Diagnostic SARS-CoV-2 Cycle Threshold Value Predicts Disease Severity, Survival, and Six-Month Sequelae in COVID-19 Symptomatic Patients

Trunfio, Mattia; Venuti, Francesco; Alladio, Francesca; Longo, Bianca Maria; Burdino, Elisa; Cerutti, Francesco; Ghisetti, Valeria; Bertucci, Roberto; Picco, Carlo; Bonora, Stefano; Perri, Giovanni Di; Calcagno, Andrea

doi:10.3390/v13020281

Cited by 64 publications

(72 citation statements)

References 53 publications

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“…Our finding that the score was associated with the time from illness onset (score lower with greater time from onset of illness) and CT (qPCR) on nasal swabs (score higher with greater viral burden on the nasal swab) suggest initial biological plausibility for the responsiveness of the score to clinical disease/viral burden. Other studies have shown an independent relationship between qPCR CT and disease outcome [34][35][36][37][38]. We did not find any direct relationship between the disease score and indicators of disease severity.…”

Section: Discussioncontrasting

confidence: 83%

A blood RNA transcriptome signature for COVID-19

et al. 2021

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Background COVID-19 is a respiratory viral infection with unique features including a more chronic course and systemic disease manifestations including multiple organ involvement; and there are differences in disease severity between ethnic groups. The immunological basis for disease has not been fully characterised. Analysis of whole-blood RNA expression may provide valuable information on disease pathogenesis. Methods We studied 45 patients with confirmed COVID-19 infection within 10 days from onset of illness and a control group of 19 asymptomatic healthy volunteers with no known exposure to COVID-19 in the previous 14 days. Relevant demographic and clinical information was collected and a blood sample was drawn from all participants for whole-blood RNA sequencing. We evaluated differentially-expressed genes in COVID-19 patients (log2 fold change ≥ 1 versus healthy controls; false-discovery rate < 0.05) and associated protein pathways and compared these to published whole-blood signatures for respiratory syncytial virus (RSV) and influenza. We developed a disease score reflecting the overall magnitude of expression of internally-validated genes and assessed the relationship between the disease score and clinical disease parameters. Results We found 135 differentially-expressed genes in the patients with COVID-19 (median age 35 years; 82% male; 36% Chinese, 53% South Asian ethnicity). Of the 117 induced genes, 14 were found in datasets from RSV and 40 from influenza; 95 genes were unique to COVID-19. Protein pathways were mostly generic responses to viral infections, including apoptosis by P53-associated pathway, but also included some unique pathways such as viral carcinogenesis. There were no major qualitative differences in pathways between ethnic groups. The composite gene-expression score was correlated with the time from onset of symptoms and nasal swab qPCR CT values (both p < 0.01) but was not related to participant age, gender, ethnicity or the presence or absence of chest X-ray abnormalities (all p > 0.05). Conclusions The whole-blood transcriptome of COVID-19 has overall similarity with other respiratory infections but there are some unique pathways that merit further exploration to determine clinical relevance. The approach to a disease score may be of value, but needs further validation in a population with a greater range of disease severity.

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Section: Discussioncontrasting

confidence: 83%

A blood RNA transcriptome signature for COVID-19

et al. 2021

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“…Our findings are supported by previous reports that have shown SARS-CoV-2 Ct values in NP swabs to be predictive of disease severity and worse outcomes [8][9][10][11]. SARS-CoV-2 Ct in NP swabs is an appealing method as it is easily accessible and used in most algorithms for COVID-19 diagnosis on hospital admission.…”

Section: Discussionsupporting

confidence: 89%

The Impact of SARS-CoV-2 Viral Load on the Mortality of Hospitalized Patients: A Retrospective Analysis

