2. Immunomodulatory and anti-inflammatory agents
As previously reported the SARS-Cov-2 infection can be associated, especially in severe form, to the exaggerate activation of inflammatory processes and the development of cytokine storm. Based on this consideration, several drugs with immunomodulatory properties are currently evaluated in patients with COVID-19. These drugs include both synthetic and biological medicines that are able to modulate specific inflammatory pathways through the inhibition of human interleukin-6 receptor (IL-6R), of the metabolism, motility and chemotaxis of polymorphonuclear cells, of Janus kinase (JAK) or TNF-α production.
One of the first drugs used in patients with COVID-19 was tocilizumab. This is a monoclonal antibody that inhibits ligand binding to the IL-6R and that is authorized for the treatment of rheumatoid arthritis and systemic juvenile idiopathic arthritis [47 ]. Scientific evidence suggests that the IL-6 pathway plays a key role in guiding the inflammatory immune response at the level of pulmonary alveoli in patients affected by COVID-19. Indeed, this immune response produces damage to the lung parenchyma, which significantly reduces respiratory function [48,49 ]. The drug was first tested in China to reduce lung complications in 21 patients with severe SARS-CoV-2 infection [50 ]. The treatment was associated with a reduction of oxygen requirement, resolution of computed tomography (CT) lesions, normalization of lymphocyte count, reduction of C-reactive protein levels, hospital discharge, with average hospitalization duration of 13,5 days. Given the achieved clinical outcomes, the drug is currently used in several Italian hospitals, including the Cotugno Hospital in Naples. Since tocilizumab seems able to prevent the hyperactivation of inflammatory pathway, its use can be expected also in early stages for patients with not severe COVID-19. Currently three clinical studies, including one that was authorized by the AIFA, are ongoing [51-53 ]. Sarilumab belongs to the same drug class of tocilizumab and 3 trials are underway to evaluate the efficacy and safety of this drug, alone or in combination with standard care, in almost 1,500 patients with COVID-19 [54-56 ].
Two other drugs, chloroquine and hydroxychloroquine, are commonly off-label used in Chinese and Italian clinical centers for the treatment of COVID-19 [57 ]. These compounds are authorized as antimalarial drugs and for the treatment of autoimmune diseases, including lupus and rheumatoid arthritis. Even though both drugs are considered to be safe with adverse events that are generally mild and transitory, they can be associated with cardiovascular disorders, including prolongation of QT that can be life-threatening [58 ]. Some preclinical studies showed that chloroquine has antiviral activity against SARS coronavirus [59 ], human coronavirus OC43 [60 ] and influenza A H5N1 [61 ] suggesting a possible role in SARS-Cov-2 infection [62,63 ]. Further studies found that chloroquine interferes with terminal glycosylation of the functional ACE 2 receptor, negatively influencing the virus-receptor binding. Indeed, results of a clinical study showed that the combination remdesivir/chloroquine or hydroxychloroquine is highly effective in control of SARS-Cov-2 infection [20,64,65 ]. Both drugs are currently used in Italy in patients with SARS-Cov-2 infections, including outpatients in early stages of disease, and, given their particular safety profile, the AIFA recommended to healthcare professionals to perform a careful evaluation of the patient, particularly in cases of cardiac conduction disorders, glucose-6-phosphate dehydrogenase deficiency or the presence of other concomitant therapies [66 ].
Another drug able to reduce the cytokine storm is colchicine that is authorized for the treatment of acute attack of gouty arthritis and pericarditis. The drug reduces the inflammatory response through several mechanisms: the inhibition of the metabolism, motility and chemotaxis of polymorphonuclear cells, the inhibition of the adhesion and recruitment of neutrophils and the modulation of leukocyte-mediated inflammatory activities [67-71 ]. On March 2020 a phase 3 clinical study (COLCORONA) began. This study will enroll 6,000 outpatients with COVID-19 with the following characteristics: age ≥ 40 years; diagnosis of COVID-19 in the past 24 hours; at least one risk factor between age>70 years, diabetes, uncontrolled hypertension, asthma or COPD, heart failure, fever ≥38.4 ° C in the last 48 hours, dyspnea, pancytopenia or high neutrophil count and low lymphocyte count; patients not of childbearing age or using contraception methods [72 ].
