COVID-19 in Patients with Myasthenia Gravis: Mechanisms of Respiratory Failure
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.333460
Source of Support: None, Conflict of Interest: None
Keywords: Myasthenia gravis, COVID-19, respiratory failure, pulmonary complications, myasthenic crisis
The novel 2019 coronavirus disease (COVID-19) is caused by Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2). The main complication of COVID-19 is respiratory failure. Observational studies have documented several neurological complications or associations either during or after COVID-19. However, direct causality is uncertain., Data from the current COVID-19 pandemic regarding specific risks and outcomes for patients with neuromuscular disease are unknown. This report describes clinical course of COVID-19 in a patient with thymomatous MG in pharmacological remission and discusses the possible mechanisms of respiratory failure in patients with MG and COVID-19.
A 35-year-old man, a known patient of thymomatous MG (anti-acetylcholine-receptor antibody positive (Anti-Ach-Rab+) since 2008, underwent thymectomy (thymoma grade IIb) in 2011. Between 2011 and 2014 his myasthenic status was stable, Myasthenia Gravis Foundation of America (MGFA) Class I, on prednisolone and azathioprine. Towards the end of 2015 he developed an episode of melena. Diagnostic evaluation showed aplastic anemia which was attributed initially to azathioprine and the drug was discontinued. However, as pancytopenia continues to worsen, diagnosis was reviewed and the diagnostic possibility of aplastic anemia due to thymoma was considered. He was started on cyclosporine A and was continued on prednisolone. The blood counts and anemia steadily improved. At the last follow-up, six months before the current admission blood counts and hemoglobin were stable and myasthenia was in pharmacological remission on cyclosporine and prednisolone. He presented to Emergency Medicine Department (EMD) with high grade fever with chills and productive cough of five-day and breathlessness of two-day duration.
On the initial evaluation in EMD, he was afebrile, normotensive, normal heart rate, and tachypnoeic requiring 6 L of nasal oxygen (SpO2 96%). Arterial blood gases (ABG) showed hypoxemic (pH 7.35, PaO2 64.9 mmHg, PaCO2 35.7 mmHg) respiratory failure. High resolution CT (HRCT) thorax revealed multiple focal and confluent areas of ground glass opacities, with areas of consolidation, COVID-19 reporting and data system score (CO-RADS) was 5 and CT severity score was 18/25 [Figure 1]. In view of low PaO2/FiO2 ratio, he was electively intubated and put on mechanical ventilation. Complete blood picture revealed normal Hb (14 g/dl), thrombocytopenia (86000/mcL), normal leukocyte (5900/mcL) count and lymphopenia (10%). Acute phase reactants: Elevated levels of IL-6 204.8 pg/mL (<1.5 pg/mL), C-Reactive protein 1.8 mg/dL (<10 mg/L), and ferritin 491 ng/mL (20-250 ng/L) and normal levels D-dimer 0.61 ng/mL (<250 ng/L). Endobronchial washings was tested positive for SARS-CoV-2 (RT-PCR). Cyclosporine A was stopped and for COVID-19 infection he was started on cefaperazone and sulbactum combination, and for COVID-19 clarithromycin, low molecular weight heparin and dexamethasone. He was put on prone ventilation as the PaO2/FiO2 ratios worsened. On hospital day-9 he had melena and endo-tracheal bleeding. Low molecular heparin was stopped and test for HIT antibodies was negative. He received multiple platelet transfusions over the next seven days (platelet counts range 12,000-56,000/mcL). On hospital day-11 he had new-onset high grade fever, drop in blood pressure and fluctuations in PaO2/FiO2 ratios. He was started on inotropes and injection polymyxin B as the blood and endobronchial secretion cultures grew extensively drug resistant Klebsiella pneumoniae. He had percutaneous tracheostomy on hospital day-15 as there was difficulty to wean him of the ventilation. During the subsequent hospital course his condition stabilized and he was weaned off from ventilator and decannulated on day-25. There was no new-onset weakness during the entire hospital stay. At the time of discharge electrodiagnostic test revealed normal motor and sensory nerve conduction studies and normal no decrement on repetitive nerve stimulation studies. He was discharged in a stable condition with advice of respiratory exercises and supportive medication. Follow-up at one month of discharge he is stable and has no myasthenic symptoms. He was restarted on cyclosporine A for aplastic anemia.
Our patient was in pharmacological remission prior to COVID-19. He had a turbulent hospital course, developed hypoxemic respiratory failure secondary to pulmonary complications of COVID-19 requiring mechanical ventilation and tracheostomy. His hospital course was further complicated by gram-negative septicemia and internal organ bleeding due to aplastic anemia. Cyclosporine A treatment might have been a risk factor for COVID-19 infection and gram-negative septicemia. He had no new-onset weakness or worsening of myasthenic weakness. Respiratory failure in our patient was due to pulmonary complications of COVID-19. The disease course in our patient was complicated by the aplastic anemia.