Machado¹,

Salvador²,

Oliveira³

et al. 2021

Cureus

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IntroductionCoronavirus disease 2019 (COVID-19) has emerged worldwide since December 2019. The standard method for diagnosis is via nucleic acid amplification testing, usually with a reverse-transcription polymerase chain reaction (RT-PCR). Hospitalized infected individuals may require ventilation and may have higher mortality rates. We aim to evaluate the clinical impact of nasopharyngeal viral load on these outcomes. Materials and methodsWe conducted a retrospective cohort study of patients hospitalized with COVID-19 from 17 March 2020 to 1 June 2020 at a tertiary care hospital. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load was assessed using cycle threshold (Ct) values from an RT-PCR assay applied to nasopharyngeal swab samples. We compared the clinical characteristics of survivors vs. non-survivors and assessed whether the viral load was independently associated with in-hospital 30-day mortality. ResultsWe evaluated 197 patients. Thirty-day mortality was verified in 71 (36%) subjects. In the adjusted effects model, only the E-gene Ct value [odd ratio (OR) .873; confidence interval (CI) 95% .769-.992; p .037], age, the number of days of symptoms before admission, lactate dehydrogenase (LDH), and the oxygen saturation (SatO 2 )-to-fraction of inspired oxygen (FiO 2 ) ratio remained significantly associated with 30-day mortality.There was no identified association between the viral loads and disease severity, the need for ventilation, or length of stay. DiscussionOur results are, in part, concordant with previous papers. One possible limitation to our study is the fact that possibly included disproportionately more patients with poorer outcomes since hospitalization was required. Therefore, further research is required. ConclusionSARS-CoV-2 viral load on admission may be an independent predictor of 30-day mortality among hospitalized patients with COVID-19. Providing this information to clinicians could potentially be used to guide risk stratification.

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“…Secondly, confusion surrounds the terminology used by studies assessing COVID-19 severity and the amount of virus at diagnosis. Once again, what has been found to predict COVID-19 severity is not the viral inoculum but the amount of virus that is locally replicating since at least few days before detection, as the shorter median period from disease onset to swab collection among the studies is 5 days (de la Calle et al, 2021;Trunfio et al, 2021). No evidence is yet available on the quantitative change from the amount of the viral inoculum to the amount of detected virus at symptom onset nor at diagnosis to support or reject this hypothesis, but the epistemological difference is substantial.…”

Section: Viral Replication Cut-offmentioning

confidence: 99%

On the SARS-CoV-2 “Variolation Hypothesis”: No Association Between Viral Load of Index Cases and COVID-19 Severity of Secondary Cases

et al. 2021

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Background: Emerging evidence supports the “variolation hypothesis” in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), but the derivative idea that the viral load of index cases may predict disease severity in secondary cases could be unsubstantiated. We assessed whether the prevalence of symptomatic infections, hospitalization, and deaths in household contacts of 2019 novel coronavirus disease (COVID-19) cases differed according to the SARS-CoV-2 PCR cycle threshold (Ct) from nasal-pharyngeal swab at diagnosis of linked index cases.Methods: Cross-sectional study on household contacts of COVID-19 cases randomly sampled from all the infections diagnosed in March at our Microbiology Laboratory (Amedeo di Savoia, Turin). Data were retrospectively collected by phone interviews and from the Piedmont regional platform for COVID-19 emergency. Index cases were classified as high (HVl) and low viral load (LVl) according to two exploratory cut-offs of RdRp gene Ct value. Secondary cases were defined as swab confirmed or symptom based likely when not tested but presenting compatible clinical picture.Results: One hundred thirty-two index cases of whom 87.9% symptomatic and 289 household contacts were included. The latter were male and Caucasian in 44.3 and 95.8% of cases, with a median age of 34 years (19–57). Seventy-four were swab confirmed and other 28 were symptom based likely secondary cases. Considering both, the contacts of HVl and LVl did not differ in the prevalence of symptomatic infections nor COVID-19-related hospitalization and death. No difference in median Ct of index cases between symptomatic and asymptomatic, hospitalized and not hospitalized, or deceased and survived secondary cases was found. Negative findings were confirmed after adjusting for differences in time between COVID-19 onset and swab collection of index cases (median 5 days) and after removing pediatric secondary cases.Conclusions: The amount of SARS-CoV-2 of the source at diagnosis does not predict clinical outcomes of linked secondary cases. Considering the impelling release of assays for SARS-CoV-2 RNA exact quantification, these negative findings should inform clinical and public health strategies on how to interpret and use the data.

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Diagnostic SARS-CoV-2 Cycle Threshold Value Predicts Disease Severity, Survival, and Six-Month Sequelae in COVID-19 Symptomatic Patients

Cited by 64 publications

References 53 publications

A blood RNA transcriptome signature for COVID-19

A blood RNA transcriptome signature for COVID-19

The Impact of SARS-CoV-2 Viral Load on the Mortality of Hospitalized Patients: A Retrospective Analysis

On the SARS-CoV-2 “Variolation Hypothesis”: No Association Between Viral Load of Index Cases and COVID-19 Severity of Secondary Cases

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