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1.
PLoS Genet ; 18(3): e1010042, 2022 03.
Article in English | MEDLINE | ID: covidwho-1793655

ABSTRACT

In November 2021, the COVID-19 pandemic death toll surpassed five million individuals. We applied Mendelian randomization including >3,000 blood proteins as exposures to identify potential biomarkers that may indicate risk for hospitalization or need for respiratory support or death due to COVID-19, respectively. After multiple testing correction, using genetic instruments and under the assumptions of Mendelian Randomization, our results were consistent with higher blood levels of five proteins GCNT4, CD207, RAB14, C1GALT1C1, and ABO being causally associated with an increased risk of hospitalization or respiratory support/death due to COVID-19 (ORs = 1.12-1.35). Higher levels of FAAH2 were solely associated with an increased risk of hospitalization (OR = 1.19). On the contrary, higher levels of SELL, SELE, and PECAM-1 decrease risk of hospitalization or need for respiratory support/death (ORs = 0.80-0.91). Higher levels of LCTL, SFTPD, KEL, and ATP2A3 were solely associated with a decreased risk of hospitalization (ORs = 0.86-0.93), whilst higher levels of ICAM-1 were solely associated with a decreased risk of respiratory support/death of COVID-19 (OR = 0.84). Our findings implicate blood group markers and binding proteins in both hospitalization and need for respiratory support/death. They, additionally, suggest that higher levels of endocannabinoid enzymes may increase the risk of hospitalization. Our research replicates findings of blood markers previously associated with COVID-19 and prioritises additional blood markers for risk prediction of severe forms of COVID-19. Furthermore, we pinpoint druggable targets potentially implicated in disease pathology.


Subject(s)
Blood Proteins/metabolism , COVID-19/blood , COVID-19/pathology , Biomarkers/analysis , Biomarkers/blood , Blood Proteins/analysis , Blood Proteins/genetics , COVID-19/diagnosis , COVID-19/mortality , Causality , Genome-Wide Association Study , Hospitalization , Humans , Mendelian Randomization Analysis , Mortality , Pandemics , Polymorphism, Single Nucleotide , Prognosis , Proteome/analysis , Proteome/genetics , Proteome/metabolism , Respiratory Insufficiency/blood , Respiratory Insufficiency/diagnosis , Respiratory Insufficiency/mortality , Respiratory Insufficiency/pathology , Risk Factors , SARS-CoV-2/physiology , Severity of Illness Index
2.
Int J Mol Sci ; 23(3)2022 Jan 29.
Article in English | MEDLINE | ID: covidwho-1667195

ABSTRACT

(1) Background: In COVID-19 survivors there is an increased prevalence of pulmonary fibrosis of which the underlying molecular mechanisms are poorly understood; (2) Methods: In this multicentric study, n = 12 patients who succumbed to COVID-19 due to progressive respiratory failure were assigned to an early and late group (death within ≤7 and >7 days of hospitalization, respectively) and compared to n = 11 healthy controls; mRNA and protein expression as well as biological pathway analysis were performed to gain insights into the evolution of pulmonary fibrogenesis in COVID-19; (3) Results: Median duration of hospitalization until death was 3 (IQR25-75, 3-3.75) and 14 (12.5-14) days in the early and late group, respectively. Fifty-eight out of 770 analyzed genes showed a significantly altered expression signature in COVID-19 compared to controls in a time-dependent manner. The entire study group showed an increased expression of BST2 and IL1R1, independent of hospitalization time. In the early group there was increased activity of inflammation-related genes and pathways, while fibrosis-related genes (particularly PDGFRB) and pathways dominated in the late group; (4) Conclusions: After the first week of hospitalization, there is a shift from pro-inflammatory to fibrogenic activity in severe COVID-19. IL1R1 and PDGFRB may serve as potential therapeutic targets in future studies.


Subject(s)
COVID-19/genetics , COVID-19/metabolism , Pulmonary Fibrosis/pathology , Aged , COVID-19/mortality , Female , Hospital Mortality/trends , Hospitalization , Humans , Lung/pathology , Male , Middle Aged , Pulmonary Fibrosis/metabolism , Respiratory Insufficiency/pathology , SARS-CoV-2/pathogenicity
3.
Front Immunol ; 12: 708101, 2021.
Article in English | MEDLINE | ID: covidwho-1365543

