COVID-19 Pneumonitis Low Dose Lung Radiotherapy (COLOR-19)
COVID-19 Pneumonitis Low Dose Lung Radiotherapy (COLOR-19)
Low-dose radiotherapy treatment delivered to both lungs in patients with immune-related
 pneumonia following COVID-19 infection is backed up by biological and clinical bases that
 justify its use as a possible therapeutic option in these patients. This is a preliminary
 exploratory study (non-pharmacological interventional) to evaluate the feasibility and
 tolerability of low-dose radiotherapy treatment of SARS-Cov-2 immune-mediated pneumonia, for
 the subsequent implementation of a phase II study.This is a preliminary, monocentric,
 single-arm, interventional, non-pharmacological exploratory study. All enrolled patients will
 be treated with low-dose radiotherapy. Participants will undergo irradiation of the lungs,
 administered in a single fraction at the average prescription dose of 0.7 Gy (further details
 in the dedicated section).
BACKGROUND

 Since the first case of Severe Acute Respiratory Syndrome - Coronavirus - 2 (SARS-CoV-2)
 infection and its subsequent clinical manifestation (COronaVIrus Disease 19, COVID-19) in the
 city of Wuhan (Hubei, China) in December 2019, contagion abruptly spread to different regions
 of China and, subsequently, to all continents. To date, 1 521 252 cases have been confirmed
 worldwide. With the first case ascertained in Lombardy at the end of February 2020, Italy
 soon became the first European country to face the exponential growth in the number of
 infected people (to date -May 3, 2020-210,717 total cases, currently positive 100,179).The
 disease turned into an actual health emergency due to the rapid spread and the need of
 hospitalization and respiratory function support in Intensive Care Unit (ICU) for a
 significant fraction of the patients. However, the clinical presentation of COVID-19 is
 non-specific and extremely heterogeneous. Many patients are asymptomatic or exhibit mild
 symptoms, which include cough, fever, general malaise with myalgias, anosmia and ageusia. The
 most common changes in blood tests include lymphopenia, thrombocytopenia and increased
 C-reactive protein and ferritin.

 As emerged by clinical data, the viral infection could be divided into three different
 phases: stage I, asymptomatic incubation period with little or undetectable viral load; stage
 II, mild symptomatic period with considerable and detectable viral load; stage III, severe
 symptomatic period with high viral load.

 The definitive diagnosis requires a positive molecular test with Real Time PCR (RT-PCR)
 method for SARS-CoV-2 on nasopharyngeal swab. However, this technique suffers from
 sub-optimal sensitivity, which may require repetition on bronchoalveolar lavage. The
 execution of chest CT is therefore essential, as it is characterized by high sensitivity and
 can detect highly suggestive findings even in patients with negative RT-PCR.

 Although the majority of infections resolve spontaneously without the need for specific
 therapy, up to 20% of patients can develop severe clinical pictures with pneumonia
 characterized by dyspnea, tachypnea and hypoxemia that requires treatment in a hospital
 setting. Pulmonary involvement is typically bilateral, peripheral and basal in most cases,
 presenting on CT scan with multifocal ground glass opacities and interstitial infiltrations;
 complete resolution usually takes several weeks. Despite active treatment, about 5-10% of
 cases can precipitate, often suddenly, into critical conditions including respiratory
 failure, ARDS and multi-organ dysfunction that require ICU admission and are burdened with
 high mortality.

 Even though the understanding of the pathogenesis of COVID-19 is still incomplete, the
 central role of the immune response in determining the development of severe clinical
 pictures is increasingly being defined. Organ damage could therefore not be induced by the
 direct effect of the infection, but mediated by an uncontrolled immune response resulting in
 the development of a "cytokine storm", as suggested by the high levels of inflammatory
 cytokines (among which interleukin 6 (IL-6), tumor necrosis factor (TNF) and interferon γ
 (IFNγ) play a major role) in patients who exhibit severe or fatal disease. To date, no drug
 has been approved with a specific indication for the treatment of COVID-19. The current
 treatment encompasses antiviral agents approved for other viral infections, including
 protease inhibitors (lopinavir and ritonavir), anti-influenza drugs (oseltamivir and arbidol)
 and compassionate use of nucleotide analogues. Several studies are evaluating the possible
 effectiveness of the inhibition of pro-inflammatory cytokines activity in preventing or
 treating severe COVID-19, through the use of immunomodulators (chloroquine and
 hydroxychloroquine) or monoclonal antibodies such as tocilizumab, which targets the IL-6
 receptor. Despite promising preliminary results, a multitude of patients need an immediate
 treatment while the results of ongoing clinical trials are awaited.

