Comparison between RT-qPCR for SARS-CoV-2 and expanded triage in sputum of symptomatic and asymptomatic COVID-19 subjects in Ecuador

BMC Infectious Diseases volume 21, Article number: 558 (2021) 

Abstract

Background

The quantitative reverse transcriptase-polymerase chain reaction (RT-qPCR) effectively detects the SARS-COV-2 virus. SARS-CoV-2 Nevertheless, some critical gaps remain in the identification and monitoring of asymptomatic people.

Methods

This retrospective study included 733 asymptomatic and symptomatic COVID-19 subjects, who were submitted to the RT-qPCR test. The objective was to assess the efficacy of an expanded triage of subjects undergoing the RT-qPCR test for SARS-COV-2 to identify the largest possible number of COVID-19 cases in a hospital setting in Ecuador. SARS-CoV-2 Firstly, the sensitivity and specificity as well as the predictive values of an expanded triage method were calculated. In addition, the Kappa coefficient was also determined to assess the concordance between laboratory test results and the expanded triage.

Results

Of a total of 733 sputum samples; 229 were RT-qPCR-positive (31.2%) and mortality rate reached 1.2%. Overall sensitivity and specificity were 86.0% (95% confidence interval: 81.0–90.0%) and 37.0% (95% confidence interval: 32.0–41.0%) respectively, with a diagnostic accuracy of 52.0% and a Kappa coefficient of 0.73. An association between the positivity of the test and its performance before 10 days was found.

Conclusions

The clinical sensitivity for COVID-19 detection was within acceptable standards, but the specificity still fell below the values of reference. The lack of symptoms did not always mean to have a negative SARS-COV-2 RT-qPCR test. The expanded triage identified a still unnoticed percentage of asymptomatic subjects showing positive results for the SARS-COV-2 RT-qPCR test. The study also revealed a significant relationship between the number of RT-qPCR-positive cases and the performance of the molecular diagnosis within the first 10 days of COVID-19 in the symptomatic group.

For More Information: https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-021-06272-8

Analysis of the Study of the Expression of Apoptosis Markers (CD95) and Intercellular Adhesion Markers (CD54) in Healthy Individuals and Patients Who Underwent COVID-19 When Using the Drug Mercureid

Authors: Sergey N Gusev1*, Velichko LN2, Bogdanova AV2, Khramenko NI2, Konovalova NV2 Published Date: 26-08-2021

Abstract

SARS-CoV-2, the pathogen, which is responsible for coronavirus disease 2019 (COVID-19), has caused unprecedented morbidity and mortality worldwide. Scientific and clinical evidence testifies about long-term COVID-19 effects that can affect many organ systems. Cellular damage, overproduction of proinflammatory cytokines and procoagulant abnormalities caused by SARS-CoV-2 infection may lead to these consequences. After suffering from COVID-19, a negative PCR test is only the beginning of a difficult path to full recovery. 61 % of patients will continue to have the signs of post-covid syndrome with the risk of developing serious COVID-19 health complications for a long time. Post-COVID syndrome is an underestimated large-scale problem that can lead to the collapse of the healthcare system in the nearest future.

The treatment and prevention of post-covid syndrome require integrated rather than organ or disease specific approaches and there is an urgent need to conduct a special research to establish the risk factors.

For this purpose, we studied the expression of markers of apoptosis (CD95) and intercellular adhesion (CD54) in healthy individuals and patients who underwent COVID-19, as well as the efficacy of the drug Mercureid for the treatment of post-covid syndrome.

The expression level of the apoptosis marker CD95 in patients who underwent COVID-19 is 1.7-2.5 times higher than the norm and the intercellular adhesion marker CD54 is 2.9-4.4 times higher. This fact indicates a persistent high level of dysfunctional immune response in the short term after recovery. The severity of the expression of the intercellular adhesion molecule (ICAM-1, CD54) shows the involvement of the endothelium of the vascular wall in the inflammatory process as one of the mechanisms of the pathogenesis of post-covid syndrome.

