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Abstract

A potential relationship between COVID-19 infection and new onset myasthenia gravis (MG) has been suggested by the coexistence of these two diseases in a number of reports. This study aimed to assess their relationship by reviewing case studies of COVID-19 followed by new onset MG published between 01 December 2019 and 30 June 2023 identified by a search of PubMed/Medline database. In addition, we reviewed evidence in favour and against a potential cause and effect association, and described possible mechanisms that would underpin such a relationship. We identified 14 publications that reported 18 cases. Analysis showed the following features: age 19–83 years; 10 men/8 women; median time interval between COVID-19 and MG (17, 5–56 days); autoimmune comorbidities (4); generalised MG (14); ocular MG (4); thymoma (3); antiacetylcholine receptor antibody (16); antimuscle-specific kinase antibodies (2). All patients improved following treatment. Proof of direct causality between the two conditions can only be established in time by confirming epidemiological increase in the incidence of MG or elucidating pathogenic mechanisms to substantiate a possible cause-effect association, or both.

Keywords

Autoimmune myasthenia gravis COVID-19

Background

Autoimmune myasthenia gravis (MG) is a disorder caused by immune-mediated destruction and/or dysfunction of the postsynaptic component of the neuromuscular junction (NMJ), which produces a blockage in transmission of nerve impulses.¹ From an immunopathological point of view, autoimmune MG is a prototype autoimmune disorder mediated by B cells and dependent on T helper cells (Th) as the main culprits are autoantibodies directed against various components of the NMJ.² Although the pathogenesis of MG is well characterised and is one of the best understood autoimmune disorders, its causes have not been precisely elucidated. The general consensus is that MG, like many other autoimmune non-monogenic diseases, is a multi-factorial disorder, triggered through epigenetic mechanisms by several exogenous factors which bombard an individual genetically predisposed to autoimmunity.³^,⁴ Certain viruses, such as Epstein-Barr virus (EBV), human immunodeficiency viruses (HIV), poliomyelitis virus or human T lymphocyte oncovirus, have been proposed as plausible external triggers.¹^,⁵

Coronavirus disease 2019 (COVID-19) produced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first isolated in Wuhan, China, in December 2019. In addition to its acute, primarily respiratory manifestations, the virus also affected other organ systems.⁶ Several studies identified numerous neurological symptoms as COVID-19 complications; these varied from localized effects, such as anosmia/hyposmia, to more generalized symptoms such as headache, vertigo, mood changes, fatigue and muscle pain.⁷ Reports suggest that most of the neurological symptoms and syndromes associated with COVID-19 target the central nervous system (CNS) (i.e., cerebrovascular diseases, encephalitis/encephalopathy, multiple sclerosis and anti-myelin oligodendrocyte glycoprotein antibody-associated disease).⁸ However, there have been reported cases of Guillain-Barré Syndrome, Miller-Fischer Syndrome and other peripheral neuropathies potentially associated with COVID-19.⁹^,¹⁰ In addition, there are a few reports of damage to the NMJ as a complication of SARS-CoV-2 infection.¹¹

A potential relationship between COVID-19 and MG has been suggested by the coexistence of these two diseases in a number of reports. ¹² Several investigators have reported the evolution of COVID-19 in patients with pre-existing MG and outline risk factors such as long-term corticosteroid therapy, recent rituximab treatment or old age, that lead to unfavourable outcomes.¹³^,¹⁴ Conversely, cases of new-onset autoimmune MG have been reported worldwide by several groups, following COVID-19 or any type of vaccination against it.^15–34 Moreover, one study reported a case in which MG appeared as an initial symptom of COVID-19.³⁵

The purpose of this present review was to assess the relationship between COVID-19 infection and new onset MG by reviewing case studies published between 01 December 2019 and 30 June 2023 identified by a search of PubMed/Medline database. In addition, we reviewed evidence in favour and against a potential cause and effect association, and described possible mechanisms that would underpin such a relationship.

