Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 20 de 42
Filter
1.
EBioMedicine ; 75: 103809, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1638088

ABSTRACT

BACKGROUND: Mathematical modelling may aid in understanding the complex interactions between injury and immune response in critical illness. METHODS: We utilize a system biology model of COVID-19 to analyze the effect of altering baseline patient characteristics on the outcome of immunomodulatory therapies. We create example parameter sets meant to mimic diverse patient types. For each patient type, we define the optimal treatment, identify biologic programs responsible for clinical responses, and predict biomarkers of those programs. FINDINGS: Model states representing older and hyperinflamed patients respond better to immunomodulation than those representing obese and diabetic patients. The disparate clinical responses are driven by distinct biologic programs. Optimal treatment initiation time is determined by neutrophil recruitment, systemic cytokine expression, systemic microthrombosis and the renin-angiotensin system (RAS) in older patients, and by RAS, systemic microthrombosis and trans IL6 signalling for hyperinflamed patients. For older and hyperinflamed patients, IL6 modulating therapy is predicted to be optimal when initiated very early (<4th day of infection) and broad immunosuppression therapy (corticosteroids) is predicted to be optimally initiated later in the disease (7th - 9th day of infection). We show that markers of biologic programs identified by the model correspond to clinically identified markers of disease severity. INTERPRETATION: We demonstrate that modelling of COVID-19 pathobiology can suggest biomarkers that predict optimal response to a given immunomodulatory treatment. Mathematical modelling thus constitutes a novel adjunct to predictive enrichment and may aid in the reduction of heterogeneity in critical care trials. FUNDING: C.V. received a Marie Sklodowska Curie Actions Individual Fellowship (MSCA-IF-GF-2020-101028945). R.K.J.'s research is supported by R01-CA208205, and U01-CA 224348, R35-CA197743 and grants from the National Foundation for Cancer Research, Jane's Trust Foundation, Advanced Medical Research Foundation and Harvard Ludwig Cancer Center. No funder had a role in production or approval of this manuscript.


Subject(s)
COVID-19/immunology , Models, Immunological , Respiratory Distress Syndrome/immunology , SARS-CoV-2/immunology , Aged , COVID-19/prevention & control , Clinical Trials as Topic , Female , Humans , Male , Respiratory Distress Syndrome/prevention & control
2.
Med Hypotheses ; 144: 109976, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-1386300

ABSTRACT

Several attempts to control the dreadfulness of SARS-CoV-2 are still underway. Based on the literature evidences we have speculated a prospective contemporary remedy, which was categorized into Specificity, Remedy, and a Conveyor. In which, pros and cons were discussed and inferred the possible alternatives. (a) Specificity: Implicit to express the ACE2 receptors in conveyor cells to deceive SARS-CoV-2 frompreponetargets. (b) Remedy: As depletion of pulmonary surfactants causes strong acute respiratory distress syndrome, we propose an entity of a cost-effective artificialsurfactantsystem as a remedy to pulmonary complications. (c) Conveyor: We propose red blood cells (RBCs) as a conveyor with embedded artificial surfactant and protruding ACE2 receptors for the target-specific delivery. Overall we postulate focused insights by employing a combinational contemporary strategy to steer towards a prospective direction on combating SARS-CoV-2.


Subject(s)
Angiotensin-Converting Enzyme 2/therapeutic use , COVID-19/virology , Erythrocytes , Pulmonary Surfactants/therapeutic use , Receptors, Virus/therapeutic use , SARS-CoV-2/physiology , Viral Tropism , Angiotensin-Converting Enzyme 2/administration & dosage , COVID-19/complications , COVID-19/prevention & control , Drug Costs , Drug Delivery Systems , Humans , Pulmonary Alveoli/drug effects , Pulmonary Alveoli/virology , Pulmonary Surfactants/administration & dosage , Pulmonary Surfactants/chemical synthesis , Pulmonary Surfactants/economics , Receptors, Virus/administration & dosage , Respiratory Distress Syndrome/prevention & control
3.
Front Immunol ; 12: 673693, 2021.
Article in English | MEDLINE | ID: covidwho-1365541

