Use of Remdesivir in The Treatment of COVID-19 Infection Among Sudanese Patients - Case Series

Introduction: COVID-19 infection is a viral pandemic started in 2019, all societies have the susceptibility of getting infected. Remdesivir is an anti-retroviral agent, with a broad spectrum of activity. Remdesivir activity against COVID-19 had been studied in both in vitro and in vivo, but still considered new for COVID-19 treatment and not available in all countries. The aim of our study was to report the use of remdesivir among Sudanese population and report the adverse events related to the course of treatment. Methods: case series study was conducted in Imperial Hospital reporting the three cases who received Remdesivir for treating COVID-19 infection. Cases presentation: Three cases had received remdesivir for treating COVID-19 infection, side effects reported were elevated liver enzymes, profound hypotension and hypoalbuminemia. Discussion: All three patients were severe cases of COVID-19 admitted to the ICU. Unexpectedly, severe resistant hypotension was the cause of death in 2 cases who received remdesivir. Increased liver enzymes was noticed in one case. In the other hand, hypoalbuminemia was noticed in one case as well.

. Remdesivir is an antiretroviral agent, with a broad spectrum of activity. It is a pro-drug, which was rstly developed to be used for the treatment of the Ebola outbreak [3]. Recently, it was proposed to treat COVID-19 infection [4,5].
Remdesivir activity against COVID-19 had been studied in both in vitro and in vivo, but still considered new for COVID-19 treatment and not available in all countries [6,7]. Although, some remdesivir trials had no enough power [8], other large scale clinical trials were done [9] . The aim of our study was to report the use of remdesivir among Sudanese population and report the adverse events related to the course of treatment.

Methods
Case series study design was implemented. All cases were described in details. The data were collected retrospectively from the medical records. Con dentiality of participants was assured through the use of an anonymous research tool. Informed consents from surrogate decision makers were obtained, voluntary, by contacting them through their registered phone numbers. The collected data were used strictly for the purpose of the study objectives.
Case-1 Presentation 26 th complaining of cough, shortness of breath and fatigue. The symptoms started 2 weeks ago with dry cough only. The patient's co-morbid conditions were hypertension and renal transplant 10 years ago with no other co-morbidity. Oxygen therapy was initiated through a non-rebreathing mask by a rate of 15 litre/minute, oxygen saturation was 97% with the mask. The patient was transferred for dialysis on day 2, the 28 th of November. On day 4, the 29 th of November, the patient started being anxious with oxygen drop to 88%, then immediately transferred to the isolation ICU. Table 1. below illustrates the medications received by the patient.
Chest computed tomography was done for the patient on the rst day of hospital arrival, shown in gure 1. below.
On day 2 of the ICU, day 5 of hospital admission, the patient was on and off CPAP mask ventilation. Remdesivir was started on the 4th of December, day 5 of the ICU, with a loading dose of 200 mg in 250 mL normal saline intravenously followed by a maintenance dose of 100 mg in 250 mL normal saline daily, planned for 10 days. The patient was stable with mildly elevated serum creatinine, 1.7 mg/dl, and adequate urine output. The patient was seen by a nephrologist. On the 6th of December, the dose of enoxaparin was switched to the therapeutic dose, 80 mg B.D. On the 4th day of the remdesivir treatment, profound hypotension occurred and vasopressors were started. Despite the maximum dose of noradrenaline and dopamine along with normal saline, the hypotension persisted. Profound bradycardia occurred with a pulse rate of 36 bpm, and marked drop of oxygen saturation to 52% on CPAP mask. The patient was deceased 35 minutes later on the 7th of December, 2020. result was received on the 5 th of December. SARS-COV-2 RNA by PCR was detected, while, SARS-COV-2 antibody was negative. The patient was complaining of shortness of breath for 3 days. His comorbidities were, diabetes mellitus (DM) on insulin treatment, and a history of Ca colon operated 2 years ago and he was on oral chemotherapy. The patient had no other co-morbid conditions. A con rmatory test by using RT-PCR was done on the 10 th of December ( IgG 12.04, IgM 0.243). The medications in table 1. above, were given to the patient since day 1 and planned for 10 days, besides 1.5 litres of uids. The patient was admitted to the isolation ICU on the same day of hospital arrival. Remdesivir was started on day 1, the 8 th of December 2020. A loading dose of 200 mg was given in 250 mL of normal saline followed by a maintenance dose of 100 mg I.V in 250 mL of normal saline daily, planned for 10 days. On admission, the SPO 2 was 92%, CPAP was applied. Table 2. below illustrated the daily vital signs of the patient.  Chest computed tomography was done for the patient on the rst day of hospital arrival, the 8 th of December, shown in gure 2. below.
On day 2 in the ICU, the patient started doing better and getting stable. On day 3, the GCS was reducing and the patient started deteriorating. Nasogastric feeding was started and I.V uids were increased to 3 litters per day alongside the same plan. On day 6, severe hypotension had occurred to the patient, to an extent that blood pressure was undetectable on any monitor or manual devices. Hypotension was resistant to uids and vasopressors which eventually lead to the death of the patient. The patient was deceased on day 6, the 13th of December, as a result of severe refractory hypotension..

