Viral RNA load in plasma is associated with critical illness and a dysregulated host response in COVID-19

Abstract Background COVID-19 can course with respiratory and extrapulmonary disease. SARS-CoV-2 RNA is detected in respiratory samples but also in blood, stool and urine. Severe COVID-19 is characterized by a dysregulated host response to this virus. We studied whether viral RNAemia or viral RNA load in plasma is associated with severe COVID-19 and also to this dysregulated response. Methods A total of 250 patients with COVID-19 were recruited (50 outpatients, 100 hospitalized ward patients and 100 critically ill). Viral RNA detection and quantification in plasma was performed using droplet digital PCR, targeting the N1 and N2 regions of the SARS-CoV-2 nucleoprotein gene. The association between SARS-CoV-2 RNAemia and viral RNA load in plasma with severity was evaluated by multivariate logistic regression. Correlations between viral RNA load and biomarkers evidencing dysregulation of host response were evaluated by calculating the Spearman correlation coefficients. Results The frequency of viral RNAemia was higher in the critically ill patients (78%) compared to ward patients (27%) and outpatients (2%) (p < 0.001). Critical patients had higher viral RNA loads in plasma than non-critically ill patients, with non-survivors showing the highest values. When outpatients and ward patients were compared, viral RNAemia did not show significant associations in the multivariate analysis. In contrast, when ward patients were compared with ICU patients, both viral RNAemia and viral RNA load in plasma were associated with critical illness (OR [CI 95%], p): RNAemia (3.92 [1.183–12.968], 0.025), viral RNA load (N1) (1.962 [1.244–3.096], 0.004); viral RNA load (N2) (2.229 [1.382–3.595], 0.001). Viral RNA load in plasma correlated with higher levels of chemokines (CXCL10, CCL2), biomarkers indicative of a systemic inflammatory response (IL-6, CRP, ferritin), activation of NK cells (IL-15), endothelial dysfunction (VCAM-1, angiopoietin-2, ICAM-1), coagulation activation (D-Dimer and INR), tissue damage (LDH, GPT), neutrophil response (neutrophils counts, myeloperoxidase, GM-CSF) and immunodepression (PD-L1, IL-10, lymphopenia and monocytopenia). Conclusions SARS-CoV-2 RNAemia and viral RNA load in plasma are associated with critical illness in COVID-19. Viral RNA load in plasma correlates with key signatures of dysregulated host responses, suggesting a major role of uncontrolled viral replication in the pathogenesis of this disease.

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Viral RNA load in plasma is associated with critical illness and a dysregulated host response in COVID-19

10.1101/2020.08.25.20154252 ◽

2020 ◽

Cited By ~ 2

Author(s):

Jesús F Bermejo-Martin ◽

Milagros González-Rivera ◽

Raquel Almansa ◽

Dariela Micheloud ◽

Ana P. Tedim ◽

...

Keyword(s):