The use of Mercureid made it possible to reduce the overexpression of CD95 in 73.4 % of patients that led to the restoration of the number of CD4+/CD8+ T-cells, which are crucial in the restoration of functionally active antiviral and antitumor immunity of patients. Also, the use of Mercureid led to a normalization of ICAM-1 (CD54) levels in 75.8 % of patients.

The pharmacological properties of the new targeted immunotherapy drug Mercureid provide new therapeutic opportunities for the physician to influence a number of therapeutic targets, such as CD95, ICAM-1 (CD54), to reduce the risk of post-COVID complications.

For More Information: https://athenaeumpub.com/analysis-of-the-study-of-the-expression-of-apoptosis-markers-cd95-and-intercellular-adhesion-markers-cd54-in-healthy-individuals-and-patients-who-underwent-covid-19-when-using-the-drug-mercureid/

Pathological findings in organs and tissues of patients with COVID-19: A systematic review

Authors: Sasha Peiris 1 2Hector Mesa 3Agnes Aysola 4Juan Manivel 5Joao Toledo 1 2Marcio Borges-Sa 6Sylvain Aldighieri 1 2Ludovic Reveiz 2 7

Abstract

Background: Coronavirus disease (COVID-19) is the pandemic caused by SARS-CoV-2 that has caused more than 2.2 million deaths worldwide. We summarize the reported pathologic findings on biopsy and autopsy in patients with severe/fatal COVID-19 and documented the presence and/or effect of SARS-CoV-2 in all organs.

Methods and findings: A systematic search of the PubMed, Embase, MedRxiv, Lilacs and Epistemonikos databases from January to August 2020 for all case reports and case series that reported histopathologic findings of COVID-19 infection at autopsy or tissue biopsy was performed. 603 COVID-19 cases from 75 of 451 screened studies met inclusion criteria. The most common pathologic findings were lungs: diffuse alveolar damage (DAD) (92%) and superimposed acute bronchopneumonia (27%); liver: hepatitis (21%), heart: myocarditis (11.4%). Vasculitis was common only in skin biopsies (25%). Microthrombi were described in the placenta (57.9%), lung (38%), kidney (20%), Central Nervous System (CNS) (18%), and gastrointestinal (GI) tract (2%). Injury of endothelial cells was common in the lung (18%) and heart (4%). Hemodynamic changes such as necrosis due to hypoxia/hypoperfusion, edema and congestion were common in kidney (53%), liver (48%), CNS (31%) and GI tract (18%). SARS-CoV-2 viral particles were demonstrated within organ-specific cells in the trachea, lung, liver, large intestine, kidney, CNS either by electron microscopy, immunofluorescence, or immunohistochemistry. Additional tissues were positive by Polymerase Chain Reaction (PCR) tests only. The included studies were from numerous countries, some were not peer reviewed, and some studies were performed by subspecialists, resulting in variable and inconsistent reporting or over statement of the reported findings.

Conclusions: The main pathologic findings of severe/fatal COVID-19 infection are DAD, changes related to coagulopathy and/or hemodynamic compromise. In addition, according to the observed organ damage myocarditis may be associated with sequelae.

For More Information: https://pubmed.ncbi.nlm.nih.gov/33909679/

Cytokeratin 18 cell death assays as biomarkers for quantification of apoptosis and necrosis in COVID-19: a prospective, observational study

Authors: Brandon Michael Henry1http://orcid.org/0000-0002-1211-8247Isaac Cheruiyot2, Stefanie W Benoit3,4, Fabian Sanchis-Gomar5,6http://orcid.org/0000-0001-9523-9054Giuseppe Lippi7, Justin Benoit8 Correspondence to Dr Brandon Michael Henry, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA;

Abstract

Background The mechanism by which SARS-CoV-2 triggers cell damage and necrosis are yet to be fully elucidated. We sought to quantify epithelial cell death in patients with COVID-19, with an estimation of relative contributions of apoptosis and necrosis.

