SARS-CoV-2 RNAaemia predicts clinical deterioration and extrapulmonary complications from COVID-19

AbstractBackgroundThe determinants of COVID-19 disease severity and extrapulmonary complications (EPCs) are poorly understood. We characterise the relationships between SARS-CoV-2 RNAaemia and disease severity, clinical deterioration, and specific EPCs.MethodsWe used quantitative (qPCR) and digital (dPCR) PCR to quantify SARS-CoV-2 RNA from nasopharyngeal swabs and plasma in 191 patients presenting to the Emergency Department (ED) 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 characterised the role of RNAaemia in predicting clinical severity and EPCs using elastic net regression.Findings23·0% (44/191) of SARS-CoV-2 positive patients had viral RNA detected in plasma by dPCR, compared to 1·4% (2/147) by qPCR. Most patients with serial measurements had undetectable RNAaemia 10 days after onset of symptoms, but took 16 days to reach maximum severity, and 33 days for symptoms to resolve. Initially RNAaemic patients were more likely to manifest severe disease (OR 6·72 [95% CI, 2·45 – 19·79]), worsening of disease severity (OR 2·43 [95% CI, 1·07 - 5·38]), and EPCs (OR 2·81 [95% CI, 1·26 – 6·36]). RNA load correlated with maximum severity (r = 0·47 [95% CI, 0·20 - 0·67]).InterpretationdPCR is more sensitive than qPCR for the detection of SARS-CoV-2 RNAaemia, which is a robust predictor of eventual COVID-19 severity and oxygen requirements, as well as EPCs. Since many COVID-19 therapies are initiated on the basis of oxygen requirements, RNAaemia on presentation might serve to direct early initiation of appropriate therapies for the patients most likely to deteriorate.FundingNIH/NIAID (Grants R01A153133, R01AI137272, and 3U19AI057229 – 17W1 COVID SUPP #2) and a donation from Eva Grove.Research in contextEvidence before this studyThe varied clinical manifestations of COVID-19 have directed attention to the distribution of SARS-CoV-2 in the body. Although most concentrated and tested for in the nasopharynx, SARS-CoV-2 RNA has been found in blood, stool, and numerous tissues, raising questions about dissemination of viral RNA throughout the body, and the role of this process in disease severity and extrapulmonary complications. Recent studies have detected low levels of SARS-CoV-2 RNA in blood using either quantitative reverse transcriptase real-time PCR (qPCR) or droplet digital PCR (dPCR), and have associated RNAaemia with disease severity and biomarkers of dysregulated immune response.Added value of this studyWe quantified SARS-CoV-2 RNA in the nasopharynx and plasma of patients presenting to the Emergency Department with COVID-19, and found an array-based dPCR platform to be markedly more sensitive than qPCR for detection of SARS-CoV-2 RNA, with a simplified workflow well-suited to clinical adoption. We collected serial plasma samples during patients’ course of illness, and showed that SARS-CoV-2 RNAaemia peaks early, while clinical condition often continues to worsen. Our findings confirm the association between RNAaemia and disease severity, and additionally demonstrate a role for RNAaemia in predicting future deterioration and specific extrapulmonary complications.Implications of all the available evidenceVariation in SARS-CoV-2 RNAaemia may help explain disparities in disease severity and extrapulmonary complications from COVID-19. Testing for RNAaemia with dPCR early in the course of illness may help guide patient triage and management.

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Dissecting the role of genetic modifiers of hemoglobinopathies: A futuristic approach towards precision medicine

10.21203/rs.3.rs-285113/v1 ◽

2021 ◽

Author(s):

Priya Hariharan ◽

Manju Gorivale ◽

Pratibha Sawant ◽

Pallavi Mehta ◽

Anita Nadkarni

Keyword(s):

