How Covid-19 damages lungs explained

Authors: mINT oCTOBER 31, 2022


SARS-CoV-2 is the third novel coronavirus to cause human outbreaks in the 21st century, following SARS-CoV in 2003 and MERS-CoV in 2012.

Covid-19: The virus attacks mitochondria, continuing an ancient battle that began in the primordial soup

Kingston (Canada), (The Conversation): Viruses and bacteria have a very long history. Because viruses can’t reproduce without a host, they’ve been attacking bacteria for millions of years. Some of those bacteria eventually became mitochondria, synergistically adapting to life within eukaryotic cells (cells that have a nucleus containing chromosomes).

Ultimately, mitochondria became the powerhouses within all human cells.

Fast-forward to the rise of novel coronaviruses like SARS-CoV-2, and the global spread of COVID-19. Approximately five per cent of people infected with SARS-CoV-2 suffer respiratory failure (low blood oxygen) requiring hospitalization. In Canada about 1.1 per cent of infected patients (almost 46,000 people) have died.

This is the story of how a team, assembled during the pandemic, recognized the mechanism by which these viruses were causing lung injury and lowering oxygen levels in patients: It is a throwback to the primitive war between viruses and bacteria — more specifically, between this novel virus and the evolutionary offspring of bacteria, our mitochondria.

SARS-CoV-2 is the third novel coronavirus to cause human outbreaks in the 21st century, following SARS-CoV in 2003 and MERS-CoV in 2012. We need to better understand how coronaviruses cause lung injury to prepare for the next pandemic.

How COVID-19 affects lungs

People with severe COVID-19 pneumonia often arrive at the hospital with unusually low oxygen levels. They have two unusual features distinct from patients with other types of pneumonia:

First, they suffer widespread injury to their lower airway (the alveoli, which is where oxygen is taken up).

Second, they shunt blood to unventilated areas of the lung, which is called ventilation-perfusion mismatch. This means blood is going to parts of the lung where it won’t get sufficiently oxygenated.

Together, these abnormalities lower blood oxygen. However, the cause of these abnormalities was unknown. In 2020, our team of 20 researchers at three Canadian universities set about to unravel this mystery. We proposed that SARS-CoV-2 worsened COVID-19 pneumonia by targeting mitochondria in airway epithelial cells (the cells that line the airways) and pulmonary artery smooth muscle cells.

We already knew that mitochondria are not just the powerhouse of the cell, but also its main consumers and sensors of oxygen. Mitochondria control the process of programmed cell death (called apoptosis), and they regulate the distribution of blood flow in the lung by a mechanism called hypoxic pulmonary vasoconstriction.

This mechanism has an important function. It directs blood away from areas of pneumonia to better ventilated lobes of the lung, which optimizes oxygen-uptake. By damaging the mitochondria in the smooth muscle cells of the pulmonary artery, the virus allows blood flow to continue into areas of pneumonia, which also lowers oxygen levels.

It appeared plausible that SARS-CoV-2 was damaging mitochondria. The results of this damage — an increase in apoptosis in airway epithelial cells, and loss of hypoxic pulmonary vasoconstriction — were making lung injury and hypoxemia (low blood oxygen) worse.

Our discovery, published in Redox Biology, explains how SARS-CoV-2, the coronavirus that causes COVID-19 pneumonia, reduces blood oxygen levels.

We show that SARS-CoV-2 kills airway epithelial cells by damaging their mitochondria. This results in fluid accumulation in the lower airways, interfering with oxygen uptake. We also show that SARS-CoV-2 damages mitochondria in the pulmonary artery smooth muscle cells, which inhibits hypoxic pulmonary vasoconstriction and lowers oxygen levels.

Attacking mitochondria

Coronaviruses damage mitochondria in two ways: by regulating mitochondria-related gene expression, and by direct protein-protein interactions. When SARS-CoV-2 infects a cell, it hijacks the host’s protein synthesis machinery to make new virus copies. However, these viral proteins also target host proteins, causing them to malfunction. We soon learned that many of the host cellular proteins targeted by SARS-CoV-2 were in the mitochondria.

Viral proteins fragment the mitochondria, depriving cells of energy and interfering with their oxygen-sensing capability. The viral attack on mitochondria starts within hours of infection, turning on genes that break the mitochondria into pieces (called mitochondrial fission) and make their membranes leaky (an early step in apoptosis called mitochondrial depolarization).

In our experiments, we didn’t need to use a replicating virus to damage the mitochondria — simply introducing single SARS-CoV-2 proteins was enough to cause these adverse effects. This mitochondrial damage also occurred with other coronaviruses that we studied.

We are now developing drugs that may one day counteract COVID-19 by blocking mitochondrial fission and apoptosis, or by preserving hypoxic pulmonary vasoconstriction. Our drug discovery efforts have already enabled us to identify a promising mitochondrial fission inhibitor, called Drpitor1a.

Our team’s infectious diseases expert, Gerald Evans, notes that this discovery also has the potential to help us understand Long COVID. “The predominant features of that condition — fatigue and neurologic dysfunction — could be due to the lingering effects of mitochondrial damage caused by SARS-CoV-2 infection,” he explains.

The ongoing evolutionary battle

This research also has an interesting evolutionary angle. Considering that mitochondria were once bacteria, before being adopted by cells back in the primordial soup, our findings reveal an Alien versus Predator scenario in which viruses are attacking “bacteria.”

Bacteria are regularly attacked by viruses, called bacteriophages, that need a host to replicate in. The bacteria in turn fight back, using an ancient form of immune system called the CRISPR-cas system, that chops up the viruses’ genetic material. Humans have recently exploited this CRISPR-cas system for a Nobel Prize-winning gene editing discovery.

The ongoing competition between bacteria and viruses is a very old one; and recall that our mitochondria were once bacteria. So perhaps it’s not surprising at all that SARS-CoV-2 attacks our mitochondria as part of the COVID-19 syndrome.

Pandemic pivot

The original team members on this project are heart and lung researchers with expertise in mitochondrial biology. In early 2020 we pivoted to apply that in another field — virology — in an effort to make a small contribution to the COVID-19 puzzle.

The diverse team we put together also brought expertise in mitochondrial biology, cardiopulmonary physiology, SARS-CoV-2, transcriptomics, synthetic chemistry, molecular imaging and infectious diseases.

Our discovery owes a lot to our virology collaborators. Early in the pandemic, University of Toronto virologist Gary Levy offered us a mouse coronavirus (MHV-1) to work with, which we used to make a model of COVID-19 pneumonia. Che Colpitts, a virologist at Queen’s University, helped us study the mitochondrial injury caused by another human beta coronavirus, HCoV-OC43.

Finally, Arinjay Banerjee and his expert SARS-CoV-2 virology team at Vaccine and Infectious Disease Organization (VIDO) in Saskatoon performed key studies of human SARS-CoV-2 in airway epithelial cells. VIDO is one of the few Canadian centres equipped to handle the highly infectious SARS-CoV-2 virus.

Our team’s super-resolution microscopy expert, Jeff Mewburn, notes the specific challenges the team had to contend with.

“Having to follow numerous and extensive COVID-19 protocols, they were still able to exhibit incredible flexibility to retool and refocus our laboratory specifically on the study of coronavirus infection and its effects on cellular/mitochondrial functions, so very relevant to our global situation,” he said.

Our discovery will hopefully be translated into new medicines to counter future pandemics.

