Therapeutic effects of adenosine in high flow 21% oxygen aereosol in patients with Covid19-pneumonia

Abstract

Background SARS-Cov2 infection may trigger lung inflammation and acute-respiratory-distress-syndrome (ARDS) that requires active ventilation and may have fatal outcome. Considering the severity of the disease and the lack of active treatments, 14 patients with Covid-19 and severe lung inflammation received inhaled adenosine in the attempt to therapeutically compensate for the oxygen-related loss of the endogenous adenosine!A2A adenosine receptor (A2AR)-mediated mitigation of the lung-destructing inflammatory damage. This off label-treatment was based on preclinical studies in mice with LPS-induced ARDS, where inhaled adenosine/A2AR agonists protected oxygenated lungs from the deadly inflammatory damage. The treatment was allowed, considering that adenosine has several clinical applications. Patients and treatment Fourteen consecutively enrolled patients with Covid19-related interstitial pneumonitis and PaO2/FiO2 ratio<300 received off-label-treatment with 9 mg inhaled adenosine every 12 hours in the first 24 hours and subsequently, every 24 days for the next 4 days. Fifty-two patients with analogue features and hospitalized between February and April 2020, who did not receive adenosine, were considered as a historical control group. Patients monitoring also included hemodynamic/hematochemical studies, CTscans, and SARS-CoV2-tests. Results The treatment was well tolerated with no hemodynamic change and one case of moderate bronchospasm. A significant increase (> 30%) in the PaO2/FiO2-ratio was reported in 13 out of 14 patients treated with adenosine compared with that observed in 7 out of52 patients in the control within 15 days. Additionally, we recorded a mean PaO2/FiO2-ratio increase (215 ± 45 vs. 464 ± 136, P = 0.0002) in patients receiving adenosine and no change in the control group (210±75 vs. 250±85 at 120 hours, P>0.05). A radiological response was demonstrated in 7 patients who received adenosine, while SARS-CoV-2 RNA load rapidly decreased in 13 cases within 7 days while no changes were recorded in the control group within 15 days. There was one Covid-19 related death in the experimental group and 11in the control group. Conclusion Our short-term analysis suggests the overall safety and beneficial therapeutic effect of inhaled adenosine in patients with Covid-19-inflammatory lung disease suggesting further investigation in controlled clinical trials. Background Covid-19 outbreak has been declared as pandemic by the WHO reporting more than 4 million new cases worldwide with 300,000 related deaths [1]. Almost 20% of these patients developed interstitial pneumonitis that may evolve in ARDS requiring hyperoxic active ventilation, with mostly fatal outcomes [2–5]. The pathogenesis of the Covid-19-related lung injury is still controversial; however, a massive and uncoordinated release of inflammatory cytokines and a post-ischemic reaction to micro-vascular damage and micro-embolization seem to be involved [5–10]. Due to the acute medical need, different drugs are tested in ongoing trials aimed to hamper the effects of the cytokines involved the first phases of the inflammatory process [11–14]. However, mAbs to IL1β (Kanakinumab), IL6-Receptor (Tocilizumab) and inhibitors of Janus kinases (JAK)-1/2 (Baricitinib and Ruxolitinib) did not produce satisfactory clinical outcomes in patients with Covid19-related interstitial pneumonitis [14–16]. The most recent clinical evidences highlight a 20–30% mortality rate in patients with Covid19-related lung injury requiring active oxygen ventilation and depending on the classification of patients, time of intervention and how critical their illness is [17–19]. These reports are leading to the suspicions that some iatrogenic complication other than a mechanical lung damage does occur [17–19]. Accordingly, we carried out a clinical investigation based on insights and therapeutic suggestions offered in preclinical studies and paper with the self-explanatory title: “Oxygenation inhibits the physiological tissue-protecting mechanism and thereby exacerbates acute inflammatory lung injury” [20]. Based on the results of those preclinical studies in mice we hypothesized that mechanical ventilation and hyper-oxygenation lead to the unacceptable inflammatory side effects in patients with Covid19-related severe pulmonary complications. We further assumed, that the otherwise life-saving oxygenation also weakens the local tissue hypoxia-driven and adenosine A2A receptor (A2AR)-mediated anti-inflammatory mechanism [21–23]. Without this major physiological anti-inflammatory lung tissue protection, the neutrophils, lung macrophages and pulmonary natural killer cells in lungs are no longer inhibited and are unleashed to destroy the still healthy lung [20, 24–26].