1. Introduction
Since the outbreak of COVID-19 epidemic, clinicians started a real “gold rush” to find the best therapeutic option among those currently available for infectious and inflammatory diseases [1]. Waiting for a vaccine, the study of COVID-19 clinical characteristics proved effective in directing towards meaningful medical choices.
Three main stages represent COVID-19 infection clinical course. In the first phase, the virus replicates within the host cells and patients may experience symptoms as dry cough, fever, and general weakness and malaise [2]. In the second phase, the progression of the disease is characterised by the development of a bilateral interstitial pneumonia and by morphological changes in host’s lungs [3]. Respiratory symptoms, which could be stable in the first phase of pneumonia, could worsen, due to both direct effects of the virus and host’s immune response, leading to clinical instability and severe hypoxemia [4]. Only in a limited number of cases (third phase), patients experience a “cytokine storm” and following hyper-inflammatory state, with local and systemic consequences [5]. Among them, at the lung level, arterial and venous vasculopathy, with thrombosis of the small vessels and evolution towards serious and sometimes permanent lung lesions. A progressive alteration of inflammatory and coagulation parameters, such as C-reactive Protein (PCR), ferritin, pro-inflammatory cytokines, consumption of clotting factors, and increased levels of the fragments of fibrin degradation (D-dimer), have been observed [6, 7].
In this complex scenario, therapeutic strategies have focused on viral growth containment in the first and second phase of the disease, and on inflammation and coagulation control, in the second and third phases (Table 1 ) [8]. When COVID-19 pandemic spread to Italy, the Italian Medicines Agency (AIFA) approved the off-label use of the antiviral combinations lopinavir/ritonavir and darunavir/cobicistat, the use of antimalarials chloroquine and hydroxychloroquine (HCQ), the antibiotic azithromycin, and the anticoagulant enoxaparin [9]. Clinical experience also suggested the use of tocilizumab, a humanized monoclonal antibody against interleukin (IL)-6 receptor [10].
However, the search for early and emergency effective treatments for COVID-19 infection may have led to loss of sight of treatments safety. From the beginning of COVID-19 pandemic, concerns about HCQ efficacy and safety raised [11] and subsequently AIFA suspended its use in SARS-CoV-2 patients out of clinical trials on May 29th 2020 [12]. Moreover, based on available evidence concerning the efficacy and safety of fixed associations darunavir/cobicistat and lopinavir/ritonavir, AIFA also suspended their use out of clinical trials on July 17th 2020 [13, 14].
Prevalence of adverse drug reactions (ADRs) in COVID-19 patients has not yet been deeply evaluated, but results from observational studies suggest that its frequency could be high in this population [15]. The majority of ADRs includes gastrointestinal and liver system disorders. Nevertheless, potential harmful ADRs should be closely monitored, and pharmacovigilance monitors’, toxicologists’ and clinical pharmacologists’ support in COVID-19 Units should be carefully considered in order to better manage COVID-19 therapies [16]. In particular, good quality information regarding drug-drug interactions (DDIs)-related ADRs are still lacking.
In this context, the aim of the present case-series study is to describe clinical and pharmacological characteristics of SARS-CoV-2 inpatients, focusing on ADRs, particularly those related to DDIs.