ABSTRACT

Background: Thymosin alpha 1 (Tα1) is widely used to treat patients with COVID-19 in China; however, its efficacy remains unclear. This study aimed to explore the efficacy of Tα1 as a COVID-19 therapy. Methods: We performed a multicenter cohort study in five tertiary hospitals in the Hubei province of China between December 2019 and March 2020. The patient non-recovery rate was used as the primary outcome. Results: All crude outcomes, including non-recovery rate (65/306 vs. 290/1,976, p = 0.003), in-hospital mortality rate (62/306 vs. 271/1,976, p = 0.003), intubation rate (31/306 vs. 106/1,976, p = 0.001), acute respiratory distress syndrome (ARDS) incidence (104/306 vs. 499/1,976, p = 0.001), acute kidney injury (AKI) incidence (26/306 vs. 66/1,976, p < 0.001), and length of intensive care unit (ICU) stay (14.9 ± 12.7 vs. 8.7 ± 8.2 days, p < 0.001), were significantly higher in the Tα1 treatment group. After adjusting for confounding factors, Tα1 use was found to be significantly associated with a higher non-recovery rate than non-Tα1 use (OR 1.5, 95% CI 1.1-2.1, p = 0.028). An increased risk of non-recovery rate associated with Tα1 use was observed in the patient subgroups with maximum sequential organ failure assessment (SOFA) scores ≥2 (OR 2.0, 95%CI 1.4-2.9, p = 0.024), a record of ICU admission (OR 5.4, 95%CI 2.1-14.0, p < 0.001), and lower PaO2/FiO2 values (OR 1.9, 95%CI 1.1-3.4, p = 0.046). Furthermore, later initiation of Tα1 use was associated with a higher non-recovery rate. Conclusion: Tα1 use in COVID-19 patients was associated with an increased non-recovery rate, especially in those with greater disease severity.


Subject(s)
COVID-19/drug therapy , Respiratory Distress Syndrome/epidemiology , Thymalfasin/adverse effects , Adult , Aged , COVID-19/complications , COVID-19/diagnosis , COVID-19/mortality , Female , Hospital Mortality , Humans , Intensive Care Units/statistics & numerical data , Length of Stay/statistics & numerical data , Logistic Models , Male , Middle Aged , Organ Dysfunction Scores , Prognosis , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/prevention & control , Retrospective Studies , Risk Assessment/statistics & numerical data , Thymalfasin/administration & dosage , Treatment Outcome
4.
Front Immunol ; 12: 726909, 2021.
Article in English | MEDLINE | ID: covidwho-1359195

ABSTRACT

Mesenchymal stem cells (MSCs) have been widely used in preclinical and clinical trials for various diseases and have shown great potential in the treatment of sepsis and coronavirus disease (COVID-19). Inflammatory factors play vital roles in the pathogenesis of diseases. The interaction between inflammatory factors is extremely complex. Once the dynamics of inflammatory factors are unbalanced, inflammatory responses and cytokine storm syndrome develop, leading to disease exacerbation and even death. Stem cells have become ideal candidates for the treatment of such diseases due to their immunosuppressive and anti-inflammatory properties. However, the mechanisms by which stem cells affect inflammation and immune regulation are still unclear. This article discusses the therapeutic mechanism and potential value of MSCs in the treatment of sepsis and the novel COVID-19, outlines how MSCs mediate innate and acquired immunity at both the cellular and molecular levels, and described the anti-inflammatory mechanisms and related molecular pathways. Finally, we review the safety and efficacy of stem cell therapy in these two diseases at the preclinical and clinical levels.