Laboratory Biomarkers for Diagnosis and Prognosis in COVID-19

Authors: Denise Battaglini, 1 , 2 , 3 Miquéias Lopes-Pacheco, 4 Hugo C. Castro-Faria-Neto, 5 Paolo Pelosi, 1 , 2 and Patricia R. M. Rocco 4 , 6 , 7 , * Front Immunol. 2022; 13: 857573.  Apr 27.  2022 doi: 10.3389/fimmu.2022.857573 PMCID: PMC9091347 PMID: 35572561


Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) causes a wide spectrum of clinical manifestations, with progression to multiorgan failure in the most severe cases. Several biomarkers can be altered in coronavirus disease 2019 (COVID-19), and they can be associated with diagnosis, prognosis, and outcomes. The most used biomarkers in COVID-19 include several proinflammatory cytokines, neuron-specific enolase (NSE), lactate dehydrogenase (LDH), aspartate transaminase (AST), neutrophil count, neutrophils-to-lymphocytes ratio, troponins, creatine kinase (MB), myoglobin, D-dimer, brain natriuretic peptide (BNP), and its N-terminal pro-hormone (NT-proBNP). Some of these biomarkers can be readily used to predict disease severity, hospitalization, intensive care unit (ICU) admission, and mortality, while others, such as metabolomic and proteomic analysis, have not yet translated to clinical practice. This narrative review aims to identify laboratory biomarkers that have shown significant diagnostic and prognostic value for risk stratification in COVID-19 and discuss the possible clinical application of novel analytic strategies, like metabolomics and proteomics. Future research should focus on identifying a limited but essential number of laboratory biomarkers to easily predict prognosis and outcome in severe COVID-19.


Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) causes a wide spectrum of clinical manifestations, from mild respiratory symptoms to pneumonia and, in more severe cases, multiple organ failure (1). The mechanisms underlying multisystem involvement may include an unbalanced immune response that facilitates the progression of coronavirus disease-2019 (COVID-19). This hypothesis has been confirmed by laboratory biomarker alterations, showing greater potential for abnormal immune response, mainly an increase in neutrophil counts and a substantial reduction in lymphocyte counts, thus altering the neutrophil-to-lymphocyte ratio. Such an abnormal immune response is driven by an increased serum concentration of many pro-inflammatory mediators. These include interleukin (IL)-1β, IL-2, IL-6, IL-8, interferon (IFN)-γ-induced protein 10, granulocyte colony-stimulating factor, monocyte chemoattractant protein 1, macrophage inflammatory protein-1α, and tumor necrosis factor-α, among others (25). Nevertheless, the inflammatory cytokine storm in patients with COVID-19 is less injurious than that observed in patients with sepsis or acute respiratory distress syndrome (ARDS) but without COVID-19 (6), thus raising questions regarding the mechanisms underlying multiorgan involvement in COVID-19.

Several biomarkers other than cytokines have been found altered in COVID-19, and are associated with diagnosis, prognosis and outcomes (7). Some of these biomarkers can be easily used to predict disease severity, hospitalization, intensive care unit (ICU) admission, and mortality, while others, like metabolomic and proteomic analysis, are still of purely investigational concern and difficult to translate into clinical practice, despite their prognostic potential (810).

The aim of this narrative review is to identify laboratory biomarkers that have shown significant diagnostic and prognostic value for risk stratification in COVID-19 and to discuss the possible clinical application of novel analytic strategies, such as metabolomics and proteomics.

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Potential for Multiorgan Involvement in COVID-19

SARS-CoV-2 is an enveloped, single-stranded ribonucleic acid (ssRNA) virus. The SARS-CoV-2 genome is composed of two polypeptides encoded between two open-reading frames that are processed by viral proteases to produce nonstructural proteins (11). These proteins are involved in viral replication and suppression of host innate immune defense. On the other hand, structural proteins of SARS-CoV-2 include the spike (S), envelope (E), and nucleocapsid (N) protein, as well as the membrane (M) glycoprotein. The S protein is a transmembrane glycoprotein that is located on the viral surface and cleaved by host-cell proteases. After anchoring the S protein, SARS-CoV-2 enters host cells via angiotensin receptor-2 (ACE2), thus activating transmembrane serine protease 2 (TMPRSS2), cathepsin B and L. The E protein is a glycoprotein involved in virion maturation and pathogenesis, while the M protein is involved in viral assembly and delineates the shape of the viral envelope; finally, the N protein binds directly to viral RNA (11). The pathogenic mechanisms of SARS-CoV-2 include 1) direct epithelial damage, 2) dysregulated immune response, 3) ACE2 dysregulation and downregulation of the renin-angiotensin- aldosterone system (RAAS), 4) direct endothelial damage, and, possibly, 5) tissue fibrosis (11). Hence, patients with severe COVID-19 are at high risk of multiple organ involvement and, ultimately, death. Indeed, the virus has been identified in multiple tissues, including endothelial, liver, kidney, pulmonary, and neuronal cells, suggesting direct invasion as possible pathological mechanism underlying systemic effects (1). Therefore, laboratory biomarkers of organ damage play a key role in the diagnosis, prediction, and prognosis of patients at high risk of multiorgan involvement, and their use should be implemented in clinical practice (1). Table 1 summarizes the most investigated biomarkers in COVID-19, while Figure 1 depicts possible multiorgan involvement in COVID-19. In the following section, we will describe individual organ systems and how they can be affected by severe COVID-19, associated laboratory and clinical biomarkers of damage, severity, and outcome, and their potential utility for patient management.

Table 1

Laboratory biomarkers in COVID-19.

BiomarkersClinical significance
Pulmonary functionNSEDyspnea
LDH, ASTMortality at admission, longer IMV
Surfactant protein-D, angiopoietin-2, TREM-1, TREM-2Severity
Thiol, ferritin, LDHARDS development
Platelet count, neutrophils/lymphocyte ratio, CRP, D-dimer, ferritinSurvival at extubation
Kynurenine, p-cresol sulphateLonger IMV
Metabolomic/proteomic: PPAR, D-arginine, D-ornithine, TRP, alpha linoleicFibrosis
Inflammation and infectionPCTSeverity, mortality
Neutrophil countClinical outcome, mortality
Neutrophil/lymphocyte ratioSeverity, mortality
Lymphocyte count, CD3+, 4+, 8+, 25+, 127-, NK cellsSeverity, mortality
Cardiovascular functionNPs, troponinsCV disease, inflammation, mortality
CK-MB, myoglobin, D-dimer, BNP, NT-proBNP, neutrophil/lymphocyte ratioPrognosis
Coagulation and hemostasisD-dimerMortality
Plasma fibrinogenHyperinflammation, severity
sVCAM-1, vWF, thrombomodulin, sTNFRI, HS, C5b9, PAI-1, alpha-2 antiplasminSeverity
vWF, ADAMTS13Mortality
Endothelial dysfunctionSeverity of pulmonary impairment
Metabolic systemHDL cholesterolRisk of hospitalization
LDL cholesterolInflammation
Vitamin AARDS development, mortality
Metabolomic/proteomic: cAMPMortality
Thyroid hormonesSeverity, mortality
Neurological manifestationsGFAP, NfL, tau, S100B, NSE, inflammatory markersInflammation, severity
D-dimer, LDH, ESR, CRP, lymphocytes, PCT, creatinineOccurrence of ischemic stroke
Kidney and liver functionUrine 11-dehydro-thromboxane B2, 8-hydroxy-2’-deoxyguanosine, L-FABPHospitalization
N-acetyl-β-D-glucosaminidase, β2-microglobulin, α1-microglobulin, L-FABPHyperinflammation
PCT, arterial saturation of oxygen, blood urea nitrogenAcute kidney injury
CreatinineAcute kidney injury, mortality
Urine blood, urine weightMortality
Albumin, direct albumin, neutrophils, lymphocytes, mean corpuscular hemoglobinSeverity

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ADAMTS, a disintegrin and metalloproteinase with thrombospondin motifs, ARDS, acute respiratory distress syndrome, AST, aspartate aminotransferase, BNP, brain natriuretic peptide, cAMP, adenosine cyclic monophosphate, CD, cluster differentiation, CK-MB, creatine kinase, CRP, C-reactive protein, CV, cardiovascular, ESR, erythrocyte sedimentation rate, GFAP, glial fibrillary acidic protein, HDL, high density lipoproteins, HS, heparan sulfate, IMV, invasive mechanical ventilation, L-FABP, liver-type fatty acid binding protein, LDH, lactate dehydrogenase, LDL, low density lipoproteins, MR-proADM, mid-regional pro-adrenomedullin, NfL, neurofilament light polypeptide, NK, natural killer, NPs, natriuretic peptides, NSE, neuron specific enolase, NT-proBNP, N-terminal pro-hormone, PAI, plasminogen activator inhibitor, PCT, procalcitonin, PPAR, peroxisome proliferator-activated receptors, sTNFRI soluble tumor necrosis factor receptor I, sVCAM-1, vascular cells adhesion molecule-1, TREM, triggering receptor expressed on myeloid cells, TRP, transient receptor potential channel, vWF, von Willebrand.

