A Case of Ocular Myasthenia Gravis Seen by Rheumatology as Suspected Mononeuritis Multiplex in an Adult Male Shortly after Pfizerbiontech Sars-Cov-2 Vaccination

Background/Aims Myasthenia gravis (MG) is an antibody-mediated autoimmune disease targeting proteins at the postsynaptic membrane of the neuromuscular junction. MG is thought to occur in genetically susceptible individuals following an environmental trigger. SARS-CoV-2 infection has been associated with new-onset autoimmune disease, new-onset MG, and exacerbations of pre-existing MG, with molecular mimicry between SARS-CoV-2 epitopes and autoantigen-induced autoreactivity thought to be part of the underlying mechanism. We report a case of newonset ocular MG following first dose Pfizer-BioNTech BNT162b2 SARS-COV2 vaccination which was referred to rheumatology as suspected mononeuritis multiplex. Methods A 53-year-old man of East Asian ethnicity presented to the emergency department (ED) with sudden onset diplopia and left lateral gaze restriction 7 days after receiving his first dose of the Pfizer-BioNTech BNT162b2 SARS-COV2 vaccination. He had longstanding myopia and dry eyes but no other medical history, no regular medications or significant family history. He was a current smoker, with a 50-pack year history. He did not drink alcohol or use any recreational drugs. He was found to have an isolated left VI cranial nerve (CN) palsy with an otherwise normal ocular and physical examination. Blood tests were unremarkable apart from raised cholesterol, and he was discharged with a suspected self-limiting microvascular CN lesion. Three weeks later he presented to ED with worsening diplopia, increasingly restricted eye movements, headache, nausea, vomiting and blurred vision. Ophthalmology assessment noted new right sided CN III and VI palsy, persistent left CN VI palsy, and vertical diplopia in all fields of gaze. Neurological and physical examination were normal. Bloods including an autoimmune screen were unremarkable. SARS-CoV-2 Spike antibodies were positive consistent with SARS-CoV-2 vaccination but not infection. Intracranial and thoracic imaging were unremarkable. He was referred to and seen by both rheumatology and neurology as a case of suspected mononeuritis multiplex. Results A diagnosis of ocular MG was confirmed with positive serum acetylcholine receptor antibodies, and he was started on prednisolone, and pyridostigmine to good effect. Daily forced vital capacity (FVC) showed no respiratory muscle involvement, and nerve conduction studies and electromyography were normal, excluding secondary generalisation. Conclusion A review of the literature found 14 reported cases of new-onset MG all within 4 weeks following SARS-CoV-2 vaccine. Whilst these cases provide interesting insights into the pathogenesis of autoimmune conditions such as MG, they are not epidemiological studies to inform vaccine safety. Ultimately, current evidence suggests that the risks of SARS-COV-2 infection outweigh the risk of vaccine-related adverse events, therefore we suggest clinicians should be aware of potential new-onset autoimmune conditions, but support the safety of SARSCOV2 vaccination. Further, research into possible immunological mechanisms behind this phenomenon, including identifying potential epitopes inducing molecular mimicry, could help establish the likelihood of a causative link.

Management of patients with cognitive impairment.

The management of patients with cognitive impairment (CI) is one of the urgent problems of modern medicine. Issues of diagnostics and therapy of patients with CI and their high mortality during the period of coronavirus infection are discussed. A wide prevalence of patients with mild CI (MCI), an important role of neuropsychological research in establishing CI, and frequent diagnosis of CI only at the stage of dementia were noted. In our country, CI is poorly diagnosed, the most common cause of CI in the elderly - Alzheimer's disease (AD) - is rarely established, patients are observed for a long time with a diagnosis of cerebrovascular disease (CVD). Some non-drug and drug methods can reduce the manifestations of CI, improve the quality of life of both the patients themselves and those around them. In severe CI, socio-psychological methods, stimulating patients to feasible household and social, physical and mental activity, and avoiding prolonged hospitalization are of primary importance. In addition to lifestyle changes, much attention in CI is given to the prevention of stroke, the treatment of arterial hypertension and diabetes mellitus. At the stage of dementia, cholinomimetic drugs (acetylcholinesterase inhibitors, donepezil, rivastigmine, galantamine) and the glutamate receptor blocker memantine are used. The use of choline alfoscerate in CI and the results of the multicenter, placebo-controlled ASCOMALVA study are discussed, in which, in patients with AD and CVD, the addition of choline alfoscerate to donepezil reduced the severity of CI, manifestations of depression, anxiety, and apathy. A new oral form of choline alfoscerate (Cerpechol) is reported that may improve patient compliance and be used in patients with swallowing disorders.Copyright © 2023 Ima-Press Publishing House. All rights reserved.