ABSTRACT

Background: Plasma levels of C-reactive protein (CRP), induced by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) triggering COVID-19, can rise surprisingly high. The increase of the CRP concentration as well as a certain threshold concentration of CRP are indicative of clinical deterioration to artificial ventilation. In COVID-19, virus-induced lung injury and the subsequent massive onset of inflammation often drives pulmonary fibrosis. Fibrosis of the lung usually proceeds as sequela to a severe course of COVID-19 and its consequences only show months later. CRP-mediated complement- and macrophage activation is suspected to be the main driver of pulmonary fibrosis and subsequent organ failure in COVID-19. Recently, CRP apheresis was introduced to selectively remove CRP from human blood plasma. Case Report: A 53-year-old, SARS-CoV-2 positive, male patient with the risk factor diabetes type 2 was referred with dyspnea, fever and fulminant increase of CRP. The patient's lungs already showed a pattern enhancement as an early sign of incipient pneumonia. The oxygen saturation of the blood was ≤ 89%. CRP apheresis using the selective CRP adsorber (PentraSorb® CRP) was started immediately. CRP apheresis was performed via peripheral venous access on 4 successive days. CRP concentrations before CRP apheresis ranged from 47 to 133 mg/l. The removal of CRP was very effective with up to 79% depletion within one apheresis session and 1.2 to 2.14 plasma volumes were processed in each session. No apheresis-associated side effects were observed. It was at no point necessary to transfer the patient to the Intensive Care Unit or to intubate him due to respiratory failure. 10 days after the first positive SARS-CoV-2 test, CRP levels stayed below 20 mg/l and the patient no longer exhibited fever. Fourteen days after the first positive SARS-CoV-2 test, the lungs showed no sign of pneumonia on X-ray. Conclusion: This is the first report on CRP apheresis in an early COVID-19 patient with fulminant CRP increase. Despite a poor prognosis due to his diabetes and biomarker profile, the patient was not ventilated, and the onset of pneumonia was reverted.


Subject(s)
Blood Component Removal/methods , C-Reactive Protein/metabolism , COVID-19/therapy , Respiratory Insufficiency/prevention & control , C-Reactive Protein/analysis , C-Reactive Protein/immunology , COVID-19/blood , COVID-19/complications , COVID-19/immunology , Humans , Lung/diagnostic imaging , Lung/immunology , Male , Middle Aged , Respiratory Insufficiency/immunology , Respiratory Insufficiency/pathology , Respiratory Insufficiency/virology , SARS-CoV-2/immunology , SARS-CoV-2/isolation & purification , Treatment Outcome
4.
J Pediatr Hematol Oncol ; 43(6): e859-e860, 2021 08 01.
Article in English | MEDLINE | ID: covidwho-1348084

ABSTRACT

The novel coronavirus, SARS-CoV-2, causes much more severe disease in adults than in children. Although it is anticipated that immune compromised children and children with cancer may be at higher risk of developing severe or fatal COVID-19, there are no currently published reports of fatal disease in a child with cancer. Because of the discrepancy in disease severity between adult and pediatric patients, we report the case of an adolescent with pulmonary metastatic osteosarcoma who died of COVID-19 early in the course of the pandemic in New York City in the hope that heightening awareness that pulmonary metastatic disease may predispose to a more severe outcome will increase surveillance in this vulnerable population.


Subject(s)
Bone Neoplasms/pathology , COVID-19/complications , Lung Neoplasms/secondary , Osteosarcoma/pathology , Respiratory Insufficiency/pathology , SARS-CoV-2/isolation & purification , Bone Neoplasms/complications , Bone Neoplasms/virology , COVID-19/virology , Child , Humans , Lung Neoplasms/complications , Lung Neoplasms/virology , Male , Osteosarcoma/complications , Osteosarcoma/virology , Respiratory Insufficiency/etiology , Severity of Illness Index
5.
Immunity ; 54(7): 1594-1610.e11, 2021 07 13.
Article in English | MEDLINE | ID: covidwho-1281436

ABSTRACT

COVID-19 can cause severe neurological symptoms, but the underlying pathophysiological mechanisms are unclear. Here, we interrogated the brain stems and olfactory bulbs in postmortem patients who had COVID-19 using imaging mass cytometry to understand the local immune response at a spatially resolved, high-dimensional, single-cell level and compared their immune map to non-COVID respiratory failure, multiple sclerosis, and control patients. We observed substantial immune activation in the central nervous system with pronounced neuropathology (astrocytosis, axonal damage, and blood-brain-barrier leakage) and detected viral antigen in ACE2-receptor-positive cells enriched in the vascular compartment. Microglial nodules and the perivascular compartment represented COVID-19-specific, microanatomic-immune niches with context-specific cellular interactions enriched for activated CD8+ T cells. Altered brain T-cell-microglial interactions were linked to clinical measures of systemic inflammation and disturbed hemostasis. This study identifies profound neuroinflammation with activation of innate and adaptive immune cells as correlates of COVID-19 neuropathology, with implications for potential therapeutic strategies.


Subject(s)
Brain/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , Microglia/immunology , Blood-Brain Barrier/immunology , Blood-Brain Barrier/metabolism , Blood-Brain Barrier/pathology , Brain/metabolism , Brain/pathology , CD8-Positive T-Lymphocytes/metabolism , COVID-19/pathology , Cell Communication , Central Nervous System/immunology , Central Nervous System/metabolism , Central Nervous System/pathology , Humans , Immune Checkpoint Proteins/metabolism , Inflammation , Lymphocyte Activation , Multiple Sclerosis/immunology , Multiple Sclerosis/pathology , Olfactory Bulb/immunology , Olfactory Bulb/metabolism , Olfactory Bulb/pathology , Respiratory Insufficiency/immunology , Respiratory Insufficiency/pathology , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/metabolism , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism
6.
Mycoses ; 64(10): 1223-1229, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1280362