Methods Blood samples were collected prospectively from adult patients presenting to the emergency department. Circulating levels of caspase-cleaved (apoptosis) and total cytokeratin 18 (CK-18) (total cell death) were determined using M30 and M65 enzyme assays, respectively. Intact CK-18 (necrosis) was estimated by subtracting M30 levels from M65.

Results A total of 52 COVID-19 patients and 27 matched sick controls (with respiratory symptoms not due to COVID-19) were enrolled. Compared with sick controls, COVID-19 patients had higher levels of M65 (p = 0.046, total cell death) and M30 (p = 0.0079, apoptosis). Hospitalised COVID-19 patients had higher levels of M65 (p= 0.014) and intact CK-18 (p= 0.004, necrosis) than discharged patients. Intensive care unit (ICU)-admitted COVID-19 patients had higher levels of M65 (p= 0.004), M30 (p= 0.004) and intact CK-18 (p= 0.033) than hospitalised non-ICU admitted patients. In multivariable logistic regression, elevated levels of M65, M30 and intact CK-18 were associated with increased odds of ICU admission (OR=22.05, p=0.014, OR=19.71, p=0.012 and OR=14.12, p=0.016, respectively).

Conclusion Necrosis appears to be the main driver of hospitalization, whereas apoptosis and necrosis appear to drive ICU admission. Elevated levels CK-18 levels are independent predictors of severe disease, and could be useful for risk stratification of COVID-19 patients and in assessment of therapeutic efficacy in early-phase COVID-19 clinical trials.

For More Information: https://jcp.bmj.com/content/early/2021/03/30/jclinpath-2020-207242

Characteristics of SARS-CoV-2 and COVID-19

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible and pathogenic coronavirus that emerged in late 2019 and has caused a pandemic of acute respiratory disease, named ‘coronavirus disease 2019’ (COVID-19), which threatens human health and public safety. In this Review, we describe the basic virology of SARS-CoV-2, including genomic characteristics and receptor use, highlighting its key difference from previously known coronaviruses. We summarize current knowledge of clinical, epidemiological and pathological features of COVID-19, as well as recent progress in animal models and antiviral treatment approaches for SARS-CoV-2 infection. We also discuss the potential wildlife hosts and zoonotic origin of this emerging virus in detail.

Introduction

Coronaviruses are a diverse group of viruses infecting many different animals, and they can cause mild to severe respiratory infections in humans. In 2002 and 2012, respectively, two highly pathogenic coronaviruses with zoonotic origin, severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), emerged in humans and caused fatal respiratory illness, making emerging coronaviruses a new public health concern in the twenty-first century1. At the end of 2019, a novel coronavirus designated as SARS-CoV-2 emerged in the city of Wuhan, China, and caused an outbreak of unusual viral pneumonia. Being highly transmissible, this novel coronavirus disease, also known as coronavirus disease 2019 (COVID-19), has spread fast all over the world2,3. It has overwhelmingly surpassed SARS and MERS in terms of both the number of infected people and the spatial range of epidemic areas. The ongoing outbreak of COVID-19 has posed an extraordinary threat to global public health4,5. In this Review, we summarize the current understanding of the nature of SARS-CoV-2 and COVID-19. On the basis of recently published findings, this comprehensive Review covers the basic biology of SARS-CoV-2, including the genetic characteristics, the potential zoonotic origin and its receptor binding. Furthermore, we will discuss the clinical and epidemiological features, diagnosis of and countermeasures against COVID-19.

Emergence and spread

In late December 2019, several health facilities in Wuhan, in Hubei province in China, reported clusters of patients with pneumonia of unknown cause6. Similarly to patients with SARS and MERS, these patients showed symptoms of viral pneumonia, including fever, cough and chest discomfort, and in severe cases dyspnea and bilateral lung infiltration6,7. Among the first 27 documented hospitalized patients, most cases were epidemiologically linked to Huanan Seafood Wholesale Market, a wet market located in downtown Wuhan, which sells not only seafood but also live animals, including poultry and wildlife4,8. According to a retrospective study, the onset of the first known case dates back to 8 December 2019 (ref.9). On 31 December, Wuhan Municipal Health Commission notified the public of a pneumonia outbreak of unidentified cause and informed the World Health Organization (WHO)9 (Fig. 1).

figure1
Fig. 1: Timeline of the key events of the COVID-19 outbreak.