Myasthenia gravis

The clinical consequence of immune-mediated transmission blockage at the NMJ is the presence of the myasthenic phenomenon, defined as muscle fatigability that is exacerbated during sustained muscle activity and diminishes gradually in the resting state.¹ At onset, the muscles most often involved are the extrinsic ocular muscles, followed by the pharyngeal and laryngeal muscles, while proximal limb muscles and respiratory muscles are seldomly affected.¹^,³⁶ Therefore, MG most frequently manifests at onset with diplopia and palpebral ptosis, closely followed by dysphagia and dysphonia.¹ During its course, limb weakness or generalized weakness occurs, with episodes of acute respiratory failure.^1,36 A positive diagnosis of MG is supported by a minimum of one of the following paraclinical criteria: elevated serum titers of antibodies directed against various structures of the postsynaptic components of the NMJ; a decrement of >10% in slow repetitive nerve stimulation (RNS); increased jitter during single-fibre electromyography (SF-EMG).¹^,^36,37

MG is heterogeneous in terms of its many clinical and paraclinical characteristics that vary between patients and have an impact on its management and prognosis. The condition is classified as a generalized form or a pure ocular form, the latter being more frequent in the Asian population.³⁸ According to the onset age of 50 years, generalized MG can be subdivided into early-onset MG (EOMG) and late-onset MG (LOMG).³⁹ EOMG is more frequent among women that have thymic hyperplasia and elevated titers of anti-acetylcholine receptor (AchR) antibodies, while LOMG usually occurs in men with no thymus abnormalities.^40,41 Overall, 10–15% of patients with MG have a thymoma, while 30–45% of patients with thymomas have MG.³⁶^,⁴² Antibodies against AchR have been detected in approximately 85% of patients with generalized MG, in 40% of patients with ocular MG cases and in all cases associated with thymoma.^43–45 Some patients (1–10%) have autoantibodies against muscle specific receptor tyrosine-kinase (MuSK) or lipoprotein receptor-related protein 4 (LRP4) (7%).⁴⁶^,⁴⁷ Striatal structures such as ryanodine receptor, titin and voltage-gated potassium channel Kv, are mainly encountered in cases with thymoma.⁴⁶^,⁴⁷

Viral infections as possible triggers of MG

The thymus is believed to play a central role in the pathogenesis of MG because it is the primary lymphoid organ where thymocytes undergo positive and negative selection to become mature, functioning T lymphocytes.⁴⁷ Abnormalities in the expression of AchR α subunits on the surface of medullar thymic epithelial cells generate anti-AchR-specific T cells.⁴⁸ The intrathymic activation of these particular T cells marks the beginning of the immunopathogenesis of MG, that leads to the export into the peripheral immune system of autoreactive anti-AchR Th cells, which in turn stimulate B cells to produce autoantibodies.⁴⁸ However, the initial cause that triggers these immunopathological events is yet to be identified. Previous viral infections have been implicated because several studies have detected high levels of interferon type I and II in the thymus of myasthenic patients. These cytokines, which are produced as a response to infection, have been shown to increase AchR α subunit expression on thymic epithelial and myoid cells.⁴⁹ Moreover, EBV has been isolated from hyperplasic thymic tissues harvested from patients with MG.⁵ Despite the lack of evidence establishing a direct causality, EBV remains a plausible candidate due to its ability to stimulate the activation and survival of infected B cells.⁴⁹

Several mechanisms have been suggested as the means by which infections can generate autoimmunity. One mechanism is molecular mimicry, which can generate cross-reactivity. According to this mechanism, an initial immune response triggered by an infection generates a much wider immune reaction, leading to the release of T lymphocytes that attack self-antigens that are structurally similar to those of the initial infectious pathogen.⁵⁰ Another mechanism is epitope spreading by which the immune response to an infection expands towards non-dominant epitopes situated on both the same and different peptides.⁵¹ A third mechanism is bystander activation which follows initial localized inflammation caused by an infectious agent and implies an antigen independent activation of autoreactive B and T cells, which extends outside the initially affected site.⁵²