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Figure 1

COVID-19 multiple organ dysfunction. This figure shows the potential for multiorgan involvement in COVID-19. Respiratory (AIP, acute interstitial pneumonia; ARDS, acute respiratory distress syndrome; DAD, diffuse alveolar damage), renal, cardiovascular, coagulative/hemostatic, liver, gastrointestinal, metabolic/endocrine, and cerebral functions and systems, as well as their possible alterations, are presented.

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Diagnostic and Prognostic Value of Biomarkers

Biomarkers reflecting multiple organ involvement and/or pharmacological effects have been widely examined in critically ill patients. Some of these biomarkers are also used to monitor dysfunction in distinct organs at the same time, due to their redundancy or non-specificity. However, the most appropriate biomarkers to be studied in critically ill patients with COVID-19 have yet to be defined. Figure 2 depicts a proposed algorithm for critical care management which includes the investigation of biomarkers in severe COVID-19 patients at ICU admission.

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Figure 2

Proposed algorithm for the management of patients with COVID-19 at ICU admission. This figure shows a potential algorithm for initial patient management at ICU admission, including the most useful biomarkers to be used in the COVID-19 critical care setting. Neurological system: sequential transcranial doppler (TCD) and/or optic nerve sheath diameter (ONSD) in sedated patients for whom conventional neurological evaluation is impossible. Cardiovascular system: electrocardiogram and echocardiography, as well as continuous monitoring of mean arterial pressure (MAP) and heart rate (HR), are suggested on ICU admission. Respiratory system: computed tomography (CT) scan is the gold standard; if not feasible, chest X-ray, CT angiography, and/or lung ultrasound should be performed. Lactate dehydrogenase (LDH), C-reactive protein (CRP), neuron specific enolase (NSE), neurofilament light polypeptide (NfL), glial fibrillary acidic protein (GFAP), thyrotropic stimulating hormone (TSH), NGAL, aspartate transaminase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (γGT), interleukin-6 (IL-6). BNP, brain natriuretic peptide; UN, urea nitrogen; NT-proBNP, N-terminal pro-hormone.

Respiratory System

The lungs are usually the organs affected primarily by SARS-CoV-2, due to their large and highly vascularized surface area (11). The pathogenesis of COVID-19 in the lung includes an initial phase of local inflammation, endothelial cell damage, and antifibrinolytic activation in the upper and lower respiratory tracts, followed by repair mechanisms that can elicit the restoration of normal pulmonary architecture. Inflammation is followed by platelet recruitment with degranulation, clot formation, altered vessel permeability, and accumulation of leukocytes in the injury site, leading to the recruitment of other inflammatory cells with the involvement of specific cytokines (i.e., IL-4, IL-13, transforming growth factor-β) that are also responsible for pro-fibrotic activity (12).

SARS-CoV-2 lung infection causes a wide variety of clinical manifestations and symptoms, from asymptomatic, mild, and moderate disease to severe COVID-19. Severe and critical illness accounts for up to 14% and 5% of cases, respectively, with the ARDS occurring in 10-20% of patients; multiorgan failure and death may supervene (1314). Various phenotypes have been identified by computed tomography (CT) (1516), including phenotype L or 1, which is characterized by low compliance, altered ventilation and perfusion, and shunting with focal hypo/hyper-perfused ground-glass opacities; and phenotype H or 2, which is identified by an inhomogeneous distribution of atelectasis with a patchy ARDS-like pattern (1718). Progressive evolution of COVID-19 (19) may lead to phenotype F, caused by mechanical stretch of lung epithelial cells and pathological fibro-proliferation and remodeling of the extracellular matrix, with increased expression of pro-fibrotic markers, as is mainly typical of severe forms of lung disease (20).

Although not specific to pulmonary disease, several biomarkers of different stages of lung involvement in COVID-19 have been identified and have been associated with pulmonary and systemic hyperinflammation and fibrotic damage (12). In the early disease course, neuron-specific enolase (NSE) can be used to differentiate patients who are going to develop dyspnea (21). On admission, higher lymphocyte and platelet counts and lower ferritin, D-dimer, lactate dehydrogenase (LDH), and aspartate transaminase (AST) have all been associated with lower risk of mortality in COVID-19 patients who ultimately required intubation and mechanical ventilation (22). Surfactant protein-D, angiopoietin-2, triggering receptor expressed on myeloid cell (TREM)-1, and TREM-2 levels were found to be higher in mild/moderate and severe/critical COVID-19 pneumonia than in asymptomatic and uncomplicated cases. Moreover, these biomarkers correlated well with clinical severity (2324). In severe COVID-19 cases, total thiol, ferritin, and LDH were identified as prognostic biomarkers for ARDS development (25). At extubation, COVID-19 survivors had higher platelet counts and neutrophil-to-lymphocyte ratios and lower C-reactive protein (CRP), D-dimer, ferritin, LDH, and AST (22).

Infection and Systemic Inflammatory Response

Following SARS-CoV-2 invasion of the host cells, the virus replicates at the infection site, thus triggering activation of the innate and adaptive immune responses (26). Neutrophils are rapidly recruited to infection foci, while innate cells recognize the virus and secrete multiple cytokines. Antigen-presenting cells recognize viral antigens which are carried to the local lymph nodes, while activating the T-helper cell response, which is also responsible for stimulating B cells to secrete antibodies (27). The systemic immune-inflammatory response is activated; if left unchecked, this may progress to multiorgan illness (28).

Patients with severe COVID-19 are highly susceptible to superimposed bacterial, fungal, and viral infections, including ventilator-associated pneumonia and bloodstream infection, among others (2930). As for systemic biomarkers of infection, procalcitonin is a predictor of disease severity (31), and can be useful to guide antimicrobial stewardship (3233). Another study found an association between procalcitonin and mortality in COVID-19 patients more than 75 years old (34). Neutrophil count was also predictive of clinical outcome in hospitalized COVID-19 patients (35), while the neutrophil-to-lymphocyte ratio was strongly associated with severity and mortality in COVID-19 (36). Additionally, total lymphocyte count, cluster differentiation (CD)3+, CD4+, CD8+, CD25+, CD127 T cells, and natural killer (NK) cells were found to be depressed in severe COVID-19 (37), whereas C-reactive protein, erythrocyte sedimentation rate, and IL-6 – common markers of inflammation – were elevated (38).

Cardiovascular System

SARS-CoV-2 can directly trigger endothelial dysfunction, causing a status known as COVID-19-associated coagulopathy. After viral entry into the cells, increased vascular permeability and tissue factor expression in subendothelial cells, with activation of platelets and leukocytes, may trigger the coagulation cascade. Endothelial damage and a generalized inflammatory state are drivers of thrombosis, which can contribute to cardiovascular manifestations (39).

Cardiovascular manifestations of COVID-19 are frequently reported (240). Acute heart failure and exacerbation of chronic heart failure are reported in up to 20-30% of hospitalized patients, and carry high mortality rates, especially in patients with severe comorbidities (4143). Acute coronary syndrome has been reported in a high proportion of patients, probably because of plaque rupture, coronary spasm, or microthrombi triggered by systemic inflammation and cytokine storm (44). In general, the mechanisms underlying cardiovascular manifestations include increased cardiac workload, hypoxemia, hypervolemia, myocardial injury, arrhythmias, myocarditis, stress-induced cardiomyopathy, acute kidney injury, and, as noted above, systemic inflammatory response with the release of several cytokines and chemokines (45). Triggering mechanisms may be attributed to an imbalance between heightened cardiac workload and reduced oxygen supply secondary to systemic conditions, with possible type-2 myocardial infarction (46).

