key: cord-0917729-u8pp7c84
authors: Jakubíková, Michala; Týblová, Michaela; Tesař, Adam; Horáková, Magda; Vlažná, Daniela; Ryšánková, Irena; Nováková, Iveta; Dolečková, Kristýna; Dušek, Pavel; Piťha, Jiří; Voháňka, Stanislav; Bednařík, Josef
title: Predictive factors for a severe course of COVID‐19 infection in myasthenia gravis patients with an overall impact on myasthenic outcome status and survival
date: 2021-06-25
journal: Eur J Neurol
DOI: 10.1111/ene.14951
sha: a9ee08c324e298bcad5aafc34ef994bdc969079f
doc_id: 917729
cord_uid: u8pp7c84

BACKGROUND AND PURPOSE: Myasthenia gravis (MG) patients could be a vulnerable group in the pandemic era of coronavirus 2019 (COVID‐19) mainly due to respiratory muscle weakness, older age and long‐term immunosuppressive treatment. We aimed to define factors predicting the severity of COVID‐19 in MG patients and risk of MG exacerbation during COVID‐19. METHODS: We evaluated clinical features and outcomes after COVID‐19 in 93 MG patients. RESULTS: Thirty‐five patients (38%) had severe pneumonia and we recorded 10 deaths (11%) due to COVID‐19. Higher forced vital capacity (FVC) values tested before COVID‐19 were shown to be protective against severe infection (95% CI 0.934–0.98) as well as good control of MG measured by the quantified myasthenia gravis score (95% CI 1.047–1.232). Long‐term chronic corticosteroid treatment worsened the course of COVID‐19 in MG patients (95% CI 1.784–111.43) and this impact was positively associated with dosage (p = 0.005). Treatment using azathioprine (95% CI 0.448–2.935), mycophenolate mofetil (95% CI 0.91–12.515) and ciclosporin (95% CI 0.029–2.212) did not influence the course of COVID‐19. MG patients treated with rituximab had a high risk of death caused by COVID‐19 (95% CI 3.216–383.971). Exacerbation of MG during infection was relatively rare (15%) and was not caused by remdesivir, convalescent plasma or favipiravir (95% CI 0.885–10.87). CONCLUSIONS: As the most important predictors of severe COVID‐19 in MG patients we identified unsatisfied condition of MG with lower FVC, previous long‐term corticosteroid treatment especially in higher doses, older age, the presence of cancer, and recent rituximab treatment.

Coronavirus disease 2019 is caused by the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in which the host reaction can include antibody-mediated inflammation and a cytokine storm that is thought to have a major impact on the outcome [1] . Chen et al. [2] found that the risk of severe disease course increases with age and with certain types of comorbidities.

Myasthenia gravis (MG) is an autoimmune neuromuscular disease that carries the risk of respiratory muscle weakness, the treatment for which, for more than half the patients older than 60 years of age, is immunosuppressive therapy. These three main factors could play an important role in COVID-19 infection increasing the likelihood of SARS CoV-2 complications in MG patients [3] .

Among various trigger factors for MG exacerbation and crisis, infections are the most common cause [4, 5] . Some drugs, which are being tested for COVID-19 treatment such as inosine pranobex [6] , hydroxychloroquine and some antibiotics (azithromycin) [7, 8] , may also adversely affect MG patients, especially those with bulbar symptoms and/or with severe muscle weakness who are at greater risk for another destabilization of myasthenic symptoms due to such risk medication. Treatment considerations in MG with are even more complex. MG is treatable with corticosteroids (CS), long-term immunosuppressive drugs, intravenous immunoglobulins (IVIG) and plasmapheresis, or biologic treatment in refractory forms. CS normally used in MG are very controversial in COVID -19 cases. In the early stages, CS can prolong viremia [9] , as they inhibit immune reactions by acting on migration and chemokine production, but in contrast they can be beneficial during acute respiratory distress syndrome. However, there is still scant evidence on the positive effect of CS treatment for this critical condition [10] .

Immunosuppressive treatment can affect the risk of infections and some therapies are associated with an increased risk from particular types of pathogens. The use of biologic agents in generalized MG is generally limited to therapy-refractory cases [11] and long-term use of rituximab is also associated with an increased risk of severe infection [12] . Furthermore, there may be a reduction in the production of COVID-19 antibodies and the risk of a more severe disease course in patients who have developed this infection recently after administration of rituximab [13] .