By metagenomic RNA sequencing and virus isolation from bronchoalveolar lavage fluid samples from patients with severe pneumonia, independent teams of Chinese scientists identified that the causative agent of this emerging disease is a betacoronavirus that had never been seen before6,10,11. On 9 January 2020, the result of this etiological identification was publicly announced (Fig. 1). The first genome sequence of the novel coronavirus was published on the Virological website on 10 January, and more nearly complete genome sequences determined by different research institutes were then released via the GISAID database on 12 January7. Later, more patients with no history of exposure to Huanan Seafood Wholesale Market were identified. Several familial clusters of infection were reported, and nosocomial infection also occurred in health-care facilities. All these cases provided clear evidence for human-to-human transmission of the new virus4,12,13,14. As the outbreak coincided with the approach of the lunar New Year, travel between cities before the festival facilitated virus transmission in China. This novel coronavirus pneumonia soon spread to other cities in Hubei province and to other parts of China. Within 1 month, it had spread massively to all 34 provinces of China. The number of confirmed cases suddenly increased, with thousands of new cases diagnosed daily during late January15. On 30 January, the WHO declared the novel coronavirus outbreak a public health emergency of international concern16. On 11 February, the International Committee on Taxonomy of Viruses named the novel coronavirus ‘SARS-CoV-2’, and the WHO named the disease ‘COVID-19’ (ref.17).

The outbreak of COVID-19 in China reached an epidemic peak in February. According to the National Health Commission of China, the total number of cases continued to rise sharply in early February at an average rate of more than 3,000 newly confirmed cases per day. To control COVID-19, China implemented unprecedentedly strict public health measures. The city of Wuhan was shut down on 23 January, and all travel and transportation connecting the city was blocked. In the following couple of weeks, all outdoor activities and gatherings were restricted, and public facilities were closed in most cities as well as in countryside18. Owing to these measures, the daily number of new cases in China started to decrease steadily19.

However, despite the declining trend in China, the international spread of COVID-19 accelerated from late February. Large clusters of infection have been reported from an increasing number of countries18. The high transmission efficiency of SARS-CoV-2 and the abundance of international travel enabled rapid worldwide spread of COVID-19. On 11 March 2020, the WHO officially characterized the global COVID-19 outbreak as a pandemic20. Since March, while COVID-19 in China has become effectively controlled, the case numbers in Europe, the USA and other regions have jumped sharply. According to the COVID-19 dashboard of the Center for System Science and Engineering at Johns Hopkins University, as of 11 August 2020, 216 countries and regions from all six continents had reported more than 20 million cases of COVID-19, and more than 733,000 patients had died21. High mortality occurred especially when health-care resources were overwhelmed. The USA is the country with the largest number of cases so far.

Although genetic evidence suggests that SARS-CoV-2 is a natural virus that likely originated in animals, there is no conclusion yet about when and where the virus first entered humans. As some of the first reported cases in Wuhan had no epidemiological link to the seafood market22, it has been suggested that the market may not be the initial source of human infection with SARS-CoV-2. One study from France detected SARS-CoV-2 by PCR in a stored sample from a patient who had pneumonia at the end of 2019, suggesting SARS-CoV-2 might have spread there much earlier than the generally known starting time of the outbreak in France23. However, this individual early report cannot give a solid answer to the origin of SARS-CoV-2 and contamination, and thus a false positive result cannot be excluded. To address this highly controversial issue, further retrospective investigations involving a larger number of banked samples from patients, animals and environments need to be conducted worldwide with well-validated assays.