Cardiac biomarkers (47), electrocardiography (ECG), and transthoracic echocardiography (TTE) play a pivotal role in risk stratification and early detection of cardiovascular complications, as well as to guide treatment (4849). Recent evidence confirmed that cardiac biomarkers, including natriuretic peptides (NPs) and troponins, may reflect cardiovascular involvement and inflammation in COVID-19, and are strongly associated with poor prognosis and mortality (415053). In some cases, troponin elevation in COVID-19 has been associated with ECG changes (54), ICU admission, and in-hospital death (5556). However, despite the confirmed prognostic impact of troponins, routine testing is still a matter of debate, because of several other variables that have been associated with outcome and prognosis (48). Additionally, pre-existing cardiac disease and/or acute stress injury may justify mild elevations in cardiac troponins, while myocarditis, Takotsubo syndrome, type 2 myocardial infarction triggered by severe respiratory failure, systemic hypoxemia, or shock are mostly associated with more marked increase in troponins (445758). Other cardiac and non-cardiac biomarkers are common findings in COVID-19-associated cardiovascular disease, including creatine kinase (CK)-MB, myoglobin, D-dimer, brain natriuretic peptide (BNP) and its N-terminal pro-hormone (NT-proBNP), and neutrophil-to-lymphocyte ratio (555961). Myoglobin seems to offer higher prognostic accuracy than other cardiac-specific biomarkers (troponins and CK-MB) in COVID-19 (62). Moreover, mid-regional pro-adrenomedullin (MR-proADM) levels were found to be associated with endothelial dysfunction and mortality in COVID-19, potentially making it an optimal biomarker for the prediction of survival in this patient population (63). Nevertheless, only limited evidence exists so far to define any of these biomarkers as an independent predictor of prognosis in COVID-19 (4864).

Coagulation and Hemostasis

Coagulation derangement is a well-known systemic effect of COVID-19 that can originate from direct or indirect viral impact on the endothelium, or from immunothrombosis (65). COVID-19 can cause alterations in the coagulation cascade, with imbalance of the regulatory mechanisms of coagulation and fibrinolysis, altered platelet function, and a hyperinflammatory response (1165). In this context, D-dimer has been identified among the first altered coagulation biomarkers in COVID-19, and is predictive of mortality on admission (66). Similarly, plasma fibrinogen appears to be associated with hyperinflammation and disease severity in COVID-19 (67). A coagulopathy signature diagnostic of COVID-19 has been identified, including elevated levels of soluble vascular cell adhesion molecule (sVCAM)-1 (68), von Willebrand Factor (vWF), thrombomodulin, soluble tumor necrosis factor (TNF) receptor I (sTNFRI), heparan sulfate, C5b9 complement, plasminogen activator inhibitor (PAI)-1, and alpha-2 antiplasmin, among others. Some of these markers, such as sVCAM-1, vWF, sTNFRI, and heparan sulfate, were also associated with disease severity (69). Fibrinogen, thrombin peak, vWF, and ADAMTS13 at admission and elevated vWF : Ag to ADAMTS13 activity ratio were associated with severity and higher risk of death (7071). Endothelial dysfunction seems to be persistent after resolution of COVID-19, and directly associated with the severity of pulmonary impairment (72).

Metabolic Function

Sphingolipid metabolism regulates the inflammation and immune response through the conversion of sphingosine to sphingosine 1-phosphate, increasing the release of lymphocytes into the blood, with subsequent systemic inflammation and release of cytokines and chemokines in COVID-19 (73). Like lipid metabolism, fat-soluble vitamins such as vitamin D have been implicated in suppressing the cytokine storm and enhancing the immune response (74). Investigating lipid metabolism and its biomarkers could thus be of diagnostic and prognostic value in COVID-19.

Metabolic comorbidities including obesity, diabetes, cardiovascular, and hypertension have been associated with poor prognosis in COVID-19 (75). A certain degree of metabolic dysregulation has been found in COVID-19, possibly due to immune-triggered inflammation and hypercoagulability, as well as microbial changes in host physiology (1076). Indeed, COVID-19 patients with lower levels of high-density lipoprotein (HDL) cholesterol are more susceptible to hospitalization, while low-density lipoprotein (LDL) cholesterol was associated with higher inflammation (77). Critically ill patients with COVID-19 showed significantly lower levels of vitamin A than non-critical ones, and this was associated with higher inflammation (78). Vitamin A levels below 0.2 mg/L were significantly associated with the developments of ARDS and higher mortality (78). Vitamin D, a well-known regulator of phosphate and calcium metabolism with immunomodulatory functions, seems to not influence mortality or hospital length of stay in COVID-19 (7980). Finally, thyroid hormones showed marked association with disease severity and mortality, suggesting the importance of early assessment of thyroid function – and, when necessary, initiation of treatment – in hospitalized COVID-19 patients (81).

Neurologic Involvement

Pathogenetic mechanisms of SARS-CoV-2 neurologic manifestations include possible spreading of the virus across the blood-brain barrier via leukocyte migration or sluggish movement of blood within the microcirculation, thus binding to endothelial cells. Cells which may present ACE2 receptors, including neurons, astrocytes, and oligodendrocytes, can all be affected directly by viral entry and activate the local immune response. As a consequence of neuronal involvement, several biomarkers of neuroinflammation and damage can be detected (82).

Although COVID-19 rarely affects the brain as a primary manifestation, neurological complications are common in this patient population (8284). Patients with neurological complications, compared to those without, may experience longer hospital stays, and the duration of mechanical ventilation can be associated with the risk of developing new neurological complications (8485). CT and magnetic resonance imaging (MRI) are considered the gold standard for detecting cerebral derangements, although the use of methods which involve exposure to ionizing radiation in non-primarily brain-injured patients can only be justified in case of high suspicion of neurological complications (86). The use of multimodal neuromonitoring has received increasing attention as a means of identifying patients at higher risk of brain derangement because of its low cost, speed, safety, and ready availability. However, the use of neuromonitoring tools is still mainly limited to specific settings (i.e., ICU) and patient populations (i.e., those with primary brain injury) (84).

Other than imaging, blood biomarkers can detect brain damage and predict prognosis efficiently. Blood biomarkers for the study of brain derangements include glial fibrillary acidic protein (GFAP), neurofilament light polypeptide (NfL), tau, S100B calcium binding protein, NSE, and inflammatory markers. Increased GFAP staining has been found in postmortem analysis of brain tissue from patients with COVID-19 (87), and NfL was significantly associated with COVID-19 status (88). Another study reported that GFAP was increased in both moderate and severe COVID-19 cases, whereas serum NfL was increased only in severe cases compared to controls (89). However, another study reported that serum NfL, although elevated across patients hospitalized with COVID-19, was not associated with neurological manifestations. Additionally, the usual close correlation between cerebrospinal fluid and serum NfL was not found, suggesting serum NfL elevation in the non-neurological patients may reflect peripheral nerve damage in response to severe illness (90). In COVID-19 patients with altered NfL and GFAP, values of these markers had normalized in all individuals at 6-month follow-up, suggesting that post-COVID-19 neurological sequelae may be not accompanied by ongoing brain injury (91). Inflammatory and coagulatory markers like D-dimer, LDH, erythrocyte sedimentation rate (ESR), and CRP were independently associated with the occurrence of ischemic stroke in COVID-19 (9293), while higher age, diabetes mellitus, and hypertension were found not to be significant predictors of stroke in this population, despite being known predictors of non-COVID-19 stroke (93). Levels of lymphocytes, procalcitonin, and creatinine were higher in COVID-19 stroke patients (94). S100B was higher in patients with mild and severe COVID-19 than in healthy controls, and may be a marker of disease severity (95). Antiphospholipid antibodies (i.e., anti-phosphatidylserine/prothrombin) were higher in COVID-19 patients, particularly those with neurological manifestations, than in controls. In contrast, anticardiolipin antibodies were not associated with neurologic involvement in COVID-19 (96).

Kidney and Liver

COVID-19 may cause kidney and liver injury by either direct infection of cells, via host immune clearance and immune tolerance disorders, endothelium-associated vasculitis, thrombus formation, metabolism and glucose disorder, or tissue hypoxia. As a consequence, biomarkers of endothelial, renal, hepatic, vascular, or hypoxic damage can help in the detection of new organ involvement and assist in determining prognosis (97).