Subject(s)
COVID-19/therapy , Cytokine Release Syndrome/therapy , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells/immunology , SARS-CoV-2/immunology , COVID-19/immunology , COVID-19/pathology , Cell- and Tissue-Based Therapy/methods , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/pathology , Humans , Respiratory Distress Syndrome/immunology , Respiratory Distress Syndrome/pathology , Respiratory Distress Syndrome/prevention & control
5.
Elife ; 92020 04 27.
Article in English | MEDLINE | ID: covidwho-1344522

ABSTRACT

COVID-19 patients can present with pulmonary edema early in disease. We propose that this is due to a local vascular problem because of activation of bradykinin 1 receptor (B1R) and B2R on endothelial cells in the lungs. SARS-CoV-2 enters the cell via ACE2 that next to its role in RAAS is needed to inactivate des-Arg9 bradykinin, the potent ligand of the B1R. Without ACE2 acting as a guardian to inactivate the ligands of B1R, the lung environment is prone for local vascular leakage leading to angioedema. Here, we hypothesize that a kinin-dependent local lung angioedema via B1R and eventually B2R is an important feature of COVID-19. We propose that blocking the B2R and inhibiting plasma kallikrein activity might have an ameliorating effect on early disease caused by COVID-19 and might prevent acute respiratory distress syndrome (ARDS). In addition, this pathway might indirectly be responsive to anti-inflammatory agents.


The COVID-19 pandemic represents an unprecedented threat to global health. Millions of cases have been confirmed around the world, and hundreds of thousands of people have lost their lives. Common symptoms include a fever and persistent cough and COVID-19 patients also often experience an excess of fluid in the lungs, which makes it difficult to breathe. In some cases, this develops into a life-threatening condition whereby the lungs cannot provide the body's vital organs with enough oxygen. The SARS-CoV-2 virus, which causes COVID-19, enters the lining of the lungs via an enzyme called the ACE2 receptor, which is present on the outer surface of the lungs' cells. The related coronavirus that was responsible for the SARS outbreak in the early 2000s also needs the ACE2 receptor to enter the cells of the lungs. In SARS, the levels of ACE2 in the lung decline during the infection. Studies with mice have previously revealed that a shortage of ACE2 leads to increased levels of a hormone called angiotensin II, which regulates blood pressure. As a result, much attention has turned to the potential link between this hormone system in relation to COVID-19. However, other mouse studies have shown that ACE2 protects against a build-up of fluid in the lungs caused by a different molecule made by the body. This molecule, which is actually a small fragment of a protein, lowers blood pressure and causes fluid to leak out of blood vessels. It belongs to a family of molecules known as kinins, and ACE2 is known to inactivate certain kinins. This led van de Veerdonk et al. to propose that the excess of fluid in the lungs seen in COVID-19 patients may be because kinins are not being neutralized due to the shortage of the ACE2 receptor. This had not been hypothesized before, even though the mechanism could be the same in SARS which has been researched for the past 17 years. If this hypothesis is correct, it would mean that directly inhibiting the receptor for the kinins (or the proteins that they come from) may be the only way to stop fluid leaking into the lungs of COVID-19 patients in the early stage of disease. This hypothesis is unproven, and more work is needed to see if it is clinically relevant. If that work provides a proof of concept, it means that existing treatments and registered drugs could potentially help patients with COVID-19, by preventing the need for mechanical ventilation and saving many lives.


Subject(s)
Antiviral Agents/therapeutic use , Coronavirus Infections/drug therapy , Coronavirus Infections/pathology , Drug Development , Pneumonia, Viral/drug therapy , Pneumonia, Viral/pathology , Angioedema/drug therapy , Angioedema/metabolism , Angioedema/pathology , Anti-Inflammatory Agents/therapeutic use , Betacoronavirus/physiology , Bradykinin Receptor Antagonists/therapeutic use , COVID-19 , Coronavirus Infections/metabolism , Endothelial Cells/metabolism , Endothelial Cells/pathology , Humans , Inflammation/immunology , Inflammation/pathology , Kallikreins/metabolism , Kinins/metabolism , Lung/metabolism , Lung/pathology , Pandemics , Pneumonia, Viral/metabolism , Receptor, Bradykinin B1/metabolism , Receptor, Bradykinin B2/metabolism , Respiratory Distress Syndrome/drug therapy , Respiratory Distress Syndrome/pathology , Respiratory Distress Syndrome/prevention & control , SARS-CoV-2 , Signal Transduction
6.
Reumatol Clin (Engl Ed) ; 17(7): 371-375, 2021.
Article in English | MEDLINE | ID: covidwho-1322338