Management of patients with cognitive impairment.

The management of patients with cognitive impairment (CI) is one of the urgent problems of modern medicine. Issues of diagnostics and therapy of patients with CI and their high mortality during the period of coronavirus infection are discussed. A wide prevalence of patients with mild CI (MCI), an important role of neuropsychological research in establishing CI, and frequent diagnosis of CI only at the stage of dementia were noted. In our country, CI is poorly diagnosed, the most common cause of CI in the elderly - Alzheimer's disease (AD) - is rarely established, patients are observed for a long time with a diagnosis of cerebrovascular disease (CVD). Some non-drug and drug methods can reduce the manifestations of CI, improve the quality of life of both the patients themselves and those around them. In severe CI, socio-psychological methods, stimulating patients to feasible household and social, physical and mental activity, and avoiding prolonged hospitalization are of primary importance. In addition to lifestyle changes, much attention in CI is given to the prevention of stroke, the treatment of arterial hypertension and diabetes mellitus. At the stage of dementia, cholinomimetic drugs (acetylcholinesterase inhibitors, donepezil, rivastigmine, galantamine) and the glutamate receptor blocker memantine are used. The use of choline alfoscerate in CI and the results of the multicenter, placebo-controlled ASCOMALVA study are discussed, in which, in patients with AD and CVD, the addition of choline alfoscerate to donepezil reduced the severity of CI, manifestations of depression, anxiety, and apathy. A new oral form of choline alfoscerate (Cerpechol) is reported that may improve patient compliance and be used in patients with swallowing disorders.Copyright © 2023 Ima-Press Publishing House. All rights reserved.

Physiological Metrics Collected from Wearable Devices Identify Inflammatory and Clinical Inflammatory Bowel Disease Flares

BACKGROUND: Inflammatory bowel disease (IBD) flares are common and unpredictable. Disease monitoring relies on symptom reporting or single timepoint assessments of stool, blood, imaging, or endoscopy-these are inconvenient and invasive and do not always reflect the patient perspective. Advances in wearable technology allow for passive, continuous and non-invasive assessment of physiological metrics including heart rate variability (HRV), the measure of small time differences between each heartbeat, a marker of autonomic nervous system function. Our group has previously demonstrated that changes in autonomic function precedes an IBD flare, can predict psychological state transitions and even identify inflammatory events including SARS-CoV-2 infection. To develop algorithms that can predict IBD flares using wearable device signatures, we launched a national wearable device study called The IBD Forecast study. To assess data quality and feasibility, the first 125 Apple Watch users to enroll were evaluated. METHOD(S): The IBD Forecast study is a prospective cohort study enrolling anyone >=18 years of age in the United States (US) with IBD who is willing to (1) use a commercially available wearable device, (2) download our custom eHive app and (3) answer daily survey questions. HRV metrics (mean of the standard deviations of all the NN intervals [SDNN]) were analyzed using a mixed-effect cosigner model that incorporated body mass index, age, and sex. SDNN is a time domain HRV index that reflects both sympathetic and parasympathetic nervous system activity and is calculated from the variance of intervals between adjacent QRS complexes (the normal-to-normal [NN] intervals). Clinical flare was assessed with daily Patient Reported Outcome (PRO)-2 surveys (flare;PRO-2 Crohn's disease >7, PRO-2 ulcerative colitis >2). Inflammatory flare was assessed via patient reported C-reactive protein (CRP), with inflammatory flare defined as >5 mg/L. RESULT(S): The first 125 study participants were enrolled across 29 states in the US (Table 1). Circadian features of changes of HRV were modelled (Figure 1). The mesor, or midline of the circadian pattern of the SDNN was higher in those with clinical flare (mean 44.43;95% CI 41.25-47.75) compared to those in clinical remission (mean 43.03;95% CI 39.94-46.22) (p<0.004). The mesor of the circadian pattern of the SDNN was lower in those with an inflammatory flare (mean 38.16;95% CI 30.86-45.72) compared to those with normal inflammatory markers (mean 49.51;95% CI 43.12-56.26) (p<0.001). CONCLUSION(S): Longitudinally collected HRV metrics from a commonly worn commercial wearable device can identify symptomatic and inflammatory flares. This preliminary analysis of a small proportion of the IBD Forecast Study cohort demonstrates the feasibility of using wearable devices to identify, and may potentially predict, IBD flares. [Formula presented] [Formula presented]Copyright © 2023

SARS-CoV-2 spike ectodomain targets α7 nicotinic acetylcholine receptors.

