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• W3109016170 abstract "The kinetics of the SARS-CoV-2 viral load in respiratory airways and other tissues is of great interest to understand the pathogenesis, course, and the management of COVID-19 patients. Therefore, we read with much interest the systematic literature review recently published in the Journal of Infection by Walsh et al.1Walsh K.A. Jordan K. Clyne B. Rohde D. Drummond L. Byrne P. et al.SARS-CoV-2 detection, viral load and infectivity over the course of an infection.J Infect. 2020; 81: 357-371https://doi.org/10.1016/j.jinf.2020.06.067Abstract Full Text Full Text PDF PubMed Scopus (432) Google Scholar, concluding that viral load in upper respiratory samples peaks around the time of symptoms onset or a few days thereafter, and becomes undetectable about two weeks after symptom onset; moreover, there is evidence of prolonged virus detection in stool samples, with unclear clinical significance. Information regarding the use of other samples to improve patients’ management is lacking or inconsistent.1Walsh K.A. Jordan K. Clyne B. Rohde D. Drummond L. Byrne P. et al.SARS-CoV-2 detection, viral load and infectivity over the course of an infection.J Infect. 2020; 81: 357-371https://doi.org/10.1016/j.jinf.2020.06.067Abstract Full Text Full Text PDF PubMed Scopus (432) Google Scholar, 2Zhu N. Zhang D. Wang W. Li X. Yang B. Song J. et al.A novel coronavirus from patients with pneumonia in China, 2019.N Engl J Med. 2020 Feb 20; 382: 727-733https://10.1056/NEJMoa2001017Crossref PubMed Scopus (16620) Google Scholar, 3Wang W. Xu Y. Gao R. Lu R. Han K. Wu G. et al.Detection of SARS-CoV-2 in different types of clinical specimens.JAMA. 2020 Mar 11; https://10.1001/jama.2020.3786Crossref Scopus (3483) Google Scholar Thus, the risk factors for bloodstream infection and the clinical meaning of SARS-CoV-2 RNAemia detection has not yet been completely elucidated. In this regard, we conducted a prospective multicentre cohort study of consecutive COVID-19 adult patients aimed to identify the factors associated with the detection of SARS-CoV-2 RNAemia at hospital admission and if its presence is associated with an unfavourable outcome, defined as intensive care unit (ICU) admission and/or death. Information regarding the study design and the methodology used is provided in the Supplementary Materials file. Seventy-two patients were included, with a median age of 61 years old. Forty-one (56.9%) were male and 41 (56.9%) had a Charlson comorbidity index ≥3 (Table 1). After their evaluation in the emergency room, sixty-three (87.5%) patients were admitted to the hospital, and nine (12.5%) were managed in an outpatient´ setting. SARS-CoV-2 RNAemia was detected in eleven (15.3%) patients, 10 of them admitted to the hospital (Table 1).Table 1Demographics and baseline characteristics of patients with and without SARS-CoV-2 RNAemia.Variables, N (%)N = 72 patientsORaP-valuebWith viremia (N = 11)Without viremia (N = 61)DemographicsAge (median [IQR])66 (57–77)61 (52–75)[..]0.531Male sex6 (54.5%)35 (57.4%)0.891 (0.245–3.241)1.000Underlying conditionsAny underlying chronic disease8 (72.7%)40 (65.6%)1.400 (0.336–5.839)0.908Chronic kidney disease2 (18.2%)7 (11.5%)1.714 (0.306–9.599)0.901Chronic liver disease3 (27.3%)0 (0.0%)0.116 (0.060–0.222)0.001Connective tissue disease2 (18.2%)4 (6.4%)3.167 (0.504–19.883)0.489Solid organ transplantation4 (36.4%)1 (1.6%)34.284 (3.346–351.308)0.001Charlson index ≥ 38 (72.7%)33 (54.1%)2.236 (0.547–9.354)0.413Previous TreatmentPrevious statins1 (9.1%)12 (19.7%)0.408 (0.048–3.507)0.679Previous ACEI1 (9.1%)12 (19.7%)0.408 (0.048–3.507)0.647Clinical symptoms at diagnosisArthro-myalgias5 (45.5%)7 (11.5%)6.429 (1.547–26.709)0.019Weakness4 (36.4%)20 (32.8%)1.171 (0.307–4.473)1.000Cough7 (63.6%)38 (62.3%)1.059 (0.279–4.018)1.000Dyspnoea7 (63.6%)24 (42.9%)2.233 (0.612–8.890)0.206Coryza0 (0%)3 (4.9%)0.841 (0.758–0.932)1.000Odynophagia1 (9.1%)7 (11.5%)0.771 (0.085–6.9711.000Diarrhoea4 (36.6%)12 (19.7%)2.333 (0.586–9.286)0.406Headache3 (27.3%)12 (19.7%)1.531 (0.352–6.6560.867Anosmia1 (9.1%)11 (18%)0.455 (0.053–3.929)0.770Dysgeusia1 (9.1%)9 (14.8%)0.578 (0.066–5.081)0.979Vital signs, exploration, and severity scores at diagnosisTemperature( °C, median [IQR])36.4 (36–37.8)36.6 (36.1–37.6)[..]0.982SBP < 90 mmHg0 (0%)2 (3.3%)0.843 (0.762–0.933)1.000DBP < 60 mmHg2 (18.2%)1 (1.6%)13.333 (1.094–162.532)0.088SatO2< 95% at diagnosis6 (54.5%)15 (24.6%)3.680 (0.981–13.806)0.099HR ≥ 100 bpm (N = 64)6 (66.7%)15 (27.3%)5.333 (1.181–24.085)0.051RR ≥ 20 bpm(N = 60)1 (9.1%)0 (0%)0.169 (0.096–0.289)0.409qSOFA ≥ 21 (9.1%)11 (18%)0.455 (0.053–3.929)0.770Chest x-ray findingsPneumonia9 (81.8%)47 (77%)1.340 (0.259–6.940)1.000Bilateral infiltrates8 (88.9%)32 (78.0%)2.250 (0.248–20.438)0.665CURB-65 ≥ 25 (55.5%)15 (31.9%)2.556 (0.681–9.587)0.291Laboratory resultsLeucocytes(x103/µL, median [IQR])5.22 (3.47–7.06)7.00 (5.24–9.20)[..]0.030Leucocytes > 11,000 /μL1 (9.1%)8 (13.1%)0.663 (0.074–5.896)1.000Neutrophils(x103/µL, median [IQR])3.49 (2.96–5.90)4.79 (3.30–6.88)[..]0.348Neutrophils > 7500 /μL1 (9.1%)11 (18.0%)0.455 (0.053–3.929)0.677Lymphocytes(103/µL median [IQR])0.58 (0.39–1.24)1.36(0.92–1.80)[..]0.002Lymphocytes < 1000 /µL7 (63.6%)18 (29.5%)4.181 (1.088–16.063)0.065Platelets(x103/µL, median [IQR])158 (129–201)248(175–325)[..]0.002Platelets < 130,000 /μL3 (27.3%)4 (6.6%)5.344 (1.006–28.383)0.067Haemoglobin(g/L, median [IQR])13 (11.2–15.1)13.8(12.10–14.8)[..]0.191AST(IU/L, median [IQR]) (N = 63)37 (26–68)26(20–41)[..]0.074AST > 30 IU/L8 (72.7%)19 (36.5%)4.632 (1.095–19.587)0.063ALT (IU/L, median [IQR]) (N = 70)33 (17–40)23(17–44)[..]0.374ALT > 40 IU/L2 (18.2%)16 (27.1%)0.597 (0.116–3.067)0.805Bilirubin(mg/dL, mean ± SD) (N = 61)0.59 (0.36–0.68)0.46(0.35–0.81)[..]0.911Sodium < 135 mEq/L (N = 71)2 (18.2%)4 (6.7%)3.111 (0.495–19.541)0.501Potassium > 5 mEq/L (N = 70)2 (18.2%)1 (1.7%)12.889 (1.057–157.184)0.095Creatinine > 1.3 mg/dL (N = 62)4 (44.4%)6 (10.7%)6.667(1.395–31.849)0.035C-reactive protein(mg/L, median [IQR]) (N = 71)97.9 (33.9–205.0)44.9 (17.1–98.5)[..]0.187C-reactive protein > 100 mg/L (N = 71)5 (45.5%)14 (23.3%)2.738 (0.725–10.343)0.249Ferritin(ng/L, median [IQR]) (N = 63)625.6 (366.5–1009.2)442 (191.4–817.3)[..]0.275Ferritin > 1000 ng/mL (N = 63)2 (20%)10 (18.9%)1.075 (0.197–5.858)1.000D-dimers(ng/L, median [IQR]) (N = 70)1430 (770–2620)620 (380–1140)[..]0.043D-dimers > 600 ng/mL (N = 70)10 (90.9%)30 (58.8%)9.667 (1.163–80.337)0.033LDH(UI/L, median [IQR]) (N = 65)450 (312–660)251.5 (213.0–320.5)[..]0.001LDH > 300 UI/L(N = 65)9 (81.8%)17 (31.5%)9.794 (1.907–50.302)0.006SARS-CoV-2 in nasopharynxLog10 copies/mL, median (IQR)7.3 (6.6–8.8)6.6 (5.1–7.9)[..]0.262Hospital admission10 (90.9%)53 (86.9%)1.509 (0.170–13.432)1.000TreatmentsAntiviral treatment9 (81.8%)55 (90.2%)1.244 (0.339–4.563)0.772LPV/r0 (0%)5 (8.2%)0.836 (0.755–0.929)0.734Hydroxychloroquine1 (9.1%)21 (34.4%)0.190 (0.023–1.591)0.186LPV/r + hydroxychloroquine6 (54.5%)24 (39.3%)1.850 (0.508–6.742)0.542LPV/r + hydroxychloroquine + IFN-β2 (18.2%)2 (3.3%)6.551 (0.818–52.56)0.204Remdesivir0 (0%)7 (11.5%)0.831 (0.744–0.921)0.529Tocilizumab3 (27.3%)4 (6.6%)5.344 (1.006–28.383)0.114Initial antibacterial treatment5 (45.5%)25 (41%)1.200 (0.330–4.367)1.000ACEI: angiotensin-converting enzyme inhibitors; SBP: systolic blood pressure; DBP: diastolic blood pressure; HR: heart rate; RR: respiratory rate. AST: aspartate aminotransferase; ALT: alanine aminotransferase; LDH: lactate dehydrogenase; LPV/r: lopinavir/ritonavir; IFN-β: beta interferon. aRisk estimation from Chi-squared test, Student´s t-test and U-value from the Mann-Whitney´s test. 95% confidence intervals, according to indication, appear in parentheses. bTwo-tailed test. Open table in a new tab ACEI: angiotensin-converting enzyme inhibitors; SBP: systolic blood pressure; DBP: diastolic blood pressure; HR: heart rate; RR: respiratory rate. AST: aspartate aminotransferase; ALT: alanine aminotransferase; LDH: lactate dehydrogenase; LPV/r: lopinavir/ritonavir; IFN-β: beta interferon. aRisk estimation from Chi-squared test, Student´s t-test and U-value from the Mann-Whitney´s test. 95% confidence intervals, according to indication, appear in parentheses. bTwo-tailed test. Arthro-myalgias were the only symptom more frequently observed in COVID-19 patients with SARS-CoV-2 RNAemia compared to those without RNAemia. SARS-CoV-2 RNAemia was detected more frequently in patients with chronic liver disease (27.3% vs. 0.0%, P = 0.001) and in solid organ transplant (SOT) recipients (36.4% vs. 1.6%, P = 0.001). Fifty-six (77.8%) patients had pneumonia, 49 (87.5%) of them were admitted to the hospital; 20 (35.7%) of the pneumonia cases presented a CURB-65 score ≥2, with no differences between the groups with and without RNAemia (Table 1). Other laboratory analytical and chest X-rays data, and therapy, in patients with and without SARS-CoV-2 RNAemia are detailed in Table 1. The median viral load in plasma for the 11 patients with SARS-CoV-2 RNAemia was 2.88 Log10 copies/mL (IQR, 2.43–4.07) and the median viral load in NP swabs of the 72 patients was 6.98 Log10 copies/mL (IQR, 5.15–8.20). There was no significant difference in the viral load in NP swabs between patients with (7.29 Log10 copies/mL [IQR, 6.56–8.78]) and without RNAemia (6.64 Log10 copies/mL [5.14–7.86], P = 0.262) (Supplementary Figure 1), and we didn't find a correlation between the viral load in NP and blood samples for the eleven patients with RNAemia (Supplementary Figure 2). Additionally, we found a unique case (1.4%) of co-infection with metapneumovirus and parainfluenza virus 3, both detected in blood of a patient without RNAemia. As for their clinical outcomes, patients with SARS-CoV-2 RNAemia required more frequently ICU admission (45.50% vs. 8.2%, P = 0.005), showed more frequently acute respiratory distress syndrome (ARDS) (54.5% vs. 9.8%, P = 0.01) and required in more cases invasive mechanical ventilation (36.4% vs. 6.6%, P = 0.018). Mortality (36.4% vs. 4.9%, P = 0.007) and unfavourable outcome (63.6% vs. 13.1%, P = 