As part of multiorgan involvement in COVID-19, kidney function might be altered directly by viral invasion or may occur secondary to multiple organ failure due to systemic inflammation or aggressive therapies (98). Around 25% of patients hospitalized with COVID-19 were reported to develop acute kidney injury, including low molecular weight proteinuria, Fanconi syndrome, and tubular injury (98). Moreover, regional inflammation, endothelial injury, and microthrombi have been identified as major causative factors of renal pathology in COVID-19. This is also sustained by the fact that anti-inflammatory drugs, such as steroids, play a key role in limiting renal disease progression (98). Classic diagnostic biomarkers of kidney damage include creatinine, neutrophil gelatinase-associated lipocalin (NGAL), cystatin C, kidney injury molecule-1 (KIM-1), blood and urinary urea nitrogen, and urinary proteins (99100).

Novel urinary biomarkers have been proposed in COVID-19, including urine 11-dehydro-thromboxane B2, 8-hydroxy-2′-deoxyguanosine, and liver-type fatty acid binding protein (L-FABP) levels, all of which were higher in this patient cohort at the time of hospitalization (101). N-acetyl-β-D-glucosaminidase, β2-microglobulin, α1-microglobulin, and L-FABP, which are all markers of tubular injury, were significantly associated with inflammation, as were IL-6 levels (102). Indeed, another observational study confirmed the association between pro-inflammatory cytokines, urinary cytokines, and urinary kidney injury markers (103). Procalcitonin was associated with acute kidney injury in COVID-19, and a score including simple and easily accessible variables such as procalcitonin, arterial saturation of oxygen, and blood urea nitrogen was shown to be predictive of acute kidney injury (104).

Altered serum creatinine levels with decreased kidney function at admission and up to 24 hours thereafter were significantly associated with acute kidney injury and in-hospital mortality (105). Additionally, urine blood >0.03 mg/dL and urine specific gravity >1.026 were associated with acute kidney injury, ICU admission, and higher mortality (106).

Abnormal liver and hepatobiliary function have been also identified in COVID-19 (107). A systematic review and meta-analysis showed a cumulative prevalence of liver disease of 24% in COVID-19, with possible alterations in albuminemia, liver enzymes, and total bilirubin (108). Recent findings showed that some liver and renal biomarkers, including albumin, direct bilirubin, neutrophil and lymphocyte counts, and mean corpuscular hemoglobin, are associated with risk of developing severe COVID-19 (107). Moreover, the presence of pre-existing liver fibrosis with silent liver injury significantly influenced mortality in COVID-19 (109)

Future Perspectives: Metabolomic and Proteomic Biomarkers and Machine Learning Models

Given the significant immune dysregulation of COVID-19 patients, the interplay between metabolism and immunity may play a pivotal role in the disease course (110). Additionally, oxygen deprivation may affect homeostasis in tissues and organs such as the lung, brain, kidney, and liver. The modulation of oxygen homeostasis and response to hypoxia is mainly mediated by glycolysis and the lactate cycle. This has increased research interest in proteomic and metabolomic methods to investigate pathways linked to energy production and amino acid metabolism in patients with SARS-CoV-2 infections (110). Metabolomic analyses in COVID-19 patients with and without pulmonary fibrosis revealed that pathways including the peroxisome proliferator-activated receptor (PPAR), D-arginine and D-ornithine metabolism, inflammatory tryptophan metabolic pathway (TRP), and alpha-linolenic acid metabolism were significantly increased in fibrotic lungs, thus suggesting that PPAR signaling is one of the main pathways involved in the formation and development of lung fibrosis in COVID-19 (9). A proteomic and metabolomic analysis identified hypoxanthine and betaine as predictors of ICU stay, and early ICU admission, elevated creatinine, and D-dimer were found to be associated with these pathways (8). Longer duration of invasive mechanical ventilation was associated with the kynurenine and p-cresol sulfate pathways (8). Several markers of metabolic function identified via metabolomic analysis were associated with in-hospital mortality, including cyclic adenosine monophosphate (cAMP), which plays a role in SARS-CoV2 endocytosis in the initial phase of the disease (10). Another major signature of the serum metabolome in COVID-19 was lactic acid, as well as spermidine and spermine. Many other metabolites were commonly increased, including glutamate, aspartate, phenylalanine, β-alanine, ornithine, arachidonic acid, choline, and xanthine (110). Recent machine learning models have been developed to support decision making and risk stratification in COVID-19. Most predictive models rely on demographic and clinical variables. However, biomarkers have recently shown good correlation with severity of disease and mortality in COVID-19 modeling (111). One example was a large study of 2,895 consecutive patients with COVID-19 in whom three biomarkers measured at admission were found to reflect pathobiological axes of myocardial injury, altered coagulation, and inflammation. The machine learning model concluded that patients with low levels of these biomarkers were at lower risk of critical disease and in-hospital mortality (112). In conclusion, the alterations found in the serum metabolome of patients with COVID-19 may reflect a more complex systemic derangement affecting carbon and nitrogen liver metabolism, but further research is needed to completely understand the impact of these alterations on routine clinical practice. Machine learning models can be promising in risk stratification in COVID-19. However, further investigations are needed to develop mathematical models that can help clinicians select the right parameters and interpret results.


Laboratory biomarkers have shown significant diagnostic and prognostic value for risk stratification in COVID-19. Furthermore, novel analytic strategies including metabolomics and proteomics offer interesting insights for early detection of patients at higher risk of severe disease and death. However, their limited availability restricts their widespread clinical use. Further investigations are warranted to identify a core set of laboratory biomarkers which can be used in daily clinical practice to easily predict prognosis and outcome in hospitalized patients with severe COVID-19.

Author Contributions

DB and ML-P: review, design, writing, editing. HC-F-N and PP: editing. PR: review, design, editing, senior contribution. All authors contributed to the article and approved the submitted version.


This work was supported by the Brazilian Council for Scientific and Technological Development (COVID-19-CNPq; 401700/2020-8 and 403485/2020-7); Rio de Janeiro State Research Foundation (COVID-19-FAPERJ; E-26/210.181/2020); and Funding Authority for Studies and Projects (01200008.00), Brazil.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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The authors express their gratitude to Mrs. Moira Elizabeth Schottler and Mr Filippe Vasconcellos for their assistance in editing the paper.

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ACE2, angiotensin receptor 2; ARDS, acute respiratory distress syndrome; AST, aspartate transaminase; BNP, brain natriuretic peptide; cAMP, cyclic adenosine monophosphate; CD, cluster differentiation; CK, creatine kinase; COVID-19, coronavirus disease 2019; CRP, C-reactive protein; CT, computed tomography; ECG, electrocardiography; ESR, erythrocyte sedimentation rate; GFAP, glial fibrillary acidic protein; HDL, high-density lipoprotein; ICU, intensive care unit; IL, interleukin; KIM, kidney injury molecule; L-FABP, liver-type fatty acid binding protein; LDH, lactate dehydrogenase; LDL, low-density lipoprotein; MR-proADM, mid-regional pro-adrenomedullin; MRI, magnetic resonance imaging; NfL, neurofilament light polypeptide; NGAL, neutrophil gelatinase-associated lipocalin; NK, natural killer; NP, natriuretic peptides; NSE, neuron-specific enolase; NT-proBNP, N-terminal pro-hormone BNP; PPAR, peroxisome proliferator-activated receptor; RASS, renin-angiotensin- aldosterone system; SARS-CoV-2, severe acute respiratory syndrome-coronavirus-2; ssRNA, single-stranded ribonucleic acid; sTNFRI, soluble TNF receptor I; sVCAM, soluble vascular cell adhesion molecule; TMPRSS2, transmembrane serine protease 2; TNF, tumor necrosis factor; TREM, triggering receptor expressed on myeloid cell; TRP, tryptophan metabolic pathway; TTE, transthoracic electrocardiography; vWF, von Willebrand Factor.