Virus entry into animal cells is initiated by attachment to target macromolecules located on host cells. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) trimeric spike glycoprotein targets host angiotensin converting enzyme 2 to gain cellular access. The SARS-CoV-2 glycoprotein contains a neurotoxin-like region that has sequence similarities to the rabies virus and the HIV glycoproteins, as well as to snake neurotoxins, which interact with nicotinic acetylcholine receptor (nAChR) subtypes via this region. Using a peptide of the neurotoxin-like region of SARS-CoV-2 (SARS-CoV-2 glycoprotein peptide [SCoV2P]), we identified that this area moderately inhibits α3ß2, α3ß4, and α4ß2 subtypes, while potentiating and inhibiting α7 nAChRs. These nAChR subtypes are found in target tissues including the nose, lung, central nervous system, and immune cells. Importantly, SCoV2P potentiates and inhibits ACh-induced α7 nAChR responses by an allosteric mechanism, with nicotine enhancing these effects. Live-cell confocal microscopy was used to confirm that SCoV2P interacts with α7 nAChRs in transfected neuronal-like N2a and human embryonic kidney 293 cells. The SARS-CoV-2 ectodomain functionally potentiates and inhibits the α7 subtype with nanomolar potency. Our functional findings identify that the α7 nAChR is a target for the SARS-CoV-2 glycoprotein, providing a new aspect to our understanding of SARS-CoV-2 and host cell interactions, in addition to disease pathogenesis.

Neuroimmune nexus in the pathophysiology and therapy of inflammatory disorders: Role of α7 nicotinic acetylcholine receptors.

The α7-nicotinic acetylcholine receptor (α7nAChR) is a key protein in the cholinergic anti-inflammatory pathway (CAP) that links the nervous and immune systems. Initially, the pathway was discovered based on the observation that vagal nerve stimulation (VNS) reduced the systemic inflammatory response in septic animals. Subsequent studies form a foundation for the leading hypothesis about the central role of the spleen in CAP activation. VNS evokes noradrenergic stimulation of ACh release from T cells in the spleen, which in turn activates α7nAChRs on the surface of macrophages. α7nAChR-mediated signaling in macrophages reduces inflammatory cytokine secretion and modifies apoptosis, proliferation, and macrophage polarization, eventually reducing the systemic inflammatory response. A protective role of the CAP has been demonstrated in preclinical studies for multiple diseases including sepsis, metabolic disease, cardiovascular diseases, arthritis, Crohn's disease, ulcerative colitis, endometriosis, and potentially COVID-19, sparking interest in using bioelectronic and pharmacological approaches to target α7nAChRs for treating inflammatory conditions in patients. Despite a keen interest, many aspects of the cholinergic pathway are still unknown. α7nAChRs are expressed on many other subsets of immune cells that can affect the development of inflammation differently. There are also other sources of ACh that modify immune cell functions. How the interplay of ACh and α7nAChR on different cells and in various tissues contributes to the anti-inflammatory responses requires additional study. This review provides an update on basic and translational studies of the CAP in inflammatory diseases, the relevant pharmacology of α7nAChR-activated drugs and raises some questions that require further investigation.

A new case of myasthenia gravis following COVID-19 Vaccination

Background: Myasthenia gravis (MG) is an autoimmune disease of unknown etiology. Infections are known as a major cause of MG exacerbations. A few studies have shown an association between new onset MG and SARS-CoV-2 infection. Case presentation: We have reported a case of new onset myasthenia gravis in a 68-year-old man presented with bulbar symptoms a few days after receiving COVID-19 vaccine (Sinopharm vaccine). The disease was confirmed by high titer of antibody against acetylcholine receptor and electrophysiological examinations. Conclusion(s): Among the adverse effects reported with the COVID-19 vaccine, new onset myasthenia gravis is very rare. The underlying mechanism is unknown but the immune response after vaccination and molecular mimicry theory has been proposed.Copyright © 2022

Seroprevalence of COVID-19 among out patients with chronic respiratory disease in a tertiary care hospital in India