Over the past decade, the focus on autoimmunity has shifted from the adaptive immune system to the innate one. More precisely, the latter appears to be the missing link between infections and autoimmunity, because the Toll-like receptors (TLR) activated by several pathogens can trigger not only innate immune reactions but also activate the adaptive immune response.⁵³ The alteration of the thymic microenvironment, as is the case for EBV infection, and the activation of antigen-presenting cells by TLR will have important effects on cells of the adaptive immune system; activation of autoreactive T cells and dysfunction of T regulatory cells (Treg) are thought to drive the autoimmune response.⁴⁹ A rationale for its validity in MG is the fact that high concentrations of certain TLRs, especially TLR 4 and TLR 3, have been isolated from the thymus of myasthenic patients.⁴⁹^,⁵⁴ Additionally, high levels of TLR 7 and TLR 9 were detected in the thymus of patients with MG and active EBV infection.⁵⁵ Moreover, intrathymic titers of TLR 7 correlated with high levels of interferon β.⁵⁵ Further support for this hypothesis was provided by an in vivo and in vitro study, that found double-stranded ribonucleic acid (RNA) signalling via TLR 3 lead to AchR hyper expression on the surface of thymic epithelial cells.⁵⁴ Therefore, evidence suggests viral infections are implicated, since TLR3 and TLR7 recognize viral single- or double- stranded RNA.⁵⁶

New-onset MG post SARS-COV-2 infection

The incidence of MG is low; one systematic review estimated 0.25–2.0 per 1,000,000 per year and another slightly higher at 3–30 per 1,000,000 per year. ⁵⁷^,⁵⁸ Accordingly, there is a paucity of data on MG as a complication of SARS-CoV-2 infection. However, in spite of the rarity, a potential cause-effect relationship has been suggested by several cases of new-onset autoimmune MG following COVID-19 infecton.¹²

We searched the PubMed/Medline database for studies in adults published between 01 December 2019 and 30 June 2023 using “new-onset”, “autoimmune Myasthenia gravis”, “COVID-19”, “SARS-CoV-2 infection” and “post-infectious” as keywords/terms. There was no specificity for language. We excluded juvenile MG because it has a different differential diagnosis and management approach. Furthermore, we did not include cases of MG aggravated post SARS-CoV-2 infection, because these have already been the subject of a previous review.⁵⁹

Our literature search identified 14 publications that reported 18 cases in the specified time frame (Table 1).^15–28 An additional publication that presented the case of an 86-year-old man with generalized muscle weakness, diplopia, ocular ptosis and dyspnoea in the subacute phase of COVID-19 was inconclusive.⁶⁰ For this patient, the diagnosis of MG was not supported by paraclinical investigations (i.e., no data were provided on RNS, SF-EMG or edrophonium/neostigmine test, and AchR and MuSK antibodies were within the normal range). Considering the fact that a differential diagnosis with other central or peripheral nervous system diseases was unclear (i.e., lack of data regarding brain MRI, electroencephalogram or cerebrospinal fluid analysis), this case was more suggestive of a mitochondrial disorder than MG.⁶¹ In all publications included in our literature review, MG diagnosis was supported by clinical features and specific paraclinical investigations (i.e., RNS and/or serum levels of antibodies against AchR, MuSK, titin or LRP4). In some cases, SF-EMG was performed. All patients had undergone chest computed tomography (CT) or MRI to assess their thymic morphology and brain CT or MRI to exclude other possible neurological disorders. However, in one report from a 48-year-old Spanish man, there was no mention of RNS/SF-EMG and myasthenic symptoms were reported to have disappeared completely by the second day of hospitalization.¹⁵ In spite of these concerns, we included this case in our review because the patient had elevated titers of AchR antibodies and MG was the most probable cause. In a case from the USA, also without RNS/SF-EMG data, an 83-year-old man was diagnosed as having MG based on elevated serum titres of antibodies against AchR and positive response to corticosteroids and azathioprine.²⁸ While he had signs and symptoms of COVID-19, no details of laboratory diagnosis were provided in the case report. In all other cases, a positive COVID-19 diagnosis was made by nasopharyngeal/sputum/cerebrospinal fluid swab reverse transcriptase polymerase chain reaction (RT-PCR) positive for SARS-CoV-2, or by serum levels of SARS-CoV-2 antibodies.