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Risk of severe COVID-19 disease with ACE inhibitors and angiotensin receptor blockers: cohort study including 8.3 million people

  1. Julia Hippisley-Cox1, Duncan Young2,3, Carol Coupland4, Keith M Channon5, Pui San Tan6, David A Harrison7, Kathryn Rowan8,  Paul Aveyard6, Ian D Pavord9, Peter J Watkinson5,10
  2. Correspondence to Prof Julia Hippisley-Cox, Primary Care Health Sciences, University of Oxford, Oxford OX1 



There is uncertainty about the associations of angiotensive enzyme (ACE) inhibitor and angiotensin receptor blocker (ARB) drugs with COVID-19 disease. We studied whether patients prescribed these drugs had altered risks of contracting severe COVID-19 disease and receiving associated intensive care unit (ICU) admission.


This was a prospective cohort study using routinely collected data from 1205 general practices in England with 8.28 million participants aged 20–99 years. We used Cox proportional hazards models to derive adjusted HRs for exposure to ACE inhibitor and ARB drugs adjusted for sociodemographic factors, concurrent medications and geographical region. The primary outcomes were: (a) COVID-19 RT-PCR diagnosed disease and (b) COVID-19 disease resulting in ICU care.


Of 19 486 patients who had COVID-19 disease, 1286 received ICU care. ACE inhibitors were associated with a significantly reduced risk of COVID-19 disease (adjusted HR 0.71, 95% CI 0.67 to 0.74) but no increased risk of ICU care (adjusted HR 0.89, 95% CI 0.75 to 1.06) after adjusting for a wide range of confounders. Adjusted HRs for ARBs were 0.63 (95% CI 0.59 to 0.67) for COVID-19 disease and 1.02 (95% CI 0.83 to 1.25) for ICU care.

There were significant interactions between ethnicity and ACE inhibitors and ARBs for COVID-19 disease. The risk of COVID-19 disease associated with ACE inhibitors was higher in Caribbean (adjusted HR 1.05, 95% CI 0.87 to 1.28) and Black African (adjusted HR 1.31, 95% CI 1.08 to 1.59) groups than the white group (adjusted HR 0.66, 95% CI 0.63 to 0.70). A higher risk of COVID-19 with ARBs was seen for Black African (adjusted HR 1.24, 95% CI 0.99 to 1.58) than the white (adjusted HR 0.56, 95% CI 0.52 to 0.62) group.


ACE inhibitors and ARBs are associated with reduced risks of COVID-19 disease after adjusting for a wide range of variables. Neither ACE inhibitors nor ARBs are associated with significantly increased risks of receiving ICU care. Variations between different ethnic groups raise the possibility of ethnic-specific effects of ACE inhibitors/ARBs on COVID-19 disease susceptibility and severity which deserves further study.

Here’s what we know so far about the long-term symptoms ofCOVID-19

July 26, 2020 3.56pm EDT

We’re now all too familiar with the common symptoms of COVID-19: a fever, dry cough and fatigue. Some people also experience aches and pains, a sore throat, and loss of taste or smell.

Sufferers with mild illness might expect to get better after a few weeks. But there’s mounting evidence this isn’t the case, and COVID-19 may leave a long-lasting impression on its victims – not just the most severely affected or the elderly and frail.

It’s not just an infection of the lungs

On the surface, COVID-19 is a lung disease. The SARS-CoV-2 coronavirus infects cells of the respiratory tract and can cause life-threatening pneumonia.

However, the full range of symptoms affects multiple parts of the body. An app that records daily symptoms developed at King’s College London has tracked the progress of more than 4 million COVID-19 patients in the United Kingdom, Sweden and the United States.

Besides the well-described symptoms of fever, cough and loss of smell are other effects, including fatigue, rash, headache, abdominal pain and diarrhoea. People who develop more severe forms of the disease also report confusion, severe muscle pains, cough and shortness of breath.

About 20% of those infected with COVID-19 require hospitalisation to treat their pneumonia, and many need assistance with oxygen. In about 5% of cases the pneumonia becomes so severe patients are admitted to intensive care for breathing support.

It trips the immune system

People with severe COVID-19 seem to show an altered immune response even in the disease’s early stages. They have fewer circulating immune cells, which fail to efficiently control the virus, and instead suffer an exaggerated inflammatory response (the “cytokine storm”).

This is increasingly recognised as one of the main factors that makes the disease so serious in some patients. Suppressing this exaggerated response with the immunosuppressant dexamethasone remains the only treatment that reduces death rates in those who require oxygen support or intensive care.

Read more: Dexamethasone: the cheap, old and boring drug that’s a potential coronavirus treatment

Patients with severe COVID-19 describe a far more complex range of symptoms than would normally be seen with pneumonia alone. This can include brain inflammation (encephalitis), causing confusion and reduced consciousness. Up to 6% of severe sufferers may have a stroke.

Pathology studies and autopsies of patients who died from COVID-19 reveal the expected features of severe pneumonia or acute respiratory distress syndrome (ARDS), with extensive inflammation and scarring. ARDS occurs when there’s sudden and widespread inflammation in the lungs, resulting in shortness of breath and blueish skin.

Uniquely, however, they also reveal the virus seems to directly cause inflammation of the small capillaries or blood vessels, not just in the lungs but in multiple organs, leading to blood clots and damage to the kidney and heart.

Persistent symptoms ‘deeply frustrating’

Anyone with a severe disease would be expected to suffer long-lasting consequences. But COVID-19 seems to have persistent symptoms even in those with milder forms of the illness.

Social media is replete with stories of survivors afflicted by ongoing symptoms. Support groups have emerged on Slack and Facebook hosting thousands of people, some still suffering more than 60 days after infection. They call themselves “long-termers” or “long-haulers”.

One of the most well-known sufferers is Paul Garner, an infectious disease specialist at the Liverpool School of Tropical Medicine in the UK. He was infected in late March and his symptoms continue. In a blog post published by the British Medical Journal he describes having a:

…muggy head, upset stomach, tinnitus (ringing in the ears), pins and needles, breathlessness, dizziness and arthritis in the hands.

These symptoms have waxed and waned but not yet resolved. He says this is:

…deeply frustrating. A lot of people start doubting themselves… Their partners wonder if there is something psychologically wrong with them.

So far, only one peer-reviewed study has reported results on the long-term symptoms of COVID-19 infection: a single group of 143 survivors from Rome. Most of them did not need hospitalization and all were assessed at least 60 days after infection. They reported a worsened quality of life in 44.1% of cases, including symptoms of persistent fatigue (53.1%), breathlessness (43.4%), joint pain (27.3%), and chest pain (21.7%).

How does coronavirus kill? Clinicians trace a ferocious rampage through the body, from brain to toes

Authors: By Meredith WadmanJennifer Couzin-FrankelJocelyn KaiserCatherine MatacicApr. 17, 2020 , 6:45 PM

On rounds in a 20-bed intensive care unit one recent day, physician Joshua Denson assessed two patients with seizures, many with respiratory failure and others whose kidneys were on a dangerous downhill slide. Days earlier, his rounds had been interrupted as his team tried, and failed, to resuscitate a young woman whose heart had stopped. All shared one thing, says Denson, a pulmonary and critical care physician at the Tulane University School of Medicine. “They are all COVID positive.”

As the number of confirmed cases of COVID-19 surges past 2.2 million globally and deaths surpass 150,000, clinicians and pathologists are struggling to understand the damage wrought by the coronavirus as it tears through the body. They are realizing that although the lungs are ground zero, its reach can extend to many organs including the heart and blood vessels, kidneys, gut, and brain.

“[The disease] can attack almost anything in the body with devastating consequences,” says cardiologist Harlan Krumholz of Yale University and Yale-New Haven Hospital, who is leading multiple efforts to gather clinical data on COVID-19. “Its ferocity is breathtaking and humbling.”

Understanding the rampage could help the doctors on the front lines treat the fraction of infected people who become desperately and sometimes mysteriously ill. Does a dangerous, newly observed tendency to blood clotting transform some mild cases into life-threatening emergencies? Is an overzealous immune response behind the worst cases, suggesting treatment with immune-suppressing drugs could help? What explains the startlingly low blood oxygen that some physicians are reporting in patients who nonetheless are not gasping for breath? “Taking a systems approach may be beneficial as we start thinking about therapies,” says Nilam Mangalmurti, a pulmonary intensivist at the Hospital of the University of Pennsylvania (HUP).