ABSTRACT

BACKGROUND: An increasing number of reports have described the COVID-19-associated pulmonary aspergillosis (CAPA) as being a further contributing factor to mortality. Based on a recent consensus statement supported by international medical mycology societies, it has been proposed to define CAPA as possible, probable, or proven on the basis of sample validity and thus diagnostic certainty. Considering current challenges associated with proven diagnoses, there is pressing need to study the epidemiology of proven CAPA. METHODS: We report the incidence of histologically diagnosed CAPA in a series of 45 consecutive COVID-19 laboratory-confirmed autopsies, performed at Padova University Hospital during the first and second wave of the pandemic. Clinical data, laboratory data and radiological features were also collected for each case. RESULTS: Proven CAPA was detected in 9 (20%) cases, mainly in the second wave of the pandemic (7/17 vs. 2/28 of the first wave). The population of CAPA patients consisted of seven males and two females, with a median age of 74 years. Seven patients were admitted to the intensive care unit. All patients had at least two comorbidities, and concomitant lung diseases were detected in three cases. CONCLUSION: We found a high frequency of proven CAPA among patients with severe COVID-19 thus confirming at least in part the alarming epidemiological data of this important complication recently reported as probable CAPA.


Subject(s)
COVID-19/epidemiology , Invasive Pulmonary Aspergillosis/epidemiology , Respiratory Insufficiency/mortality , Aged , Aged, 80 and over , Aspergillus , COVID-19/mortality , COVID-19/pathology , Comorbidity , Female , Humans , Intensive Care Units , Invasive Pulmonary Aspergillosis/mortality , Invasive Pulmonary Aspergillosis/pathology , Male , Middle Aged , Respiratory Insufficiency/microbiology , Respiratory Insufficiency/pathology , SARS-CoV-2
7.
Am J Physiol Lung Cell Mol Physiol ; 321(1): L213-L218, 2021 07 01.
Article in English | MEDLINE | ID: covidwho-1234311

ABSTRACT

The renin-angiotensin system (RAS) is fundamental to COVID-19 pathobiology, due to the interaction between the SARS-CoV-2 virus and the angiotensin-converting enzyme 2 (ACE2) coreceptor for cellular entry. The prevailing hypothesis is that SARS-CoV-2-ACE2 interactions lead to an imbalance of the RAS, favoring proinflammatory angiotensin II (ANG II)-related signaling at the expense of the anti-inflammatory ANG-(1-7)-mediated alternative pathway. Indeed, multiple clinical trials targeting this pathway in COVID-19 are underway. Therefore, precise measurement of circulating RAS components is critical to understand the interplay of the RAS on COVID-19 outcomes. Multiple challenges exist in measuring the RAS in COVID-19, including improper patient controls, ex vivo degradation and low concentrations of angiotensins, and unvalidated laboratory assays. Here, we conducted a prospective pilot study to enroll 33 patients with moderate and severe COVID-19 and physiologically matched COVID-19-negative controls to quantify the circulating RAS. Our enrollment strategy led to physiological matching of COVID-19-negative and COVID-19-positive moderate hypoxic respiratory failure cohorts, in contrast to the severe COVID-19 cohort, which had increased severity of illness, prolonged intensive care unit (ICU) stay, and increased mortality. Circulating ANG II and ANG-(1-7) levels were measured in the low picomolar (pM) range. We found no significant differences in circulating RAS peptides or peptidases between these three cohorts. The combined moderate and severe COVID-19-positive cohorts demonstrated a mild reduction in ACE activity compared with COVID-19-negative controls (2.2 ± 0.9 × 105 vs. 2.9 ± 0.8 × 105 RFU/mL, P = 0.03). These methods may be useful in designing larger studies to physiologically match patients and quantify the RAS in COVID-19 RAS augmenting clinical trials.


Subject(s)
Angiotensin II/blood , Angiotensin I/blood , Angiotensin-Converting Enzyme 2/blood , COVID-19/blood , Peptide Fragments/blood , Renin-Angiotensin System , Respiratory Insufficiency/blood , SARS-CoV-2/metabolism , Adult , Aged , COVID-19/pathology , COVID-19/physiopathology , Female , Humans , Male , Middle Aged , Pilot Projects , Respiratory Insufficiency/pathology , Respiratory Insufficiency/physiopathology
8.
Medicina (Kaunas) ; 57(4)2021 Mar 24.
Article in English | MEDLINE | ID: covidwho-1154448

ABSTRACT

Background: Establishing the diagnosis of COVID-19 and Pneumocystisjirovecii pulmonary coinfection is difficult due to clinical and radiological similarities that exist between the two disorders. For the moment, fungal coinfections are underestimated in COVID-19 patients. Case presentation: We report the case of a 52-year-old male patient, who presented to the emergency department for severe dyspnea and died 17 h later. The RT-PCR test performed at his admission was negative for SARS-CoV-2. Retesting of lung fragments collected during autopsy revealed a positive result for SARS-CoV-2. Histopathological examination showed preexisting lesions, due to comorbidities, as well as recent lesions: massive lung thromboses, alveolar exudate rich in foam cells, suprapleural and intra-alveolar Pneumocystisjirovecii cystic forms, and bilateral adrenal hemorrhage. Conclusion: COVID-19 and P.jirovecii coinfection should be considered, particularly in critically ill patients, and we recommend the systematic search for P. jirovecii in respiratory samples.