ABSTRACT

COVID-19 is a newly emerged disease that has become a global public health challenge. Due to a lack of knowledge about the virus, a significant number of potential targets for using a particular drug have been proposed. Five cases with a clinical history of biopolymers in the gluteal region that developed iatrogenic allogenosis (IA) are presented here. The 5 cases were put under colchicine treatment for IA crisis and had non-specific symptoms (headache, cough without dyspnea, and arthralgias) with a positive SARS-CoV-2 test. Their close contacts had mild to severe symptoms and three of them died. In the SARS-CoV-2 infection different inflammatory pathways are altered where colchicine reduces cytokine levels as well as the activation of macrophages, neutrophils, and the inflammasome. The possible mechanisms that colchicine may use to prevent acute respiratory distress syndrome (ARDS) in patients with COVID-19 infection are also reviewed in this article.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , COVID-19/drug therapy , Colchicine/therapeutic use , Respiratory Distress Syndrome/prevention & control , Tubulin Modulators/therapeutic use , Adult , COVID-19/complications , COVID-19/diagnosis , Female , Humans , Middle Aged , Respiratory Distress Syndrome/virology , Severity of Illness Index
7.
Pharmacol Res ; 159: 104965, 2020 09.
Article in English | MEDLINE | ID: covidwho-1279676

ABSTRACT

Little is still known about the clinical features associated with the occurrence of acute respiratory distress syndrome (ARDS) in hospitalized patients with Coronavirus disease 2019 (COVID-19). The aim of the present study was to describe the prevalence of pre-admission antithrombotic therapies in patients with COVID-19 and to investigate the potential association between antithrombotic therapy and ARDS, as disease clinical presentation, or in-hospital mortality. We enrolled 192 consecutive patients with laboratory-confirmed COVID-19 admitted to emergency department of five Italian hospitals. The study population was divided in two groups according to the evidence of ARDS at chest computed tomography at admission. Propensity score weighting adjusted regression analysis was performed to assess the risk ARDS at admission, and death during hospitalization, in patients treated or not with antiplatelet and anticoagulant agents. ARDS was reported in 73 cases (38 %), who showed more likely hypertension compared to those without ARDS (57.8 % vs 49.6 %; P = 0.005). Thirty-five patients (18.5 %) died during the hospitalization. Not survived COVID-19 patients showed a statistically significant increased age (77 ± 8.31 vs 65.57 ± 8.31; P = 0.001), hypertension (77.1 % vs 53.5 %; P = 0.018) and coronary artery disease prevalence (28.6 % vs 10.2 %; P = 0.009). Both unadjusted and adjusted regression analyses showed no difference in the risk of ARDS at admission, or death during hospitalization, between patients treated or not with antiplatelets or anticoagulants. Pre-admission antithrombotic therapy, both antiplatelet and anticoagulant, does not seem to show a protective effect in severe forms of COVID-19 with ARDS at presentation and rapidly evolving toward death.


Subject(s)
Betacoronavirus , Coronavirus Infections/drug therapy , Fibrinolytic Agents/therapeutic use , Pneumonia, Viral/drug therapy , Aged , Aged, 80 and over , COVID-19 , Coronavirus Infections/complications , Coronavirus Infections/mortality , Drug Administration Schedule , Female , Fibrinolytic Agents/administration & dosage , Hospital Mortality , Humans , Italy/epidemiology , Male , Middle Aged , Pandemics , Patient Admission , Pneumonia, Viral/complications , Pneumonia, Viral/mortality , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/mortality , Respiratory Distress Syndrome/prevention & control , SARS-CoV-2
8.
Immunity ; 54(7): 1463-1477.e11, 2021 07 13.
Article in English | MEDLINE | ID: covidwho-1263294