Critical Illness ◽

Critically Ill ◽

Critically Ill Patients ◽

Host Response ◽

Correlation Coefficients ◽

Digital Pcr ◽

Viral Rna ◽

Host Responses ◽

Nucleoprotein Gene ◽

Pcr Targeting

AbstractBackgroundCOVID-19 can course with respiratory and extrapulmonary disease. SARS-CoV-2 RNA is detected in respiratory samples but also in blood, stool and urine. Severe COVID-19 is characterised by a dysregulated host response to this virus. We studied whether viral RNAemia or viral RNA load in plasma are associated to severe COVID-19 and also to this dysregulated response.Methods250 patients with COVID-19 were recruited (50 outpatients, 100 hospitalised ward patients, and 100 critically ill). Viral RNA detection and quantification in plasma was performed using droplet digital PCR, targeting the N1 and N2 regions of the SARS-CoV-2 nucleoprotein gene. The association between SARS-CoV-2 RNAemia and viral RNA load in plasma with severity was evaluated by multivariate logistic regression. Correlations between viral RNA load and biomarkers evidencing dysregulation of host response were evaluated by calculating the Spearman correlation coefficients.Resultsthe frequency of viral RNAemia was higher in the critically ill patients (78%) compared to ward patients (27%) and outpatients (2%) (p<0.001). Critical patients had higher viral RNA loads in plasma than non-critically ill patients, with non survivors showing the highest values. When outpatients and ward patients were compared, viral RNAemia did not show significant associations in the multivariate analysis. In contrast, when ward patients were compared with ICU patients, both viral RNAemia and viral RNA load in plasma were associated with critical illness (OR [CI 95%], p): RNAemia (3.92 [1.183 - 12.968], 0.025), viral RNA load (N1) (1.962 [1.244 - 3.096], 0.004); viral RNA load (N2) (2.229 [1.382 - 3.595], 0.001). Viral RNA load in plasma correlated with higher levels of chemokines (CXCL10, CCL2), biomarkers indicative of a systemic inflammatory response (IL-6, CRP, Ferritin), activation of NK cells (IL-15), endothelial dysfunction (VCAM-1, angiopoietin-2, ICAM-1), coagulation activation (D-Dimer and INR), tissue damage (LDH, GPT), neutrophil response (neutrophils counts, myeloperoxidase, GM-CSF) and immunodepression (PD-L1, IL-10, lymphopenia and monocytopenia).ConclusionsSARS-CoV-2 RNAemia and viral RNA load in plasma are associated to critical illness in COVID-19. Viral RNA load in plasma correlates with key signatures of dysregulated host responses, suggesting a major role of uncontrolled viral replication in the pathogenesis of this disease.

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Critical Illness Outcomes Study: An Observational Cohort Of Critically Ill Patients

10.1164/ajrccm-conference.2012.185.1_meetingabstracts.a6788 ◽

2012 ◽

Author(s):

Jonathan E. Sevransky ◽

William Checkley ◽

Timothy D. Girard ◽

Steven M. Pastores ◽

Sajid Shahul ◽

...

Keyword(s):

Critical Illness ◽

Critically Ill ◽

Critically Ill Patients ◽

Observational Cohort ◽

Outcomes Study ◽

Illness Outcomes

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Acute Respiratory Distress Syndrome and Time to Weaning Off the Invasive Mechanical Ventilator among Patients with COVID-19 Pneumonia

Journal of Clinical Medicine ◽

10.3390/jcm10132935 ◽

2021 ◽

Vol 10 (13) ◽

pp. 2935

Author(s):

Jose Bordon ◽

Ozan Akca ◽

Stephen Furmanek ◽

Rodrigo Silva Cavallazzi ◽

Sally Suliman ◽

...

Keyword(s):

Acute Respiratory Distress Syndrome ◽

Critical Illness ◽

Respiratory Distress Syndrome ◽

Respiratory Distress ◽

Critically Ill ◽

Critically Ill Patients ◽

Distress Syndrome ◽

Invasive Mechanical Ventilation ◽

Overall Mortality

Acute respiratory distress syndrome (ARDS) due to coronavirus disease 2019 (COVID-19) pneumonia is the main cause of the pandemic’s death toll. The assessment of ARDS and time on invasive mechanical ventilation (IMV) could enhance the characterization of outcomes and management of this condition. This is a city-wide retrospective study of hospitalized patients with COVID-19 pneumonia from 5 March 2020 to 30 June 2020. Patients with critical illness were compared with those with non-critical illness. We examined the severity of ARDS and other factors associated with (i) weaning patients off IMV and (ii) mortality in a city-wide study in Louisville, KY. Of 522 patients with COVID-19 pneumonia, 219 (41.9%) were critically ill. Among critically ill patients, the median age was 60 years; 53% were male, 55% were White and 32% were African American. Of all critically ill patients, 52% had ARDS, and 38% of these had severe ARDS. Of the 25% of patients who were weaned off IMV, those with severe ARDS were weaned within eleven days versus five days for those without severe ARDS, p = 0.023. The overall mortality for critically ill patients was 22% versus 1% for those not critically ill. Furthermore, the 14-day mortality was 31% for patients with severe ARDS and 12% for patients without severe ARDS, p = 0.019. Patients with severe ARDS versus non-severe ARDS needed twice as long to wean off IMV (eleven versus five days) and had double the 14-day mortality of patients without severe ARDS.

