Discussion
SARS-CoV-2 is associated with a wide range of symptoms ranging from a mild clinical phenotype with fever and cough to severe respiratory and/or multi-organ failure. SARS-CoV-2 has considerable morbidity and mortality, particularly among older patients with co-morbidities35. A significant factor contributing to the morbidity and mortality of this infection is the pulmonary and systemic inflammatory response as noted above36. We were struck by the minimal clinical findings in this high-risk, male with a co-existing malignancy. Our patient was on chronic everolimus therapy for metastatic neuroendocrine tumor. As noted above, everolimus is an mTOR inhibitor that may target both viral replication and inflammation. We speculate whether our patient’s minimal clinical symptoms throughout his infection could be linked to the anti-inflammatory effect of the drug. Everolimus may reduce the SARS-CoV-2 inflammatory state, improve the quality of life, and perhaps prolong survival from this devastating disease. This speculation is supported by several case studies. Among 18 hospitalized COVID-19 positive renal transplant patients, three were on chronic everolimus37. A 60 years old male and a 40 years old female were maintained on everolimus and did well; one 40 years old male had everolimus stopped and died from infection complications. Among 10 COVID-19 tuberous sclerosis/lymphangioleiomatosis patients, five were on sirolimus or everolimus and only one was briefly hospitalized and recovered; four of five patients not on mTOR inhibitors were hospitalized and one died38. A 45 years old T3 paraplegic pancreas-kidney transplant male with asthma and chronic renal insufficiency maintained on everolimus developed RT-PCR positive SARS-CoV-2 and had an eight days hospitalization with transient symptoms39. Among 111 SARS-CoV-2 positive liver transplant patients, immunosuppression with mycophenolate was associated with severe disease (risk ratio = 5.3); immunosuppression with mTOR inhibitors—tacrolimus or everolimus yielded fewer severe cases (tacrolimus risk ratio = 0.54 and everolimus risk ratio = 0.77)40.
An interesting facet of this case is the sustained positivity of the patient’s SARS-CoV-2 test. He was repeatedly tested for viral RNA clearance by nasal swab RT-PCR secondary to his immunocompromised state, and because he required a negative test prior to treatment at the oncology clinic. Many SARS-CoV-2 infected individuals have persistently positive RT-PCR tests for weeks to months after clinical recovery41. Based on viral culture, the percent of these individuals who remain infectious approaches zero by 10 to 15 days after the onset of symptoms41-43. However, shedding of infectious SARS-CoV-2 has been demonstrated by viral culture or inferred by the presence of subgenomic RNA in a subset of individuals, including immunosuppressed hosts, for months following infection44,45. We lack Cq values for multiple tests on our patient, but the reported positivity implies a Cq less than 39. Likely our patient had low quantities of viral RNA or viral RNA fragments that were non-infectious.
The persistent positivity of his SARS-CoV-2 testing may be potentially secondary to the immunosuppressive effects of everolimus46. mTOR inhibitors inhibit dendritic cell maturation and function and T cell proliferation. In our case, possible hampered anti-viral defense was reversed with interferon supplementation with subsequent T cell activation to fight the SARS-CoV-2 infection. Our patient was able to clear the viral RNA after the administration of the first of a total of four treatments of pegylated interferon-α2a while continuing treatment with everolimus. Presence of RT-PCR positivity for one to two months after SARS-CoV-2 infection is not rare47, and does not always represent infectious virions.
Interferons have been successfully used in the treatment of viral infections, such as hepatitis C, multiple sclerosis, hematologic malignancies, in particular the Philadelphia-negative myeloproliferative neoplasms and neuroendocrine tumors48-50. In SARS-CoV-2, interferon therapy in phase 2 and phase 3 randomized clinical trials have shown reduced the duration of virus infection, reduced inflammatory markers including IL6 and CRP and reduced mortality when administered early51-58. As a note of caution, type I interferons administered in later stages may cause progressive tissue damage leading to a deleterious hyperinflammation characterized by the excessive macrophage activation and hypercoagulation seen in patients with acute disease36. Interestingly, pharmacologic interferon treatment inhibits inflammation early by repressing the NLRP3 inflammasome via STAT132. We hypothesized that administration of interferon in our patient who was minimally symptomatic would strengthen anti-viral defense and potentially lead to viral RNA clearance. Our results support the hypothesis.