What follows is a snapshot of the fast-evolving understanding of how the virus attacks cells around the body, especially in the roughly 5% of patients who become critically ill. Despite the more than 1000 papers now spilling into journals and onto preprint servers every week, a clear picture is elusive, as the virus acts like no pathogen humanity has ever seen. Without larger, prospective controlled studies that are only now being launched, scientists must pull information from small studies and case reports, often published at warp speed and not yet peer reviewed. “We need to keep a very open mind as this phenomenon goes forward,” says Nancy Reau, a liver transplant physician who has been treating COVID-19 patients at Rush University Medical Center. “We are still learning.”

The infection begins

When an infected person expels virus-laden droplets and someone else inhales them, the novel coronavirus, called SARS-CoV-2, enters the nose and throat. It finds a welcome home in the lining of the nose, according to a preprint from scientists at the Wellcome Sanger Institute and elsewhere. They found that cells there are rich in a cell-surface receptor called angiotensin-converting enzyme 2 (ACE2). Throughout the body, the presence of ACE2, which normally helps regulate blood pressure, marks tissues vulnerable to infection, because the virus requires that receptor to enter a cell. Once inside, the virus hijacks the cell’s machinery, making myriad copies of itself and invading new cells.

As the virus multiplies, an infected person may shed copious amounts of it, especially during the first week or so. Symptoms may be absent at this point. Or the virus’ new victim may develop a fever, dry cough, sore throat, loss of smell and taste, or head and body aches.

If the immune system doesn’t beat back SARS-CoV-2 during this initial phase, the virus then marches down the windpipe to attack the lungs, where it can turn deadly. The thinner, distant branches of the lung’s respiratory tree end in tiny air sacs called alveoli, each lined by a single layer of cells that are also rich in ACE2 receptors.

Normally, oxygen crosses the alveoli into the capillaries, tiny blood vessels that lie beside the air sacs; the oxygen is then carried to the rest of the body. But as the immune system wars with the invader, the battle itself disrupts this healthy oxygen transfer. Front-line white blood cells release inflammatory molecules called chemokines, which in turn summon more immune cells that target and kill virus-infected cells, leaving a stew of fluid and dead cells—pus—behind. This is the underlying pathology of pneumonia, with its corresponding symptoms: coughing; fever; and rapid, shallow respiration (see graphic). Some COVID-19 patients recover, sometimes with no more support than oxygen breathed in through nasal prongs.

But others deteriorate, often quite suddenly, developing a condition called acute respiratory distress syndrome (ARDS). Oxygen levels in their blood plummet and they struggle ever harder to breathe. On x-rays and computed tomography scans, their lungs are riddled with white opacities where black space—air—should be. Commonly, these patients end up on ventilators. Many die. Autopsies show their alveoli became stuffed with fluid, white blood cells, mucus, and the detritus of destroyed lung cells.

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Clinical determinants of the severity of COVID-19: A systematic review and meta-analysis




We aimed to systematically identify the possible risk factors responsible for severe cases.


We searched PubMed, Embase, Web of science and Cochrane Library for epidemiological studies of confirmed COVID-19, which include information about clinical characteristics and severity of patients’ disease. We analyzed the potential associations between clinical characteristics and severe cases.


We identified a total of 41 eligible studies including 21060 patients with COVID-19. Severe cases were potentially associated with advanced age (Standard Mean Difference (SMD) = 1.73, 95% CI: 1.34–2.12), male gender (Odds Ratio (OR) = 1.51, 95% CI:1.33–1.71), obesity (OR = 1.89, 95% CI: 1.44–2.46), history of smoking (OR = 1.40, 95% CI:1.06–1.85), hypertension (OR = 2.42, 95% CI: 2.03–2.88), diabetes (OR = 2.40, 95% CI: 1.98–2.91), coronary heart disease (OR: 2.87, 95% CI: 2.22–3.71), chronic kidney disease (CKD) (OR = 2.97, 95% CI: 1.63–5.41), cerebrovascular disease (OR = 2.47, 95% CI: 1.54–3.97), chronic obstructive pulmonary disease (COPD) (OR = 2.88, 95% CI: 1.89–4.38), malignancy (OR = 2.60, 95% CI: 2.00–3.40), and chronic liver disease (OR = 1.51, 95% CI: 1.06–2.17). Acute respiratory distress syndrome (ARDS) (OR = 39.59, 95% CI: 19.99–78.41), shock (OR = 21.50, 95% CI: 10.49–44.06) and acute kidney injury (AKI) (OR = 8.84, 95% CI: 4.34–18.00) were most likely to prevent recovery. In summary, patients with severe conditions had a higher rate of comorbidities and complications than patients with non-severe conditions.


Patients who were male, with advanced age, obesity, a history of smoking, hypertension, diabetes, malignancy, coronary heart disease, hypertension, chronic liver disease, COPD, or CKD are more likely to develop severe COVID-19 symptoms. ARDS, shock and AKI were thought to be the main hinderances to recovery.

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Coronavirus and the Nervous System

What is SARS-CoV-2 and COVID-19?

Coronaviruses are common causes of usually mild to moderate upper respiratory tract illnesses like the common cold, with symptoms that may include runny nose, fever, sore throat, cough, or a general feeling of being ill. However, a new coronavirus called Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) emerged and spread to cause the COVID-19 pandemic.

COVID-19, which means Coronavirus disease 2019, is an infectious disease that can affect people of all ages in many ways. It is most dangerous when the virus spreads from the upper respiratory tract into the lungs to cause viral pneumonia and lung damage leading to Acute Respiratory Distress Syndrome (ARDS). When severe, this impairs the body’s ability to maintain critical levels of oxygen in the blood stream—which can cause multiple body systems to fail and can be fatal.

What do we know about the effects of SARS-CoV-2 and COVID-19 on the nervous system?

Much of the research to date has focused on the acute infection and saving lives. These strategies have included preventing infection with vaccines, treating COVID-19 symptoms with medicines or antibodies, and reducing complications in infected individuals.

Research shows the many neurological symptoms of COVID-19 are likely a result of the body’s widespread immune response to infection rather than the virus directly infecting the brain or nervous system. In some people, the SARS-CoV-2 infection causes an overreactive response of the immune system which can also damage body systems. Changes in the immune system have been seen in studies of the cerebrospinal fluid, which bathes the brain, in people who have been infected by SARS-CoV-2. This includes the presence of antibodies—proteins made by the immune system to fight the virus—that may also react with the nervous system. Although still under intense investigation, there is no evidence of widespread viral infection in the brain. Scientists are still learning how the virus affects the brain and other organs in the long-term. Research is just beginning to focus on the role of autoimmune reactions and other changes that cause the set of symptoms that some people experience after their initial recovery. It is unknown if injury to the nervous system or other body organs cause lingering effects that will resolve over time, or whether COVID-19 infection sets up a more persistent or even chronic disorder.

What are the immediate (acute) effects of SARS-CoV-2 and COVID-19 on the brain?

Most people infected with SARS-CoV-2 virus will have no or mild to moderate symptoms associated with the brain or nervous system. However, most individuals hospitalized due to the virus do have symptoms related to the brain or nervous system, most commonly including muscle aches, headaches, dizziness, and altered taste and smell. Some people with COVID-19 either initially have, or develop in the hospital, a dramatic state of confusion called delirium. Although rare, COVID-19 can cause seizures or major strokes. Muscular weakness, nerve injury, and pain syndromes are common in people who require intensive care during infections. There are also very rare reports of conditions that develop after SARS-CoV-2 infection, as they sometimes do with other types of infections. These disorders of inflammation in the nervous system include Guillain-Barré syndrome (which affects nerves), transverse myelitis (which affects the spinal cord), and acute necrotizing leukoencephalopathy (which affects the brain).