Disease Severity ◽

Phenotypic Variability ◽

Globin Gene ◽

Gene Promoter ◽

Clinical Severity ◽

Genetic Modifiers ◽

Promoter Polymorphisms ◽

Cumulative Impact ◽

Remarkable Result

Abstract Introduction: Hemoglobinopathies though a monogenic disorder, show phenotypic variability. Hence, understanding the genetics underlying the heritable sub-phenotypes of hemoglobinopathies, specific to each population, would be prognostically useful and could inform personalized therapeutics. This study aimed to evaluate the role of genetic modifiers leading to higher HbF production with cumulative impact of the modifiers on disease severity. Materials and methods:200 patients [100 β-thalassemia homozygotes,100 Sickle Cell Anemia], and 50 healthy controls were recruited. Primary screening followed with molecular analysis for confirming the β-hemoglobinopathy was performed. Co-existing α-thalassemia and the polymorphisms located in 3 genetic loci linked to HbF regulation were screened.Results: The most remarkable result was the association of SNPs with clinically relevant phenotypic groups. The γ-globin gene promoter polymorphisms [-158 C→T,+25 G→A],BCL11A rs1427407 G→T,-3 bp HBS1L-MYB rs66650371 and rs9399137 T→C polymorphisms were correlated with higher HbF, in group that has lower disease severity score (P<0.00001), milder clinical presentation, and a significant delay in the age of the first transfusion.Conclusion:Our study emphasizes the complex genetic interactions underlying the disease phenotype that may be a prognostic marker for predicting the clinical severity and assist in disease management.

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Exuberant elevation of IP-10, MCP-3 and IL-1ra during SARS-CoV-2 infection is associated with disease severity and fatal outcome

10.1101/2020.03.02.20029975 ◽

2020 ◽

Cited By ~ 72

Author(s):

Yang Yang ◽

Chenguang Shen ◽

Jinxiu Li ◽

Jing Yuan ◽

Minghui Yang ◽

...

Keyword(s):

Disease Severity ◽

Fatal Outcome ◽

Area Under The Curve ◽

Receiver Operating Characteristics ◽

Plasma Samples ◽

Cytokine Storm ◽

Operating Characteristics ◽

Case Number ◽

Novel Therapeutic

The outbreak of Coronavirus Disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, December 2019, and continuously poses a serious threat to public health. Our previous study has shown that cytokine storm occurred during SARS-CoV-2 infection, while the detailed role of cytokines in the disease severity and progression remained unclear due to the limited case number. In this study, we examined 48 cytokines in the plasma samples from 53 COVID-19 cases, among whom 34 were severe cases, and the others moderate. Results showed that 14 cytokines were significantly elevated upon admission in COVID-19 cases. Moreover, IP-10, MCP-3, and IL-1ra were significantly higher in severe cases, and highly associated with the PaO2/FaO2 and Murray score. Furthermore, the three cytokines were independent predictors for the progression of COVID-19, and the combination of IP-10, MCP-3 and IL-1ra showed the biggest area under the curve (AUC) of the receiver-operating characteristics (ROC) calculations. Serial detection of IP-10, MCP-3 and IL-1ra in 14 severe cases showed that the continuous high levels of these cytokines were associated with disease deterioration and fatal outcome. In conclusion, we report biomarkers that closely associated with disease severity and outcome of COVID-19. These findings add to our understanding of the immunopathologic mechanisms of SARS-CoV-2 infection, providing novel therapeutic targets and strategy.

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Role of Lung Ultrasound in Predicting Clinical Severity and Fatality in COVID-19 Pneumonia

Journal of Personalized Medicine ◽

10.3390/jpm11080757 ◽

2021 ◽

Vol 11 (8) ◽

pp. 757

Author(s):

Ivan Skopljanac ◽

Mirela Pavicic Ivelja ◽

Ognjen Barcot ◽

Ivan Brdar ◽

Kresimir Dolic ◽

...

Keyword(s):

Hospital Admission ◽

Disease Severity ◽

Predictive Power ◽

Lung Ultrasound ◽

Clinical Severity ◽

Imaging Method ◽

High Flow Nasal Cannula ◽

Severity Of The Disease

Background: Lung ultrasound (LUS) is a useful imaging method for identifying COVID-19 pneumonia. The aim of this study was to explore the role of LUS in predicting the severity of the disease and fatality in patients with COVID-19. Methods: This was a single-center, follow-up study, conducted from 1 November 2020, to 22 March 2021. The LUS protocol was based on the assessment of 14 lung zones with a total score up to 42, which was compared to the disease severity and fatality. Results: A total of 133 patients with COVID-19 pneumonia confirmed by RT-PCR were enrolled, with a median time from hospital admission to lung ultrasound of one day. The LUS score was correlated with clinical severity at hospital admission (Spearman’s rho 0.40, 95% CI 0.24 to 0.53, p < 0.001). Patients with higher LUS scores were experiencing greater disease severity; a high flow nasal cannula had an odds ratio of 1.43 (5% CI 1.17–1.74) in patients with LUS score > 29; the same score also predicted the need for mechanical ventilation (1.25, [1.07–1.48]). An LUS score > 30 (1.41 [1.18–1.68]) and age over 68 (1.26 [1.11–1.43]) were significant predictors of fatality. Conclusions: LUS at hospital admission is shown to have a high predictive power of the severity and fatality of COVID-19 pneumonia.