Table 1.

Main features of the 18 cases of new onset autoimmune Myasthenia Gravis post COVID-19 infection.

No.	Reference	Country	Sex	Age, y	Autoimmune comorbidities and/or family history	SARS-CoV-2 diagnosis	Time interval COVID-19 to MG, days	Clinical panel of MG	Abnormal serum autoantibodies	RNS and/or SFEMG	Thymus pathology
1	Pérez Álvarez et al. 2020¹⁵	Spain	M	48	Psoriasis	RT-PCR (sputum; chest CT	10	Diplopia (OMG)	anti-AchR elevated	–	None
2	Restivo et al. 2020¹⁶	Italy	M	64	None	RT-PCR (nasopharyngeal)	5	Diplopia, limb weakness	anti-AchR elevated	RNS abnormal decrement	None
3	Restivo et al. 2020¹⁶	Italy	M	68	None	RT-PCR (nasopharyngeal)	7	Diplopia, dysphagia, limb weakness	anti-AchR elevated	RNS abnormal decrement	None
4	Restivo et al. 2020¹⁶	Italy	F	71	None	RT-PCR (nasopharyngeal); chest CT	5	Diplopia, palpebral ptosis, hypophonia, dysphagia, respiratory failure	anti-AchR elevated	RNS abnormal decrement	None
5	Huber, et al. 2020¹⁷	Germany	F	21	Hashimoto’s thyroiditis	Negative RT-PCR (nasopharyngeal, CSF); serum SARS-CoV-2 antibodies	21	Diplopia, palpebral ptosis (OMG)	anti-AchR elevated	No decrement in RNS	None
6	Sriwastava et al. 2021¹⁸	USA	F	65	None	RT-PCR (nasopharyngeal)	11	Palpebral ptosis, diplopia (OMG)	anti-AchR elevated; anti-striational antibodies elevated	RNS abnormal decrement	None
7	Muhammed et al. 2021 ¹⁹	UK	F	24	None	serum SARS-CoV-2 antibodies	28	Diplopia, palpebral ptosis, dysphagia, dysphonia, limb weakness	anti-MuSK – elevated	RNS abnormal decrement; abnormal SFEMG	None
8	Bhandarwar et al. 2021²⁰	India	M	61	None	RT-PCR (nasopharyngeal); chest CT	56	Dysphagia, dyspnoea, limb weakness	anti-AchR elevated	–	initial chest CT – normal thymus; chest CT repeated at 8 weeks – thymoma
9	Muralidhar Reddy et al. 2021²¹	India	M	65	None	RT-PCR (nasopharyngeal); serum SARS-CoV-2 Ab,	42	Dysphagia, dysphonia	anti-AchR elevated	RNS abnormal decrement	None
10	Karimi et al. 2021²²	Iran	F	61	None	RT-PCR (nasopharyngeal); chest CT	32	Dysphagia, dysphonia, palpebral ptosis, diplopia, dyspnoea, limb weakness	anti-AchR elevated	RNS abnormal decrement	thymoma
11	Karimi et al. 2021²²	Iran	M	57	None	RT-PCR (nasopharyngeal); chest CT	10	diplopia, palpebral ptosis, dysphagia, limb weakness	anti-AchR elevated	RNS abnormal decrement	None
12	Karimi et al. 2021²²	Iran	F	38	None	RT-PCR (nasopharyngeal); chest CT	28	Palpebral ptosis, dysphagia, diplopia, limb weakness	anti-AchR elevated	RNS abnormal decrement	None
13	Assini et al. 2021²³	Italy	M	77	None	RT-PCR (nasopharyngeal); chest CT	56	Dysphagia, dysphonia, diplopia, palpebral ptosis	anti-MuSK repeated at 3m using cell-based- immunoassay elevated	RNS abnormal decrement	None
14	Taheri et al. 2022²⁴	Iran	F	35	None	RT-PCR (nasopharyngeal; chest CT	11	Limb weakness, diplopia, palpebral ptosis,	anti-AchR elevated	abnormal SFEMG	None
15	Croitoru et al. 2022²⁵	Romania	M	78	None	RT-PCR (nasopharyngeal); chest CT	9	Diplopia, palpebral ptosis, dysphonia, dysphagia	anti-AchR elevated	RNS abnormal decrement	None
16	De Giglio et al. 2023²⁶	Italy	M	74	Graves’ disease	RT-PCR (nasopharyngeal)	30	Diplopia (OMG)	anti-AchR elevated	abnormal SFEMG	None
17	Tereshko et al. 2023²⁷	Italy	F	19	Hashimoto’s thyroiditis, autoimmune gastritis	RT-PCR (nasopharyngeal)	13	Dysphonia, dysphagia, diplopia, palpebral ptosis	anti-AchR elevated	abnormal decrement, abnormal SFEMG	thymic hyperplasia
18	Chatterjee et al. 2022²⁸	USA	M	83	None	–	28	limb weakness, dyspnoea, dysphonia, dysphagia, bilateral ptosis	anti-AchR elevated	–	None