In contrast, IVIG therapy has the potential to be beneficial in conjunction with COVID-19 infection and acute myasthenic exacerbation [3, 14, 15] through its immunomodulatory effect, thereby suppressing cytokine storm syndrome [16] . However, we have to be aware of the risk of thromboembolic complications associated with IVIG treatment, which may accentuate the hypercoagulable state during COVID-19 [17] .

In this second phase of severe COVID-19, some immunotherapies might have the potential to attenuate or even prevent critical illness [18] . A very promising cure also seems to be tocilizumab (interleukin 6 [IL-6] inhibitor), which is currently in clinical trials for the treatment of severe cases of COVID-19 [19] and offers the possibility of this therapy being used in myasthenic patients with a more severe course of COVID-19 in addition to IVIG therapy. This is because IL-6, which is also involved in the immunopathogenesis of MG [20] and COVID-19 and levels of IL-6 also correlated with increased mortality due to COVID-19 infection [21] .

Our primary goal was to determine the important predictive factors of the severity of COVID-19 in 93 patients with MG including treatment modalities, comorbidities and degree of MG control, and identify which therapies should be modified in those patients with confirmed SARS-CoV-2 infection if possible. Secondly, we wanted to identify the impact of a severe course of COVID-19 and its therapy on MG patients and risk of MG exacerbation. We applied the Shapiro−Wilk normality test for all parameters. With the exception of weight, height and forced vital capacity (FVC), the test values were below the level of significance (p = 0.05). Therefore, we used the median and interquartile range for the descriptive characteristics (see Table 1 ). An odds ratio (OR) with a 95% confidence interval (95% CI) was calculated to estimate the dif- 

We identified 93 MG patients with confirmed COVID-19. Some 35 patients (38%) were diagnosed with severe pneumonia and we recorded 10 deaths (11%) due to COVID-19. The majority of patients (72 subjects, 77%) were treated with acetylcholinesterase inhibitors and with CS (75 subjects, 80%). Forty-four patients (47%) had another type of immunosuppressive therapy, namely azathioprine, mycophenolate mofetil, cyclosporine or tacrolimus. Six patients were treated with biologic therapy (four with rituximab, one with the study drug anti-neonatal Fc receptor immunoglobulin and one with glatiramer acetate). Seven patients were also treated with IVIG due to worsening myasthenic symptoms during COVID-19. The results are summarized in Table 1 .

Older patients had a higher chance of suffering from severe COVID-19 pneumonia (OR 1.062, 95% CI 1.037-1.088, p < 0.001).

Conversely, higher FVC (%) was associated with lower odds of se- OR results are plotted in Figure 2 .

The specific treatment of COVID-19 pneumonia did not pose a risk in MG (11 patients were treated using remdesivir, one with favipiravir, one with inosine pranobex and four with convalescent plasma The reason may be faster deterioration of respiratory parameters in unstable MG patients during COVID-19 infection and faster progression of pneumonia in the field of impaired cellular immunity due to chronic CS therapy. It is known that long-term oral CS treatment clearly increases the risk of serious infections as a result of shortterm lymphopenia due to suppressing T-cell activation and differentiation [27] . Equally, the use of CS seemed to protract SARS-CoV-2 viral clearance, and in MERS-CoV-infected patients (also from the group of beta coronaviruses related to SARS) the use of systemic CS was found to be one of the most significant factors that contributed to increased mortality [28] .

York, USA who were treated with chronic CS were more likely to require hospitalization for COVID-19 than patients who were not receiving CS [29] as is also evidenced by our conclusions. However, these two parameters are strongly associated with each other, and from our statistical analysis we are not able to distinguish exactly what has a greater influence on the course of COVID-19 in MG patients, whether it is the severity of MG before infection or the dose of CS. This is followed by the question of how to use CS in MG COVID-19 patients, at which disease stage, and at which dosage [21] . As reported by the World Health Organization (WHO) regarding COVID-19, steroids should not be routinely given for the treatment of viral pneumonia outside of clinical trials [30] . There is no conclusive evidence to support the use of CS in the treatment of viral respiratory infection and their use remains controversial in COVID-19. Analysis has revealed no beneficial effects and, in some cases, harmful effects [31] especially in the case of long-term oral CS treatment before COVID-19 as is also evidenced by our results.

Other additional risk factors for infection during chronic treatment with CS are higher doses, longer durations of therapy and older age [32] . In our cohort, older MG patients had a slightly higher chance of suffering from severe COVID-19 pneumonia, so age can be con- 

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. 

The data that support the findings of this study are available from the corresponding author upon reasonable request.

https://orcid.org/0000-0001-5554-4839

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