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Regulation and Prognostic Relevance of Symmetric Dimethylarginine Serum Concentrations in Critical Illness and Sepsis

Mediators of Inflammation ◽

10.1155/2013/413826 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 14

Author(s):

Alexander Koch ◽

Ralf Weiskirchen ◽

Jan Bruensing ◽

Hanna Dückers ◽

Lukas Buendgens ◽

...

Keyword(s):

Critical Illness ◽

Critically Ill ◽

Critically Ill Patients ◽

Multiorgan Failure ◽

Microvascular Dysfunction ◽

Serum Levels ◽

Serum Concentrations ◽

Symmetric Dimethylarginine ◽

Term Survival ◽

Severity Scores

In systemic inflammation and sepsis, endothelial activation and microvascular dysfunction are characteristic features that promote multiorgan failure. As symmetric dimethylarginine (SDMA) impacts vascular tension and integrity via modulating nitric oxide (NO) pathways, we investigated circulating SDMA in critical illness and sepsis. 247 critically ill patients (160 with sepsis, 87 without sepsis) were studied prospectively upon admission to the medical intensive care unit (ICU) and on day 7, in comparison to 84 healthy controls. SDMA serum levels were significantly elevated in critically ill patients at admission to ICU compared to controls and remained stably elevated during the first week of ICU treatment. The highest SDMA levels were found in patients with sepsis. SDMA levels closely correlated with disease severity scores, biomarkers of inflammation, and organ failure (renal, hepatic, and circulatory). We identified SDMA serum concentrations at admission as an independent prognostic biomarker in critically ill patients not only for short-term mortality at the ICU but also for unfavourable long-term survival. Thus, the significant increase of circulating SDMA in critically ill patients indicates a potential pathogenic involvement in endothelial dysfunction during sepsis and may be useful for mortality risk stratification at the ICU.

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A Comparison of Blood Pathogen Detection Among Droplet Digital PCR, Metagenomic Next-Generation Sequencing, and Blood Culture in Critically Ill Patients With Suspected Bloodstream Infections

Frontiers in Microbiology ◽

10.3389/fmicb.2021.641202 ◽

2021 ◽

Vol 12 ◽

Author(s):

Bangchuan Hu ◽

Yue Tao ◽

Ziqiang Shao ◽

Yang Zheng ◽

Run Zhang ◽

...

Keyword(s):

Next Generation Sequencing ◽

Blood Culture ◽

Critically Ill ◽

Critically Ill Patients ◽

Pathogen Detection ◽

Bloodstream Infections ◽

Digital Pcr ◽

Droplet Digital Pcr ◽

Next Generation ◽

Generation Sequencing

Metagenomic next-generation sequencing (mNGS) and droplet digital PCR (ddPCR) have recently demonstrated a great potential for pathogen detection. However, few studies have been undertaken to compare these two nucleic acid detection methods for identifying pathogens in patients with bloodstream infections (BSIs). This prospective study was thus conducted to compare these two methods for diagnostic applications in a clinical setting for critically ill patients with suspected BSIs. Upon suspicion of BSIs, whole blood samples were simultaneously drawn for ddPCR covering 20 common isolated pathogens and four antimicrobial resistance (AMR) genes, mNGS, and blood culture. Then, a head-to-head comparison was performed between ddPCR and mNGS. A total of 60 episodes of suspected BSIs were investigated in 45 critically ill patients, and ddPCR was positive in 50 (83.3%), mNGS in 41 (68.3%, not including viruses), and blood culture in 10 (16.7%) episodes. Of the 10 positive blood cultures, nine were concordantly identified by both mNGS and ddPCR methods. The head-to-head comparison showed that ddPCR was more rapid (~4 h vs. ~2 days) and sensitive (88 vs. 53 detectable pathogens) than mNGS within the detection range of ddPCR, while mNGS detected a broader range of pathogens (126 vs. 88 detectable pathogens, including viruses) than ddPCR. In addition, a total of 17 AMR genes, including 14 blaKPC and 3 mecA genes, were exclusively identified by ddPCR. Based on their respective limitations and strengths, the ddPCR method is more useful for rapid detection of common isolated pathogens as well as AMR genes in critically ill patients with suspected BSI, whereas mNGS testing is more appropriate for the diagnosis of BSI where classic microbiological or molecular diagnostic approaches fail to identify causative pathogens.