0.001), were also more frequent in patients with SARS-CoV-2 RNAemia (Table 2).Table 2Clinical outcomes of patients with and without SARS-CoV-2 RNAemia.Variables N (%)N = 72 patientsORaP-valuebWith viremia (N = 11)Without viremia (N = 61)ARDS6 (54.5%)6 (9.8%)11.0 (2.563–47.112)0.001IMV4 (36.4%)4 (6.6%)8.143 (1.656–40.041)0.018Multiple organ failure1 (9.1%)0 (0%)0.141 (0.079–0.250)0.331ICU admission5 (45.5%)5 (8.2%)9.33 (2.086–41.765)0.005Length of stayDays, median (IQR)5 (0–19)6 (2.5–11)[..]0.440Mortality4 (36.4%)3 (4.9%)11.048 (2.039–59.868)0.007Unfavourable outcome (ICU admission and/or death)7 (63.6)8 (13.1)11.59 (2.76–48.73)0.001ARDS: Acute Respiratory Distress Syndrome; IMV: invasive mechanical ventilation; ICU: Intensive Care Unit. aRisk estimation from Chi-squared test, Student´s t-test and U-value from the Mann-Whitney´s test. 95% confidence intervals, according to indication, appear in parentheses. bTwo-tailed test. Open table in a new tab ARDS: Acute Respiratory Distress Syndrome; IMV: invasive mechanical ventilation; ICU: Intensive Care Unit. aRisk estimation from Chi-squared test, Student´s t-test and U-value from the Mann-Whitney´s test. 95% confidence intervals, according to indication, appear in parentheses. bTwo-tailed test. Results from other studies show discordant rates of SARS-CoV-2 detection in serum, ranging from 10.4% to 74.1%,2Zhu N. Zhang D. Wang W. Li X. Yang B. Song J. et al.A novel coronavirus from patients with pneumonia in China, 2019.N Engl J Med. 2020 Feb 20; 382: 727-733https://10.1056/NEJMoa2001017Crossref PubMed Scopus (16620) Google Scholar, 4Liang W. Liang H. Ou L. Chen B. Chen A. Li C. et al.Development and validation of a clinical risk score to predict the occurrence of critical illness in hospitalized patients with COVID-19.JAMA Intern Med. 2020 May 12; https://10.1001/jamainternmed.2020.2033Crossref Scopus (811) Google Scholar, 5Hagman K. Hedenstierna M. Gille-Johnson P. Hammas B. Grabbe M. Dillner J. et al.SARS-CoV-2 RNA in serum as predictor of severe outcome in COVID-19: a retrospective cohort study.Clin Infect Dis. 2020 Aug 28; https://10.1093/cid/ciaa1285PubMed Google Scholar, 6Veyer D. Kerneis S. Poulet G. Wack M. Robillard N. Taly V. et al.Highly sensitive quantification of plasma SARS-CoV-2 RNA shelds light on its potential clinical value.Clin Infect Dis. 2020 Aug 17; https://10.1093/cid/ciaa1196Crossref PubMed Scopus (62) Google Scholar, 7Prebensen C. Hre P.L.M. Jonassen C. Rangberg A. Blomfeldt A. Svensson M. 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 Sep 5; https://10.1093/cid/ciaa1338PubMed Google Scholar while other authors do not find any patient8Zou L. Ruan F. Huang M. Liang L. Huang H. Hong Z. et al.SARS-CoV-2 viral load in upper respiratory specimens of infected patients.N Engl J Med. 2020 Mar 19; 382: 1177-1179https://10.1056/NEJMc2001737Crossref PubMed Scopus (3211) Google Scholar or report only 1% of RNAemia.2Zhu N. Zhang D. Wang W. Li X. Yang B. Song J. et al.A novel coronavirus from patients with pneumonia in China, 2019.N Engl J Med. 2020 Feb 20; 382: 727-733https://10.1056/NEJMoa2001017Crossref PubMed Scopus (16620) Google Scholar Veyer et al. also found higher frequency of SARS-CoV-2 RNAemia in more severely ill patients, however they were included at the time of respiratory deterioration and those with pre-existing unstable chronic disorders