Viremia occurs frequently during COVID-19 infection
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Multiple clinical studies report that SARS-CoV-2 plasma RNA or viremia is detectable in approximately 12% to 30% of COVID-19 patients, demonstrating that viremia occurs with notable frequency during infection.
The relationship between SARS-CoV-2 viral load and risk of disease progression remains largely undefined in coronavirus disease 2019 (COVID-19). Here, we quantify SARS-CoV-2 viral load from participants with a diverse range of COVID-19 disease severity, including those requiring hospitalization, outpatients with mild disease, and individuals with resolved infection. We detected SARS-CoV-2 plasma RNA in 27% of hospitalized participants, and 13% of outpatients diagnosed with COVID-19. Amongst the participants hospitalized with COVID-19, we report that a higher prevalence of detectable SARS-CoV-2 plasma viral load is associated with worse respiratory disease severity, lower absolute lymphocyte counts, and increased markers of inflammation, including C-reactive protein and IL-6. SARS-CoV-2 viral loads, especially plasma viremia, are associated with increased risk of mortality. Our data show that SARS-CoV-2 viral loads may aid in the risk stratification of patients with COVID-19, and therefore its role in disease pathogenesis should be further explored. In this study, Massachusetts Consortium for Pathogen Readiness (MassCPR) investigators assess the relationship between SARS-CoV-2 viral load and COVID-19 disease severity and report that the levels of detectable viral RNA, especially in plasma, correlates with severity of respiratory disease, inflammatory markers and predicted risk of death.
Subject terms: Prognostic markers, Viral infection In this study, Massachusetts Consortium for Pathogen Readiness (MassCPR) investigators assess the relationship between SARS-CoV-2 viral load and COVID-19 disease severity and report that the levels of detectable viral RNA, especially in plasma, correlates with severity of respiratory disease, inflammatory markers and predicted risk of death. status released display-pdf yes is-olf no is-manuscript no is-preprint no is-journal-matter no is-scanned no is-retracted no Received 2020 Jul 15; Accepted 2020 Sep 22; Collection date 2020.
In addition, there is a suggestion that detectable plasma viremia using a qualitative viral detection assay may correlate with disease severity 14 , although studies to date have been hampered by the lack of viral load quantification. Together, these findings suggest the importance of systemic SARS-CoV-2 viral circulation but little is known about the prevalence and magnitude of plasma viremia in predicting COVID-19 outcomes.
Results Participant characteristics and SARS-CoV-2 viral loads We enrolled 88 hospitalized participants with COVID-19, 94 symptomatic individuals who were evaluated in a respiratory infection clinic, of whom 16 were diagnosed with COVID-19 by standard clinical testing of nasopharyngeal swabs, and 53 participants diagnosed with COVID-19, who had symptomatically recovered. Table 1 shows baseline demographic information, disease severity, and hospital outcomes. Hospitalized participants were significantly older than both symptomatic outpatients and individuals recovered from COVID-19 (Kruskal–Wallis P < 0.001).
Symptomatic nasopharyngeal swab positive (NP+) and negative (NP−) individuals were evaluated at an outpatient respiratory infection clinic. Recovered individuals included participants who had previously been diagnosed with COVID-19, but whose symptoms have since resolved. P values are from a Χ 2 analysis. Levels of SARS-CoV-2 viral load were significantly correlated between each of the different respiratory specimen types (nasopharyngeal vs oropharyngeal Spearman’s r = 0.34, P = 0.03; nasopharyngeal vs. sputum r = 0.39, P = 0.03, oropharyngeal vs. sputum r = 0.56, P = 0.001, Supplementary Fig. 2 ).
Two of the 16 (13%) COVID-19 diagnosed outpatients were found to also have detectable SARS-CoV-2 plasma viremia, compared to none of the 74 outpatients with negative clinical nasopharyngeal testing for SARS-CoV-2 RNA and none of the 53 recovered individuals who had previously been diagnosed with COVID-19. None of the 18 plasma samples from intensive care unit participants collected in the pre-COVID era were found to have detectable plasma SARS-CoV-2 RNA. Detectable respiratory tract SARS-CoV-2 RNA was common regardless of disease severity (Supplementary Fig. 3 ).
In contrast to prior reports suggesting that the SARS-CoV-2 viral infection is largely confined to the respiratory and gastrointestinal tracts 15 , 16 , we were able to detect plasma viremia in a substantial proportion of both hospitalized and non-hospitalized participants. The prevalence of SARS-CoV-2 plasma viremia was lower than that found in respiratory secretions, but detectable plasma viremia had a clear relationship with concurrent clinical disease severity, lower absolute lymphocyte count, higher levels of inflammation and increased risk of death.