Subject(s)
COVID-19/pathology , Lung/pathology , Pneumonia, Pneumocystis/pathology , Respiratory Insufficiency/pathology , Thrombosis/pathology , Acute Kidney Injury/complications , Acute-On-Chronic Liver Failure/complications , Adrenal Gland Diseases/complications , Adrenal Gland Diseases/pathology , Autopsy , COVID-19/complications , Coinfection/pathology , Exudates and Transudates , Fatal Outcome , Fibrosis , Foam Cells/pathology , Hemorrhage/complications , Hemorrhage/pathology , Humans , Hypertension/complications , Liver Diseases, Alcoholic/complications , Male , Middle Aged , Myocardial Ischemia/complications , Pneumonia, Pneumocystis/complications , Pulmonary Artery/pathology , Pulmonary Veins/pathology , Respiratory Insufficiency/etiology , SARS-CoV-2 , Thrombosis/etiology
9.
Virchows Arch ; 479(4): 827-833, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1012211

ABSTRACT

We present results from clinical, radiologic, gas exchange, lung mechanics, and fibre-optic bronchoscopy-guided transbronchial biopsies in a case of acute respiratory failure due to SARS-CoV-2 (Covid-19). This report highlights the pulmonary, immunological, and inflammatory changes found during acute diffuse alveolar damage and the later organizing phase. An early diffuse alveolar damage pattern with predominant epithelial involvement with active recruitment of T cells and monocytes was observed followed by a late organizing pattern with pneumocyte hyperplasia, inflammatory infiltration, prominent endotheliitis, and secondary germinal centers. The patient's deterioration paralleling the late immuno-pathological findings based the decision to administer intravenous corticosteroids, resulting in clinical, gasometric, and radiologic improvement. We believe that real-time clinicopathological correlation, along with the description of the immunological processes at play, will contribute to the full clinical picture of Covid-19 and might lead to a more rational approach in the precise timing of anti-inflammatory, anti-cytokine, or steroid therapies.


Subject(s)
Bronchi/pathology , COVID-19/drug therapy , Steroids/therapeutic use , Aged , Alveolar Epithelial Cells/metabolism , Alveolar Epithelial Cells/virology , Biopsy/methods , Bronchi/virology , COVID-19/pathology , COVID-19/virology , Humans , Lung/pathology , Male , Pulmonary Alveoli/metabolism , Pulmonary Alveoli/virology , Respiratory Insufficiency/drug therapy , Respiratory Insufficiency/pathology , Respiratory Insufficiency/virology , SARS-CoV-2/isolation & purification
10.
Platelets ; 32(4): 560-567, 2021 May 19.
Article in English | MEDLINE | ID: covidwho-998117

ABSTRACT

The aim of this study (NCT04343053) is to investigate the relationship between platelet activation, myocardial injury, and mortality in patients affected by Coronavirus disease 2019 (COVID-19). Fifty-four patients with respiratory failure due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection were enrolled as cases. Eleven patients with the same clinical presentation, but negative for SARS-CoV-2 infection, were included as controls. Blood samples were collected at three different time points (inclusion [T1], after 7 ± 2 days [T2] and 14 ± 2 days [T3]). Platelet aggregation by light transmittance aggregometry and the circulating levels of soluble CD40 ligand (sCD40L) and P-selectin were measured. Platelet biomarkers did not differ between cases and controls, except for sCD40L which was higher in COVID-19 patients (p = .003). In COVID-19 patients, P-selectin and sCD40L levels decreased from T1 to T3 and were higher in cases requiring admission to intensive care unit (p = .004 and p = .008, respectively). Patients with myocardial injury (37%), as well as those who died (30%), had higher values of all biomarkers of platelet activation (p < .05 for all). Myocardial injury was an independent predictor of mortality. In COVID-19 patients admitted to hospital for respiratory failure, heightened platelet activation is associated with severity of illness, myocardial injury, and mortality.ClinicalTrials.gov number: NCT04343053.