Case-3 presentation
75 years old male was presented to the Emergency Isolation room at Imperial hospital on the 18 th of December 2020, with generalized fatigue and fever for 1 week, and hemiparesis. Co-morbid conditions of the patient were pacemaker device and BPH condition, which was operated 5 years ago. Oxygen saturation with CPAP mask was 87%. The patient was diagnosed with COVID-19 pneumonia and sepsis which were con rmed by PCR and CT-Chest. An incidence of haemorrhagic stroke was con rmed through brain imaging. The patient was admitted to the Isolation ICU immediately, with reduced GCS (9/15). Respiratory support was initiated with physiotherapy and prone positioning for 16

Discussion
Our patients were aged between 62 and 78 years, as in published studies [9,10 ]. All our study cases were males, as COVID-19 infection was more prevalent in males [10,11,12]. In our study, Case-2 was diabetic, diabetes is known to be associated with COVID-19 severity of infection [2]. This comorbidity was reported for 25% and 16% of patients who received remdesivir [9,10]. Remdesivir is considered a viable treatment option in severe infections [13,14 ]. Cases were put on non-invasive ventilation, in contrast with study [10] reporting that non-invasive ventilation was less common. Remdesivir doses administered for our patients were, 200 mg intravenously loading dose followed by 100 mg daily dose, which were the recommended doses [9,15]. All cases had received antibiotics and steroids along with remdesivir, this was in line with [9]. Hypoalbuminemia was reported in patients taking remdesivir [9], as in, case-3 of our study. But case-2 had hypoalbminemia on presentation. Case-1 and 2 patients had 4 and 6 treatment days with remdesivir respectively, with no improvement, in contrast to published trials in which remdesivir treatment course of 5 days had shown signi cant improvements [16,17]. Our second case patient received remdesivir after 4 days of presentation of COVID-19 symptoms, which is consistent with published literature reporting that the e cacy of remdesivir is higher in patients who received it within 10 days of symptoms presentation [18]. While another study concluded that delayed treatment initiation with remdesivir was bene cial as well [19]. In the other hand, our rst case had symptoms for more than 10 days before remdesivir treatment. Liver enzymes abnormalities had been reported among patients who received remdesivir [4,10,20]. For such cases, treatment course should be stopped [14]. In our second case, liver enzymes were extremely elevated since day 3 of treatment, but remdesivir course had not been discontinued. Two of our cases were deceased and that was expected, as per a case series study in US , in which 50% of patients with severe COVID-19 infection on remdesivir were deceased [21]. Also, in a clinical study only 3% of patients on remdesivir had clinical improvement on day 7 [9]. In another study, compassionate use of remdesivir resulted in improvements in 69% of patients [10]. The cause of death for both cases was severe resistant hypotension, which was reported as a serious event in remdesivir use [10,20]. The limitations of our study were the observational nature of case series that cannot establish direct causeeffect relationships. Also, the data were collected retrospectively from the medical records of the patients which had some missing medical results.

Conclusion
All three patients were severe cases of COVID-19 admitted to the ICU. Unexpectedly, severe resistant hypotension was the cause of death in 2 cases who received remdesivir. Increased liver enzymes was noticed in one case. In the other hand, hypoalbuminemia was noticed in one case as well.

Recommendations
Wider studies regarding remdesivir use among patients in Sudan must be conducted extensively in order to study this unexpected fatal event and assess the association of this event to remdesivir use, as well as, to report the frequency of the side effects.  Chest computed tomography of case-1 on hospital arrival