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Within three months of the onset of acute SARS-CoV-2 (COVID-19) infections, new and persistent symptoms were noted in survivors. While the world’s medical and research communities focus on saving lives following COVID-19 infection, a relentless march of new cases of Post-COVID Syndrome (PCS) continues to spread around the globe as a second COVID-related pandemic. Efforts to define the physiology of PCS, a multisystem, multi-symptom illness, continue without success, in part due to the markedly different case presentations.

Using a transcriptomic assessment of persistently ill cases of PCS, we show the presence of (i) molecular hypometabolism (MHM) and proliferative physiology; (ii) elevated levels of ribosomal stress responses and a concomitant increase in gene activation of TGFBR; and (iii) common co-expression of CD14 and Toll Receptor 4, correlated to exposure of amplified microbial growth in a water-damaged environment, specifically Actinobacteria and endotoxin, respectively, compared to recovered PCS cases. Total symptom scores and visual contrast sensitivity (VCS) results showed statistically significant differences.

The data reported here supports the concept that PCS occurs in patients with additional environmental exposures and enhanced TGF signaling. In a strikingly similar condition called Chronic Inflammatory Response Syndrome (CIRS), named in 2010, the transcriptomic abnormalities were identified to respond to treatment with FDA-cleared medications, with salutary benefits for affected cases. Though sparsely reported, PCS cases share proteomic findings with CIRS. While additional studies are indicated, a new approach to the treatment of PCS is suggested.