 RATIONALE

 Although most COVID-19 infections resolve spontaneously without the need for specific
 therapy, up to 20% of patients can develop severe clinical pictures with
 interstitial-alveolar pneumonia characterized by dyspnoea, tachypnea and hypoxemia up to an
 acute respiratory distress syndrome (ARDS), severe respiratory failure and multi-organ
 dysfunction requiring ICU hospitalization and burdened with high mortality.

 To date, the pathogenesis of SARS-CoV-2 pneumonia is poorly understood, but the
 immune-inflammatory response to infection is progressively emerging as pivotal in the
 development of severe clinical manifestations. An adequate viral load might stimulate the
 immune cells to synthesize pro-inflammatory cytokines as interleukin 1 and 6 (IL-1, IL-6),
 tumor necrosis factor α (TNF α) and attract macrophages, responsible for the secretion of
 several chemokines that could trigger an unregulated "cytokine storm". A few reports of
 histological analysis of lung tissue specimens from COVID-19 patients highlighted nonspecific
 inflammatory changes with the appearance of edema, hyaline membranes and an inflammatory
 infiltrate dominated mainly by lymphocytes. Peripheral blood tests often reveal
 lymphocytopenia and a high neutrophil count are found, especially in case of severe disease,
 with a high value of neutrophil to lymphocyte ratio (NLR), and a relevant increase in
 circulating pro-inflammatory cytokines levels.

 While vaccines and drugs directly targeting the virus are currently being developed and are
 not yet available, preventing the excessive and uncontrolled cytokine release and
 inflammatory response could be the key to avoid the occurrence of severe disease.

 Different clinical trials are exploring this path, evaluating immunomodulators and monoclonal
 antibodies targeting mediators such as interleukin 6(IL-6).

 Although conventionally fractionated (1.8-2 Gy/fraction) and hypofractionated (> 3 Gy
 fraction) radiotherapy, used in the field of neoplastic diseases, provides its therapeutic
 effect also inducing pro-inflammatory molecules, it has widely been documented in the first
 decades of the last century that low-dose radiotherapy (LD-RT) is potentially effective and
 relatively safe in the control of acute and/or chronic inflammatory diseases (e.g. skin
 diseases such as psoriasis, necrotizing abscesses, tendonitis, impingement syndrome).

 Many studies reported the effectiveness of radiation treatment after a single application,
 with a prompt improvement of symptoms, usually occurring within 24 ours and often definitive
 or long-lasting. Low dose radiotherapy exerts its effect on several cells involved in the
 immune response: endothelial cells, polymorphonuclear leukocytes, lymphocytes and
 macrophages. This is true also for pneumonia.

 Endothelial cells play a crucial role in the inflammation process, both for the "homing"
 process of leukocytes, and for the expression of a wide variety of cytokines and growth
 factors. Different studies have shown that a dose of 0.5 Gy induces an over-expression of
 tumor growth factor β (TGF-β), which has immunosuppressive activity and leads to a reduction
 in leukocyte adhesion on endothelial cells.

 The leukocyte "rolling" on the endothelium in the sites where inflammation is present
 represents the initial step of the inflammatory cascade. The effects of LD-RT were analyzed
 in vitro; after radiation doses of 0.3 - 0.6 Gy, there was a 25-40% reduction in adhesion
 compared to control after 24 hours from irradiation.

 Ionizing radiation at doses below 1 Gy are also capable to polarize macrophages towards the
 M2 anti-inflammatory phenotype. Conversely, doses greater than 1 Gy tend to induce
 polarization towards the M1 pro-inflammatory subtype. The use of low doses of radiation seems
 to act on macrophages also reducing their cytotoxic action, reducing the production of nitric
 oxide (NO) through to the inhibitory action on the enzyme cytokine inducible nitric oxide
 synthetase (iNOS) .