were excluded.6Veyer D. Kerneis S. Poulet G. Wack M. Robillard N. Taly V. et al.Highly sensitive quantification of plasma SARS-CoV-2 RNA shelds light on its potential clinical value.Clin Infect Dis. 2020 Aug 17; https://10.1093/cid/ciaa1196Crossref PubMed Scopus (62) Google Scholar Most patients presented with chronic underlying diseases (66.7%), a percentage that shows high variability, from the 23.7% reported by Guan et al.9Guan W.J. Ni Z.Y. Hu Y. Liang W.H. Ou C.Q. He J.X. et al.Clinical characteristics of coronavirus disease 2019 in China.N Engl J Med. 2020 Apr 30; 382: 1708-1720https://10.1056/NEJMoa2002032Crossref PubMed Scopus (18405) Google Scholar to higher percentages (79%) depending on the number and type of the comorbidities considered in each case.5Hagman K. Hedenstierna M. Gille-Johnson P. Hammas B. Grabbe M. Dillner J. et al.SARS-CoV-2 RNA in serum as predictor of severe outcome in COVID-19: a retrospective cohort study.Clin Infect Dis. 2020 Aug 28; https://10.1093/cid/ciaa1285PubMed Google Scholar Our results confirm those from Prebensen et al. who did not find an association between the viral load in NP samples and the presence of SARS-CoV-2 RNAemia nor correlation with the viral load in blood.7Prebensen C. Hre P.L.M. Jonassen C. Rangberg A. Blomfeldt A. Svensson M. 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 Sep 5; https://10.1093/cid/ciaa1338PubMed Google Scholar In the present study, the worst clinical evolution and outcome in patients with RNAemia and the lack of correlation between the viral load in NP samples and blood, besides the absence of difference in the NP viral load between patients with and without SARS-CoV-2 RNAemia, support that it is a better indicator of the clinical evolution of COVID-19 patients than NP viral load. SARS-CoV-2 RNAemia has been shown to be associated with high levels of IL-6 in critically ill COVID-19 patients, and both factors were related to mortality.4Liang W. Liang H. Ou L. Chen B. Chen A. Li C. et al.Development and validation of a clinical risk score to predict the occurrence of critical illness in hospitalized patients with COVID-19.JAMA Intern Med. 2020 May 12; https://10.1001/jamainternmed.2020.2033Crossref Scopus (811) Google Scholar According to our experience, the levels of d-dimers, which are also used as markers of inflammation, were also higher in patients with SARS-CoV-2 RNAemia. The frequency of patients with elevated levels of AST and LDH, and those with decreased counts of lymphocytes and platelets were in agreement with previous reports,2Zhu N. Zhang D. Wang W. Li X. Yang B. Song J. et al.A novel coronavirus from patients with pneumonia in China, 2019.N Engl J Med. 2020 Feb 20; 382: 727-733https://10.1056/NEJMoa2001017Crossref PubMed Scopus (16620) Google Scholar, 9Guan W.J. Ni Z.Y. Hu Y. Liang W.H. Ou C.Q. He J.X. et al.Clinical characteristics of coronavirus disease 2019 in China.N Engl J Med. 2020 Apr 30; 382: 1708-1720https://10.1056/NEJMoa2002032Crossref PubMed Scopus (18405) Google Scholar, 10Salto-Alejandre S. Roca-Oporto C. Martin-Gutierrez G. Aviles M.D. Gomez-Gonzalez C. Navarro-Amuedo M.D. et al.A quick prediction tool for unfavorable outcome in COVID-19 inpatients: development and internal validation.J Infect. 