Background: Unexpectedly, COVID-19 was less prevalent in Chronic Respiratory Disease(CRD) than in the general population (Gupta N et al. Lung India. 2021;38(5):454-9). The vaccine and infection-related immune status of CRD patients is unknown. Aims and Objectives: Our primary objective was to study the cross sectional seroprevalence among chronic respiratory disease patients attending the Pulmonary medicine outpatients service and comparing it with the national seroprevalence data. Method(s): Consecutive subjects with CRD were recruited. History of past COVID 19 infection and other relevant information was obtained. Blood sample was taken for Roche Elecsys SARS-CoV-2 assay to detect anti-N and anti-S antibodies. Result(s): We recruited 364 patients(Asthma & COPD-100 each, Bronchiectasis, ILD & PTB-sequelae- 50 each and other restrictive diseases-14). The overall seroprevalence in CRD(Anti-S) was 85.16%, which was significantly higher than the 4th national serosurvey seroprevalence of 67.60%(p=0.001) (ICMR, Ministry of Health and Family Welfare;2021). Asthma had the highest seroprevalence, which was higher than COPD [93% vs 78%, p=0.027] and bronchiectasis [93% vs 80%, p=0.018]. Seroprevalence dropped with increasing age: <40 yrs: 93%, 41-60 yrs: 87% and >= 61 yrs: 77% (p=0.004). Patients on inhaled-steroids had higher seroprevalence than those without (89% vs 80%;p=0.026) and those on inhaled-anticholinergics (89% VS 79%;p=0.013). Conclusion(s): COVID-19 seroprevalence is higher in CRD than in the general population. Asthmatics had the highest prevalence and the seroprevalence dropped with increasing age.

Physiological Metrics Collected from Wearable Devices Identify Inflammatory and Clinical Inflammatory Bowel Disease Flares

BACKGROUND: Inflammatory bowel disease (IBD) flares are common and unpredictable. Disease monitoring relies on symptom reporting or single timepoint assessments of stool, blood, imaging, or endoscopy-these are inconvenient and invasive and do not always reflect the patient perspective. Advances in wearable technology allow for passive, continuous and non-invasive assessment of physiological metrics including heart rate variability (HRV), the measure of small time differences between each heartbeat, a marker of autonomic nervous system function. Our group has previously demonstrated that changes in autonomic function precedes an IBD flare, can predict psychological state transitions and even identify inflammatory events including SARS-CoV-2 infection. To develop algorithms that can predict IBD flares using wearable device signatures, we launched a national wearable device study called The IBD Forecast study. To assess data quality and feasibility, the first 125 Apple Watch users to enroll were evaluated. METHOD(S): The IBD Forecast study is a prospective cohort study enrolling anyone >=18 years of age in the United States (US) with IBD who is willing to (1) use a commercially available wearable device, (2) download our custom eHive app and (3) answer daily survey questions. HRV metrics (mean of the standard deviations of all the NN intervals [SDNN]) were analyzed using a mixed-effect cosigner model that incorporated body mass index, age, and sex. SDNN is a time domain HRV index that reflects both sympathetic and parasympathetic nervous system activity and is calculated from the variance of intervals between adjacent QRS complexes (the normal-to-normal [NN] intervals). Clinical flare was assessed with daily Patient Reported Outcome (PRO)-2 surveys (flare;PRO-2 Crohn's disease >7, PRO-2 ulcerative colitis >2). Inflammatory flare was assessed via patient reported C-reactive protein (CRP), with inflammatory flare defined as >5 mg/L. RESULT(S): The first 125 study participants were enrolled across 29 states in the US (Table 1). Circadian features of changes of HRV were modelled (Figure 1). The mesor, or midline of the circadian pattern of the SDNN was higher in those with clinical flare (mean 44.43;95% CI 41.25-47.75) compared to those in clinical remission (mean 43.03;95% CI 39.94-46.22) (p<0.004). The mesor of the circadian pattern of the SDNN was lower in those with an inflammatory flare (mean 38.16;95% CI 30.86-45.72) compared to those with normal inflammatory markers (mean 49.51;95% CI 43.12-56.26) (p<0.001). CONCLUSION(S): Longitudinally collected HRV metrics from a commonly worn commercial wearable device can identify symptomatic and inflammatory flares. This preliminary analysis of a small proportion of the IBD Forecast Study cohort demonstrates the feasibility of using wearable devices to identify, and may potentially predict, IBD flares. (Table Presented).

Dual effects of supplemental oxygen on pulmonary infection, inflammatory lung injury, and neuromodulation in aging and COVID-19.

