SARS-CoV-2 RNA detected in blood samples from patients with COVID-19 is not associated with infectious virus

Andersson, M.; Arancibia - Carcamo, C. V.; Auckland, K.; Baillie, J. K.; Barnes, E.; Beneke, T.; Bibi, S.; Carroll, M.; Crook, D.; Dingle, K.; Dold, C.; Downs, L. O.; Dunn, L.; Eyre, D. W.; Gilbert Jaramillo, J.; Harvala Simmonds, H.; Hoosdally, S.; Ijaz, S.; James, T.; James, W.; Jeffery, K.; Justice, A.; Klenerman, P.; Knight, J. C.; Knight, M.; Liu, X.; Lumley, S. F.; Matthews, P. C.; McNaughton, A. L.; Mentzer, A. J.; Mongkolsapaya, J.; Oakley, S.; Oliveira, M. S.; Peto, T.; Ploeg, R. J.; Ratcliff, J.; Roberts, D. J.; Rudkin, J.; Screaton, G.; Semple, M. G.; Skelley, D. T.; Simmonds, P.

Background: Laboratory diagnosis of SARS-CoV-2 infection (the cause of COVID-19) uses PCR to detect viral RNA (vRNA) in respiratory samples. SARS-CoV-2 RNA has also been detected in other sample types, but there is limited understanding of the clinical or laboratory significance of its detection in blood. Methods: We undertook a systematic literature review to assimilate the evidence for the frequency of vRNA in blood, and to identify associated clinical characteristics. We performed RT-PCR in serum samples from a UK clinical cohort of acute and convalescent COVID-19 cases (n=212), together with convalescent plasma samples collected by NHS Blood and Transplant (NHSBT) (n=212 additional samples). To determine whether PCR-positive blood samples could pose an infection risk, we attempted virus isolation from a subset of RNA-positive samples. Results: We identified 28 relevant studies, reporting SARS-CoV-2 RNA in 0-76% of blood samples; pooled estimate 10% (95%CI 5-18%). Among serum samples from our clinical cohort, 27/212 (12.7%) had SARS-CoV-2 RNA detected by RT-PCR. RNA detection occurred in samples up to day 20 post symptom onset, and was associated with more severe disease (multivariable odds ratio 7.5). Across clinical and convalescent samples collected [≥]28 days post symptom onset, 0/244 (0%, 95%CI 0.0-1.5%) had vRNA detected. Among our PCR-positive samples, cycle threshold (ct) values were high (range 33.5-44.8), suggesting low vRNA copy numbers. PCR-positive sera inoculated into cell culture did not produce any cytopathic effect or yield an increase in detectable SARS-CoV-2 RNA. Conclusions: vRNA was detectable at low viral loads in a minority of serum samples collected in acute infection, but was not associated with infectious SARS-CoV-2 (within the limitations of the assays used). This work helps to inform biosafety precautions for handling blood products from patients with current or previous COVID-19.