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Critically Ill vs. Non-Critically Ill Patients With COVID-19 Pneumonia: Clinical Features, Laboratory Findings, and Prediction

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2021.550456 ◽

2021 ◽

Vol 11 ◽

Author(s):

Wandong Hong ◽

Qin Chen ◽

Songzan Qian ◽

Zarrin Basharat ◽

Vincent Zimmer ◽

...

Keyword(s):

Critical Illness ◽

Disease Severity ◽

Critically Ill ◽

Clinical Features ◽

Critically Ill Patients ◽

Interleukin 6 ◽

Discharge Rate ◽

Laboratory Data ◽

Laboratory Findings ◽

Laboratory Parameters

ObjectivesThe objective of this study was to investigate the clinical features and laboratory findings of patients with and without critical COVID-19 pneumonia and identify predictors for the critical form of the disease.MethodsDemographic, clinical, and laboratory data of 63 COVID-19 pneumonia patients were retrospectively reviewed. Laboratory parameters were also collected within 3–5 days, 7–9 days, and 11–14 days of hospitalization. Outcomes were followed up until March 12, 2020.ResultsTwenty-two patients developed critically ill pneumonia; one of them died. Upon admission, older patients with critical illness were more likely to report cough and dyspnoea with higher respiration rates and had a greater possibility of abnormal laboratory parameters than patients without critical illness. When compared with the non-critically ill patients, patients with serious illness had a lower discharge rate and longer hospital stays, with a trend towards higher mortality. The interleukin-6 level in patients upon hospital admission was important in predicting disease severity and was associated with the length of hospitalization.ConclusionsMany differences in clinical features and laboratory findings were observed between patients exhibiting non-critically ill and critically ill COVID-19 pneumonia. Non-critically ill COVID-19 pneumonia also needs aggressive treatments. Interleukin-6 was a superior predictor of disease severity.

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Guidelines for the Diagnosis and Management of Critical Illness-Related Corticosteroid Insufficiency (CIRCI) in Critically Ill Patients (Part I)

Critical Care Medicine ◽

10.1097/ccm.0000000000002737 ◽

2017 ◽

Vol 45 (12) ◽

pp. 2078-2088 ◽

Cited By ~ 95

Author(s):

Djillali Annane ◽

Stephen M. Pastores ◽

Bram Rochwerg ◽

Wiebke Arlt ◽

Robert A. Balk ◽

...

Keyword(s):

Critical Illness ◽

Critically Ill ◽

Critically Ill Patients ◽

Diagnosis And Management ◽

Corticosteroid Insufficiency

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Association Effects Of Comorbid Versus Uncomorbid Diabetes And Blood Glucose Concentrations On Short-term Outcomes In Patients With Critical Illness: A Real-World Study Based On Propensity Score Analyses

10.21203/rs.3.rs-44274/v1 ◽

2020 ◽

Author(s):

Shan Lin ◽

Shanhui Ge ◽

Wanmei He ◽

Mian Zeng

Keyword(s):