Clinical studies have shown a significant positive correlation between age and the likelihood of being infected with SARS-CoV-2. This increased susceptibility is positively correlated with chronic inflammation and compromised neurocognitive functions. Postmortem analyses suggest that acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), with systemic and lung hyperinflammation, can cause significant morbidity and mortality in COVID-19 patients. Supraphysiological supplemental oxygen, also known as hyperoxia, is commonly used to treat decreased blood oxygen saturation in COVID-19 patients. However, prolonged exposure to hyperoxia alone can cause oxygen toxicity, due to an excessive increase in the levels of reactive oxygen species (ROS), which can overwhelm the cellular antioxidant capacity. Subsequently, this causes oxidative cellular damage and increased levels of aging biomarkers, such as telomere shortening and inflammaging. The oxidative stress in the lungs and brain can compromise innate immunity, resulting in an increased susceptibility to secondary lung infections, impaired neurocognitive functions, and dysregulated hyperinflammation, which can lead to ALI/ARDS, and even death. Studies indicate that lung inflammation is regulated by the central nervous system, notably, the cholinergic anti-inflammatory pathway (CAIP), which is innervated by the vagus nerve and α7 nicotinic acetylcholine receptors (α7nAChRs) on lung cells, particularly lung macrophages. The activation of α7nAChRs attenuates oxygen toxicity in the lungs and improves clinical outcomes by restoring hyperoxia-compromised innate immunity. Mechanistically, α7nAChR agonist (e.g., GAT 107 and GTS-21) can regulate redox signaling by 1) activating Nrf2, a master regulator of the antioxidant response and a cytoprotective defense system, which can decrease cellular damage caused by ROS and 2) inhibiting the activation of the NF-κB-mediated inflammatory response. Notably, GTS-21 has been shown to be safe and it improves neurocognitive functions in humans. Therefore, targeting the α7nAChR may represent a viable therapeutic approach for attenuating dysregulated hyperinflammation-mediated ARDS and sepsis in COVID-19 patients receiving prolonged oxygen therapy.

The potential for traditional Chinese therapy in treating sleep disorders caused by COVID-19 through the cholinergic anti-inflammatory pathway.

Since the outbreak of Coronavirus disease (COVID-19) in 2019, it has spread rapidly across the globe. Sleep disorders caused by COVID-19 have become a major concern for COVID-19 patients and recovered patients. So far, there's no effective therapy on this. Traditional Chinese therapy (TCT) has a great effect on sleep disorders, with rare side effects and no obvious withdrawal symptoms. The cholinergic anti-inflammatory pathway, a neuroregulatory pathway in the central nervous system that uses cholinergic neurons and neurotransmitters to suppress inflammatory responses, has been reported to be associated with sleep disorders and psychiatric symptoms. Many studies have shown that TCT activates the cholinergic anti-inflammatory pathway (CAP), inhibits inflammation, and relieves associated symptoms. Therefore, we believe that TCT may be a potential therapeutic strategy to alleviate sleep disorders induced by COVID-19 through CAP. In this review, we analyzed the relationship between cytokine storm induced by Coronavirus and sleep disorders, explained the influence of CAP on sleep disorders, discussed the TCT's effect on CAP, and summarized the treatment effect of TCT on sleep disorders. Based on these practical researches and theoretical basis, we propose potential strategies to effectively improve the sleep disorders caused by COVID-19.

Cholinergic dysfunction in COVID-19: frantic search and hoping for the best.

A novel coronavirus known as severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is a potential cause of acute respiratory infection called coronavirus disease 2019 (COVID-19). The binding of SARS-CoV-2 with angiotensin-converting enzyme 2 (ACE2) induces a series of inflammatory cellular events with cytopathic effects leading to cell injury and hyperinflammation. Severe SARS-CoV-2 infection may lead to dysautonomia and sympathetic storm due to dysfunction of the autonomic nervous system (ANS). Therefore, this review aimed to elucidate the critical role of the cholinergic system (CS) in SARS-CoV-2 infection. The CS forms a multi-faceted network performing diverse functions in the body due to its distribution in the neuronal and non-neuronal cells. Acetylcholine (ACh) acts on two main types of receptors which are nicotinic receptors (NRs) and muscarinic receptors (MRs). NRs induce T cell anergy with impairment of antigen-mediated signal transduction. Nicotine through activation of T cell NRs inhibits the expression and release of the pro-inflammatory cytokines. NRs play important anti-inflammatory effects while MRs promote inflammation by inducing the release of pro-inflammatory cytokines. SARS-CoV-2 infection can affect the morphological and functional stability of CS through the disruption of cholinergic receptors. SARS-CoV-2 spike protein is similar to neurotoxins, which can bind to nicotinic acetylcholine receptors (nAChR) in the ANS and brain. Therefore, cholinergic receptors mainly nAChR and related cholinergic agonists may affect the pathogenesis of SARS-CoV-2 infection. Cholinergic dysfunction in COVID-19 is due to dysregulation of nAChR by SARS-CoV-2 promoting the central sympathetic drive with the development of the sympathetic storm. As well, nAChR activators through interaction with diverse signaling pathways can reduce the risk of inflammatory disorders in COVID-19. In addition, nAChR activators may mitigate endothelial dysfunction (ED), oxidative stress (OS), and associated coagulopathy in COVID-19. Similarly, nAChR activators may improve OS, inflammatory changes, and cytokine storm in COVID-19. Therefore, nAChR activators like varenicline in virtue of its anti-inflammatory and anti-oxidant effects with direct anti-SARS-CoV-2 effect could be effective in the management of COVID-19.