Subject(s)
Blood Platelets/metabolism , COVID-19 , Heart Injuries , Myocardium , Respiratory Insufficiency , SARS-CoV-2/metabolism , Aged , Aged, 80 and over , Biomarkers/blood , CD40 Ligand/blood , COVID-19/blood , COVID-19/mortality , COVID-19/pathology , Female , Heart Injuries/blood , Heart Injuries/mortality , Heart Injuries/pathology , Heart Injuries/virology , Humans , Male , Middle Aged , Myocardium/metabolism , Myocardium/pathology , P-Selectin/blood , Platelet Aggregation , Respiratory Insufficiency/blood , Respiratory Insufficiency/mortality , Respiratory Insufficiency/pathology , Respiratory Insufficiency/virology
11.
Cytokine ; 138: 155389, 2021 02.
Article in English | MEDLINE | ID: covidwho-973995

ABSTRACT

BACKGROUND: The infection caused by SARS CoV-2 has been postulated to induce a cytokine storm syndrome that results in organ failure and even death in a considerable number of patients. However, the inflammatory response in Corona virus disease-19 (Covid-19) and its potential to cause collateral organ damage has not been fully elucidated to date. This study aims to characterize the acute cytokine response in a cohort of critically ill Covid-19 patients. METHOD: 24 adults with PCR-confirmed Covid-19 were included at time of admission to intensive care a median of eleven days after initial symptoms. Eleven adult patients admitted for elective abdominal surgery with preoperative plasma samples served as controls. All patients were included after informed consent was obtained. 27 cytokines were quantified in plasma. The expression of inflammatory mediators was then related to routine inflammatory markers, SAPS3, SOFA score, organ failure and 30-day mortality. RESULTS: A general increase in cytokine expression was observed in all Covid-19 patients. A strong correlation between respiratory failure and IL-1ra, IL-4, IL-6, IL-8 and IP-10 expression was observed. Acute kidney injury development correlated well with increased levels of IL-1ra, IL-6, IL-8, IL-17a, IP-10 and MCP-1. Generally, the cohort demonstrated weaker correlations between cytokine expression and 30-day mortality out of which IL-8 showed the strongest signal in terms of mortality. CONCLUSION: The present study found that respiratory failure, acute kidney injury and 30-day mortality in critically ill Covid-19 patients are associated with moderate increases of a broad range of inflammatory mediators at time of admission.


Subject(s)
Acute Kidney Injury/pathology , COVID-19/pathology , Cytokine Release Syndrome/mortality , Cytokines/blood , Respiratory Insufficiency/pathology , Acute Kidney Injury/virology , Aged , Biomarkers/blood , COVID-19/blood , COVID-19/mortality , Critical Illness , Cytokine Release Syndrome/pathology , Female , Humans , Male , Middle Aged , Respiratory Insufficiency/virology , SARS-CoV-2/immunology
12.
FEBS J ; 287(17): 3681-3688, 2020 09.
Article in English | MEDLINE | ID: covidwho-960853

ABSTRACT

In coronavirus disease 2019 (COVID-19), higher morbidity and mortality are associated with age, male gender, and comorbidities, such as chronic lung diseases, cardiovascular pathologies, hypertension, kidney diseases, diabetes mellitus, and obesity. All of the above conditions are characterized by increased sympathetic discharge, which may exert significant detrimental effects on COVID-19 patients, through actions on the lungs, heart, blood vessels, kidneys, metabolism, and/or immune system. Furthermore, COVID-19 may also increase sympathetic discharge, through changes in blood gases (chronic intermittent hypoxia, hyperpnea), angiotensin-converting enzyme (ACE)1/ACE2 imbalance, immune/inflammatory factors, or emotional distress. Nevertheless, the potential role of the sympathetic nervous system has not yet been considered in the pathophysiology of COVID-19. In our opinion, sympathetic overactivation could represent a so-far undervalued mechanism for a vicious circle between COVID-19 and comorbidities.


Subject(s)
COVID-19/metabolism , Coronary Disease/metabolism , Diabetes Mellitus/metabolism , Hypertension/metabolism , Kidney Failure, Chronic/metabolism , Obesity/metabolism , Respiratory Insufficiency/metabolism , Sympathetic Nervous System/metabolism , COVID-19/mortality , COVID-19/pathology , COVID-19/virology , Comorbidity , Coronary Disease/mortality , Coronary Disease/pathology , Coronary Disease/virology , Diabetes Mellitus/mortality , Diabetes Mellitus/pathology , Diabetes Mellitus/virology , Female , Humans , Hypertension/mortality , Hypertension/pathology , Hypertension/virology , Kidney Failure, Chronic/mortality , Kidney Failure, Chronic/pathology , Kidney Failure, Chronic/virology , Male , Obesity/mortality , Obesity/pathology , Obesity/virology , Respiratory Insufficiency/mortality , Respiratory Insufficiency/pathology , Respiratory Insufficiency/virology , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Severity of Illness Index , Sex Factors , Survival Analysis , Sympathetic Nervous System/physiopathology , Sympathetic Nervous System/virology
13.
J Infect Dis ; 222(11): 1794-1797, 2020 11 09.
Article in English | MEDLINE | ID: covidwho-919298

ABSTRACT

The Fibrosis-4 Index (FIB-4), developed to predict fibrosis in liver disease, was used to identify patients with coronavirus disease 2019 who will require ventilator support as well as those associated with 30-day mortality. Multivariate analysis found obesity (odds ratio [OR], 4.5), diabetes mellitus (OR, 2.55), and FIB-4 ≥2.67 (OR, 3.09) independently associated with need for mechanical ventilation. When controlling for ventilator use, sex, and comorbid conditions, FIB-4 ≥2.67 was also associated with increased 30-day mortality (OR, 8.4 [95% confidence interval, 2.23-31.7]). Although it may not be measuring hepatic fibrosis, its components suggest that increases in FIB-4 may be reflecting systemic inflammation associated with poor outcomes.