These results suggest that the detection and quantification of viral RNA levels may aid in the risk stratification of patients hospitalized with COVID-19. The associations between SARS-CoV-2 viral load with levels of CRP and IL-6 results also indicate that active viral infection could contribute to the hyperinflammatory state that is a hallmark of severe COVID-19 25 . However, the causes of inflammation in COVID-19 could be multifactorial, especially as a subset of participants had elevated inflammatory markers without detectable plasma viremia.
Although additional infectivity studies are needed to confirm that plasma viremia represents infectious virions, these previously published support the concept that COVID-19 should be considered more than an isolated respiratory tract infection and that endothelial infection and systemic circulation of infectious SARS-CoV-2 virions may be contributing to the increasing reports of extrapulmonary and micro- and macrovascular complications of COVID-19 that are often disproportionate to the degree of disease severity 9 – 12 , 29 – 32 .
Methods Participant enrollment and sample collection We enrolled hospitalized and non-hospitalized participants with
Background Patients with coronavirus disease 2019 (COVID-19) have a high prevalence of detectable troponin and myocardial injury. In addition, a subset of patients with COVID-19 has detectable severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral loads. The objective of this study was to understand the relationship among SARS-CoV-2 viremia, detectable troponin, and myocardial injury in hospitalized patients with COVID-19. Methods SARS-CoV-2 plasma viral load was measured in plasma samples drawn from patients hospitalized for COVID-19 at 2 academic medical centers. Baseline characteristics and clinically obtained high-sensitivity cardiac troponin T (hs-cTnT) values were abstracted from the medical record. The main outcome was detectable hs-cTnT (≥6 ng/mL) and myocardial injury (hs-cTnT ≥14 ng/mL; >99th percentile for assay). Results A total of 70 hospitalized patients with COVID-19 were included in this study, with 39% females and median age 58 ± 17 years; 21 patients (30%) were found to have detectable SARS-CoV-2 viral load and were classified in the viremia group. Patients with viremia were significantly older than those without viremia. All of the patients with viremia (100%) had detectable troponin during hospitalization compared with 59% of patients without viremia (P = 0.0003). Myocardial injury was seen in 76% of patients with viremia and 38% of those patients without viremia (P = 0.004). Conclusions Hospitalized patients with COVID-19 with SARS-CoV-2 viremia have a significantly higher prevalence of detectable troponin and myocardial injury during their hospitalization compared with patients who did not. This first report of the relationship among SARS-CoV-2 viremia, detectable troponin, and myocardial injury in patients with COVID-19 points to additional mechanistic pathways that require deeper study to understand the complex interplay among these unique findings, cardiovascular outcomes, and mortality in COVID-19.
The main outcome was detectable hs-cTnT (≥6 ng/mL) and myocardial injury (hs-cTnT ≥14 ng/mL; >99th percentile for assay). Results A total of 70 hospitalized patients with COVID-19 were included in this study, with 39% females and median age 58 ± 17 years; 21 patients (30%) were found to have detectable SARS-CoV-2 viral load and were classified in the viremia group. Patients with viremia were significantly older than those without viremia. All of the patients with viremia (100%) had detectable troponin during hospitalization compared with 59% of patients without viremia ( P = 0.0003).
Myocardial injury was seen in 76% of patients with viremia and 38% of those patients without viremia ( P = 0.004). Conclusions Hospitalized patients with COVID-19 with SARS-CoV-2 viremia have a significantly higher prevalence of detectable troponin and myocardial injury during their hospitalization compared with patients who did not. This first report of the relationship among SARS-CoV-2 viremia, detectable troponin, and myocardial injury in patients with COVID-19 points to additional mechanistic pathways that require deeper study to understand the complex interplay among these unique findings, cardiovascular outcomes, and mortality in COVID-19.
4 Early data indicate that the presence of detectable troponin is associated with worse outcomes in patients with COVID-19, and the highest elevations correlate with the poorest outcomes. 5 Mechanisms of myocardial injury and detectable troponin in patients with COVID-19 are currently unknown, with proposed hypotheses invoking several possibilities, including direct viral myocardial injury and immune-mediated
Results Among 70 patients hospitalized with COVID-19, 21 patients (30%) had detectable SARS-CoV-2 viremia. In those with viremia, median viral load was 2.4 log 10 RNA copies/mL (range 1.8-3.8 log 10 RNA copies/mL). Baseline characteristics of the cohort are presented in Table 1 . Patients with viremia were significantly older (67 ± 13 years vs 54 ± 17 years, P = 0.001), with a trend toward fewer females with viremia compared to those without viremia (24% vs 45%, P = 0.1). There were no significant differences in race or body mass index between groups.