For More Information: https://www.nature.com/articles/s41579-020-00459-7

Overweight/obesity as the potentially most important lifestyle factor associated with signs of pneumonia in COVID-19

PLOS
  • Published: November 18, 2020

Abstract

Objective

The occurrence of pneumonia separates severe cases of COVID-19 from the majority of cases with mild disease. However, the factors determining whether or not pneumonia develops remain to be fully uncovered. We therefore explored the associations of several lifestyle factors with signs of pneumonia in COVID-19.

Methods

Between May and July 2020, we conducted an online survey of 201 adults in Germany who had recently gone through COVID-19, predominantly as outpatients. Of these, 165 had a PCR-based diagnosis and 36 had a retrospective diagnosis by antibody testing. The survey covered demographic information, eight lifestyle factors, comorbidities and medication use. We defined the main outcome as the presence vs. the absence of signs of pneumonia, represented by dyspnea, the requirement for oxygen therapy or intubation.

Results

Signs of pneumonia occurred in 39 of the 165 individuals with a PCR-based diagnosis of COVID-19 (23.6%). Among the lifestyle factors examined, only overweight/obesity was associated with signs of pneumonia (odds ratio 2.68 (1.29–5.59) p = 0.008). The observed association remained significant after multivariate adjustment, with BMI as a metric variable, and also after including the antibody-positive individuals into the analysis.

Conclusions

This exploratory study finds an association of overweight/obesity with signs of pneumonia in COVID-19. This finding suggests that a signal proportional to body fat mass, such as the hormone leptin, impairs the body’s ability to clear SARS-CoV-2 before pneumonia develops. This hypothesis concurs with previous work and should be investigated further to possibly reduce the proportion of severe cases of COVID-19.

For More Information: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0237799

Hyperglycemia in Acute COVID-19 is Characterized by Adipose Tissue Dysfunction and Insulin Resistance

Authors: Reiterer MRajan MGómez-Banoy NLau JDGomez-Escobar LGGilani AAlvarez-Mulett SSholle ETChandar VBram YHoffman KRubio-Navarro AUhl SShukla APGoyal PtenOever BRAlonso LCSchwartz RESchenck EJSafford MM

Abstract 


COVID-19 has proven to be a metabolic disease resulting in adverse outcomes in individuals with diabetes or obesity. Patients infected with SARS-CoV-2 and hyperglycemia suffer from longer hospital stays, higher risk of developing acute respiratory distress syndrome (ARDS), and increased mortality compared to those who do not develop hyperglycemia. Nevertheless, the pathophysiological mechanism(s) of hyperglycemia in COVID-19 remains poorly characterized. Here we show that insulin resistance rather than pancreatic beta cell failure is the prevalent cause of hyperglycemia in COVID-19 patients with ARDS, independent of glucocorticoid treatment. A screen of protein hormones that regulate glucose homeostasis reveals that the insulin sensitizing adipokine adiponectin is reduced in hyperglycemic COVID-19 patients. Hamsters infected with SARS-CoV-2 also have diminished expression of adiponectin. Together these data suggest that adipose tissue dysfunction may be a driver of insulin resistance and adverse outcomes in acute COVID-19.

The deadly COVID-19 pandemic is underscored by the high morbidity and mortality rates seen in certain vulnerable populations, including patients with diabetes mellitus (DM), obesity, cardiovascular disease, and advanced age, with the latter associated with many chronic cardiometabolic diseases 14 . Hyperglycemia with or without a history of DM is a strong predictor of in-hospital adverse outcomes, portending a 7-fold higher mortality compared to patients with well-controlled blood glucose levels 5 . Hyperglycemia may be seen as a biomarker that predicts poor prognosis. A retrospective study that compared hyperglycemic patients that were treated with insulin against those who were not showed increased mortality in those receiving insulin 6 . However, it remains unclear whether insulin treatment is a surrogate for increased hyperglycemia and overall morbidity, or whether it is an actual causative factor for death. There is thus uncertainty regarding specific treatments for hyperglycemia in acute COVID-19 7 .

