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.
Here we provide a retrospective analysis of 14 hospitalized patients with Covid19-related inflammatory lung injury who received nebulised adenosine. Our results showed no adverse events and a treatment response rate, considered as an at least30%-increase in PaO2/FiO2ratio at 15 days, in 13 out of14 adenosine-treated patients (92%). The response rate was much higher than that reported in the analogue52control patients who only showed a treatment response rate of only 13.5% at 15 days. On these bases, our adenosine treatment fulfilled the prefixed statistical endpoint of activity of 70% in the first 14 consecutively treated patients and could be considered for further studies. The clinical results of the treatment were very promising considering that patients’ symptoms (respiratory as well as fever, asthenia, headache) declined within 4 days from the beginning of the treatment. Eight of the adenosine-treated patients could be released from the hospital within one from since the beginning of the treatment with adenosine. These clinical results were also supported by radiological imaging study whose results showed a significant improvement in the signs of interstitial lung pneumonitis in 6 out of 10 studied patients. As an additional and unexpected finding we also detected a significant decrease in SARS-Cov-2 viral load. These results were not observed in our control group of patients where PaO2/FiO2ratio and clinic-radiological improvement as well as SARS-Cov-2 disappearance did not occur in less than 30 days. However, limitations of the present study are both the small patient sample size and the historical nature of the comparison; despite these facts, the death rate in the group of patients receiving adenosine was 7.14% (1/14 patient), while those recorded in the group of patients who did not receive adenosine was 21.11% (11/52 patients). The results observed in our historical group were, therefore, in line with those reported worldwide for similar patients. Our findings seem to confirm the results of the preclinical studies in mice were intra-bronchial administration of A2 receptor agonists could restore the anti-inflammatory and tissue protective effects of oxygen-dampened adenosine system. Presently, we do not have enough information to explain the effect of inhaled adenosine therapy on SARS-Cov-2 load; however, it can be hypothesized that adenosine given in hypoxic conditions is able to induce the following effects: i) to restore an appropriate virus-specific immune-response previously attenuated by the inflammatory storm; ii) to exert a direct anti-viral host effect mediated throughout the A2R pathway; iii) to convert the intracellular adenosine in pro-apoptotic metabolites (like deoxy-adenosine/deoxy-ATP) in some infected cells. The latter effect should be investigated in future studies. In this light, there is large concordance on the fact that mechanical damage to the lung associated to active ventilation can add to the SARS-CoV-2 -induced lung damage . On the other hand, it is now widely known that abuse of hyperoxic breathing itself can inhibit the major physiological tissue-protecting hypoxia-A2-adenosinergic mechanism leading to massive tissue damage consequences. Our treatment was aimed to restore the A2 adenosine receptors signaling and thereby ensuring again the protection of healthy lung tissue–even in the presence of continuing oxygenation.
In agreement with the previous preclinical studies, we showed that our treatment strategy in this small patients’ series, could result in an accelerated increase in PaO2/FiO2ratio and performance status and an antiviral effect. In this view, inhaled adenosine is the first treatment for Covid-19 aimed to exert rapidly both clinical benefit and antiviral activity in critical patients. We believe that our results definitely deserve to be investigated in controlled clinical trials supported by both clinical as well as an immune-biological monitoring and expertise. Considering the dramatic consequence that Covid-19 outbreak is determining worldwide, these results, if confirmed in a complete clinical trial assessment, could greatly improve how we treat and cure these patients.
Reference & Source information: https://journals.plos.org/
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