Critical Illness ◽

Glycemic Control ◽

Critically Ill ◽

Critically Ill Patients ◽

Cox Model ◽

Inverse Probability Weighting ◽

Probability Weighting ◽

Optimal Range ◽

Short Term ◽

Inverse Probability

Abstract Background: The effects of combined diabetes and glycemic control strategies on the short-term prognosis in patients with a critical illness are currently ambiguous. The objectives of our study were to determine whether comorbid diabetes affects short-term prognosis and the optimal range of glycemic control in critically ill patients.Methods: We performed this study with the critical care database. The primary outcomes were 28-day mortality in critically ill patients with comorbid diabetes and the optimal range of glycemic control. Association of comorbid diabetes with 28-day mortality was assessed by multivariable Cox regression model with inverse probability weighting. Smooth curves were applied to fit the association for glucose and 28-day mortality.Results: Of the 33,680 patients enrolled in the study, 8,701 (25.83%) had diabetic comorbidity. Cox model with inverse probability weighting showed that the 28-day mortality rate was reduced by 29% (HR=0.71, 95% CI 0.67-0.76) in the group with diabetes in comparison to the group without diabetes. The E value of 2.17 indicated robustness to unmeasured confounders. The effect of the association between comorbid diabetes and 28-day mortality was generally in line for all subgroup variables, significant interactions were observed for glucose on first day, admission type, and use of insulin or not (Interaction P <0.05). A V-shaped relationship was observed between glucose concentrations and 28-day mortality in patients without diabetes, with the lowest 28-day mortality corresponding to the glucose level was 101.75 mg/dl (95% CI 94.64-105.80 mg/dl); whereas in patients with comorbid diabetes, the effect of glucose concentration on 28-day mortality was structurally softer than in those with uncomorbid diabetes. Lastly, of all patients, hyperglycemia had the greatest deleterious effect on patients admitted to CSRU.Conclusions: Our study further confirmed the protective effect of comorbid diabetes on the short-term prognosis of critically ill patients, resulting in an approximately 29% reduction in 28-day mortality. Besides, we also demonstrated the personalized glycemic control strategy for critically ill patients. Lastly, clinicians should be aware of the occurrence and the prompt management of hyperglycemia in critically ill patients admitted to the CSRU.

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Myopathy and Neuropathy Acquired in the Intensive Care Unit

Mayo Clinic Critical and Neurocritical Care Board Review ◽

10.1093/med/9780190862923.003.0097 ◽

2019 ◽

pp. 677-684

Author(s):

Priya S. Dhawan ◽

Jennifer A. Tracy

Keyword(s):

Skeletal Muscle ◽

Intensive Care Unit ◽

At Risk ◽

Intensive Care ◽

Peripheral Neuropathy ◽

Critical Illness ◽

Critically Ill ◽

Critically Ill Patients ◽

Critical Illness Polyneuropathy ◽

Muscle Disorder

Acquired weakness in critically ill patients is common, affecting between one-third to one-half of patients in the intensive care unit (ICU). Exposure to simultaneous stressors such as metabolic derangements, fluid and electrolyte shifts, infection, catabolic stress, and medications put patients in the ICU at risk for damage to both nerve and skeletal muscle with substantial and often lasting morbidity. Critical illness polyneuropathy is a length-dependent, axonal peripheral neuropathy occurring in patients in the ICU and unrelated to the primary illness. Critical illness myopathy is an ICU-associated muscle disorder occurring independently of denervation and uniquely identified by electrophysiologic and histologic characteristics.

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The need to know: experiences of critically ill patients

American Journal of Critical Care ◽

10.4037/ajcc2000.9.3.192 ◽

2000 ◽

Vol 9 (3) ◽

pp. 192-198 ◽

Cited By ~ 40

Author(s):

JE Hupcey ◽

HE Zimmerman

Keyword(s):

Intensive Care Unit ◽

Intensive Care ◽

Critical Illness ◽

Critically Ill ◽

Nursing Staff ◽

Critically Ill Patients ◽

Second Phase ◽

The Past ◽

Intensive Care Unit Nurses ◽

Vivid Memories

BACKGROUND: Critically ill patients vary in their memories of their experience in the intensive care unit. Some have little recall and need to learn about their critical illness. Others have more vivid memories of their experiences, some of which were extremely unpleasant. Patients' not knowing what was happening may have exacerbated the unpleasant experiences. OBJECTIVES: To elicit the experience of knowing for critically ill patients and to explore the differences in perceptions between patients who were intubated and those who were not intubated during the illness. METHODS: Grounded theory was used to explore the meaning of knowing and not knowing and the process by which knowing occurs. Unstructured interviews were done with 14 patients. RESULTS: Knowing had 2 phases: the need to know (1) during and (2) after the critical illness. The first phase had 3 facets: needing information, needing to be oriented, and having confusing perceptions. The second phase had 2 facets: needing information about what had happened and piecing together events. Many experiences with knowing during and after a critical illness were similar for both intubated and nonintubated patients. The main difference was the intensity of the experience in some categories. CONCLUSIONS: Critically ill patients have a strong need to know throughout and after their time in the intensive care unit. Nurses must address this need for constant reorientation to the past and present in these patients. In addition, adequate nursing staff must be available for these patients.

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