Subject(s)
COVID-19/pathology , COVID-19/therapy , Respiration, Artificial , Adult , Aged , COVID-19/mortality , Female , Hospitalization , Humans , Liver Diseases/mortality , Liver Diseases/pathology , Male , Middle Aged , Multivariate Analysis , Odds Ratio , Respiratory Insufficiency/pathology , Respiratory Insufficiency/therapy , Respiratory Insufficiency/virology , Risk Factors
15.
Mol Med ; 26(1): 95, 2020 10 14.
Article in English | MEDLINE | ID: covidwho-873932

ABSTRACT

Pulmonary fibrosis arises from the repeated epithelial mild injuries and insufficient repair lead to over activation of fibroblasts and excessive deposition of extracellular matrix, which result in a mechanical stretched niche. However, increasing mechanical stress likely exists before the establishment of fibrosis since early micro injuries increase local vascular permeability and prompt cytoskeletal remodeling which alter cellular mechanical forces. It is noteworthy that COVID-19 patients with severe hypoxemia will receive mechanical ventilation as supportive treatment and subsequent pathology studies indicate lung fibrosis pattern. At advanced stages, mechanical stress originates mainly from the stiff matrix since boundaries between stiff and compliant parts of the tissue could generate mechanical stress. Therefore, mechanical stress has a significant role in the whole development process of pulmonary fibrosis. The alveoli are covered by abundant capillaries and function as the main gas exchange unit. Constantly subject to variety of damages, the alveolar epithelium injuries were recently recognized to play a vital role in the onset and development of idiopathic pulmonary fibrosis. In this review, we summarize the literature regarding the effects of mechanical stress on the fundamental cells constituting the alveoli in the process of pulmonary fibrosis, particularly on epithelial cells, capillary endothelial cells, fibroblasts, mast cells, macrophages and stem cells. Finally, we briefly review this issue from a more comprehensive perspective: the metabolic and epigenetic regulation.


Subject(s)
Coronavirus Infections/immunology , Epigenesis, Genetic/immunology , Idiopathic Pulmonary Fibrosis/immunology , Mechanotransduction, Cellular/immunology , Pneumonia, Viral/immunology , Pulmonary Embolism/immunology , Respiratory Insufficiency/immunology , Alveolar Epithelial Cells/immunology , Alveolar Epithelial Cells/pathology , Betacoronavirus/immunology , Betacoronavirus/pathogenicity , Biomechanical Phenomena , COVID-19 , Coronavirus Infections/genetics , Coronavirus Infections/pathology , Coronavirus Infections/virology , Cytokines/genetics , Cytokines/immunology , Endothelial Cells/immunology , Endothelial Cells/pathology , Fibroblasts/immunology , Fibroblasts/pathology , Humans , Idiopathic Pulmonary Fibrosis/genetics , Idiopathic Pulmonary Fibrosis/pathology , Idiopathic Pulmonary Fibrosis/virology , Lung/blood supply , Lung/immunology , Lung/pathology , Macrophages/immunology , Macrophages/pathology , Mechanotransduction, Cellular/genetics , Pandemics , Pneumonia, Viral/genetics , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Pulmonary Embolism/genetics , Pulmonary Embolism/pathology , Pulmonary Embolism/virology , Respiratory Insufficiency/genetics , Respiratory Insufficiency/pathology , Respiratory Insufficiency/virology , SARS-CoV-2 , Stress, Mechanical
16.
Rev Med Virol ; 31(3): e2177, 2021 05.
Article in English | MEDLINE | ID: covidwho-815925

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel human respiratory viral infection that has rapidly progressed into a pandemic, causing significant morbidity and mortality. Blood clotting disorders and acute respiratory failure have surfaced as the major complications among the severe cases of coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection. Remarkably, more than 70% of deaths related to COVID-19 are attributed to clotting-associated complications such as pulmonary embolism, strokes and multi-organ failure. These vascular complications have been confirmed by autopsy. This study summarizes the current understanding and explains the possible mechanisms of the blood clotting disorder, emphasizing the role of (1) hypoxia-related activation of coagulation factors like tissue factor, a significant player in triggering coagulation cascade, (2) cytokine storm and activation of neutrophils and the release of neutrophil extracellular traps and (3) immobility and ICU related risk factors.


