Cystic fibrosis improves COVID-19 survival and provides clues for treatment of SARS-CoV-2

Abstract

Systemic pools of ATP are elevated in individuals homozygous for cystic fibrosis (CF) as evidenced by elevated blood and plasma ATP levels. This elevated ATP level seems to provide benefit in the presence of advanced solid tumors (Abraham et al., Nature Medicine 2(5):593–596, 1996). We published in this journal a paper showing that IV ATP can elevate the depleted ATP pools of advanced cancer patients up to levels found in CF patients with subsequent clinical, biochemical, and quality of life (QOL) improvements (Rapaport et al., Purinergic Signalling 11(2): 251–262, 2015). We hypothesize that the elevated ATP levels seen in CF patients may be benefiting CF patients in another way: by improving their survival after contracting COVID-19. We discuss here the reasoning behind this hypothesis and suggest how these findings might be applied clinically in the general population.

Case Report: Can Inhaled Adenosine Attenuate COVID-19?

“…Furthermore, it is hypothesized that the natural and high concentrations of adenosine in patients with CF lead to A2A and A2B receptors recognizing more antiinflammatory signals than those seen in patients without CF. Interestingly, the elderly and those with many underlying chronic disease states have low extracellular adenosine levels and an inability to increase adenosine/ATP export from their cells (Abraham et al, 2021). The CF data, the Italian findings, and our patients fit with the mechanisms and therapeutic options put forward herein and in the prior Frontiers in Pharmacology paper (Geiger et al, 2020).…”

“…Of interest and fitting with the hypothesis (Geiger et al, 2020) that extracellular adenosine interactions at various receptor sites are vital in the role of infection and lethality of COVID-19 and MERS-CoV (Geiger et al, 2020) is new work in cystic fibrosis (CF) (Abraham et al, 2021). Adenosine levels have been tested in patients with CF (Abraham et al, 2021) showing that they have abnormally high extracellular adenosine levels due to cellular leakage (10 to 100-fold normal) (Abraham et al, 2021). A patient with CF's propensity for pneumonia and lung supra-infection might make him/her highly susceptible to COVID-19 with an expected very high mortality rate in the population.…”

“…In multiple countries, no deaths from COVID-19 have occurred in patients with CF. It has been postulated that patients with CF have resistance to COVID-19 because they leak adenosine from inside their cells due to a dysfunction of transmembrane peptidases (where MERS-CoV binds) (Abraham et al, 2021). Furthermore, it is hypothesized that the natural and high concentrations of adenosine in patients with CF lead to A2A and A2B receptors recognizing more antiinflammatory signals than those seen in patients without CF.…”

Reply to Eisenhut

“…The limited circumstantial evidence that exists suggests, however, that few patients with CF are becoming infected with COVID-19 and those who do show little adverse effect on CF severity (36)(37)(38)(39). As a result, it has even been theorized that the elevated ATP levels seen in patients with CF may improve their survival after contracting COVID-19 (40). In fact, the results of a short-term, nonrandomized trial to mimic the elevated ATP levels seen in CF patients in elderly COVID-19 patients with comorbidities (including diabetes and obesity) showed dramatic improvement in survival following COVID-19 contraction (40).…”

“…As a result, it has even been theorized that the elevated ATP levels seen in patients with CF may improve their survival after contracting COVID-19 ( 40 ). In fact, the results of a short-term, nonrandomized trial to mimic the elevated ATP levels seen in CF patients in elderly COVID-19 patients with comorbidities (including diabetes and obesity) showed dramatic improvement in survival following COVID-19 contraction ( 40 ). These discussions point to the possibility that CFTR mutations might offer a survival benefit against COVID-19 ( 40 ) whereas analogously, hyperactivation might worsen the disease course and outcome in severe COVID-19, potentially—as proposed in our original concept—by promoting lung edema ( 2 ).…”