Abbreviations: AchR, acetylcholine receptor; CSF, cerebrospinal fluid; CT, computed tomography; F, female; M, male; MG, myasthenia gravis; MuSK, muscle specific receptor tyrosine-kinase; OMG, ocular myasthenia gravis; RNS, repetitive nerve stimulation; RT-PCR, reverse transcriptase polymerase chain reaction; SFEMG, single-fibre electromyography; - not reported;

The 18 cases we identified originated from four continents: Europe (10 cases); Middle East (4 cases); Asia (2 cases); North America (2 cases). There were 10 male and 8 female patients and ages ranged from 19–83 years. Two thirds of the cases (12) were LOMG, with a male predominance (9 men, 3 women), while for EOMG subgroup (6 cases) the majority were women (5 women, one man). Of the 18 patients, only 4 had autoimmune comorbidities (i.e., psoriasis, Grave’s disease, Hashimoto’s thyroiditis and Hashimoto’s thyroiditis and autoimmune gastritis), the remainder did not have any personal nor familial history of autoimmune diseases. Fourteen patients presented with generalized symptoms of MG and 4 patients had only ocular myasthenic symptoms. Elevated anti-AchR antibodies were reported in 16 cases, and elevated anti-MuSK antibodies were reported in 2 cases. However, in 8 case reports, anti-MuSK antibodies were not mentioned at all. In one of the two cases, where anti-MuSK antibodies were reported, the standard radioimmunoassay method yielded a negative result, but at three months from the onset of the myasthenic symptoms, anti-MuSK antibodies were detected using a cell-based immunoassay.²³

Chest CT scans showed that 15 cases had no evidence of thymus modifications. Thymoma was reported in 2 cases. In one of these cases, thymoma was not detected on the first chest CT, but a second CT, eight weeks later showed thymus modifications.²⁰ In a third case, while chest MRI showed no thymic abnormalities, histological analysis after thymic resection confirmed thymic hyperplasia.²⁷

The median time interval between COVID-19 and the clinical onset of MG was 17 days (range 5–56 days). In one case study, MG onset emerged post COVID-19 infection which followed an anti-SARS-CoV-2 booster dose vaccination.²⁵ The patient had no paraclinical signs of immunodeficiency. We suggest that this patient may have had an aberrant/abnormal immune response to SARS-CoV-2 antigens. In spite of receiving his third dose of vaccine, he contracted COVID-19, which could have initiated myasthenic pathogenesis. However, his previous recent anti-SARS-CoV-2 vaccinations could have enhanced an aberrant immune response triggered by the SARS-CoV-2 infection.

In all cases, myasthenic outcome improved following various combinations of five classes of treatment (i.e., acetylcholinesterase inhibitors; corticosteroids; plasmapheresis; human immunoglobulins; inhibitors of purine synthesis [e.g., azathioprine]).

