Francesco Ferrara 1*, Giovanni Granata 2, Chiara Pelliccia 3, Raffaele La Porta PhD 4, Antonio Vitiello 1
1: Usl Umbria 1, Perugia, Italy
2: Asl Salerno, Salerno, Italy
3: Usl Umbria 2, Terni, Italy
4: Asur Marche, Ancona, Italy
*author correspondence: francesco.ferrara@uslumbria1.it

Abstract

Reduction of pulmonary fibrotic status and reduction of hyperinflammation is essential to combat SARS-CoV-2 and avoid death. Many authors have divided the SARS-CoV-2 infection into three stages, the second and third of which are purely inflammatory and fibrotic. Waiting for the development of antiviral drugs and vaccines to give good results, the best pharmacological goal is the reduction of proinflammatory molecules. This leads to less formation of fibrotic tissue and to the resolution of the patient’s respiratory problems. In fact, in phase 3, the most serious, there is a state of overexpression of the immune system with consequent assault on all tissues and damage to the lungs. Sars cov 2 pneumonia is characterized by ”cytokine storm” and can lead to death. Acting early and with pirfenidone combination therapy can be effective. The IL-6 or IL-1 inhibitors, chloroquine / hydroxychloroquine and colchicine, which are demonstrating their anti-inflammatory efficacy, when combined with an anti-inflammatory and antifibrotic agent, such as pirfenidone, can have a winning result. The effective combined terepia allows to use non-lethal dosages and affects all the pathological steps induced by the virus. Pirfenidone has been used for years in lung diseases and has been shown to have good clinical success and good safety and tolerability.The purpose of this study is to explain the pharmacological logic behind the use of a combination therapy as an effective and safe remedy to reduce pneumonia and the consequent death from Sars CoV 2.
Keywords : pirfenidone, fibrotic, inflammation, cythokine, interleukin, Sars-CoV-2.

Introduction

Sars-CoV-2 infection leads to hyperinflammation, fibrotic and cicatricial state, lung collapse and death of the patient if he is at risk. This clinical picture must be contrasted to put an end to a global pandemic that has already caused thousands of victims and this number is expected to grow exponentially. If the health crisis that has hit the whole world lasts for a long time, it risks generating a deep economic crisis with all the activities stopped and the continuous lock dawn imposed. For these reasons, looking for a therapy that can make the virus harmless immediately is of fundamental importance. Avoiding death is a great success that allows you to have the time to find a drug directed against the virus without blocking the whole world. Preventing patient death is a success to be achieved. The excessive inflammatory state induced by the Sars-CoV-2 virus has been shown to aggravate the patient’s clinical picture. In the most serious phases of the pathology there is an excessive release of proinflammatory cytokines that lead to lung damage with extensive fibrosis and scarring of the interstitial lungs with respiratory impairment. The combined use of anti-inflammatory drugs and drugs that prevent fibrotic status can beneficially resolve the clinical picture. Today Pirfenidone is the only drug that has been shown to reduce the fibrotic state of the lung tissues and is the drug of choice in many lung diseases. Combination therapy with pirfenidone can lead, albeit indirectly, to the defeat of the virus.

The clinical aspects of three phases SARS‐CoV‐2 infection

The SARS-Cov-2 virus caused the current global pandemic. The first cases of SARS-Cov-2 infection were recorded in November 2019 in China and then rapidly spread to all countries around the world causing thousands of deaths. SARS-Cov-2 infection can rapidly cause respiratory distress syndrome. According to observational studies conducted, the majority of patients considered as severe cases present bilateral intestinal pneumonia, and an overactive inflammatory state that is not only localized to lung tissue but to all tissues of the body. SARS-Cov-2 infection has been divided by scientific opinion into three phases, the first asymptomatic or mildly symptomatic with symptoms such as mild sore throat and abdominal pain, phase two and three more severe than one, presenting with a generalized inflammatory state and respiratory distress syndrome. Evidence has shown that bilateral interstitial pneumonia, defined in this way because it attacks the intestinal tissue covering the lung alveoli, is associated with the presence of fibrotic tissue caused by excess collagen (fibrosis) in the pulmonary interstitium with hyperinflammation present. Several therapeutic treatments have been considered, and several clinical trials are underway to test their efficacy and safety, drugs such as antivirals, immunomodulants, anticoagulants are being tested to best fight SARS-Cov-2 infection.As described above, phase two and three are the most serious, and the presence of inflammation in the lungs and scar tissue and fibrotic tissue, requires immunomodulating and anti-inflammatory treatment to combat these phases, although at the moment there are no certain data that demonstrate their effectiveness and at what time they should be used, ongoing clinical trials will give us more evidence. However, based on the descriptions of symptomatology and diagnostic investigations from early observational studies, one might think that the use of a drug currently indicated for pulmonary fibrosis such as pyrfenidone could bring great benefits. We also consider that given the very complex nature of the pathophysiology of SARS-Cov-2, probably a combination of several drugs (pending the marketing of a direct and specific antiviral or vaccine) in several steps could be the most suitable treatment (1-23).