controls. Thirteen of the 19 achalasia patients (68.4%) with autoimmune disease had history of familial autoimmunity. We identified 11 achalasia (9.6%) and 5 GERD patients (4.16%) with an inflammatory condition. Compared with the GERD, the achalasia group was 3.8 times more likely to have an autoimmune disease (95% CI: 1.47-9.83), 3.0 times more likely to have thyroidopathies (95% CI: 1.00-9.03), and 3.02 times more likely to suffer from any chronic inflammatory disease (95% CI: 1.65-6.20)., Conclusions: The non-negligible number of patients with autoimmune diseases identified among the patients with idiopathic achalasia supports the hypothesis that achalasia has an autoimmune component., (© 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Idiopathic achalasia is an archetype esophageal motor disorder, causing significant impairment of eating ability and reducing quality of life. The pathophysiological underpinnings of this condition are loss of esophageal peristalsis and insufficient relaxation of the lower esophageal sphincter (LES). The clinical manifestations include dysphagia for both solids and liquids, regurgitation of esophageal contents, retrosternal chest pain, cough, aspiration, weight loss and heartburn. Even though idiopathic achalasia was first described more than 300 years ago, researchers are only now beginning to unravel its complex etiology and molecular pathology. The most recent findings indicate an autoimmune component, as suggested by the presence of circulating anti-myenteric plexus autoantibodies, and a genetic predisposition, as suggested by observed correlations with other well-defined genetic syndromes such as Allgrove syndrome and multiple endocrine neoplasia type 2 B syndrome. Viral agents (herpes, varicella zoster) have also been proposed as causative and promoting factors. Unfortunately, the therapeutic approaches available today do not resolve the causes of the disease, and only target the consequential changes to the involved tissues, such as destruction of the LES, rather than restoring or modifying the underlying pathology. New therapies should aim to stop the disease at early stages, thereby preventing the consequential changes from developing and inhibiting permanent damage. This review focuses on the known characteristics of idiopathic achalasia that will help promote understanding its pathogenesis and improve therapeutic management to positively impact the patient's quality of life., Competing Interests: Conflict-of-interest statement: The authors report no conflicts of interest.

Idiopathic achalasia is a disease of unknown etiology. The loss of myenteric plexus associated with inflammatory infiltrates and autoantibodies support the hypothesis of an autoimmune mechanism. Thirty-two patients diagnosed by high-resolution manometry with achalasia were included. Twenty-six specimens from lower esophageal sphincter muscle were compared with 5 esophagectomy biopsies (control). Immunohistochemical (biopsies) and flow cytometry (peripheral blood) analyses were performed. Circulating anti-myenteric autoantibodies were evaluated by indirect immunofluorescence. Herpes simplex virus-1 (HSV-1) infection was determined by in situ hybridization, RT-PCR, and immunohistochemistry. Histopathological analysis showed capillaritis (51%), plexitis (23%), nerve hypertrophy (16%), venulitis (7%), and fibrosis (3%). Achalasia tissue exhibited an increase in the expression of proteins involved in extracellular matrix turnover, apoptosis, proinflammatory and profibrogenic cytokines, and Tregs and Bregs versus controls (P < 0.001). Circulating Th22/Th17/Th2/Th1 percentage showed a significant increase versus healthy donors (P < 0.01). Type III achalasia patients exhibited the highest inflammatory response versus types I and II. Prevalence of both anti-myenteric antibodies and HSV-1 infection in achalasia patients was 100% versus 0% in controls. Our results suggest that achalasia is a disease with an important local and systemic inflammatory autoimmune component, associated with the presence of specific anti-myenteric autoantibodies, as well as HSV-1 infection.