Efficacy and Safety of Sirolimus in COVID-19 Infection
Efficacy and Safety of Sirolimus in COVID-19 Infection
This research is planned to illustrate the efficacy and safety of sirolimus as an adjuvant
 agent to the standard treatment protocol against COVID-19 infection
In early December 2019, several pneumonia cases of unknown origin were observed in Wuhan
 (China). A novel enveloped RNA β coronavirus was isolated and named severe acute respiratory
 syndrome coronavirus 2 (SARSCoV- 2). The new virus rapidly spread across China and worldwide.
 On March 11th 2020, the World Health Organization (WHO) declared coronavirus disease 2019
 (COVID-19) a pandemic. As of 1July 2020, COVID-19 has been confirmed in 10,357,662
 individuals globally with deaths reaching 508,055 with a morality of 5.37%. Egypt has 68,311
 confirmed cases and 2935 deaths.

 The virus mainly spreads through respiratory droplets from infected patients. The clinical
 spectrum of COVID-19 infection ranges from asymptomatic forms to severe pneumonia requiring
 hospitalization and isolation in critical care units with the need of mechanical ventilation
 due to acute respiratory distress syndrome (ARDS). Main symptoms include fever, fatigue and
 dry cough. Common laboratory findings include lymphopenia and elevated lactate dehydrogenase
 levels. Platelet count is usually normal or mildly decreased. C reactive protein (CRP) and
 erythrocyte sedimentation rate (ESR) are usually increased while procalcitonin levels are
 normal and elevation of procalcitonin usually indicates secondary bacterial infection.
 Ferritin, D-dimer, and creatine kinase elevation is associated with severe disease. Chest
 computed tomographic scans show a typical pattern of bilateral patchy shadows or ground glass
 opacity.

 Severe COVID-19 conditions are usually due to an aggressive inflammatory response known as
 "cytokine storm" that is characterized by the release of a large amount of pro-inflammatory
 cytokines. Lung injury, multiorgan failure, and unfavorable prognosis of severe COVID-19
 infection have been attributed mainly to the cytokine storm state.

 Many proinflammatory cytokines elevate in COVID-19 patients including interleukin (IL)-1,
 IL-6, IL-8, IL-10, tumor necrosis factor (TNF)-α and interferon( IFN)-Ȣ stimulating immune
 cells to invade sites of infection causing endothelial dysfunction, vascular damage, alveolar
 damage and ARDS. Cytokine storm has been reported in several viral infections including
 influenza H5N1 virus, influenza H1N1 virus, and the two coronaviruses highly related to
 COVID-19; "SARS-CoV" and "MERSCoV".

 Currently, there is no vaccine and/or specific therapeutic drugs targeting the SARS-CoV-2.
 Hence, it remains a major challenge to decide what potential therapeutic regimens to prevent
 and treat severe COVID-19 infections. Effective vaccines are essential to combat against the
 extremely contagious SARS-CoV-2. Until we have specific vaccines or therapeutic drugs
 targeting SARS-CoV-2, "repurposed" drugs have been used to treat COVID-19 patients. At
 present, treatment of SARS-CoV-2 infection are mainly repurposing the available therapeutic
 drugs and based on symptomatic conditions. Considering ARDS, followed by secondary
 infections, antibiotics, antiviral therapy, systemic corticosteroids, and anti-inflammatory
 drugs (including anti-arthritis drugs) are often used in the treatment regimens.
 Neuraminidase inhibitors, RNA synthesis inhibitors, convalescent plasma, and traditional
 herbal medicines have also been utilized in the treatment of COVID 19. Nevertheless, the
 efficacy of these treatment regimens remains to be verified by appropriately designed
 clinical trials. Sirolimus, also known as rapamycin, is an immunosuppressant that is used to
 prevent organ transplant rejection by inhibiting mammalian target of rapamycin (mTOR) kinase.
 mTOR plays a key role in viral replication. In an in vitro experiment, sirolimus has been
 shown to affect PI3K/AKT/mTOR pathway which inhibited MERS-CoV activity. Studies of patients
 hospitalized with influenza can further shed light on the antiviral effect of sirolimus. In a
 randomized clinical trial conducted on 38 patients with confirmed H1N1 pneumonia and on
 mechanical ventilator support, a group treated with corticosteroids and 2 mg/day of sirolimus
 for 14 days (N=19) showed significantly better clinical outcomes compared with the group
 treated with corticosteroids only, including shorter median duration of ventilator used.
 Delayed oseltamivir plus sirolimus treatment in pH1N1-infected mouse model further suggested
 a significant association between the sirolimus treatment and improved outcomes. At least one
 in silico study identified sirolimus as one of the 16 potential candidates for treating
 COVID-19 patients based on data from other human coronavirus infections using network-based
 drug repurposing model.
Inclusion Criteria:

 -  Adults (˃18 years) COVID-19 positive patients (confirmed by PCR).

 -  Moderate infection ( pneumonia ± leucopenia or lymphopenia ).

 Exclusion Criteria:

 -  Severe or life threatening COVID infection: Severe disease is defined as: dyspnea,
 respiratory frequency ≥ 30/min, blood oxygen saturation ≤ 93%, partial pressure of
 arterial oxygen to fraction of inspired oxygen ratio < 300, and/or lung infiltrates >
 50% within 24 to 48 hours. Life threatening disease is defined as: respiratory
 failure, septic shock, and/or multiple organ dysfunction or failure .

 -  Pregnant or lactating females.

 -  Participation in any investigational clinical study, other than observational, within
 the past 30 days; or plans to participate in such a study at any time from the day of
 enrollment until 30 days post-treatment in the current study.

 -  Allergy or hypersensitivity to sirolimus.

 -  Taking immunosuppressive drugs.

 -  Glomerular filtration rate (GFR) < 30 ml/min by CKD-EPI equation.

 -  liver cirrhosis .

 -  Decompensated heart failure.

 -  known active tuberculosis (TB) or history of incompletely treated TB.

 -  Uncontrolled systemic bacterial or fungal infections.

 -  Drugs that may affect sirolimus level: antifungals, diltiazem, verapamil, nicardipine,
 phenytoin, phenobarbital, rifampicin, carbamazepine.