ABSTRACT

Acute respiratory distress syndrome (ARDS), an inflammatory condition with high mortality rates, is common in severe COVID-19, whose risk is reduced by metformin rather than other anti-diabetic medications. Detecting of inflammasome assembly in post-mortem COVID-19 lungs, we asked whether and how metformin inhibits inflammasome activation while exerting its anti-inflammatory effect. We show that metformin inhibited NLRP3 inflammasome activation and interleukin (IL)-1ß production in cultured and alveolar macrophages along with inflammasome-independent IL-6 secretion, thus attenuating lipopolysaccharide (LPS)- and SARS-CoV-2-induced ARDS. By targeting electron transport chain complex 1 and independently of AMP-activated protein kinase (AMPK) or NF-κB, metformin blocked LPS-induced and ATP-dependent mitochondrial (mt) DNA synthesis and generation of oxidized mtDNA, an NLRP3 ligand. Myeloid-specific ablation of LPS-induced cytidine monophosphate kinase 2 (CMPK2), which is rate limiting for mtDNA synthesis, reduced ARDS severity without a direct effect on IL-6. Thus, inhibition of ATP and mtDNA synthesis is sufficient for ARDS amelioration.


Subject(s)
Adenosine Triphosphate/metabolism , DNA, Mitochondrial/biosynthesis , Inflammasomes/drug effects , Metformin/pharmacology , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Pneumonia/prevention & control , Animals , COVID-19/metabolism , COVID-19/prevention & control , Cytokines/genetics , Cytokines/metabolism , DNA, Mitochondrial/metabolism , Humans , Inflammasomes/metabolism , Interleukin-1beta/genetics , Interleukin-1beta/metabolism , Lipopolysaccharides/toxicity , Metformin/therapeutic use , Mice , Nucleoside-Phosphate Kinase/metabolism , Pneumonia/metabolism , Respiratory Distress Syndrome/chemically induced , Respiratory Distress Syndrome/prevention & control , SARS-CoV-2/pathogenicity
9.
Am J Respir Cell Mol Biol ; 64(6): 677-686, 2021 06.
Article in English | MEDLINE | ID: covidwho-1259048

ABSTRACT

There is an urgent need for new drugs for patients with acute respiratory distress syndrome (ARDS), including those with coronavirus disease (COVID-19). ARDS in influenza-infected mice is associated with reduced concentrations of liponucleotides (essential precursors for de novo phospholipid synthesis) in alveolar type II (ATII) epithelial cells. Because surfactant phospholipid synthesis is a primary function of ATII cells, we hypothesized that disrupting this process could contribute significantly to the pathogenesis of influenza-induced ARDS. The goal of this study was to determine whether parenteral liponucleotide supplementation can attenuate ARDS. C57BL/6 mice inoculated intranasally with 10,000 plaque-forming units/mouse of H1N1 influenza A/WSN/33 virus were treated with CDP (cytidine 5'-diphospho)-choline (100 µg/mouse i.p.) ± CDP -diacylglycerol 16:0/16:0 (10 µg/mouse i.p.) once daily from 1 to 5 days after inoculation (to model postexposure influenza prophylaxis) or as a single dose on Day 5 (to model treatment of patients with ongoing influenza-induced ARDS). Daily postexposure prophylaxis with CDP-choline attenuated influenza-induced hypoxemia, pulmonary edema, alterations in lung mechanics, impairment of alveolar fluid clearance, and pulmonary inflammation without altering viral replication. These effects were not recapitulated by the daily administration of CTP (cytidine triphosphate) and/or choline. Daily coadministration of CDP-diacylglycerol significantly enhanced the beneficial effects of CDP-choline and also modified the ATII cell lipidome, reversing the infection-induced decrease in phosphatidylcholine and increasing concentrations of most other lipid classes in ATII cells. Single-dose treatment with both liponucleotides at 5 days after inoculation also attenuated hypoxemia, altered lung mechanics, and inflammation. Overall, our data show that liponucleotides act rapidly to reduce disease severity in mice with severe influenza-induced ARDS.


Subject(s)
Alveolar Epithelial Cells/metabolism , Cytidine Diphosphate Choline/pharmacology , Cytidine Diphosphate Diglycerides/pharmacology , Influenza A Virus, H1N1 Subtype/metabolism , Orthomyxoviridae Infections/drug therapy , Respiratory Distress Syndrome/prevention & control , Alveolar Epithelial Cells/pathology , Alveolar Epithelial Cells/virology , Animals , COVID-19/drug therapy , COVID-19/pathology , Mice , Orthomyxoviridae Infections/complications , Orthomyxoviridae Infections/metabolism , Orthomyxoviridae Infections/pathology , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/metabolism , Respiratory Distress Syndrome/pathology , SARS-CoV-2/metabolism
10.
Clin Transl Sci ; 14(6): 2111-2116, 2021 11.
Article in English | MEDLINE | ID: covidwho-1247160

