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

Abstract

Background: The determinants of coronavirus disease 2019 (COVID-19) disease severity and extrapulmonary complications (EPCs) are poorly understood. We characterized relationships between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNAemia and disease severity, clinical deterioration, and specific EPCs.

Methods: We used quantitative and digital polymerase chain reaction (qPCR and dPCR) to quantify SARS-CoV-2 RNA from plasma in 191 patients presenting to the emergency department 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: Of SARS-CoV-2-positive patients, 23.0% (44 of 191) had viral RNA detected in plasma by dPCR, compared with 1.4% (2 of 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 RNAemic patients were more likely to manifest severe disease (odds ratio, 6.72 [95% confidence interval, 2.45-19.79]), worsening of disease severity (2.43 [1.07-5.38]), and EPCs (2.81 [1.26-6.36]). RNA loads were correlated with maximum severity (r = 0.47 [95% confidence interval, .20-.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. Because 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.

Keywords: RNAemia; SARS-CoV-2; digital PCR; extrapulmonary complications; severity prediction.

Figure 1.

Distribution of discrete and binned World Health Organization (WHO) severity scores. We classified the maximum severity of 147 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presentations using a modified WHO scoring system, with scores defined as follows: 1, asymptomatic infection; 2, symptomatic infection not requiring admission; 3, admitted without supplemental oxygen; 4, admitted, requiring oxygen by nasal cannula; 5, admitted, requiring oxygen by high-flow nasal cannula; 6, admitted, requiring mechanical ventilation; 7, admitted, requiring mechanical ventilation and vasopressors or renal replacement therapy; and 8, death from coronavirus disease 2019 (COVID-19)–related cause. A, Distribution of WHO scores. B, Distribution of binned (mild, moderate, and severe) scores.

Figure 2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNAemia and clinical severity. A, RNAemic patients had higher mean maximum World Health Organization (WHO) scores (4.80) than non-RNAemic patients (3.24; difference, 1.56 [95% confidence interval [CI], 1.00–2.11]). Severe disease developed in 40.9% of RNAemic patients, compared with 10.2% of non-RNAemic patients (difference, 30.7% [95% CI, 13.9%–47.5%]). Of initially RNAemic patients, 4.5% had mild disease, compared with 35.4% of non-RNAemic patients (difference, 30.8% [95% CI, 19.5%–42.2%]). Equivalent proportions of RNAemic (54.5%) and non-RNAemic (54.4%) patients had disease of moderate severity. B, Among patients with detectable RNAemia at enrollment (n = 44), patients with higher plasma RNA concentrations manifested more severe disease (r = 0.47 [95% CI, .20–.67]). RNA concentrations in RNAemic patients were distributed approximately log normally, so were log scaled for depiction and calculation of correlation. Dashed blue line shows linear correlation between log-scaled plasma RNA concentration and maximum clinical severity.

Figure 3.

Dynamics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNAemia and clinical severity, by modified World Health Organization (WHO) score. A, Serial plasma SARS-CoV-2 RNA concentrations and WHO scores for each of the 27 patients with longitudinal samples. Plasma RNA concentration (red gradient) and WHO scores (blue gradient) are shown with respect to the number of days since the reported onset of symptoms (not date of study enrollment) for each patient. Numbers of patients who died in the hospital are highlighted in boldface and italic. Specimens with undetectable RNAemia are represented with x’s. Fourteen of 27 patients had undetectable RNAemia by day 10, while the same proportion took 16 days to reach maximum severity, and 33 days for resolution of symptoms. B, Aggregate RNA and clinical dynamics in the 30 days after onset of symptoms. Loess regression curves represent trends in RNA and clinical dynamics. RNAemia peaked 3 days after symptom onset, while clinical severity peaked at 14 days.

Figure 4.

Presence of extrapulmonary complications (EPCs), by RNAemia. Of patients RNAemic at enrollment, ≥1 EPC developed by hospital discharge in 56.8% (25 of 44), compared with 30.6% of non-RNAemic patients (45 of 147) (difference, 26.2% [95% confidence interval, 8.3%–44.1%]). RNAemic patients tended toward higher rates of EPCs across systems, though only differences in rates of hepatobiliary (HB), hematologic, and immunologic complications were individually significant; *P < .05 (χ ² test for equality of proportions with continuity correction). Abbreviation: CV, cardiovascular.