Hypothesis: systemic low-grade tissue hypoxia as contributing causative mechanism for Long COVID
Silent hypoxia is one of the key clinical features of COVID-19 infection. Some of the hypothesized underlying causes of silent hypoxia, such as endothelial and micro-vascular dysfunction, and micro-clots inhibiting perfusion, would exert a two-fold effect, inhibiting not just the oxygenation of the blood but also the delivery of oxygen from the blood into tissues. These phenomena have been found to persist after acute infection, which would be expected to result in inhibited oxygen delivery even if arterial oxygen saturation has returned to normoxic conditions. As a consequence, it can be inferred as likely that some degree of systemic tissue hypoxia could also persist. A systemic hypoxic state would result not just generally disrupted function in various tissues, organs and systems, but also in disrupted immuno-modulatory and inflammatory processes, as hypoxia-inducible factors strongly influence both. This persistent inflammatory state would contribute to continuing vascular inflammation, making it a self-perpetuating condition, and could also result in presentation of anaemia of chronic illness, exacerbating symptoms. Hence, the expected effects of a persistent state of systemic tissue hypoxia closely match many of the observed presentations of Long COVID, suggesting it as a possible contributing causative mechanism.