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Role of ROX Index in the first assessment of COVID-19 patients in the Emergency Department

10.21203/rs.3.rs-108370/v1 ◽

2020 ◽

Author(s):

Alice Gianstefani ◽

Gabriele Farina ◽

Veronica Salvatore ◽

Francesca Alvau ◽

Maria Laura Artesiani ◽

...

Keyword(s):

Emergency Department ◽

Hospital Admission ◽

Healthcare Services ◽

Clinical Findings ◽

Clinical Severity ◽

High Rate ◽

Secondary Outcomes ◽

Index Value ◽

Suspected Diagnosis

Abstract Background: In Italy, since the first symptomatic cases of Coronavirus disease 2019 (COVID-19) appeared in late February 2020, 205.463 cases of Severe Acute Respiratory Syndrome 2 (SARS-CoV-2) were reported as of April 30, causing an high rate of hospital admission through the Emergency Department (ED).Objectives: The aim of the study was to evaluate the accuracy of ROX index in predicting hospitalization and mortality in patients with suspected diagnosis of COVID-19 in the ED. Secondary outcomes were to assess the number of readmissions and the variations of ROX index between first and second admission.Methods: This is an observational prospective monocentric study, conducted in the ED of Policlinico Sant’Orsola-Malpighi in Bologna. We enrolled 1371 consecutive patients with suspected COVID-19 and ROX index was calculated in 554 patients. Patients were followed until hospital discharge or death. Results: ROX index value < 25.7 was associated with hospitalization (AUC=0.737, 95%CI 0.696–0.779, p<0.001). ROX index < 22.3 is statistically related with higher 30-days mortality (AUC= 0.764, 95%CI 0.708-0.820, p<0.001). 8 patients were discharged and returned in the ED within the following 7 days, their mean ROX index was 30.3 (6.2; range 21.9-39.4) at the first assessment and 24.6 (5.5; 14.5-29.5) at the second assessment, (p=0.012).Conclusion: ROX index, together with laboratory, imaging and clinical findings, can help discriminate patients suspected for COVID-19 requiring hospital admission, their clinical severity and their mortality risk. Furthermore, it can be useful to better manage these patients in territorial healthcare services, especially in the hypothesis of another pandemic.

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Matrix Metalloproteinase and Their Inhibitors Concentration and Activity Variations in Aqueous Humor and Plasma of Glaucoma Patients

Revista de Chimie ◽

10.37358/rc.17.8.5775 ◽

2017 ◽

Vol 68 (8) ◽

pp. 1829-1833

Author(s):

Iulia Maria Ciotu ◽

Alina Constantin ◽

Liliana Voinea ◽

Valeriu Atanasiu

Keyword(s):

Extracellular Matrix ◽

Matrix Metalloproteinase ◽

Aqueous Humor ◽

Open Angle Glaucoma ◽

The Body ◽

Plasma Samples ◽

Open Angle ◽

Aqueous Humor Outflow ◽

Cataract Patients

Matrix metalloproteinases (MMPs) are a group of endopeptidases with the role of reorganizing the extracellular matrix of cells through the body. In aqueous humor MMPs have an important role in turnover regulation by acting on the constant remodeling of the trabecular mesh keeping at a constant level the trabecular resistance for a good aqueous humor outflow and consequently of the intraocular pressure.In this paper, we aimed to assess the levels of MMP-2/TIMP-1 and MMP-9/TIMP-2 ratio in aqueous humor samples and in the plasma of patients with open angle glaucoma and cataract patients that serves as control, and to evaluate the gelatinolytic activity MMP-2 and MMP-9 in aqueous humor samples. Aqueous humor and plasma samples were collected from 30 patients, 14 from open angle glaucoma and 16 from cataract patients. Levels of MMP-2, -9 and TIMP -1 and -2 were determined by zymography and immunoassays, using specific kits. The data obtained suggest the presence of a direct correlation between the levels and activity of MMP influencing the accumulation of abnormal matrix and may have an impact on the pathogenesis of open angle glaucoma.\

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Assessing disease severity by hsCRP as a biochemical marker for psoriasis

International Journal of Research in Dermatology ◽

10.18203/issn.2455-4529.intjresdermatol20175373 ◽

2017 ◽

Vol 3 (4) ◽

pp. 501

Author(s):

Kriti Jain ◽

Arvind Krishna ◽

B. S. Rathore

Keyword(s):