Subject(s)
COVID-19/genetics , Cytokine Release Syndrome/genetics , Disseminated Intravascular Coagulation/genetics , Hypoxia/genetics , Pulmonary Embolism/genetics , Respiratory Insufficiency/genetics , SARS-CoV-2/pathogenicity , COVID-19/blood , COVID-19/pathology , COVID-19/virology , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/pathology , Cytokine Release Syndrome/virology , Disseminated Intravascular Coagulation/blood , Disseminated Intravascular Coagulation/pathology , Disseminated Intravascular Coagulation/virology , Extracellular Traps/metabolism , Extracellular Traps/virology , Gene Expression Regulation , Humans , Hypoxia/blood , Hypoxia/pathology , Hypoxia/virology , Hypoxia-Inducible Factor 1, alpha Subunit/blood , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Interleukin-6/blood , Interleukin-6/genetics , Neutrophils/pathology , Neutrophils/virology , Pulmonary Embolism/blood , Pulmonary Embolism/pathology , Pulmonary Embolism/virology , Respiratory Insufficiency/blood , Respiratory Insufficiency/pathology , Respiratory Insufficiency/virology , SARS-CoV-2/growth & development , SARS-CoV-2/metabolism , Signal Transduction , Thromboplastin/genetics , Thromboplastin/metabolism
17.
Sci Adv ; 6(31)2020 07.
Article in English | MEDLINE | ID: covidwho-725277

ABSTRACT

The outbreak of the highly contagious and deadly severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also known as coronavirus disease 2019 (COVID-19), has posed a serious threat to public health across the globe, calling for the development of effective diagnostic markers and therapeutics. Here, we report a highly reliable severity diagnostic biomarker, acetylated 676th lysine transforming growth factor-beta-induced protein (TGFBIp K676Ac). TGFBIp K676Ac was consistently elevated in the blood of patients with SARS-CoV-2 pneumonia (n = 113), especially in patients in the intensive care unit (ICU) compared to non-ICU patients. Patients' blood samples showed increased cytokines and lymphopenia, which are exemplary indicators of SARS-CoV-2 pneumonia. Treatment with TGFBIp neutralizing antibodies suppressed the cytokine storm. The increased level of TGFBIp K676Ac in ICU patients suggests the promise of this protein as a reliable severity diagnostic biomarker for severe SARS-CoV-2 disease.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/diagnosis , Cytokine Release Syndrome/diagnosis , Extracellular Matrix Proteins/immunology , Leukocytes, Mononuclear/immunology , Pneumonia, Viral/diagnosis , Protein Processing, Post-Translational , Respiratory Insufficiency/diagnosis , Transforming Growth Factor beta/immunology , Acetylation , Antibodies, Neutralizing/pharmacology , Betacoronavirus/immunology , Biomarkers/blood , COVID-19 , Case-Control Studies , Coronavirus Infections/blood , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/pathology , Extracellular Matrix Proteins/antagonists & inhibitors , Extracellular Matrix Proteins/genetics , Gene Expression , Humans , Intensive Care Units , Leukocyte Count , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/pathology , Leukocytes, Mononuclear/virology , Lung/blood supply , Lung/drug effects , Lung/pathology , Lung/virology , Lysine/metabolism , NF-kappa B/genetics , NF-kappa B/immunology , Pandemics , Pneumonia, Viral/blood , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , Primary Cell Culture , Prognosis , Respiratory Insufficiency/blood , Respiratory Insufficiency/immunology , Respiratory Insufficiency/pathology , SARS-CoV-2 , Severity of Illness Index , Transforming Growth Factor beta/antagonists & inhibitors , Transforming Growth Factor beta/genetics
18.
Clin Immunol ; 220: 108545, 2020 11.
Article in English | MEDLINE | ID: covidwho-670405

ABSTRACT

COVID-19 rapidly turned to a global pandemic posing lethal threats to overwhelming health care capabilities, despite its relatively low mortality rate. The clinical respiratory symptoms include dry cough, fever, anosmia, breathing difficulties, and subsequent respiratory failure. No known cure is available for COVID-19. Apart from the anti-viral strategy, the supports of immune effectors and modulation of immunosuppressive mechanisms is the rationale immunomodulation approach in COVID-19 management. Diet and nutrition are essential for healthy immunity. However, a group of micronutrients plays a dominant role in immunomodulation. The deficiency of most nutrients increases the individual susceptibility to virus infection with a tendency for severe clinical presentation. Despite a shred of evidence, the supplementation of a single nutrient is not promising in the general population. Individuals at high-risk for specific nutrient deficiencies likely benefit from supplementation. The individual dietary and nutritional status assessments are critical for determining the comprehensive actions in COVID-19.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/diet therapy , Cough/diet therapy , Immunologic Factors/therapeutic use , Micronutrients/therapeutic use , Pandemics , Pneumonia, Viral/diet therapy , Betacoronavirus/drug effects , Betacoronavirus/immunology , COVID-19 , Coronavirus Infections/diagnosis , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Cough/diagnosis , Cough/immunology , Cough/pathology , Disease Management , Fever/diagnosis , Fever/diet therapy , Fever/immunology , Fever/pathology , Humans , Immunity, Cellular/drug effects , Immunity, Innate/drug effects , Olfaction Disorders/diagnosis , Olfaction Disorders/diet therapy , Olfaction Disorders/immunology , Olfaction Disorders/pathology , Pneumonia, Viral/diagnosis , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , Respiratory Insufficiency/diagnosis , Respiratory Insufficiency/diet therapy , Respiratory Insufficiency/immunology , Respiratory Insufficiency/pathology , SARS-CoV-2 , Severity of Illness Index , Trace Elements/therapeutic use , Vitamins/therapeutic use
19.
Liver Int ; 40(9): 2110-2116, 2020 09.
Article in English | MEDLINE | ID: covidwho-639586