Discussion

Despite new case reports emerging, the evidence for the link between new-onset MG following COVID-19 infection remains controversial. Given the low incidence of MG, the association may be purely coincidental.⁵⁸ Ideally, wide, population-based incidence studies would provide an accurate answer. Nevertheless, it is generally acknowledged that other coronaviruses similar in structure to SARS-CoV-2, such as Middle East Respiratory Syndrome coronavirus and SARS can cause various myopathies and neuropathies and other neuromuscular disorders.⁶²^,⁶³ Moreover, cases of new-onset MG have been reported following several different viral infections (i.e., hepatitis C and B viruses, herpes simplex virus, HIV, West Nile virus and Zika virus) although no direct causal link has been proven.¹^,⁵^,⁶⁴ The key may well reside in the intricate abnormalities of the human immune system induced by SARS-CoV-2, some of them being common to the pathogenesis of autoimmune MG

Interestingly, none of the 18 cases included in our review presented direct evidence that MG was a de novo disease caused by a viral infection, or that autoimmunity was latent/subclinical and had been exacerbated by the viral infection. The pre-existence of latent MG was a probability in the three cases with thymoma or thymic hyperplasia, because the immunopathogenic role of a “sick thymus” in generating MG has been previously established.⁶⁵ However, for the remaining 15 cases, where no thymic abnormalities were detected, the scarceness of personal and/or familial autoimmune disorders tends to tilt the scales in favour of a possible cause-effect relationship between MG and COVID-19.

Two possible mechanisms by which SARS-CoV-2 could trigger and/or amplify autoimmunity in MG have been suggested (i.e., cross-reactivity and/or a breakdown in self-tolerance).⁶⁴ Several publications investigating a possible association between MG and COVID-19, suggest molecular mimicry may have occurred involving the SARS-CoV-2 viral proteome and proteins within human tissues that could induce the cross-activation of autoreactive T and B cells through viral-induced production of pro-inflammatory cytokines.⁶⁶ In the absence of direct evidence supported by epitope data mapping, several indirect arguments might favour this hypothesis. For example, it has been shown that the SARS-CoV-2 spike glycoprotein has a commonality with the proteomes of those mammals where the course of infection is severe, while in mammals that present with a benign course of infection, the number of common peptides is low.⁶⁷ This observation is important and impacts mainly vaccine production, because no molecular mimicry between SARS-CoV-2 and AchR, MuSK or any other established autoimmune target in MG, has yet been shown. The impact of the aforementioned cross-reactivities upon autoimmunity might be an indirect one via T cell dysregulation that would lead to aberrant B cell activation and antibody secretion. The median and mean time interval between COVID-19 and onset of MG indirectly favours the molecular mimicry theory. In this scenario, MG triggered by SARS-CoV-2 could be considered as a part of the ‘post-COVID-19 syndrome’. However, in cases with a short time interval of up to one week between COVID-19 and MG, the co-occurrence of the two disorders is a much more probable hypothesis. Molecular mimicry and cross-reactivation have been shown to be implicated in other post-infectious neuro-immune disorders, such as Guillain-Barré syndrome and autoimmune encephalitis.⁶⁰

In addition, evidence is accumulating regarding the involvement of interleukin (IL)-17 in the immunopathology of MG, both in experimental animal models and humans. ^68,69 The possible molecular mimicry between the SARS-CoV-2 viral proteome and proteins within human tissues could induce cross-activation of autoreactive T and B cells through viral-induced production of pro-inflammatory cytokines. Indeed, the hyper differentiation of Th-17 lymphocytes induces further neutrophil recruitment in lung tissue by hyperproduction of IL-17,⁷⁰ which may explain not only diffuse alveolar destruction in severe forms of COVID-19, but also a high serum concentration of self-antigens. As a consequence, autoreactive B cells would differentiate, which may explain the high serum level of autoantibodies. For example, one study in induced experimental autoimmune MG in IL-17 knock out mice, observed a reduction in the severity of myasthenic symptoms and in serum level of acetylcholine receptor antibodies.⁶⁸ In another study in adult myasthenic patients, women with EOMG and no thymoma had higher titers of this IL-17A compared with controls; the authors concluded that high levels of IL-17A were associated with more severe myasthenic symptoms.⁶⁹