The interaction between MG and COVID-19 infection is complex. Patients with MG on immunosuppression treatment are theoretically at a greater risk for COVID-19. Infections are leading cause of exacerbation of MG and may sometimes precipitate myasthenic crisis. Conversely pulmonary complications and antiviral and antibiotics used in the treatment of COVID-19 may influence the disease course of MG. Hydroxychloroquine and azithromycin used in the treatment of COVID-19 may precipitate new weakness or worsen the myasthenic weakness.,,,,These complex interactions may result in respiratory failure in these patients. The possible mechanisms of respiratory failure can be: (1) myasthenic crisis precipitated by COVID-19; (2) respiratory failure due to pulmonary complications of COVID-19; and (3) both respiratory complications of COVID-19 and the myasthenic weakness as co-factors.
We reviewed the literature and analyzed the clinical characteristics of eight patients with MG and COVID-19 and respiratory failure. The analysis included only those patients with complete clinical details. [Table 1] and [Table 2].,,,,
Of the four patients with myasthenic crisis by definition, three required intubation and mechanical ventilation and one was managed by non-invasive ventilation [Table 1],,, The mean was 36.25 years (range 25-56 years); three were women; and three had thymectomy. The disease severity at admission was: MGFA-Class V (2); Class IVa (1); and Class IIa with worsening weakness MG composite 13 (1) prior to COVID-19. Three patients required rapid therapies.
Of the four patients with respiratory failure due to pulmonary complications of COVID-19, three required intubation and mechanical ventilation and one patient was managed with high-flow oxygen with a non-rebreather mask. The mean age was 61.5 years (range 35-90 years), three were males, and three had thymectomy. Two patients were in pharmacological remission and two were in MGFA-Class I prior to COVID-19 [Table 2]. All the four patients were exposed to medications (hydroxychloroquine, azithromycin) for COVID-19 infection which can aggravate myasthenic weakness. None of the patients developed new-onset or worsening weakness during the hospital course to support a myasthenic worsening. There were no major changes in the treatment for MG during the period of hospital stay.
Of the fifteen patients of MG with COVID-19 reported by Camelo-Fiho et al. eleven (73%) patients required mechanical ventilation. The clinical details reported did not provide, in how many patients the respiratory failure was due to myasthenic crisis and in how many it was due to pulmonary complications of COVID-19. Of the eleven patients requiring mechanical ventilation, MGFA class before COVID-19 was Class I in five, Class IIA in six, Class IIB in three and Class III in one. None of the eleven patients met the diagnostic criteria of myasthenic crisis. (20) But there was worsening of myasthenic weakness before mechanical ventilation and five patients required rapid therapy.
Our analysis shows distinct clinical differences between the two groups. Patients with myasthenic crisis were young women in high grade MGFA Class. Patients with respiratory failure due to pulmonary complications of COVID-19 were elderly men with stable disease state, pharmacological remission or MGFA Class I. Initial severity and worsening of myasthenic weakness was the only differentiating clinical feature between the two types of respiratory failure. COVID-19 might be the precipitating factor like any other infection. The worsening myasthenic weakness However the study sample was very small and these findings needs to be validated in a larger sample. This differentiation has therapeutic implications. Patients with myasthenic crisis require rapid therapy in addition to management of respiratory failure. Acute respiratory distress syndrome (ARDS) is one of the severe pulmonary complications of COVID-19, which needs aggressive treatment. Sometimes these patients may require extracorporeal membrane oxygenation (ECMO). The interim analysis (October 5, 2020) analysis of 91 patients with MG registered in the COVID-19 Associated Risks and Effects in Myasthenia Gravis (CARE-MG) registry reported MG worsening or crisis requiring rapid therapies in 20 (22%) patients. Worst MGFA clinical class during or immediately following COVID-19 meeting diagnostic criteria of myasthenia crisis (IVA/IVB – V) was seen in 15 (16%) patients.
Use of immunosuppressant therapies during COVID-19 pandemic remains a challenge. Immunosuppressed state may predispose the individuals to higher risk for a more severe COVID-19 course. International MG/COVID-19 Working Group suggests that patients with MG should continue their current treatment including immunosuppressive medication. Current evidence suggests that intravenous immunoglobulin (IVIg) or plasma exchange (PLEX) do not carry any additional risk of contracting COVID-19. Patients taking these therapies as maintenance therapy should continue them during COVID-19. There is growing evidence to suggest that immunosuppression might play a protective role in COVID-19. It may result in reduced immune response, that leads to an inflammatory cytokine storm and to clinical deterioration. Study by Camelo-Filho et al. suggests that immunosuppressive therapy may be associated with better outcomes and protective role.
COVID-19 in patients with MG is associated with high mortality. In CARE-MG complete recovery or discharge to home was reported in 39 (43%) patients, whereas 22 (24%) patients died due to COVID-19. In the study by Camelo-Filno et al. 30% of patients died due to COVID-19.
In conclusion the respiratory failure in patients with MG and COVID-19 are two types. (1) due to pulmonary complications of COVID-19 and (2) due to myasthenic crisis. These observations suggest that COVID-19, like other infections may precipitate myasthenic crisis in patients with severe-grade MG before COVID-19. This distinction is important from treatment point of view.
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[Table 1], [Table 2]