Regional air pollution persistence links to COVID-19 infection zoning
Authors: Antonio Frontera, Claire Martin, Kostantinos Vlachos, Giovanni Sgubin
Journal: Journal of Infection (2020)

As discussed in the Journal recently 1 the SARS-CoV-2, a new β-Coronavirus, uses the Angiotensin Converting Enzyme-2 Receptor to enter airway cells.Viral endocytosis is mediated by several factors, including clathrin, the adaptor protein-2 complex (AP2) and the adaptor-associated kinase-1 (AAK1). 2 According to a recent report, 3 COVID-19, the disease caused by SARS-CoV-2, is characterized by three clinical patterns: no symptoms, mild to moderate disease, severe pneumonia requiring admission to Intensive Care Unit (ICU) in up to 31% of the patients. 3 Thus far, there is no specific therapy for COVID-19 infection.No benefit of lopinavir-ritonavir treatment resulted in a recent trial. 4 Hydroxychloroquine, currently used in view of its "in vitro" observed effect of reduction of viral replication, seems unsatisfactory. 5 Elevated proinflammatory cytokine/chemokine responses seem associated with respiratory failure. 3 Recently, tocilizumab, an interleukin-6 inhibitor, was reported as effective in patients with severe COVID-19 pneumonia. 6 Baricitinib, another inhibitor of cytokine-release, seems an interesting anti-inflammatory drug.It is a Janus kinase inhibitor (anti-JAK) licensed for the treatment of rheumatoid arthritis (RA) with good efficacy and safety records. 7 Moreover it seems to have anti-viral effects by its affinity for AP2-associated protein AAK1, reducing SARS-CoV-2 endocytosis. 8 On this basis, we assessed the safety of baricitinib therapy combined with lopinavir-ritonavir in moderate COVID-19 pneumonia patients and we evaluated its clinical impact.All consecutive hospitalized patients (March 16th -30th) with moderate COVID-19 pneumonia, older than 18 years, were treated for 2 weeks with baricitinib tablets 4 mg/day added to ritonavir-lopinavir therapy.The last consecutive patients with moderate COVID-19 pneumonia receiving standard of care therapy (lopinavir/ritonavir tablets 250 mg/bid and hydroxychloroquine 400 mg/day/orally for 2 weeks) admitted before the date of the first baricitinib-treated patient served as controls.Antibiotics were scheduled only in the case of suspected bacterial infection.Inclusion criteria were: a. SARS-Co-V2 positivity in the nasal/oral swabs; b. presence of at least 3 of the following symptoms: fever, cough, myalgia, fatigue; c. evidence of radiological pneumonia .After discharge, patients treated with baricitinib were planned to be followed for additional 6 weeks.Exclusion criteria: history of thrombophlebitis (TP), latent tuberculosis infection (QuantiFERON Plus-test positivity, Qiagen, Germany 9 ), pregnancy and lactation.Mild to moderate COVID-19 disease definition: presence of bilateral pneumonia with or without ground glass opacity and in absence of consolidation, not requiring intubation at enrollment; arterial oxygen saturation (SpO2) > 92% at room-air, and ratio arterial oxygen partial pressure/fractional inspired oxygen (PaO2/FiO2) 10 0-30 0 mmHg.Parameters daily accessed were: fever, pulmonary function, Modified Early Warning Score (MEWS), 10 pulse rate, blood pressure.After the initial execution, radiology imaging was performed on demand.Laboratory investigations included blood cell counts with differential counts, tests for liver and kidney functions, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and procalcitonin.The trial was approved by the Azienda-USL Toscana Centro Committee for off-label use of drugs.All patients signed a written informed consent to participate to the study.Descriptive statistics, presented as median and interquartile range (IQR), were calculated using Microsoft ® Office Excel for Windows and ©2019 Minitab, LLC for Windows.Mann-Whitney U test was used for pairwise comparisons, Wilcoxon-test for paired data, Fisher's exact test for categorical variables comparisons.P values ≤ 0.05 were considered statistically significant.Twelve patients, 10 males and 2 females, with a median age of 63.5 (IQR: 57.7-72.2) years were enrolled in the hospitals in Prato and Alessandria.Clinical characteristics are shown in Table 1 .Comorbidities were similar in the two groups.Baricitinib-treatment was well tolerated with no serious adverse events (AEs).Therapy was withdrawn in 1 patient after 10 days of treatment due to consistent transaminases elevation (AST: 267 U/L; ALT: 298 U/L), probably due to the antiviral therapy rather than to the baricitinib treatment, which is mainly renalmetabolized.In addition, no bacterial or opportunistic infections, trombo-flebitis or hematologic toxicity were observed.