Autoimmune response is amplified by other immune mechanisms such as epitope spreading and bystander activation.⁶⁴ In cases where the time interval between viral infection and the MG onset is short, bystander activation appears to be the most plausible underlying mechanism.²⁹ Nevertheless, the short time interval between COVID-19 and MG can also be explained by prior latent MG, triggered by infection and mediated by a hyper-responsive innate immune system.

Breakdown in self-tolerance is due to the dysfunction of Treg cells, which play a crucial role in regulating immune responses through the suppression of T effector cells.⁶⁴ In an experimental animal model of autoimmune MG, expanded functional Treg cells attenuated muscle weakness via the potent suppression of autoreactive T and B cells.⁷¹ Additionally, in human patients with MG there have been reports of number and/or function alterations in Treg cells.⁷² For example, in one study the isolation of a relatively ‘pure’ population of Treg cells from 24 myasthenic patients was achieved.⁷² Even though the relative number of Treg cells within the peripheral T cell pool was normal, their functionality was impaired. In another study, when polyclonal stimulated Treg cells from patients with MG were co-cultured with Treg cells from healthy subjects, the Treg cells from patients were inhibited.⁷³ It has been observed that severe forms of COVID-19 are accompanied by severe lymphopenia, especially of Treg cells, due to an imbalance between IL-2 and IL-2R levels, which in turn stimulates the apoptosis of Treg cells.⁶⁴ In addition, in severe COVID-19 cases, Treg cells appear to have impaired functionality, as suggested by the fact that after the administration of allogenic normal Treg cells, patients with SARS-CoV-2 infection registered a significant improvement.⁷³

Our study had several limitations. For instance, we used the most common medical databases for our search and that may have unintentionally influenced the number and demographical characteristics of our selected cases. As a consequence, although we had no language limitation, our search identified only articles in English and Spanish. Furthermore, our search only provided cases from developed countries, because we could not gain access to all publications. Therefore, a complete systematic review and meta-analysis of global databases is required to provide a more extensive world-wide perspective of the possible relationship between de novo MG and SARS-CoV-2 infection. However, MG is a rare disease and the window of opportunity to study a possible association between the two conditions is closing as the COVID-19 pandemic fades. In addition, proof of direct causality between MG and COVID-19 can only be established either by long term follow-up of patients or elucidating the exact pathogenic mechanisms.

As is the case for many autoimmune processes, the exact causes for MG can only be presumed. Based on existing data, it is most probable that the main culprit is an abnormal activation of the immune system. Although we identified 18 cases of MG cases reported in the literature as being possibly connected to SARS-CoV-2 infection, proof of direct causality between the two conditions can only be established in time by confirming epidemiological increase in the incidence of MG or elucidating pathogenic mechanisms to substantiate a possible cause-effect association, or both. Indeed, long-term follow-up of new-onset MG cases after SARS-CoV-2 infection in vaccinated or non-vaccinated patients might provide additional insight into the association between conditions and the natural course of the disease.²¹ In the era of individualized and more target-specific therapies, clarifying the precise mechanisms by which SARs-CoV-2 derived antigens might contribute to the imbalance between Treg- and Th-17 cells would represent another major breakthrough towards developing newer, more targeted and, therefore, much more effective anti-myasthenic therapies.

Footnotes

Declaration of conflicting interests

The authors declare that there are no conflicts of interest.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

ORCID iD

Cristina Georgiana Croitoru

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Autoimmune myasthenia gravis and COVID-19. A case report-based review

Abstract

Keywords

Background

Myasthenia gravis

Viral infections as possible triggers of MG

New-onset MG post SARS-COV-2 infection

Discussion

Footnotes

Declaration of conflicting interests

Funding

ORCID iD

References