ACEi = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; COVID-19 = coronavirus disease 2019; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; SD = standard deviation. Next, we investigated the relationship among SARS-CoV-2 viremia, detectable troponin, and myocardial injury ( Figure ). During hospitalization, detectable troponin was measured in all patients with viremia (21 of 21, 100%) and in 59% (29 of 49) of those without viremia ( P = 0.0003, Figure A). Myocardial injury was present in 16 of 21 (76%) patients with viremia and 18 of 49 (38%) patients without viremia ( P = 0.004, Figure B).
We report a uniquely high rate of troponin positivity and myocardial injury among hospitalized individuals with detectable SARS-CoV-2 viremia, in contrast to patients without detectable viremia. Patients with viremia were older, more likely to be male, and tended to have more baseline cardiovascular comorbidities than those without viremia. These findings suggest that the most vulnerable patients hospitalized with COVID-19 are more likely to have SARS-CoV-2 viremia and have a greater degree of ensuing myocardial injury. This study must be assessed in the context of its limitations.
The major limitation is the small cohort size and, therefore, a limited ability to control for covariates and possible confounders. As a result, the exact relationship among patient age, sex, preexisting cardiovascular disease, SARS-CoV-2 viremia, and myocardial injury could not be completely assessed in the current study. Therefore, although these findings point toward a strong association between SARS-CoV-2 viremia and myocardial injury in patients hospitalized with COVID-19, they do not provide insight into the possible mediators and mechanism of this relationship.
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PMCID: PMC11812106 PMID: 39868965
ABSTRACT
Viremia defined as detectable SARS-CoV-2 RNA in the blood is a potential marker of disease severity and prognosis in COVID-19 patients. Here, we determined the frequency of viremia in serum of two independent COVID-19 patient cohorts within the German National Pandemic Cohort Network (German: Na tionales P andemie Ko horten N etzwerk, NAPKON) with diagnostic RT-PCR against SARS-CoV-2. A cross-sectional cohort with 1122 COVID-19 patients (German: S ektoren ue bergreifende P latform , SUEP) and 299 patients recruited in a high-resolution platform with patients at high risk to develop severe courses (German: H och a ufloesende P lattform , HAP) were tested for viremia. Our study also involved a comprehensive analysis and association of serological, diagnostic, and clinical parameters of the NAPKON medical dataset. Prevalence of viremia at the recruitment visit was 12.8% (SUEP) and 13% (HAP), respectively. Serological analysis revealed that viremic patients had lower levels of SARS-CoV-2 specific antibodies as well as lower neutralizing antibodies compared to aviremic patients. Viremia was associated with severity (<0.0001 SUEP; 0.002 HAP) and mortality of COVID-19 (both cohorts <0.0001) compared to aviremic patients. While rare, viremia was also detected in patients with mild disease (0.7%). In patients of the SUEP cohort with acute kidney disease ( p = 0.0099) and hematooncological conditions ( p = 0.0091), viremia was detected more frequently. Compared to the aviremic group, treatment with immunomodulating drugs as well as elevated levels of inflammatory markers in the blood was more frequent in the viremic group. In conclusion, our analysis revealed that detectable viremia correlates with hyperinflammatory conditions and higher risk for severe COVID-19 disease.
KEYWORDS: COVID-19, SARS-CoV-2, viremia, pros
A cross-sectional cohort with 1122 COVID-19 patients (German: S ektoren ue bergreifende P latform , SUEP) and 299 patients recruited in a high-resolution platform with patients
Serological analysis revealed that viremic patients had lower levels of SARS-CoV-2 specific antibodies as well as lower neutralizing antibodies compared to aviremic patients. Viremia was associated with severity (<0.0001 SUEP; 0.002 HAP) and mortality of COVID-19 (both cohorts <0.0001) compared to aviremic patients. While rare, viremia was also detected in patients with mild disease (0.7%). In patients of the SUEP cohort with acute kidney disease ( p = 0.0099) and hematooncological conditions ( p = 0.0091), viremia was detected more frequently.
Compared to the aviremic group, treatment with immunomodulating drugs as well as elevated levels of inflammatory markers in the blood was more frequent in the viremic group. In conclusion, our analysis revealed that detectable viremia correlates with hyperinflammatory conditions and higher risk for severe COVID-19 disease.