 Neutrophils play a central role in lung damage induced by Middle East Respiratory Syndrome
 (MERS) and SARS-CoV, and likewise in COVID-19, as they migrate into the alveoli where they
 release proteinases and trigger the innate response, with consequent development of cell
 damage and clinical presentations like ARDs (30,31). Low-dose radiation therapy is able to
 initiate the apoptotic process of polymorphonuclear granulocytes (neutrophils), thus reducing
 their cytotoxic activity (32). This treatment can therefore exert an anti-inflammatory
 activity through several mechanisms of action, with an optimal and long lasting effect
 demonstrated for a dose of 0.5 Gy (32).

 In the absence of a specific treatment, while ongoing trial are evaluating pharmacological
 approaches and vaccines, innovative approaches could be undertaken to face the emergency and
 allow a satisfactory management of the disease.

 A single fraction radiation treatment delivering low doses to the entire bilateral lung
 parenchyma (whole lung treatment) is a reasonable and conceptually valid option to inhibit
 inflammation and obtain a prompt improve of the symptoms in the short term.

 Unlike most of the drugs analyzed so far in the framework of COVID-19 infection, low dose
 radiotherapy is characterized by a minor risk of side effect (negligible, considering the
 acute phase) and could therefore represent an optimal complementary therapeutic approach due
 to its safety and absence of interaction with pharmacological treatments. Moreover, this
 treatment requires less than one hour including treatment planning and administration.

 TREATMENT DELIVERY

 The patient will undergo radiation treatment on both lungs in a single session. From the
 physical-dosimetric point of view, the treatment plan will be calculated in an isocentric
 manner. The isocenter will be positioned at a depth of 10 cm with respect to an anterior skin
 landmark specifically defined during CT-scan acquisition. The treatment plan will be
 elaborated using a field in field irradiation technique, with 2 beams each one composed by 3
 beamlets: one conformed to the volume resulting by the union of the lungs with a 2 cm margin,
 the other two will be obtained by shielding the spine and alternately one lung each. This set
 up allows to obtain a dose distribution in which the vertebral bodies receive a dose lower
 than 55 cGy with an average lung dose of 70 cGy and maximum lungs dose lower than than 90
 centigray (cGy). The Pinnacle ® treatment planning system (TPS) with Collapsed Convolution
 calculation algorithm will be used. Prescription doses were determined according to data and
 indications currently published and optimized to minimize the dose to the vertebrae.
Inclusion criteria

 -  Age ≥ 50 years

 -  Patients with confirmed diagnosis of SARS-Cov2 infection by RT-PCR on nasopharyngeal
 swab and / or bronchoalveolar lavage (BAL)

 -  Patient with Brescia Covid Respiratory Severity Scale (BCRSS) score 2-3

 -  Suggestive picture finding for interstitial pneumonia on chest X-ray and / or chest CT
 (optional)

 -  At least 3 of the following laboratory criteria:

 -  PCR> 5 times the maximum limit of the normal value

 -  Ferritin> 500 ng / ml

 -  lactate dehydrogenase (LDH) > 2 times the maximum limit of the normal value

 -  D-dimer> 3 times the maximum limit of the normal value

 -  Aspartate aminotransferase (AST)> 2 times the maximum limit of the normal value

 -  Total lymphocytes <1000 / ml

 -  Ability to understand and sign informed consent

 -  Ability to acquire and maintain the set-up necessary for the delivery of radiotherapy
 treatment

 -  A negative pregnancy test will be required of patients of childbearing age before
 starting radiotherapy treatment. Patients with reproductive potential of both sexes
 will have to agree to use an effective contraceptive method for at least 6 months from
 the date of treatment.

 Exclusion Criteria:

 -  Age <50 years

 -  Brescia Covid Respiratory Severity Scale (BCRSS) score greater than 3

 -  Patients undergoing invasive mechanical ventilation

 -  Patients with active autoimmune systemic diseases

 -  Patients with active infections that are not responsive to current treatment

 -  Patients with a positive pregnancy test

 -  Impossibility to maintain the set-up necessary for radiotherapy treatment

 -  Other concomitant treatments for COVID-19 do not represent an exclusion criterion,
 however they must be reported (specifying the starting date and dosage)