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.