The samples derive from patients of the SUEP and HAP cohorts enrolled during the acute phase of SARS-CoV-2 infection. (C) CT values in serum do not correlate with CT values from nasopharyngeal swabs. Table 1. Patient characteristics.
Number and type of reported symptoms did not differ between viremic and aviremic patients Next, we plotted symptoms that patients from the SUEP experienced during the active infection and compared the frequency in patients with and without viremia. Symptoms are grouped into general ( Figure 3 (A)), respiratory (3B), neurological (3C), and gastrointestinal symptoms (3D, Supplementary Table 2). Overall, only respiratory symptoms were significantly more likely in the viremic (92.7%) compared to the aviremic group (83.4%, OR = 0.76 – CI 0.29–1.96, p = 0.0064).
When comparing mortality in the antiviral-treated groups taking viremia and aviremic patients into account, no significant difference ( p = 0.3) is observed (Supplementary Table 3). Participants were systematically assessed regarding their co-morbidities prior to SARS-CoV-2 infection. Figure 4 (A) depicts the odds ratios of chronic illnesses of patients in SUEP.
Interestingly, administration of tocilizumab, a monoclonal antibody against IL-6, is significantly more likely in the viremic group (8.7% vs 2.5%, p = 0.0008). Cortisone and hydrocortisone (8.7% vs 4%, p = 0.0288) and dexamethasone (74.6% vs 45.6%, p < 0.0001), given to dampen the immune response in COVID-19 patients, were recorded more frequently in viremic patients. Blood parameters associated with inflammation and infection significantly correlated with SARS-CoV-2 viremia Next, we sought to investigate levels of biomarkers and laboratory values at the baseline level that were determined within the NAPKON study protocol ( Figure 5 , Table 3 ).
As we observed an increase in kidney disease and failure in the SUEP, we analysed biomarkers that are relevant for the diagnosis of kidney damage (globular filtration rate eGFR, urea, and creatinine). Table 3 summarizes that neither show pathological tendencies nor exhibit an association with viremia in the SUEP and HAP. Moreover, we analysed routine laboratory parameters measuring inflammation and infection indicative as predictors for poor outcome and increased mortality for COVID-19 [ 24 ] being CRP, procalitonin, LDH as well as IL-6. Figure 5 A + B revealed that all markers are outside the normal range in many patients during the first study visit ( Figure 5 A + B, Table 3 ).
Here, however, while respiratory symptoms were more frequently reported in the viremic group, patients otherwise did not differ in non-respiratory symptoms that could result in virus spreading into other organs such as the gastrointestinal tract. As described in other studies, the occurrence of viremia was strongly associated with the severity of disease and mortality [ 12–16 ] resulting in increased treatment with antivirals.
SARS-CoV-2, responsible for COVID-19, affects multiple bodily systems, including placenta. Understanding its effects on placental angioactive factors is vital due to its vascular implications. Herein, we hypothesized that maternal SARS-CoV-2 infection could impact placental morphology and the expression of angioactive and inflammatory factors. The study included 23 pregnant women tested for COVID-19 through reverse transcription polymerase chain reaction (RT-qPCR) and IgG serology around time of delivery and discriminated as: Viremia Group (VG, n = 6, maternal positive RT-qPCR, early infection), Serology Group (SG, n = 10, maternal positive serology, late infection), and Control Group (CG, n = 7, negative for SARS-CoV-2). PCR and immunolocalization of SARS-CoV-2 in the placenta tested negative. Placental morphology was examined using H&E-stained sections, along with immunostaining for vascular endothelial growth factor (VEGF), placental growth factor (PlGF), inducible and endothelial nitric oxide synthase (iNOS, eNOS), and cyclooxygenase 2 (COX2). SG showed a significant higher level of placental morphological changes compared to control samples, which included an increase in syncytial knots and fibrin deposits on the villous surface, and villous peripheral and central infarctions. In contrast, samples from VG exhibited more frequent vascular dilation, congestion, and chorioangiosis. Compared with the control group, immunohistochemical analysis showed significantly higher expression of VEGF (P = 0.001), COX2 (P = 0.03), and eNOS (P = 0.02) in VG. Conversely, in the SG, PlGF levels decreased (P = 0.01), while COX2 (P = 0.01) and iNOS (P = 0.01) levels were elevated. Our data suggests a temporal adaptation of the placenta to maternal SARS-CoV-2 infection, triggering structural, angioactive, and inflammatory responses, enhancing our understanding of potential placental pathways to cope with SARS-CoV-2 infection.
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