Action of the Purinergic and Cholinergic Anti-inflammatory Pathways on Oxidative Stress in Patients with Alzheimer's Disease in the Context of the COVID-19 Pandemic.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of the 2019 coronavirus disease (COVID-19), has affected more than 20 million people in Brazil and caused a global health emergency. This virus has the potential to affect various parts of the body and compromise metabolic functions. The virus-mediated neural inflammation of the nervous system is due to a storm of cytokines and oxidative stress, which are the clinical features of Alzheimer's disease (AD). This neurodegenerative disease is aggravated in cases involving SARS-CoV-2 and its inflammatory biomarkers, accelerating accumulation of ß-amyloid peptide, hyperphosphorylation of tau protein, and production of reactive oxygen species, which lead to homeostasis imbalance. The cholinergic system, through neurons and the neurotransmitter acetylcholine (ACh), modulates various physiological pathways, such as the response to stress, sleep and wakefulness, sensory information, and the cognitive system. Patients with AD have low concentrations of ACh; hence, therapeutic methods are aimed at adjusting the ACh titers available to the body for maintaining functionality. Herein, we focused on acetylcholinesterase inhibitors, responsible for the degradation of ACh in the synaptic cleft, and muscarinic and nicotinic receptor agonists of the cholinergic system owing to the therapeutic potential of the cholinergic anti-inflammatory pathway in AD associated with SARS-CoV-2 infection.

The Role of the Acetylcholine System in Common Respiratory Diseases and COVID-19.

As an indispensable component in human beings, the acetylcholine system regulates multiple physiological processes not only in neuronal tissues but also in nonneuronal tissues. However, since the concept of the "Nonneuronal cholinergic system (NNCS)" has been proposed, the role of the acetylcholine system in nonneuronal tissues has received increasing attention. A growing body of research shows that the acetylcholine system also participates in modulating inflammatory responses, regulating contraction and mucus secretion of respiratory tracts, and influencing the metastasis and invasion of lung cancer. In addition, the susceptibility and severity of respiratory tract infections caused by pathogens such as Mycobacterium Tuberculosis and the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) can also correlate with the regulation of the acetylcholine system. In this review, we summarized the major roles of the acetylcholine system in respiratory diseases. Despite existing achievements in the field of the acetylcholine system, we hope that more in-depth investigations on this topic will be conducted to unearth more possible pharmaceutical applications for the treatment of diverse respiratory diseases.

Is the post-COVID-19 syndrome a severe impairment of acetylcholine-orchestrated neuromodulation that responds to nicotine administration?

Following a SARS-CoV-2 infection, many individuals suffer from post-COVID-19 syndrome. It makes them unable to proceed with common everyday activities due to weakness, memory lapses, pain, dyspnea and other unspecific physical complaints. Several investigators could demonstrate that the SARS-CoV-2 related spike glycoprotein (SGP) attaches not only to ACE-2 receptors but also shows DNA sections highly affine to nicotinic acetylcholine receptors (nAChRs). The nAChR is the principal structure of cholinergic neuromodulation and is responsible for coordinated neuronal network interaction. Non-intrinsic viral nAChR attachment compromises integrative interneuronal communication substantially. This explains the cognitive, neuromuscular and mood impairment, as well as the vegetative symptoms, characterizing post-COVID-19 syndrome. The agonist ligand nicotine shows an up to 30-fold higher affinity to nACHRs than acetylcholine (ACh). We therefore hypothesize that this molecule could displace the virus from nAChR attachment and pave the way for unimpaired cholinergic signal transmission. Treating several individuals suffering from post-COVID-19 syndrome with a nicotine patch application, we witnessed improvements ranging from immediate and substantial to complete remission in a matter of days.

A randomized clinical trial to stimulate the cholinergic anti-inflammatory pathway in patients with moderate COVID-19-pneumonia using a slow-paced breathing technique.