Baricitinib is currently approved for the treatment of rheumatoid arthritis. It is a selective and reversible inhibitor of JAK1 and JAK2. These enzymes transduce intracellular signals for cytokines and growth factors involved in hematopoiesis, inflammation and immune function. Furthermore, baricitinib blocks the protein kinase 1 associated with AP2 (AAK1), preventing the binding of the virus to the alveolar epithelium [70 ]. A study published in The Lancet suggested that this drug could represent an additional therapeutic alternative for the treatment of COVID-19 [73 ]. A non-randomized phase II clinical trial recently started in order to evaluate the efficacy and safety of baricitinib, lopinavir/ritonavir, hydroxychloroquine and sarilumab in the treatment of 1,000 hospitalized patients with COVID-19 [74 ]. Similarly, sunitinib, fedratinib and ruxolitinib, which are all selective JAK inhibitors, may be potentially effective against SARS-CoV-2 in reducing inflammation and cytokine levels, including interferon-γ and IL-6, and virus endocytosis [75-78 ].
Aviptadil is an analogue of vasoactive intestinal polypeptide (VIP). This drug is authorized for the treatment of erectile dysfunction, sarcoidosis and acute lung damage. The rationale for its use for the treatment of ARDS is based on the results from preclinical studies showing that the VIP is highly concentrated in the lung, where it prevents the activation of caspases NMDA-induced, inhibits IL-6 and TNF-α production and protects against HCl-induced pulmonary edema [79-81 ]. In a clinical study, 8 patients with severe ARDS were treated with ascending doses of the VIP. Of these patients, 7 were successfully extubated and were alive at the five-day time point, 6 left the hospital and 1 died due to a cardiac event [82 ]. A phase II clinical trial based on patients with COVID-19 infection will begin shortly.
Eculizumab is a monoclonal antibody approved for the treatment of atypical hemolytic uremic syndrome, refractory generalized myasthenia gravis and neuromyelitis spectrum disorders. It is an inhibitor of the terminal portion of the complement cascade involved in the inflammatory response. Even though the role of complement cascade in the pathogenesis of SARS-CoV-2 infections is uncertain, many studies suggested that the inhibition of complement activation might potentially work as a therapeutic approach [83-85 ]. Based on these considerations, eculizumab will be tested in the SOLID-C19 clinical trial in the treatment of patients with severe SARS-CoV-2 and ARDS [86 ]. A phase 2/3 randomized, open-label, study is investigating the efficacy and safety of emapalumab, a monoclonal antibody targeting interferon gamma (IFNγ), and anakinra, an antagonist of IL-1R, in reducing hyper-inflammation and respiratory distress in patients with SARS-CoV-2 infection [87 ]. This study received the approval by the AIFA [88 ].
Finally, noteworthy is the use of corticosteroids. A recent document released by the WHO specified that these drugs are adjunctive therapies for COVID-19. Specifically, it is reported that, according to the results of a systematic review of observational studies, the use of corticosteroids in patients with SARS was not associated to survival benefit [89 ]. Similarly, a further systematic review of observational studies found a higher risk of mortality and secondary infections with corticosteroids administered in patients with flu [90 ]. However, this effect was not confirmed by a subsequent study [91 ]. Therefore, the WHO recommend for patients with COVID-19 to use corticosteroids only if they are indicated for another reason such as exacerbation of asthma or COPD, septic shock [92 ]. Literature data support that corticosteroids do not add clinical benefits in the treatment of COVID-19 infection [93 ]. On the other hand, some studies reported improvements in SARS patients treated with methylprednisolone, also in terms of reduction of IL-8, monocyte chemo-attractant protein‐1 and Th1 chemokine IFN‐γ‐inducible protein‐10 [94,95 ], while one case reports described positive effects of methylprednisolone on clinical outcomes of one patient with COVID-19 [96 ]. In conclusion, considering that evidence available is quite conflicting regarding to the use of corticosteroids in patients with COVID-19, as recommended by the WHO, their use should underwent a case by case evaluation.