Antiviral metabolite 3'-Deoxy-3',4'-didehydro-cytidine is detectable in serum and identifies acute viral infections including COVID-19

Mehta, R.; Chekmeneva, E.; Jackson, H.; Sands, C.; Mills, E.; Arancon, D.; Li, H. K.; Arkell, P.; Rawson, T. M.; Hammond, R.; Amran, M.; Haber, A.; Cooke, G.; Noursadeghi, M.; Kaforou, M.; Lewis, M.; Takats, Z.; Sriskandan, S.

There is a critical need for improved infectious disease diagnostics to enable rapid case identification in a viral pandemic and support targeted antimicrobial prescribing. Here we use high-resolution liquid chromatography coupled with mass spectrometry to compare the admission serum metabolome of patients attending hospital with a range of viral infections, including SARS-CoV-2, to those with bacterial infections, non-infected inflammatory conditions and healthy controls. We demonstrate for the first time that 3'-Deoxy-3',4'-didehydro-cytidine (ddhC), a free base of the only known human antiviral small molecule ddhC-triphosphate (ddhCTP), is detectable in serum. ddhC acts as an accurate biomarker for viral infections, generating an area under the receiver operating characteristic curve of 0.954 (95% confidence interval 0.923-0.986) when comparing viral to non-viral cases. Gene expression of viperin, the enzyme responsible for ddhCTP synthesis, is highly correlated with ddhC, providing a biological mechanism for its increase during viral infection. These findings underline a key future diagnostic role of ddhC in the context of pandemic preparedness and antimicrobial stewardship.