Disease Severity ◽

Age Of Onset ◽

Late Onset ◽

Severe Disease ◽

High Sensitivity ◽

The Body ◽

Clinical Severity ◽

Positive Correlation ◽

Reactive Protein ◽

Pasi Score

Background: For a complex chronic disease like psoriasis, having a biomarker to objectively assess the clinical severity can be very helpful in disease management.Methods: In a hospital based prospective study, 70 patients of psoriasis diagnosed clinically, were studied. The extent of disease severity was assessed using PASI and BSA and patients were grouped into having mild, moderate and severe disease using these scores. Serum high sensitivity C-reactive protein (hsCRP) levels were then estimated for each group.Results: Of the 70 psoriasis cases enrolled, 46 patients were male and 24 females. Patients with early onset psoriasis were associated with higher values of hsCRP than those with late onset (r=-0.063; p=0.012). A positive correlation was seen between the PASI score and hsCRP levels (r=0.891; p≤0.001). On comparing mean PASI and mean hsCRP in severity groups (mild, moderate and severe), hsCRP was higher in the group with maximum severity (p≤0.001). Conclusions: A negative correlation between the age of onset and hsCRP implies that, earlier the age of onset, higher is the value of hsCRP. Our study shows a positive correlation between the body surface area and PASI score both of which varied linearly with hsCRP values. The findings also suggest that patients with severe psoriasis have higher mean serum hsCRP levels than patients with mild psoriasiss.We proposed hsCRP as a useful marker of psoriasis severity that could be used to monitor psoriasis and, together with PASI, as a global index of disease severity.

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Role of Lung Ultrasound in the Management of Patients with Suspected SARS-Cov-2 Infection in the Emergency Department

10.21203/rs.3.rs-471145/v1 ◽

2021 ◽

Author(s):

Andrea Boccatonda ◽

Alice Grignaschi ◽

Antonella Lanotte ◽

Fabrizio Giostra ◽

Cosima Schiavone ◽

...

Keyword(s):

Emergency Department ◽

Lung Ultrasound ◽

Ultrasound Examination ◽

Hospitalization Rate ◽

Clinical Severity ◽

A Value ◽

Ultrasound Study ◽

Increased Risk ◽

Level Method

Abstract Background: the LUS score has been proposed as an optimal scheme for the ultrasound study of the patient with suspected / confirmed COVID-19 pneumonia. The aim of our study was to evaluate the use of lung ultrasound as a diagnostic tool for diagnosing SARS-CoV-2 pneumonia, and to examine the validity of LUS score for the diagnosis of COVID-19 pneumonia, and to correlate with hospitalization rate and 30-days mortality.Material & methods: a retrospective analysis was performed on all patients who were referred to the General Emergency Department of the S. Orsola-Malpighi Hospital from April 2020 to May 2020 for symptoms suspected for SARS-CoV-2 infection. The ultrasound examination was based on a common execution scheme called LUS score, as previously described.Results & Conclusions: LUS score correlates with the degree of clinical severity and respiratory failure (P/F ratio, Delta (A-a), Delta (A-a) increase). COVID-19 patients with a LUS score > 7 require the use of oxygen support; a value > 10 is associated with an increased risk of oro-tracheal intubation. The LUS score presents higher values in hospitalized patients, increasing according to the degree of care intensity. COVID-19 died patients were characterized by a mean LUS score of 11 at presentation to the emergency department. A LUS score value > 7.5 displays a sensitivity of 83% and specificity of 89% against 30-days mortality in COVID-19 patients. Lung ultrasound seems to be an optimal first level method for pneumonia detection in patients with suspected SARS-CoV-2 infection.

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Pathophysiology of COVID-19: Mechanisms Underlying Disease Severity and Progression

Physiology ◽

10.1152/physiol.00019.2020 ◽

2020 ◽

Vol 35 (5) ◽

pp. 288-301 ◽

Cited By ~ 5

Author(s):

Mary Kathryn Bohn ◽

Alexandra Hall ◽

Lusia Sepiashvili ◽

Benjamin Jung ◽

Shannon Steele ◽

...

Keyword(s):

Immune Response ◽

Organ Failure ◽

Disease Severity ◽

Viral Entry ◽

Wide Spectrum ◽

Underlying Disease ◽

Viral Clearance ◽

Clinical Severity ◽

Global Epidemiology

The global epidemiology of coronavirus disease 2019 (COVID-19) suggests a wide spectrum of clinical severity, ranging from asymptomatic to fatal. Although the clinical and laboratory characteristics of COVID-19 patients have been well characterized, the pathophysiological mechanisms underlying disease severity and progression remain unclear. This review highlights key mechanisms that have been proposed to contribute to COVID-19 progression from viral entry to multisystem organ failure, as well as the central role of the immune response in successful viral clearance or progression to death.

