Post-Acute Infection Syndrome (PAIS): A hypothesis on invisible hypoxia caused by endogenous carbon monoxide

How to explain post-exertional malaise (PEM)Post-acute infection syndromes (PAIS), including long COVID, post-VAC syndrome, and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), represent a growing and often misunderstood challenge. Despite persistent, debilitating symptoms such as fatigue and "brain fog," their exact pathophysiological mechanisms remain largely unclear.This hypothesis posits that chronically elevated endogenous production of carbon monoxide (CO), primarily through the enzyme heme oxygenase-1 (HO-1), is a previously underappreciated cause of these syndromes. Due to the extremely high affinity of CO for hemoglobin (Hb), this leads to "invisible hypoxia" at the cellular level, which remains undetected by standard diagnostics.This is partly because pulse oximetry incorrectly interprets COhb as oxygen (O2) and, due to the resulting disturbed Bohr effect, blood gas analyses will continue to show a normal ratio between O2 and carbon dioxide (CO2) and also interpret CO as O2. Special COHb diagnostics are only used in cases of acute suspected poisoning, which is not usually the case with PAIS.The resulting delayed accumulation of carboxyhemoglobin (COHb) and the resulting cell dysfunction, in conjunction with the long half-life of CO (4-6 hours in room air), offer a plausible explanation for post-exertional malaise (PEM), a key symptom of ME/CFS. In addition, oxidative stress, impaired nutrient uptake, the particular vulnerability of the child's brain, and many other conditions could be explained by this mechanism.The hypothesis is supported by existing research on mitochondrial dysfunction and oxygen utilization disorders in PAIS patients. Given the diagnostic difficulties and complexity of these syndromes, this work underscores the urgent need for interdisciplinary research to validate the role of endogenous CO in order to develop more accurate diagnostic and effective therapeutic approaches for those affected.