SARS-CoV-2 RNAemia Predicts Clinical Deterioration and Extrapulmonary Complications from COVID-19

Abstract

Background The determinants of COVID-19 disease severity and extrapulmonary complications (EPCs) are poorly understood. We characterized relationships between SARS-CoV-2 RNAemia and disease severity, clinical deterioration, and specific EPCs. Methods We used quantitative (qPCR) and digital (dPCR) PCR to quantify SARS-CoV-2 RNA from plasma in 191 patients presenting to the Emergency Department (ED) with COVID-19. We recorded patient symptoms, laboratory markers, and clinical outcomes, with a focus on oxygen requirements over time. We collected longitudinal plasma samples from a subset of patients. We characterized the role of RNAemia in predicting clinical severity and EPCs using elastic net regression. Results 23.0% (44/191) of SARS-CoV-2 positive patients had viral RNA detected in plasma by dPCR, compared to 1.4% (2/147) by qPCR. Most patients with serial measurements had undetectable RNAemia within 10 days of symptom onset, reached maximum clinical severity within 16 days, and symptom resolution within 33 days. Initially RNAaemic patients were more likely to manifest severe disease (OR 6.72 [95% CI, 2.45 – 19.79]), worsening of disease severity (OR 2.43 [95% CI, 1.07 – 5.38]), and EPCs (OR 2.81 [95% CI, 1.26 – 6.36]). RNA load correlated with maximum severity (r = 0.47 [95% CI, 0.20 – 0.67]). Conclusions dPCR is more sensitive than qPCR for the detection of SARS-CoV-2 RNAemia, which is a robust predictor of eventual COVID-19 severity and oxygen requirements, as well as EPCs. Since many COVID-19 therapies are initiated on the basis of oxygen requirements, RNAemia on presentation might serve to direct early initiation of appropriate therapies for the patients most likely to deteriorate.

Diagnostic, Prognostic, and Therapeutic Value of Droplet Digital PCR (ddPCR) in COVID-19 Patients: A Systematic Review

“…An overall of 3651 samples, from 2825 patients and 145 controls, were extracted from the 39 included studies. The studies were conducted worldwide; 16 in Asia [ 12 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ], 14 in Europe [ 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 ], and 9 in North America [ 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 ]. A minority of studies (8) included control samples [ 21 , 28 , 29 , 33 , 38 , 47 , 54 , 56 ].…”

“…Four of them showed that ddPCR can accurately quantify SARS-CoV-2 RNA levels, especially in immunocompromised patients and hospitalized patients with severe COVID-19 infections [ 23 , 37 , 46 , 49 ]. Furthermore, a study conducted by Ram-Mohan et al showed that ddPCR, compared to traditional RT-qPCR, was superior for detecting and quantifying SARS-CoV-2 RNAemia in hospitalized patients over a course of 30 days [ 52 ]. ddPCR was still able to detect RNAemia in 6.8% of patients at seven days, whereas RT-qPCR could not detect any RNAemia after three days [ 52 ].…”

“…Furthermore, a study conducted by Ram-Mohan et al showed that ddPCR, compared to traditional RT-qPCR, was superior for detecting and quantifying SARS-CoV-2 RNAemia in hospitalized patients over a course of 30 days [ 52 ]. ddPCR was still able to detect RNAemia in 6.8% of patients at seven days, whereas RT-qPCR could not detect any RNAemia after three days [ 52 ]. Notably, this study showed that the higher levels of SARS-CoV-2 RNA in the patients’ plasma were correlated with a higher probability of developing severe disease [ 52 ].…”

“…ddPCR was still able to detect RNAemia in 6.8% of patients at seven days, whereas RT-qPCR could not detect any RNAemia after three days [ 52 ]. Notably, this study showed that the higher levels of SARS-CoV-2 RNA in the patients’ plasma were correlated with a higher probability of developing severe disease [ 52 ].…”

Association Between SARS-CoV-2 RNAemia and Postacute Sequelae of COVID-19

“…The determinants of coronavirus disease 2019 (COVID-19) severity and extrapulmonary complications have now been well studied, and RNAemia (viral RNA in blood) has emerged as an important factor [ 1 , 2 ]. Much less is known about the determinants of postacute sequelae of COVID-19 (PASC), the persistence or development of new symptoms after the acute phase of infection, recently reported to affect as many as 87.4% of COVID-19 patients [ 3 , 4 ], primarily those with with moderate or worse severity [ 5 , 6 ].…”