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The Contribution of the Alkaline Pericardial Fluid of Freshwater Turtles to Acid Buffering During Prolonged Anoxia

Journal of Experimental Biology ◽

10.1242/jeb.109.1.55 ◽

1984 ◽

Vol 109 (1) ◽

pp. 55-62

Author(s):

DONALD C. JACKSON ◽

NORBERT HEISLER

Keyword(s):

Energy Supply ◽

Ionic Composition ◽

Pericardial Fluid ◽

The Body ◽

Plasma Samples ◽

Freshwater Turtles ◽

Transfer Processes ◽

Chrysemys Picta Bellii ◽

Acid Buffering

The role of buffering of the high pericardial fluid [HCO3−] of the turtle, Chrysemys picta bellii Gray, was evaluated during prolonged anoxia at 3 and 10°C. At 3°C, pericardial fluid samples were collected from groups of animals after 0, 1, 2, 4 and 8 weeks of anoxia, and the ionic composition of these samples was compared to plasma values from the same animals. At 10 °C, pericardial and plasma samples were taken from normoxic turtles and from turtles after 11 days of anoxia. The samples were analysed for total CO2 (CCOCO2), [Cl−] and [lactate−]. At 3°C, the fall in pericardial [HCO3−] and the rise in [lactate−] lagged behind the same changes in the plasma, until after about 8 weeks of anoxia the composition of pericardial fluid became identical with that of plasma. At 10 °C, pericardial [HCO3−] fell significantly after 11 days of anoxia but was still above plasma [HCO3−], while [lactate−] was essentially the same in both fluids. We conclude that the pericardial fluid does participate in the buffering of lactic acid during prolonged anoxia. However, its involvement is delayed, possibly until the energy supply for the active carrier-mediated transfer processes responsible for the high [HCO3−] gradient breaks down as a consequence of the prolonged anoxia. Analysis of the overall buffering in the body reveals that the contribution of the pericardial fluid is minor.

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SARS-CoV-2 Nucleocapsid Plasma Antigen for Diagnosis and Monitoring of COVID-19

Clinical Chemistry ◽

10.1093/clinchem/hvab216 ◽

2021 ◽

Author(s):

Hannah Wang ◽

Catherine A Hogan ◽

Michelle Verghese ◽

Daniel Solis ◽

Mamdouh Sibai ◽

...

Keyword(s):

Intensive Care ◽

Disease Severity ◽

Nucleic Acid Amplification ◽

Care Utilization ◽

Plasma Samples ◽

Antigen Concentration ◽

Clinical Sensitivity ◽

Mixed Effects Modeling ◽

Median Plasma

Abstract Background Detection of SARS-CoV-2 nucleocapsid antigen in blood has been described, but the diagnostic and prognostic role of antigenemia is not well understood. This study aimed to determine the frequency, duration, and concentration of nucleocapsid antigen in plasma and its association with COVID-19 severity. Methods We utilized an ultrasensitive electrochemiluminescence immunoassay targeting SARS-CoV-2 nucleocapsid antigen to evaluate 777 plasma samples from 104 individuals with COVID-19. We compared plasma antigen to respiratory nucleic acid amplification testing (NAAT) in 74 individuals with COVID-19 from samples collected ± 1 day of diagnostic respiratory NAAT, and in 52 SARS-CoV-2-negative individuals. We used Kruskal-Wallis tests, multivariable logistic regression, and mixed-effects modeling to evaluate whether plasma antigen concentration was associated with disease severity. Results Plasma antigen had 91.9% (95% CI 83.2-97.0%) clinical sensitivity and 94.2% (84.1-98.8%) clinical specificity. Antigen-negative plasma samples belonged to patients with later respiratory cycle thresholds (Ct) when compared with antigen-positive plasma samples. Median plasma antigen concentration (log10 fg/mL) was 5.4 (IQR 3.9-6.0) in outpatients, 6.0 (5.4-6.5) in inpatients, and 6.6 (6.1-7.2) in intensive care unit (ICU) patients. In models adjusted for age, sex, diabetes, and hypertension, plasma antigen concentration at diagnosis was associated with ICU admission (OR 2.8 [95% CI 1.2-6.2], P=.01), but not with non-ICU hospitalization. Rate of antigen decrease was not associated with disease severity. Conclusions SARS-CoV-2 plasma nucleocapsid antigen exhibited comparable diagnostic performance to upper respiratory NAAT, especially among those with late respiratory Ct. In addition to currently available tools, antigenemia may facilitate patient triage to optimize intensive care utilization.

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