Purpose: A characteristic problem occurring in COVID-19 is excessive elevations of pro-inflammatory cytokines (e.g. IL-6 and CRP) which are associated with worse clinical outcomes. Stimulation of the vagally-mediated cholinergic anti-inflammatory reflex by slow paced breathing with prolonged exhalation may present a clinically relevant way to reduce circulating IL-6. Method: Single-center randomized controlled clinical trial with enrolment of 46 patients hospitalized with confirmed severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) infection and moderate COVID-19 pneumonia (primary diagnosis). Differences between intervention (4sec inhalation, 6sec exhalation for 20 minutes 3x daily) and control group in IL-6 calculated using multilevel mixed-effect linear regression models with random slope including the covariates relevant comorbidities, COVID-19 medication, and age. Both groups received standard care. Results: Mean age was 57 years ± 13 years, N= 28 (60%) male, N=30 (65%) with relevant comorbidities. The model including group-by-time interaction revealed a significantly lower trajectory of IL-6 in the intervention group (effect size Cohens f2 = 0.11, LR-test p=.040) in the intention-to-treat sample, confirmed by per-protocol analysis (f2 = 0.15, LR-test p=.022). Exploratory analysis using the median split of practice time to predict IL-6 of the next morning indicated a dose-response relationship with beneficial effects of practice time above 45 minutes per day. Oxygen saturation remained unchanged during slow-paced breathing (95.1% ± 2.1% to 95.4% ± 1.6%). Conclusion: Patients practicing slow-paced breathing had significantly lower IL-6 values than controls with a small to medium effect size and without relevant side effects. Further trials should evaluate clinical outcomes and an earlier start of the intervention. Slow-paced breathing could be an easy to implement, low-cost, safe and feasible adjuvant therapeutic approach to reduce circulating IL-6 in moderate COVID-19 pneumonia. Clinical Trial Registration: https://www.drks.de, identifier DRKS00023971, Universal Trial Number (UTN) U1111-1263-8658.

SEROPOSITIVE MYASTHENIA GRAVIS AS THE CAUSE OF MULTIPLE FAILED EXTUBATIONS AND A PROLONGED ICU STAY FOR COVID-19 PNEUMONIA: A CASE REPORT AND BRIEF LITERATURE REVIEW

SESSION TITLE: Autoimmune Disorders: Both Primary and Secondary SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/18/2022 10:15 am - 11:10 am INTRODUCTION: Neurologic sequelae of COVID infection appear to be common. The infection may present with neurologic symptoms, unmask neurologic disease, or worsen established disease. Myasthenia gravis (MG) is an autoimmune neuromuscular disease (NMD) that does not appear to be a usual COVID sequela. We present an elderly veteran with COVID pneumonia who struggled to wean from mechanical ventilation (MV) secondary to neuromuscular weakness. He was ultimately diagnosed with seropositive MG. CASE PRESENTATION: A 79 year old male with a history of prior COVID infection complicated by need for mechanical ventilation (MV) complained of progressive cough and shortness of breath. He was admitted for treatment of community-acquired pneumonia. On hospital day 8, he developed respiratory failure, was intubated, and was transferred to the intensive care unit (ICU). He was diagnosed with COVID a second time. After antibiotics and supportive treatment, he successfully completed a spontaneous breathing trial and was extubated. Within 24 hours, he developed hypercapnia, necessitating reintubation. Given his need for repeat intubations, we ordered myositis titers and MG autoantibodies. After a fourth failed extubation, a tracheostomy was placed. On hospital day 32, his acetylcholine receptor binding antibody returned positive at 30.0, suggesting seropositive MG. His MG composite score was 11 (for ptosis and ventilator dependence). For further work-up, a CT chest excluded thymoma;a focused neurological exam was limited by sedation, and inpatient electrodiagnostics were not feasible. He received 5 days of intravenous immune globulin (40 mg), a Prednisone taper, and Rivastigmine 60 mg thrice daily. His symptoms improved and he was transferred to the floor. DISCUSSION: It is well established that coronaviruses exhibit neurotropism. However, it is unclear whether the novel coronavirus SARS-CoV-2 unmasks underlying neurologic illness or creates de novo disease. Critical care physicians are often tasked with making an initial diagnosis of neuromuscular disease (NMD). NMD is a known cause of complicated extubations. When the diaphragm and accessory respiratory muscles fatigue, respiratory decompensation ensues as full MV support is removed. In many cases, underlying illness is unmasked during this process of extubation. In our case, it is unknown whether infectious insult led to molecular mimicry and development of autoantibodies or unmasked latent neuromuscular disease. If the infection did cause his disease, it would be one of the first cases of COVID-associated MG to be published. Our case is a reminder that NMD is a secondary cause of extubation failure and may suggest MG as a cause of MV weaning failure secondary to COVID. CONCLUSIONS: Critical care physicians should be aware of this potential neuromuscular complication of COVID infection as it may complicate MV weaning, increase vent days, and prolong ICU stays. Reference #1: Collantes MEV, Espiritu AI, Sy MCC, Anlacan VMM, Jamora RDG. Neurological manifestations in covid-19 infection: A systematic review and meta-analysis. Can J Neurol Sci. 2021 Jan;48(1):66-76. Doi: 10.1017/cjn.2020.146. Epub 2020 Jul 15. PMID: 32665054. Reference #2: Huber M, Rogozinski S, Puppe W, Framme C, Hoglinger G, Hufendiek K, Wegner F. Postinfectious onset of myasthenia gravis in a COVID-19 patient. Front Neurol. 2020 Oct 6;11:576153. Doi: 10.3389/fneur.2020.576153. eCollection 2020. PMID: 33123081. Reference #3: Muralidhar Reddy Y, B SK, Osman S, Murthy JMK. Temporal association between SARS-CoV-2 and new-onset myasthenia gravis: Is it causal or coincidental? BMJ Case Rep. 2021 Jul 21;14(7):e244146. Doi: 10.1136/bcr-2021-244146. PMID: 34290032. DISCLOSURES: No relevant relationships by Jeffrey Li No relevant relationships by Anupa Nadkarni No relevant relationships by Justin Owens No relevant relationships by Jennifer Perry no disclosure on file for Hayley Sp res;