2020 Sep 25; https://10.1016/j.jinf.2020.09.023Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar although in our cohort these findings were associated with the presence of SARS-CoV-2 RNAemia. Regarding the clinical meaning of the SARS-CoV-2 RNAemia, our results agree with those reported by other authors, suggesting an association with underlying diseases and a worst clinical evolution, although without the limitations of including only patients more severely ill, or excluding those with underlying chronic diseases or receiving therapies that may influence the outcome.5Hagman K. Hedenstierna M. Gille-Johnson P. Hammas B. Grabbe M. Dillner J. et al.SARS-CoV-2 RNA in serum as predictor of severe outcome in COVID-19: a retrospective cohort study.Clin Infect Dis. 2020 Aug 28; https://10.1093/cid/ciaa1285PubMed Google Scholar, 6Veyer D. Kerneis S. Poulet G. Wack M. Robillard N. Taly V. et al.Highly sensitive quantification of plasma SARS-CoV-2 RNA shelds light on its potential clinical value.Clin Infect Dis. 2020 Aug 17; https://10.1093/cid/ciaa1196Crossref PubMed Scopus (62) Google Scholar, 7Prebensen C. Hre P.L.M. Jonassen C. Rangberg A. Blomfeldt A. Svensson M. 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 Sep 5; https://10.1093/cid/ciaa1338PubMed Google Scholar Our results show that COVD-19 patients with SARS-CoV-2 RNAemia are more likely to develop ARDS than those without RNAemia and show increased needs of ICU admission, in agreement with Prebensen et al.,7Prebensen C. Hre P.L.M. Jonassen C. Rangberg A. Blomfeldt A. Svensson M. 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 Sep 5; https://10.1093/cid/ciaa1338PubMed Google Scholar and invasive mechanical ventilation. In conclusion, the results of the present study show that the presence of the SARS-CoV-2 RNAemia, at the first evaluation in the emergency room, occurs more frequently in patients with severe underlying chronic diseases, such as chronic liver disease and solid organ transplantation, is not predicted by the viral load in the upper respiratory airways, and it is associated with unfavourable outcome. None of the study authors have conflicts of interest to declare. Supported by Plan Nacional de I + D + i 2013–2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Economía, Industria y Competitividad, Spanish Network for Research in Infectious Diseases (REIPI, RD16/0016/0001, RD16/0016/0005, RD16/0016/0007, RD16/0016/0009, RD16/0016/0010, R D16/0016/0013) cofinanced by European Development Regional Fund “A way to achieve Europe”, Operative program Intelligent Growth 2014–2020. JSC and EC received grants from the Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación, Proyectos de Investigación sobre el SARS-CoV-2 y la enfermedad COVID-19 (COV20/00580; COV20/00370). J.S.C. is a researcher belonging to the program “Nicolás Monardes” (C-0059–2018), Servicio Andaluz de Salud, Junta de Andalucía, Spain. The study protocol was approved by the Ethics Committee of Virgen Macarena and Virgen del Rocío University Hospitals (C.I. 0771-N-20) and complied the Declaration of Helsinki. All authors have approved the manuscript and its publication. Download .docx (.06 MB) Help with docx files" @default.
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• W3109016170 title "SARS-CoV-2 RNAemia is associated with severe chronic underlying diseases but not with nasopharyngeal viral load" @default.
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