ABSTRACT

SARS2-CoV-2 breakout in Italy caused a huge number of severely ill patients with a serious increase in mortality. Although lungs seem to be the main target of the infection, very few information are available about liver involvement, possibly evocating a systemic disease. Post-mortem wedge liver biopsies from 48 patients died from severe pulmonary COVID-19 disease with respiratory failure were collected from two main hospitals in northern Italy. No patient had clinical symptoms of liver disease or signs of liver failure before and during hospitalization; for each of them liver function tests were available. All liver samples showed minimal inflammation features. Histological pictures compatible with vascular alterations were observed, characterized by increase in number of portal vein branches associated with lumen massive dilatation, partial or complete luminal thrombosis of portal and sinusoidal vessels, fibrosis of portal tract, focally markedly enlarged and fibrotic. SARS-CoV-2 was found in 15 of 22 samples tested by in situ hybridization method. Our preliminary results confirm the clinical impression that liver failure is not a main concern and this organ is not the target of significant inflammatory damage. Histopathological findings are highly suggestive for marked derangement of intrahepatic blood vessel network secondary to systemic changes induced by virus that could target not only lung parenchyma but also cardiovascular system, coagulation cascade and endothelial layer of blood vessels. It still remains unclear if the mentioned changes are directly related to virus infection or if SARS-CoV-2 triggers a series of reactions leading to striking vascular alterations.


Subject(s)
Coronavirus Infections/pathology , Liver/pathology , Pneumonia, Viral/pathology , Portal Vein/pathology , Respiratory Insufficiency/pathology , Adult , Aged , Aged, 80 and over , Betacoronavirus , COVID-19 , Coronavirus Infections/complications , Female , Humans , Liver/blood supply , Liver/enzymology , Male , Middle Aged , Pandemics , Pneumonia, Viral/complications , Respiratory Insufficiency/virology , SARS-CoV-2
20.
PLoS One ; 15(7): e0235458, 2020.
Article in English | MEDLINE | ID: covidwho-638588

ABSTRACT

A recently developed pneumonia caused by SARS-CoV-2 bursting in Wuhan, China, has quickly spread across the world. We report the clinical characteristics of 82 cases of death from COVID-19 in a single center. Clinical data on 82 death cases laboratory-confirmed as SARS-CoV-2 infection were obtained from a Wuhan local hospital's electronic medical records according to previously designed standardized data collection forms. All patients were local residents of Wuhan, and a large proportion of them were diagnosed with severe illness when admitted. Due to the overwhelming of our system, a total of 14 patients (17.1%) were treated in the ICU, 83% of deaths never received Critical Care Support, only 40% had mechanical ventilation support despite 100% needing oxygen and the leading cause of death being pulmonary. Most of the patients who died were male (65.9%). More than half of the patients who died were older than 60 years (80.5%), and the median age was 72.5 years. The bulk of the patients who died had comorbidities (76.8%), including hypertension (56.1%), heart disease (20.7%), diabetes (18.3%), cerebrovascular disease (12.2%), and cancer (7.3%). Respiratory failure remained the leading cause of death (69.5%), followed by sepsis/MOF (28.0%), cardiac failure (14.6%), hemorrhage (6.1%), and renal failure (3.7%). Furthermore, respiratory, cardiac, hemorrhagic, hepatic, and renal damage were found in 100%, 89%, 80.5%, 78.0%, and 31.7% of patients, respectively. On admission, lymphopenia (89.2%), neutrophilia (74.3%), and thrombocytopenia (24.3%) were usually observed. Most patients had a high neutrophil-to-lymphocyte ratio of >5 (94.5%), high systemic immune-inflammation index of >500 (89.2%), and increased C-reactive protein (100%), lactate dehydrogenase (93.2%), and D-dimer (97.1%) levels. A high level of IL-6 (>10 pg/ml) was observed in all detected patients. The median time from initial symptoms to death was 15 days (IQR 11-20), and a significant association between aspartate aminotransferase (p = 0.002), alanine aminotransferase (p = 0.037) and time from initial symptoms to death was remarkably observed. Older males with comorbidities are more likely to develop severe disease and even die from SARS-CoV-2 infection. Respiratory failure is the main cause of COVID-19, but the virus itself and cytokine release syndrome-mediated damage to other organs, including cardiac, renal, hepatic, and hemorrhagic damage, should be taken seriously as well.


Subject(s)
Coronavirus Infections/mortality , Coronavirus Infections/pathology , Pneumonia, Viral/mortality , Pneumonia, Viral/pathology , Adult , Age Factors , Aged , Betacoronavirus , COVID-19 , Cause of Death , China/epidemiology , Comorbidity , Coronavirus Infections/epidemiology , Coronavirus Infections/therapy , Female , Humans , Male , Middle Aged , Pandemics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/therapy , Respiratory Insufficiency/pathology , Retrospective Studies , SARS-CoV-2
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