Bleeding in the brain, weakened blood vessels, and blood clots in acute infection

The SARS-CoV-2 virus attaches to a specific molecule (called a receptor) on the surface of cells in the body. This molecule is concentrated in the lung cells but is also present on certain cells that line blood vessels in the body. The infection causes some arteries and veins—including those in the brain—to  become thin, weaken, and leak. Breaks in small blood vessels have caused bleeding in the brain (so-called microbleeds) in some people with COVID-19 infection. Studies in people who have died due to COVID-19 infection show leaky blood vessels in different areas of the brain that allow water and a host of other molecules as well as blood cells that are normally excluded from the brain to move from the blood stream into the brain. This leak, as well as the resulting inflammation around blood vessels, can cause multiple small areas of damage. COVID-19 also causes blood cells to clump and form clots in arteries and veins throughout the body. These blockages reduce or block the flow of blood, oxygen, and nutrients that cells need to function and can lead to a stroke or heart attack.

stroke is a sudden interruption of continuous blood flow to the brain. A stroke occurs either when a blood vessel in the brain becomes blocked or narrowed or when a blood vessel bursts and spills blood into the brain. Strokes can damage brain cells and cause permanent disability. The blood clots and vascular (relating to the veins, capillaries, and arteries in the body) damage from COVID-19 can cause strokes even in young healthy adults who do not have the common risk factors for stroke.

COVID-19 can cause blood clots in other parts of the body, too. A blood clot in or near the heart can cause a heart attack. A heart attack orInflammation in the heart, called myocarditis, can causeheart failure, and reduce the flow of blood to other parts of the body. A blood clot in the lungs can impair breathing and cause pain. Blood clots also can damage the kidneys and other organs.

Low levels of oxygen in the body (called hypoxia) can permanently damage the brain and other vital organs in the body. Some hospitalized individuals require artificial ventilation on respirators. To avoid chest movements that oppose use of the ventilator it may be necessary to temporarily “paralyze” the person and use anesthetic drugs to put the individual to sleep. Some individuals with severe hypoxia require artificial means of bringing oxygen into their blood stream, a technique called extra corporeal membrane oxygenation (ECMO). Hypoxia combined with these intensive care unit measure generally cause cognitive disorders that show slow recovery.

Diagnostic imaging of some people who have had COVID-19 show changes in the brain’s white matter that contains the long nerve fibers, or “wires,” over which information flows from one brain region to another. These changes may be due to a lack of oxygen in the brain, the inflammatory immune system response to the virus, injury to blood vessels, or leaky blood vessels. This “diffuse white matter disease” might contribute to cognitive difficulties in people with COVID-19. Diffuse white matter disease is not uncommon in individuals requiring intensive hospital care but it not clear if it also occurs in those with mild to moderate severity of COVID-19 illness.

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The characteristics and evolution of pulmonary fibrosis in COVID-19 patients as assessed by AI-assisted chest HRCT



The characteristics and evolution of pulmonary fibrosis in patients with coronavirus disease 2019 (COVID-19) have not been adequately studied. AI-assisted chest high-resolution computed tomography (HRCT) was used to investigate the proportion of COVID-19 patients with pulmonary fibrosis, the relationship between the degree of fibrosis and the clinical classification of COVID-19, the characteristics of and risk factors for pulmonary fibrosis, and the evolution of pulmonary fibrosis after discharge. The incidence of pulmonary fibrosis in patients with severe or critical COVID-19 was significantly higher than that in patients with moderate COVID-19. There were significant differences in the degree of pulmonary inflammation and the extent of the affected area among patients with mild, moderate and severe pulmonary fibrosis. The IL-6 level in the acute stage and albumin level were independent risk factors for pulmonary fibrosis. Ground-glass opacities, linear opacities, interlobular septal thickening, reticulation, honeycombing, bronchiectasis and the extent of the affected area were significantly improved 30, 60 and 90 days after discharge compared with at discharge. The more severe the clinical classification of COVID-19, the more severe the residual pulmonary fibrosis was; however, in most patients, pulmonary fibrosis was improved or even resolved within 90 days after discharge.


Pulmonary fibrosis can occur as a serious complication of viral pneumonia, which often leads to dyspnea and impaired lung function. It significantly affects quality of life and is associated with increased mortality in severe cases [12]. Patients with confirmed severe acute respiratory syndrome coronavirus (SARS‐CoV) or Middle East respiratory syndrome coronavirus (MERS‐CoV) infections were found to have different degrees of pulmonary fibrosis after hospital discharge, and some still had residual pulmonary fibrosis and impaired lung function two years later. In addition, wheezing and dyspnea have also been reported in critically ill patients [35].

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel Betacoronavirus that is responsible for an outbreak of acute respiratory illness known as coronavirus disease 2019 (COVID-19). SARS-CoV-2 shares 85% of its genome with the bat coronavirus bat-SL-CoVZC45 [6]. However, there are still some considerable differences between SARS-CoV-2 and SARS‐CoV or MERS‐CoV. Whether COVID-19 can trigger irreversible pulmonary fibrosis deserves more investigation. George reported that COVID-19 was associated with extensive respiratory deterioration, especially acute respiratory distress syndrome (ARDS), which suggested that there could be substantial fibrotic consequences of infection with SARS-CoV-2 [7]. Moreover, it has also been shown that the pathological manifestations of COVID-19 strongly resemble those of SARS and MERS [8], with pulmonary carnification and pulmonary fibrosis in the late stages.

Chest X-rays and high-resolution computed tomography (HRCT) of the chest play important auxiliary roles in the diagnosis and management of patients with suspected cases of COVID-19 [910]. The newly applied artificial intelligence (AI)-assisted pneumonia diagnosis system has been described as an objective tool that can be used to qualitatively and quantitatively assess the progression of pulmonary inflammation [11]. At present, although COVID-19 has been classified as a global epidemic for months, the risk factors for and severity and evolution of pulmonary fibrosis have not yet been reported. In this study, this new technology was applied to investigate the pulmonary imaging characteristics and related risk factors in COVID-19 patients at the time of hospital discharge, as well as the evolution of pulmonary fibrosis 30, 60 and 90 days after discharge, with the aim of providing an important basis for the clinical diagnosis, treatment and prognostic prediction of COVID-19-related pulmonary fibrosis.

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Ivermectin to prevent hospitalizations in patients with COVID-19 (IVERCOR-COVID19) a randomized, double-blind, placebo-controlled trial



Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) has changed our lives. The scientific community has been investigating re-purposed treatments to prevent disease progression in coronavirus disease (COVID-19) patients.


To determine whether ivermectin treatment can prevent hospitalization in individuals with early COVID-19.

Design, setting and participants: A randomized, double-blind, placebo-controlled study was conducted in non-hospitalized individuals with COVID-19 in Corrientes, Argentina. Patients with SARS-CoV-2 positive nasal swabs were contacted within 48 h by telephone to invite them to participate. The trial randomized 501 patients between August 19th 2020 and February 22nd 2021.


Patients were randomized to ivermectin (N = 250) or placebo (N = 251) arms in a staggered dose, according to the patient’s weight, for 2 days.

Main outcomes and measures

The efficacy of ivermectin to prevent hospitalizations was evaluated as primary outcome. We evaluated secondary outcomes in relationship to safety and other efficacy end points.


The mean age was 42 years (SD ± 15.5) and the median time since symptom onset to the inclusion was 4 days [interquartile range 3–6]. The primary outcome of hospitalization was met in 14/250 (5.6%) individuals in ivermectin group and 21/251 (8.4%) in placebo group (odds ratio 0.65; 95% confidence interval, 0.32–1.31; p = 0.227). Time to hospitalization was not statistically different between groups. The mean time from study enrollment to invasive mechanical ventilatory support (MVS) was 5.25 days (SD ± 1.71) in ivermectin group and 10 days (SD ± 2) in placebo group, (p = 0.019). There were no statistically significant differences in the other secondary outcomes including polymerase chain reaction test negativity and safety outcomes.


Low percentage of hospitalization events, dose of ivermectin and not including only high-risk population.


Ivermectin had no significant effect on preventing hospitalization of patients with COVID-19. Patients who received ivermectin required invasive MVS earlier in their treatment. No significant differences were observed in any of the other secondary outcomes.

Trial registration NCT04529525.

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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


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.

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