This letter is concerning the article regarding post-COVID-19 gastrointestinal dysmotility [1]. While SARS-CoV-2-induced ACE-2 depletion and neuronal tropism may cause motility disorders, COVID-19-associated autoantibodies may be another mechanism for post-infectious gastrointestinal dysmotility. We were intrigued since a 54-year-old female patient of ours developed dysphagia 6 months after COVID-19. Gastric sleeve surgery was done 10 years earlier. She was on fluoxetine and was not taking opiates. Esophagogastroduodenoscopy showed a spastic esophageal stricture, but dysphagia persisted despite dilation. Esophagogram showed a dilated esophagus with narrowing of the gastroesophageal junction. Esophageal high-resolution manometry was diagnostic of type II achalasia, with normal lower esophageal sphincter (LES) pressure, high integrated relaxation pressure of 21.7 mmHg, and 100% of the swallows showing pan-esophageal pressurization. Anti-Hu, anti-Ri, and anti-Yo antibodies were negative. Ambulatory pH monitoring did not show reflux. She underwent a peroral endoscopic myotomy (POEM) for achalasia and revision from gastric sleeve to gastric bypass to prevent reflux, with complete resolution of her symptoms.
Dysphagia was found in a third of patients with SARS-CoV-2 pneumonia requiring ventilation [2]. Two reports described the development of achalasia following SARS-CoV2 pneumonia [3, 4]. A recent preprint reported the detection of SARS-CoV-2 in the LES of six out of seven patients with type II achalasia who developed COVID-19 [5]. One of these patients developed achalasia after moderate COVID-19 pneumonia. The frequency of achalasia in Venezuela was higher in 2020 and 2021 than in preceding years, and 66% of patients with achalasia had COVID-19 previously [6].
The development of achalasia was temporally related to COVID-19, but probably not causative. While SARS-CoV-2-induced ACE-2 depletion and neuronal infiltration are seen, the pathogenesis of achalasia may not involve direct viral cytopathy or renin–angiotensin–aldosterone-system (RAS) dysfunction. Achalasia results from an immunologic reaction to viral infections in individuals with specific variations in the HLA-DQ region. Autoantibodies such as anti-Glutamic acid decarboxylase-65 (anti-GAD-65) lead to selective loss of inhibitory neurons in the myenteric plexus of the LES. Biopsies of the LES and the serum of patients with achalasia showed higher anti-GAD-65 expression compared with controls [7]. SARS-CoV-2 induces autoantibodies possibly through molecular mimicry, causing multiple clinical outcomes. Anti-GAD-65 has also been associated with COVID-19 and has caused autoimmune encephalitis and transverse myelitis [8, 9]. While anti-GAD-65 was not measured in our patient, autoantibodies likely led to the pathogenesis of achalasia.
The dysregulated immunologic reaction to SARS-CoV-2 and autoantibodies produced may be another mechanism of post-COVID-19-associated autoimmune gastrointestinal dysmotility (AGID), especially with achalasia. The successful treatment AGID following SARS-CoV-2 with immunoglobulin further clarifies the role of autoantibodies in post-COVID-19 AGID [10]. The role of autoantibodies including anti-GAD-65 in the pathophysiology of achalasia and other motility disorders following COVID-19 should be investigated. The trend in the incidence of achalasia since the start of the COVID-19 pandemic should be determined. Achalasia should be excluded in patients with persistent dysphagia following COVID-19. Immunoglobulin and other immune therapies may have a role in the treatment of post-COVID-19 AGID, including achalasia. Achalasia developing following COVID-19 may improve over time as autoantibodies decrease.
Author’s contributions
F.M.: Substantial contributions to the conception and design of the work, the acquisition, analysis, and interpretation of data for the work, drafting the work or revising it critically for important intellectual content, final approval of the version to be submitted, and agreement to be accountable for all aspects of the work by ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. N.K.: Substantial contributions to the conception and design of the work, interpretation of data for the work, drafting the work or revising it critically for important intellectual content, final approval of the version to be submitted, and agreement to be accountable for all aspects of the work by ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
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Conflict of interest
None of the authors have any financial or personal conflicts of interests.
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The patient has provided informed consent. She was informed that no patient identifying information would be published.
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The IRB at UNC Health Blue Ridge reviewed the application and ruled that no IRB approval is required.
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Contributor Information
Fahad S. Mohammed, Email: fahad.mohammed@duke.edu
Nathaniel Krogel, Email: nathaniel.krogel@unchealth.unc.edu.
References
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All authors had full access to the data cited and accept the responsibility to submit it for publication.