PROGRESSIVE ASCENDING WEAKNESS AFTER THE PFIZER/BIONTECH COVID-19 VACCINE

SESSION TITLE: Autoimmune Disorders: Both Primary and Secondary SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/18/2022 10:15 am - 11:10 am INTRODUCTION: Myasthenia gravis (MG) occurs sporadically with no known causes. We present a rare case of new onset MG s/p COVID-19 vaccination. CASE PRESENTATION: A healthy 46-year-old female presented with progressing LE weakness for 3 months. Symptoms started 5 days after her initial Pfizer COVID-19 vaccine. Her workup showed negative neuroimaging, bland basic CSF studies from LP, with negative MS profile and AChR Ab. She presented again in 1 month with difficulty rising from a seated position, raising her arms above her head with blurry vision. Exam showed bilateral ptosis that improved with an ice pack test, weakness is worst in proximal muscles, but normal reflexes. Workup was again negative. Pyridostigmine was added after discharge (DC). 2 months after, she was admitted to the ICU for acute progressive fatiguability and dyspnea. EMG/NCS of the ulnar nerve showed 60-70% electrical decrement. She underwent therapeutic PLEX. Prednisone was added at DC followed by mycophenolate. 2 weeks later, she was again admitted with myasthenic crisis. She again underwent PLEX with improvement and intubation was avoided. Biweekly PLEX was started at DC. Testing for AChR, MuSK, and LRP4 Abs were initially negative, but AChR Abs were present 6 months later. She then underwent thymectomy showing hyperplasia. DISCUSSION: MG exacerbations have been attributable to infections (50%) and medications (30%). This has worsened during the COVID-19 pandemic especially when medications such as azithromycin were used to treat acute infections. While vaccine-induced flares or onset of autoimmune diseases have been described in literatures, new onset MG following vaccines is rare, limited to 1 to 3 case reports. No case, to our knowledge, correlated to the 1st dose like our patient. The temporal relationship between the COVID-19 vaccination and onset of MG symptoms in our patient could represent a correlation, but does not prove causality. Perhaps a more plausible theory is that the vaccine may have unmasked a previously unrecognized disease in high-risk patient. We ask if the COVID vaccine induces a similar cytokine storm, which hyperstimulates the immune system to a point that breaks immunologic self-tolerance. Interestingly, our patient was initially seronegative, but the presence of AChR Ab was confirmed after sensitive cell-based assays testing. Our patient may have had pre-existing self-antigens to the AChR that were released after receiving the Pfizer COVID-19 vaccine. CONCLUSIONS: The rate of COVID-19 vaccinations will soon surpass that of infections placing vulnerable individuals at risk for MG onset. Recognizing this risk will open discussions about vaccine safety. In doing so, we can begin to formulate new parameters for post-vaccination monitoring. The risks of and complications from acute COVID-19 still outweigh the rare adverse events from vaccines;thus, eligible patients should be offered the COVID-19 vaccine. Reference #1: Guidon AC, Amato AA. COVID-19 and neuromuscular disorders. Neurology. 2020 Jun 2;94(22):959-969. doi: 10.1212/WNL.0000000000009566. Epub 2020 Apr 13. PMID: 32284362. Reference #2: Tagliaferri AR, Narvaneni S, Azzam MH, Grist W. A Case of COVID-19 Vaccine Causing a Myasthenia Gravis Crisis. Cureus. 2021;13(6):e15581. Published 2021 Jun 10. doi:10.7759/cureus.15581 Reference #3: Chavez A, Pougnier C. A Case of COVID-19 Vaccine Associated New Diagnosis Myasthenia Gravis. Journal of Primary Care & Community Health. January 2021. doi:10.1177/21501327211051933 DISCLOSURES: No relevant relationships by andrew bui No relevant relationships by Sharonya Shrivastava