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.