5. Other therapies
The use of convalescent plasma therapy in patients with COVID-19 is still being debated. Convalescent plasma is a mixture of inorganic and organic compounds, water and proteins (including albumin, immunoglobulins, complement, coagulation and antithrombotic factors) (Rojas et al., 2020). This treatment was formerly evaluated in the treatment of SARS (Cheng et al., 2005), MERS (Arabi et al., 2016) and Ebola (Kraft et al., 2015), being associated with a reduction in fatality rate. For COVID-19, stringent criteria need to be satisfied in order to be a convalescent donor. Specifically, donors should have the following characteristics: aged between 18 and 65 years; absence of infectious symptomatology; a negative test for COVID-19 after 14 days of recovery (which must be repeated 48 h later and at the moment of donation) (Tiberghien et al., 2020). The main procedure to obtain plasma is apheresis, which is based on a continuous centrifugation of blood from donor. From a single apheresis 400–800 mL of plasma can be obtained (Bloch et al., 2020). Nowadays, few clinical studies were concluded and their results could provide new insights regarding to the effectiveness and safety profile of plasma therapy in COVID-19 patients. Li l et al. reported the results of an open-label, multicentre, randomized clinical trial carried out in Wuhan, from February to April 2020. The trial enrolled 103 participants (median age: 70 years) with a severe form of COVID-19, who were randomized to receive convalescent plasma in addition to standard treatment (n=52) or the standard treatment alone (n=51). The effects of both therapies were evaluated as the time to clinical improvement within 28 days (primary outcome) and on 28-day mortality, time to discharge, and the rate of viral PCR results turned from positive at baseline to negative at up to 72 hours (secondary outcomes). According to the study’s results, the convalescent plasma therapy was not associated with a statistically significant improvement in time to clinical improvement within 28 days compared with standard treatment alone. In addition, 2 patients in the convalescent plasma group experienced adverse events within hours after transfusion. Due to a decrease in the number of COVID-19 cases in late March, the study was stopped earlier; this needs to be take in consideration when the study’s results are interpreted (Li et al., 2020b). Simonovich VA et al. carried out a randomized controlled trial in 334 hospitalized adult patients with severe COVID-19 pneumonia, who were randomized to receive convalescent plasma (n=228) or placebo (n=105) in addition to standard treatment. Authors evaluated the effects of the therapy in terms of changes in patient’s clinical status 30 days after the intervention. Similarly to the previous study, no difference in terms of efficacy was found between treatments groups at day 30. Regarding to the safety profile, infusion-related adverse events were detected in 4.8% of patients in the convalescent plasma group vs. 1.9% of patients in the placebo group (odds ratio, 2.62; 95% CI, 0.57 to 12.04), even though no significant differences were found in the overall incidence of adverse events or serious adverse events (Simonovich et al., 2020). On the other hand, few small trial or case series reported that the convalescent plasma therapy might be beneficial in COVID-19 patients. For instance, Duan K et al. reported that the administration of 200 mL of convalescent plasma in 10 severe patients brought to a significant improvement in clinical symptoms along with increase of oxyhemoglobin saturation within 3 days and no severe adverse effects were observed (Duan et al., 2020). Zhang B et al. presented four critically ill patients with SARS-CoV-2 infection (including a 31-year-old pregnant woman) who received convalescent plasma and recovered from SARS-CoV-2 infection eventually and did not experience any serious adverse event (Zhang et al., 2020a). Lastly, a further case series described the effects of the convalescent plasma therapy in 5 critically ill patients with COVID-19 and ARDS, who improved after receiving the therapy (Shen et al., 2020). Despite their positive results, these studies’ findings (Duan et al., 2020; Shen et al., 2020; Zhang et al., 2020a) should be interpreted with caution considering the limited number of patients who were enrolled and the studies’ designs that did not allow making any comparison. In conclusion, based on the conflicting evidence currently available, the use of convalescent plasma needs to be considered as investigational. Regulatory agencies, such as the FDA, are releasing many documents in order to guide healthcare providers and investigators in the appropriate management of plasma therapy in the context of clinical trials (US Food and Drug Administration, 2020b).
Many studies are currently investigating the effects of vitamin D in COVID-19 patients (D’avolio et al., 2020). This interest derives from the evidence suggesting the role of vitamin D in reducing the risk of cold and acute respiratory infections (Zemb et al., 2020). Many mechanisms seem to underline this effect, including the effects of Vitamin D on cellular natural immunity and adaptive immunity through the decrease in cytokine storm (this effect was observed on interferon γ, tumor necrosis factor α and CD4+ T cell count (Ali, 2020). In addition, vitamin D improves the production of antimicrobial peptides in the respiratory epithelium, potentially reducing the risk of local infection and it seems to interact with ACE2 (Mitchell, 2020). Pizzini A et al. investigated the association between of Vitamin D status and COVID-19 presentation among 109 patients, using data from the CovILD registry. They found that low Vitamin D levels were not associated with poor clinical and radiological outcomes of COVID-19 (Pizzini et al., 2020). A further study, which was based on data from the UK Biobank, aimed to establish whether blood 25-hydroxyvitamin D concentration was associated with COVID-19 risk or not. Data were available for 348,598 UK Biobank participants, of which 449 had COVID-19 infection. Authors concluded that no association was found in terms of potential association between vitamin D concentrations and the risk of COVID-19 infection (Hastie et al., 2020). Ultimately, current evidence on a potential correlation between Vitamin D and COVID-19 is contradictory. Therefore, we should wait for results from clinical trials, which are currently underway to evaluate the effects of Vitamin D supplementation on mortality, morbidity, prevention and treatment of COVID-19 (www.clinicaltrials.gov). Currently, data on vitamins, mineral supplementation and nutraceuticals are quite scarce, although some studies are investigating their effects (Jovic et al., 2020).