Despite our early recognition of the association between hyperglycemia and perilous outcomes, the pathophysiological mechanisms that underlie hyperglycemia in COVID-19 remain undefined 8,9 . Hypotheses have included a broad range of pathologies from direct infection of islets leading to beta cell failure (BCF) and to inflammation and glucocorticoids leading to insulin resistance (IR). Although COVID-19 is primarily a respiratory tract infection, SARS-CoV-2 is known to infect other cell types and often leads to extrapulmonary consequences 10,11 ACE2 and other entry receptors for SARS-CoV-2 can be expressed on pancreatic islet cells and endocrine cells differentiated from human pluripotent stem cells are permissive to infection 12 . Early reports of unexpected diabetic ketoacidosis (DKA) in COVID-19 patients fuelled concerns for a novel form of acute onset beta cell failure. For example, one case described a patient with new onset diabetic ketoacidosis (DKA) who was found to be autoantibody negative for type 1 DM (T1DM) but showed evidence of prior SARS-CoV-2 infection based on serology results, suggesting the possibility of pancreatic beta cell dysfunction or destruction as a result of COVID-19 13 . However, given the high rates of COVID-19 during this pandemic coupled with low background rates of new onset T1DM, the connection between these two events in this case could be “true, true, and unrelated.” Recent studies disagree on whether ACE2 is expressed on pancreatic beta cells or whether the SARS-CoV-2 virus is found in pancreatic beta cells of deceased individuals with COVID-19 1416 . Conversely, the well-known connection between obesity and insulin resistance might lead to impaired immunity and more severe SARS-CoV-2 infection 17 . In fact, population level studies have reported higher risk of complications in obese patients with COVID-19 1820 . Viral infection may lead to systemic insulin resistance and worsened hyperglycemia. In sum, despite much attention, the pathophysiology of hyperglycemia in COVID-19 remains unknown.

Dexamethasone substantially reduces mortality in patients with severe COVID-19 infection requiring oxygen or invasive mechanical ventilation 21 . Glucocorticoids can also provoke hyperglycemia by inducing insulin resistance and beta cell dysfunction. The widespread usage of dexamethasone in severe SARS-CoV-2 infection is sure to exacerbate both the incidence and severity of hyperglycemia in COVID-19.

For More Information: https://europepmc.org/article/PPR/PPR303316

Blood molecular markers associated with COVID-19 immunopathology and multi-organ damage

Authors: Yan-Mei ChenYuanting ZhengYing YuYunzhi WangQingxia HuangFeng QianLei SunZhi-Gang SongZiyin ChenJinwen FengYanpeng AnJingcheng YangZhenqiang SuShanyue SunFahui DaiQinsheng ChenQinwei LuPengcheng LiYun LingZhong YangHuiru TangLeming ShiLi JinEdward C HolmesChen DingTong-Yu ZhuYong-Zhen Zhang

Abstract

COVID-19 is characterized by dysregulated immune responses, metabolic dysfunction and adverse effects on the function of multiple organs. To understand host responses to COVID-19 pathophysiology, we combined transcriptomics, proteomics, and metabolomics to identify molecular markers in peripheral blood and plasma samples of 66 COVID-19-infected patients experiencing a range of disease severities and 17 healthy controls. A large number of expressed genes, proteins, metabolites, and extracellular RNAs (exRNAs) exhibit strong associations with various clinical parameters. Multiple sets of tissue-specific proteins and exRNAs varied significantly in both mild and severe patients suggesting a potential impact on tissue function. Chronic activation of neutrophils, IFN-I signaling, and a high level of inflammatory cytokines were observed in patients with severe disease progression. In contrast, COVID-19-infected patients experiencing milder disease symptoms showed robust T-cell responses. Finally, we identified genes, proteins, and exRNAs as potential biomarkers that might assist in predicting the prognosis of SARS-CoV-2 infection. These data refine our understanding of the pathophysiology and clinical progress of COVID-19.

Proteomics, metabolomics and RNAseq data map immune responses in COVID-19 patients with different disease severity, revealing molecular makers associated with disease progression and alterations of tissue-specific proteins.

