Discussion
Reinfection with the COVID-19 has been continuously debated with alternative explanations suggested for a positive test after a previous negative PCR test in the setting of symptom resolution.1,2 Proposed causes include dynamic PCR results due to prolonged viral shedding and inaccurate or poorly sensitive tests. The repeat positive cases in these scenarios, however, occurred in asymptomatic patients.1,2 COVID-19 shedding averages 20 to 22 days after symptom onset but has been seen up to 36 days after symptom resolution.2,3 This would suggest that fluctuating results during the immediate postsymptom period may be due to variations in viral shedding load and or sampling error—especially in asymptomatic patients. On the other hand, patients who experience return of symptoms days to weeks after previous convalescence leave clinicians wondering whether this represents clinical latency with reactivation or COVID-19 reinfection. A separate case of initial COVID-19 in a patient that had subsequent clinical recovery with a negative PCR developed recurrent respiratory symptoms and had a positive PCR test only 10 days later, further highlighting the reinfection vs reactivation issue of COVID-19.2 Further understanding of this issue may have implications on the extent of natural immunity following primary infection; potential vaccine dosage schedules; and global public health policies.
Although reactivation may be plausible given his immunomodulatory therapy, our patient’s second COVID-19 symptoms started 40 days after the initial symptoms, and 26 days after the initial course resolution; previous cases of return of severe symptoms occurred between 3 and 6 days.1 Given our patient’s time course between resolution and return of symptoms, if latency is the mechanism at play, this case demonstrates an exceptionally longer latency period than the ones that have been reported. Additionally, if latency is an issue in COVID-19, using remdesivir as a treatment further complicates the understanding of this disease.
Remdesivir, a nucleoside analogue antiviral, was shown to benefit recovery in patients with severe symptoms in the Adaptive COVID-19 Treatment Trial-1 study.4 Our patient had originally been placed on a 10-day course; however, on treatment day 8, his symptoms resolved and the remdesivir was discontinued. This is a similar finding to half the patients in the 10-day arm of the study by McCreary and colleagues.5 Although our patient was asymptomatic 4 weeks after the start of remdesivir, consistent with the majority of patients in the McCreary 10-day study arm, further comparison of the presented patient is limited due to study length and follow-up considerations.5 No previous data exist on reactivation, reinfection, or long-term mortality after being treated with remdesivir for COVID-19 infection.
IVIG is being studied in the treatment of COVID-19 and bears consideration as it relates to our patient. There is no evidence that IVIG used in the treatment of autoimmune diseases increases the risk of infection compared with that of other medications used in the treatment of such diseases. Furthermore, the current guidance from the MG expert panel does not suggest that IVIG increases the risk of contracting COVID-19 aside from the risks of exposure to hospital infrastructure.6 Yet the guidance does not discuss the use of IVIG for MG in patients who are already symptomatic from COVID-19 or for patients recovering from the clinical disease or does it discuss a possible compounding risk of thromboembolic events associated with IVIG and COVID-19.6,7 Our patient received his maintenance IVIG during his first admission without any worsening of symptoms or increased oxygen requirements. The day following our patient’s next scheduled IVIG infusion—while asymptomatic—he again developed respiratory symptoms; this could suggest that IVIG did not contribute to his second clinical course nor protect against.
CP is a treatment modality that has been used and studied in previous infectious outbreaks such as the first severe acute respiratory syndrome, and the H1N1 influenza virus.8 Current data on CP for COVID-19 are limited, but early descriptive studies have shown a benefit in improvement of symptoms 5 days sooner in those requiring supplemental oxygen, but no benefit for those requiring mechanical ventilation.9 Like patients that benefitted in these studies, our patient received CP early, 6 days after first testing positive and onset of symptoms. This patient’s reinfection or return of symptoms draws into question the hindrance or even prevention of long-term immunity from administration of CP.
COVID-19 presents many challenges when managing this patient’s coexisting MG, especially as the patient was already being treated with immunosuppressing therapies. The guidance does recommend continuation of standard MG therapies during hospitalizations, including immunosuppression medications such as MMF.6 Immunosuppression is associated with worsened severity of COVID-19 symptoms, although no relation exists to degree of immunosuppression and severity.7,10 To the best of our knowledge there has been no case report of reinfection or reactivation of COVID-19 associated with immunosuppressive agents used in the treatment of MG.
Our patient also was taking pyridostigmine for the treatment of his MG. There is no evidence this medication increases the risk of infection; but the cholinergic activity can increase bronchial secretions, which could theoretically worsen the COVID-19 respiratory symptoms.6,11 During both ICU admissions, our patient continued pyridostigmine use, observing complete return to baseline after discharge. Given the possible association with worsened respiratory outcomes after the second ICU admission, the balance between managing MG symptoms and COVID-19 symptoms needs further examination.
The patient was in MC during his third presentation to the ED. Although respiratory symptoms may be difficult to differentiate from COVID-19, the additional neurologic symptoms seen in this patient allowed for quick determination of the need for MC treatment. There are many potential etiologies contributing to the development of the MC presented here, and it was likely due to multifactorial precipitants. A common cause of MC is viral upper respiratory infections, further challenging the care of these patients during this pandemic.12 Many medications have been cited as causing a MC, 2 of which our patient received during admission for COVID-19: azithromycin and levoquin.12 Although the patient did not receive hydroxychloroquine, which was still being considered as an appropriate COVID-19 treatment at the time, it also is a drug known for precipitating MC and its use scrutinized in patients with MG.12
A key aspect to diagnosing and guiding therapies in myasthenic crisis in addition to the clinical symptoms of acute weakness is respiratory assessment through the nonaerosolizing NIF test.12 Our patient’s NIF measured < 30 cmH2O when in MC, while the reference range is < 75 cmH2O, and for mechanical ventilation is recommended at 20 cmH2O. Although the patient was maintaining O2 saturation > 95%, his NIF value was concerning, and preparations were made in case of precipitous decline. Compounding the NIF assessment in this patient is his history of left phrenic nerve palsy. Without a documented baseline NIF, results were limited in determining his diaphragm strength.13 Treatment for MC includes IVIG or plasmapheresis, since this patient had failed his maintenance therapy IVIG, plasmapheresis was coordinated for definitive therapy.
Conclusions
Federal facilities have seen an increase in the amount of respiratory complaints over the past months. Although COVID-19 is a concerning diagnosis, it is crucial to consider comorbidities in the diagnostic workup of each, even with a previous recent diagnosis of COVID-19. As treatment recommendations for COVID-19 continue to fluctuate coupled with the limitations and difficulties associated with MG patients, so too treatment and evaluation must be carefully considered at each presentation.