*4.7. AIFELL Score*

The AIFELL score, developed by Levenfus et al., is a clinical prediction score used for triage purposes to assess risk and provide guidance of further diagnostic and therapeutic steps in patients suspected to have COVID-19 [6]. It can be easily applied in emergency wards, and also has an interactive website (www.aifell.net) correlating the AIFELL score to the above-mentioned Siddiqi stages. In this way, it can be used to select probable COVID-19 cases for hospitalization. Unfortunately, this score has not been evaluated in LTRs yet, but seems promising in this group of patients as well. Altered smell and/or taste is one aspect assessed by the AIFELL score, and this disease feature was only noted in one patient in this case series. Although this symptom appears to be fairly frequent in the general population, it was hardly noted in LTRs.

### *4.8. Remdesivir in Patients with Impaired Renal Function*

In this case series, six (33%) patients were treated with remdesivir, of these three had kidney failure (two were on chronic intermittent hemodialysis), which is generally considered a contraindication for remdesivir treatment.

Remdesivir (GS-5734) is a nucleoside analog with a broad antiviral activity to RNA viruses and is also still under investigation for the treatment of Ebolavirus (EBOV, the primary indication), MERS and SARS-CoV-1 [37]. As the first approved drug for COVID-19, remdesivir remains somewhat controversial in the treatment of COVID-19. Both the SOLIDARITY trial [38] and the ACTT-1 trial [39] did not show a significant survival benefit. Nevertheless, in the ACTT-1 trial, remdesivir was shown to be superior to placebo in shortening the time to recovery in adults who were hospitalized with COVID-19, and showed evidence of lower respiratory tract infection [39]. In the ACTT-1 trial, the median

recovery time improved from 15 to 10 days in patients with remdesivir compared to placebo, respectively. The lower 14-day mortality rate in the remdesivir treatment group may indicate a beneficial effect, although it was not statistically significant [39]. However, that study was not powered to evaluate mortality, and therefore mortality should be further evaluated in larger studies with different stages of COVID-19. Reducing the time to recovery by 31%, remdesivir may therefore help to reduce the number of inpatient days, with potential positive effects on hospital costs and capacity issues during the pandemic [37]. Taking the results of both trials together, it might be concluded that treating patients "relatively late" in the course of the disease, remdesivir will not improve the mortality rate in patients with COVID-19. Defining the right timing for the use of remdesivir in COVID-19 still needs further studies. Both trials had a very heterogeneous study population, making firm conclusions on remdesivir treatment difficult. If effective at all, remdesivir should probably be given early in the disease process. Currently, studies with remdesivir treatment in COVID-19 accounting for disease severity and measuring viral load of SARS-CoV-2 are still awaited. Patients with high viral loads are possibly the best candidates to treat with the antiviral drug remdesivir, but this still needs to be proven.

An important issue, especially relevant in the LTR population, is the question of how to treat patients with an impaired renal function. As a prodrug, remdesivir is predominantly metabolized by hepatic enzymes with hydrolase activity [40,41]. Routine monitoring of liver function tests is recommended, and remdesivir should be discontinued in patients with alanine aminotransferase (ALAT) ≥10 times the upper limit of normal. The proposed standard dosage is 200 mg as a single dose on day 1, followed by 100 mg once daily. In patients with an eGFR ≤30 mL/min and in patients with renal replacement therapies, remdesivir is not recommended.

However, a multicenter, retrospective study reviewing hospitalized patients with SARS-CoV-2 who received remdesivir, showed that this remdesivir treatment was not significantly associated with increased acute kidney injury (AKI) at the end of treatment in patients with an eGFR <30 mL/min compared to patients with an eGFR ≥30mL/min [42]. The advice not to prescribe remdesivir in patients with an eGFR ≤30 mL/min can be understood in the light of the paucity of clinical data in this group of patients. In animal experiments, remdesivir has been shown to be nephrotoxic in monkeys and rats; however, these doses were 2.1–3.5 fold higher than the doses used in the treatment of SARS-CoV-2 for humans [42]. Nevertheless, in the study of Ackley et al., there was a significantly higher mortality rate in patients with an eGFR <30 mL/min., attributed to the older age, more comorbidities, more frequent use of vasopressors or inotropes, and more frequent use of mechanical ventilation [42].

One case report on a LTR with an initially normal renal function who experienced renal failure after initiation of remdesivir for the treatment of COVID-19 is of concern [43]. In this patient, serum remdesivir concentrations were undetectable, but there were elevated levels of the remdesivir metabolite (GS-441524), suggesting that the metabolite could be responsible for the renal failure in this patient [42,43]. Although it should be mentioned that renal disease is a predictor of COVID-19 related mortality [44], and more than one-fourth of patients with an eGFR <30 mL/min require mechanical ventilation due to COVID-19 related respiratory failure [42], a potential renal toxicity from the accumulation of remdesivir active metabolites requires further study.