  • A multi-omics profiling of the host response to SARS-CoV2 infection in 66 clinically diagnosed and laboratory confirmed COVID-19 patients and 17 uninfected controls.
  • Significant correlations between multi-omics data and key clinical parameters.
  • Alteration of tissue-specific proteins and exRNAs.
  • Enhanced activation of immune responses is associated with COVID-19 pathogenesis.
  • Biomarkers to predict COVID-19 clinical outcomes pending clinical validation as prospective marker.

Introduction

Coronaviruses (family Coronaviridae) are a diverse group of positive-sense single-stranded RNA viruses with enveloped virions (Masters & Perlman, 2013; Cui et al2019). Coronaviruses are well known due to the emergence of Severe Acute Respiratory Syndrome (SARS) in 2002–2003 and Middle East Respiratory Syndrome (MERS) in 2012, both of which caused thousands of cases in multiple countries (Ksiazek et al2003; Bermingham et al2012; Cui et al2019). Coronaviruses naturally infect a broad range of vertebrate hosts including mammals and birds (Cui et al2019). As coronavirus primarily target epithelial cells, they are generally associated with gastrointestinal and respiratory infections (Masters & Perlman, 2013; Cui et al2019). In addition, they cause hepatic and neurological diseases of varying severity (Masters & Perlman, 2013).

The world is currently experiencing a disease pandemic (COVID-19) caused by a newly identified coronavirus called SARS-CoV-2 (Wu et al2020a). At the time of writing, there have been more than ~25 million cases of SARS-CoV-2 and ~830,000 deaths globally (WHO, 2020). The disease leads to both mild and severe respiratory manifestations, with the latter prominent in the elderly and those with underlying medical conditions such as cardiovascular and chronic respiratory disease, diabetes, and cancer (Guan et al., 2020). In addition to respiratory syndrome, mild gastrointestinal and/or cardiovascular symptoms and neurological manifestations have been documented in hospitalized COVID-19-infected patients (Gupta et al2020; Mao et al2020). These data point to the complexity of COVID-19 pathogenesis, especially in patients experiencing severe disease.

SARS-CoV-2 is able to use angiotensin-converting enzyme 2 (ACE 2) as a receptor for cell entry (Hoffmann et al2020; Zheng et al2020a; Zhou et al2020b). Aside from lungs, ACE2 is expressed in other organs including heart, liver, kidney, pancreas, and small intestines (Li et al2020; Liu et al2020; Zou et al2020; Chen et al2020a). More recently, ACE2 expression has also been found in Leydig cells in the testes (Li et al2020; Wang & Xu, 2020) and neurological tissue (Baig et al2020; Bullen et al2020; Xu & Lazartigues, 2020). As such, it is possible that these organs might also be infected by SARS-CoV-2, and recent autopsy studies have also revealed multi-organ damage including heart, liver, intestine, pancreas, brain, kidney, and spleen in fatal COVID-19-infected patients (Lax et al2020; Menter et al2020; Varga et al2020; Wichmann et al2020; Wang et al2020c). The host immune response to SARS-CoV-2 may also impact pathogenicity, resulting in severe tissue damage and, occasionally, death (Tay et al2020). Indeed, several studies have reported lymphopenia, exhausted lymphocytes, and cytokine storms in COVID-19-infected patients, especially those with severe symptoms (Blanco-Melo et al2020; Cao, 2020; Chua et al2020; Liao et al2020). Numerous clinical studies have also observed the elevation of lactate dehydrogenase (LDH), IL-6, troponin I, inflammatory markers, and D-dimer in COVID-19-infected patients (Zhou et al2020a; Wang et al2020b). However, despite the enormous burden of morbidity and mortality due to COVID-19, we know little about its pathophysiology, even though this establishes the basis for successful clinical practice, vaccine development, and drug discovery.

Using a multi-omics approach employing cutting-edge transcriptomic, proteomic, and metabolomic technologies, we identified significant molecular alterations in patients with COVID-19 compared with uninfected controls in this study. Our results refine the molecular view of COVID-19 pathophysiology associated with disease progression and clinical outcome.