ABSTRACT

This review describes the evidence for the potential benefit of vitamin D supplementation in people with respiratory diseases who may have a higher susceptibility to coronavirus disease 2019 (COVID-19) infection and its consequences. Clinical evidence indicates that vitamin D may reduce the risk of both upper and lower respiratory tract infections and offers benefit particularly in people with vitamin D deficiency. Some evidence exists for a higher incidence of active tuberculosis (TB) in patients who are deficient in vitamin D. An association between low levels of 25(OH)D (the active form of vitamin D) and COVID-19 severity of illness and mortality has also been reported. In addition, low 25(OH)D levels are associated with poor outcomes in acute respiratory distress syndrome (ARDS). The cytokine storm experienced in severe COVID-19 infections results from excessive release of pro-inflammatory cytokines. Due to its immunomodulatory effects, adequate vitamin D levels may cause a decrease in the pro-inflammatory cytokines and an increase in the anti-inflammatory cytokines during COVID-19 infections. Vitamin D deficiency was found in 82.2% of hospitalized COVID-19 cases and 47.2% of population-based controls (p < 0.0001). The available evidence warrants an evaluation of vitamin D supplementation in susceptible populations with respiratory diseases, such as TB, and particularly in those who are deficient in vitamin D. This may mitigate against serious complications of COVID-19 infections or reduce the impact of ARDS in those who have been infected.


Subject(s)
COVID-19/immunology , Dietary Supplements , Tuberculosis/immunology , Vitamin D Deficiency/diet therapy , Vitamin D/administration & dosage , COVID-19/diagnosis , COVID-19/epidemiology , COVID-19/prevention & control , Comorbidity , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/prevention & control , Cytokine Release Syndrome/virology , Disease Susceptibility/blood , Disease Susceptibility/immunology , Humans , Pandemics , Respiratory Distress Syndrome/immunology , Respiratory Distress Syndrome/prevention & control , Risk Factors , Severity of Illness Index , Tuberculosis/blood , Tuberculosis/epidemiology , Vitamin D/blood , Vitamin D Deficiency/complications , Vitamin D Deficiency/epidemiology , Vitamin D Deficiency/immunology
11.
Lancet Respir Med ; 9(4): 360-372, 2021 04.
Article in English | MEDLINE | ID: covidwho-1045088

