By Richard R. Watkins, MD, MS, FACP, FIDSA, FISAC

Professor of Internal Medicine, Northeast Ohio Medical University; Division of Infectious Diseases, Cleveland Clinic Akron General, Akron, OH

Dr. Watkins reports no financial relationships relevant to this field of study.

SYNOPSIS: A prospective cohort study found that SARS-CoV-2 plasma RNA was detected more often, and the levels were higher, in patients who were admitted to the intensive care unit and/or who died.

SOURCE: Prebensen C, My Hre PL, Jonassen C, et al. SARS-CoV-2 RNA in plasma is associated with ICU admission and mortality in patients hospitalized with COVID-19. Clin Infect Dis 2020; Sept. 5. doi:10.1093/cid/ciaa1338. [Online ahead of print].

SARS-CoV-2 can disseminate to multiple organs besides the lungs, including the heart, brain, kidneys, and gastrointestinal tract. However, the clinical significance of detecting viral ribonucleic acid (RNA) in the bloodstream is unknown. Prebensen and colleagues sought to quantify SARS-CoV-2 RNA in the plasma and upper respiratory tract of patients hospitalized with COVID-19 and to determine the association between viral RNA loads and disease severity.

The study was a prospective cohort that included adult patients admitted to a single center in Norway with COVID-19 confirmed by real time polymerase chain reaction (RT-PCR). The study’s primary endpoint was a composite of intensive care unit (ICU) admission for more than 24 hours and in-hospital mortality. RT-PCR detected SARS-CoV-2 RNA in plasma samples and upper respiratory tract swabs. Researchers estimated plasma RNA levels using the cycle threshold (Ct) value. The RNA was quantified and expressed as log10 copies/mL in plasma samples that were positive on PCR.

Of the 123 COVID-19 patients who had blood samples available, 35 (28%) reached the primary end point. Thirty-one patients were admitted to the ICU, 29 patients received mechanical ventilation, and four died. An additional four patients who had do-not-intubate orders died on regular hospital floors. All patient admissions to the ICU and deaths were attributable to COVID-19 infection.

SARS-CoV-2 RNAemia was detected in at least one sample in 58/123 (47%) patients. It also was detected in a significantly higher proportion of the patients who were admitted to the ICU or who died (80% vs. 34%, P < 0.001). Forty-eight out of 123 (39%) of patients had RNAemia detected at baseline, a median 0 [-1, 3] days before admission to the ICU. Twenty-four patients (41%) with detectable RNAemia had Ct values > 38, below the quantitation limit of 2.70 log10 copies/mL. After nine patients with baseline samples taken after ICU admission were excluded, baseline RNAemia and RNA load both were associated significantly with ICU admission and/or death. The association persisted after adjusting for age, sex, race, body mass index (BMI), diabetes mellitus, and symptom duration. No correlation was identified between days from symptom onset and RNAemia frequency or RNA load at baseline. Moreover, no correlations were found between upper respiratory Ct values and RNAemia frequency or plasma RNA loads, nor between the number of days from symptom onset to ICU admission. Finally, there was no difference in the titers of anti-SARS-CoV-2 total Ig or IgG at any time point between patients who reached the primary endpoint and those who did not.

COMMENTARY

The investigators found a high proportion of SARS-CoV-2 RNA in the blood of patients who were hospitalized with COVID-19, and they found a significantly higher frequency and level of RNAemia in the patients admitted to the ICU and in those who died. The key takeaway is the possible utility of SARS-CoV-2 RNAemia as a prognostic marker. Indeed, with the current availability of remdesivir and potentially other antiviral agents in the near future, identifying patients with early markers of severe disease is important for deciding when to initiate treatment. This is because early initiation is a crucial factor in antiviral drug efficacy.

There has not been a consistent association found between SARS-CoV-2 RNA in the nasopharynx and asymptomatic vs. symptomatic disease, or with symptomatic disease severity. Moreover, viral RNA at a local site of initial infection does not give an accurate measure of viral replication in the lower respiratory tract or dissemination of the virus via the bloodstream to other organs. Longitudinal samples from patients with a range of illness severity would provide additional insights into the utility of SARS-CoV-2 RNAemia as a prognostic marker. However, this raises the question of whether viral nucleic acid indicates the presence of viral particles and/or infected cells. Also, does detection of viral RNA in the blood indicate uncontrolled infection and a risk for complications, thus necessitating earlier intervention, i.e., antiviral therapy? These and other questions about the pathogenesis of extra-pulmonary SARS-CoV-2 will need to be elucidated to improve the precision of antiviral and anti-inflammatory therapies.

There are some limitations to the study worth mentioning. First, not every patient diagnosed with COVID-19 during the study period was included, making selection bias a concern. Second, as mentioned earlier, the presence of viral RNA does not necessarily indicate there is replication-competent virus. Third, the time between baseline testing and ICU admission was short, which limits the prognostic time window for SARS-CoV-2 RNAemia. Finally, the findings cannot determine whether RNAemia represents direct viral involvement causing extra-pulmonary pathology or whether it is just spillover from an intense pulmonary infection.

In summary, SARS-CoV-2 RNAemia may prove to be a useful clinical marker in patients with COVID-19. But further studies on the pathophysiological significance of circulating viral RNA are needed to inform prognosis and optimize therapeutic decisions.