For More Information: https://www.embopress.org/doi/full/10.15252/embj.2020105896

Circulating mitochondrial DNA is an early indicator of severe illness and mortality from COVID-19

Authors: Davide Scozzi,1Marlene Cano,2Lina Ma,2Dequan Zhou,1Ji Hong Zhu,1Jane A. O’Halloran,3Charles Goss,4Adriana M. Rauseo,3Zhiyi Liu,1Sanjaya K. Sahu,2Valentina Peritore,5Monica Rocco,6Alberto Ricci,7Rachele Amodeo,8Laura Aimati,8Mohsen Ibrahim,1,5Ramsey Hachem,2Daniel Kreisel,1Philip A. Mudd,9Hrishikesh S. Kulkarni,2,10 and Andrew E. Gelman1,11

Abstract

Background

Mitochondrial DNA (MT-DNA) are intrinsically inflammatory nucleic acids released by damaged solid organs. Whether circulating cell-free MT-DNA quantitation could be used to predict the risk of poor COVID-19 outcomes remains undetermined.

Methods

We measured circulating MT-DNA levels in prospectively collected, cell-free plasma samples from 97 subjects with COVID-19 at hospital presentation. Our primary outcome was mortality. Intensive care unit (ICU) admission, intubation, vasopressor, and renal replacement therapy requirements were secondary outcomes. Multivariate regression analysis determined whether MT-DNA levels were independent of other reported COVID-19 risk factors. Receiver operating characteristic and area under the curve assessments were used to compare MT-DNA levels with established and emerging inflammatory markers of COVID-19.

Results

Circulating MT-DNA levels were highly elevated in patients who eventually died or required ICU admission, intubation, vasopressor use, or renal replacement therapy. Multivariate regression revealed that high circulating MT-DNA was an independent risk factor for these outcomes after adjusting for age, sex, and comorbidities. We also found that circulating MT-DNA levels had a similar or superior area under the curve when compared against clinically established measures of inflammation and emerging markers currently of interest as investigational targets for COVID-19 therapy.

Conclusion

These results show that high circulating MT-DNA levels are a potential early indicator for poor COVID-19 outcomes.

For More Information: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934921/

C-Reactive Protein Level May Predict the Risk of COVID-19 Aggravation

Authors: Guyi Wang 1Chenfang Wu 1Quan Zhang 2Fang Wu 3Bo Yu 1Jianlei Lv 2Yiming Li 4Tiao Li 5Siye Zhang 1Chao Wu 6 7 8Guobao Wu 1Yanjun Zhong 1Affiliations expand

Abstract

Background: Clinical findings indicated that a fraction of coronavirus disease 2019 (COVID-19) patients diagnosed as mild early may progress to severe cases. However, it is difficult to distinguish these patients in the early stage. The present study aimed to describe the clinical characteristics of these patients, analyze related factors, and explore predictive markers of the disease aggravation.

Methods: Clinical and laboratory data of nonsevere adult COVID-19 patients in Changsha, China, were collected and analyzed on admission. A logistic regression model was adopted to analyze the association between the disease aggravation and related factors. The receiver operating characteristic curve (ROC) was utilized to analyze the prognostic ability of C-reactive protein (CRP).

Results: About 7.7% (16/209) of nonsevere adult COVID-19 patients progressed to severe cases after admission. Compared with nonsevere patients, the aggravated patients had much higher levels of CRP (median [range], 43.8 [12.3-101.9] mg/L vs 12.1 [0.1-91.4] mg/L; P = .000). A regression analysis showed that CRP was significantly associated with aggravation of nonsevere COVID-19 patients, with an area under the curve of 0.844 (95% confidence interval, 0.761-0.926) and an optimal threshold value of 26.9 mg/L.

Conclusions: CRP could be a valuable marker to anticipate the possibility of aggravation of non-severe adult COVID-19 patients, with an optimal threshold value of 26.9 mg/L.

For More Information: https://pubmed.ncbi.nlm.nih.gov/32455147/