ABSTRACT

BACKGROUND: Mechanical ventilation in intensive care for 48 h or longer is associated with the acute respiratory distress syndrome (ARDS), which might be present at the time ventilatory support is instituted or develop afterwards, predominantly during the first 5 days. Survivors of prolonged mechanical ventilation and ARDS are at risk of considerably impaired physical function that can persist for years. An early pathogenic mechanism of lung injury in mechanically ventilated, critically ill patients is inflammation-induced pulmonary fibrin deposition, leading to thrombosis of the microvasculature and hyaline membrane formation in the air sacs. The main aim of this study was to determine if nebulised heparin, which targets fibrin deposition, would limit lung injury and thereby accelerate recovery of physical function in patients with or at risk of ARDS. METHODS: The Can Heparin Administration Reduce Lung Injury (CHARLI) study was an investigator-initiated, multicentre, double-blind, randomised phase 3 trial across nine hospitals in Australia. Adult intensive care patients on invasive ventilation, with impaired oxygenation defined by a PaO2/FiO2 ratio of less than 300, and with the expectation of invasive ventilation beyond the next calendar day were recruited. Key exclusion criteria were heparin allergy, pulmonary bleeding, and platelet count less than 50 X 109/L. Patients were randomly assigned 1:1, with stratification by site and using blocks of variable size and random seed, via a web-based system, to either unfractionated heparin sodium 25 000 IU in 5 mL or identical placebo (sodium chloride 0·9% 5 mL), administered using a vibrating mesh membrane nebuliser every 6 h to day 10 while invasively ventilated. Patients, clinicians, and investigators were masked to treatment allocation. The primary outcome was the Short Form 36 Health Survey Physical Function Score (out of 100) of survivors at day 60. Prespecified secondary outcomes, which are exploratory, included development of ARDS to day 5 among at-risk patients, deterioration of the Murray Lung Injury Score (MLIS) to day 5, mortality at day 60, residence of survivors at day 60, and serious adverse events. Analyses followed the intention-to-treat principle. There was no imputation of missing data. The trial is registered with the Australian and New Zealand Clinical Trials Register, number ACTRN12612000418875 . FINDINGS: Between Sept 4, 2012, and Aug 23, 2018, 256 patients were randomised. Final follow-up was on Feb 25, 2019. We excluded three patients who revoked consent and one ineligible participant who received no intervention. Of 252 patients included in data analysis, the mean age was 58 years (SD 15), 157 (62%) were men, and 118 (47%) had ARDS. 128 (51%) patients were assigned to the heparin group and 124 (49%) to the placebo group, all of whom received their assigned intervention. Survivors in the heparin group (n=97) had similar SF-36 Physical Function Scores at day 60 compared to the placebo group (n=94; mean 53·6 [SD 31·6] vs 48·7 [35·7]; difference 4·9 [95% CI -4·8 to 14·5]; p=0·32). Compared with the placebo group, the heparin group had fewer cases of ARDS develop to day 5 among the at-risk patients (nine [15%] of 62 patients vs 21 [30%] of 71 patients; hazard ratio 0·46 [95% CI 0·22 to 0·98]; p=0·0431), less deterioration of the MLIS to day 5 (difference -0·14 [-0·26 to -0·02]; p=0·0215), similar day 60 mortality (23 [18%] of 127 patients vs 18 [15%] of 123 patients; odds ratio [OR] 1·29 [95% CI 0·66 to 2·53]; p=0·46), and more day 60 survivors at home (86 [87%] of 99 patients vs 73 [73%] of 100 patients; OR 2·45 [1·18 to 5·08]; p=0·0165). A similar number of serious adverse events occurred in each group (seven [5%] of 128 patients in the heparin group vs three [2%] of 124 patients in the placebo group; OR 2·33 [0·59 to 9·24]; p=0·23), which were a transient increase in airway pressure during nebulisation (n=3 in the heparin group), major non-pulmonary bleeding (n=2 in each group), haemoptysis (n=1 in the heparin group), tracheotomy site bleeding (n=1 in the heparin group), and hypoxaemia during nebulisation (n=1 in the placebo group). INTERPRETATION: In patients with or at risk of ARDS, nebulised heparin did not improve self-reported performance of daily physical activities, but was well tolerated and exploratory outcomes suggest less progression of lung injury and earlier return home. Further research is justified to establish if nebulised heparin accelerates recovery in those who have or are at risk of ARDS. FUNDING: Rowe Family Foundation, TR and RB Ditchfield Medical Research Endowment Fund, Patricia Madigan Charitable Trust, and The J and R McGauran Trust Fund.


Subject(s)
Critical Care/methods , Heparin/administration & dosage , Respiration, Artificial/adverse effects , Respiratory Distress Syndrome/epidemiology , Activities of Daily Living , Administration, Inhalation , Adult , Aged , Australia/epidemiology , Double-Blind Method , Female , Hemoptysis/chemically induced , Hemoptysis/epidemiology , Heparin/adverse effects , Hospital Mortality , Humans , Hypoxia/chemically induced , Hypoxia/epidemiology , Incidence , Male , Middle Aged , Nebulizers and Vaporizers , Placebos/administration & dosage , Placebos/adverse effects , Respiratory Distress Syndrome/diagnosis , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/prevention & control , Self Report/statistics & numerical data , Severity of Illness Index , Survivors/statistics & numerical data , Time Factors , Treatment Outcome
12.
Eur J Immunol ; 51(7): 1652-1659, 2021 07.
Article in English | MEDLINE | ID: covidwho-1141308

ABSTRACT

The complement system is an essential component of the innate immune system. The three complement pathways (classical, lectin, alternative) are directly or indirectly activated by the SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2). In the most severe forms of COVID-19, overactivation of the complement system may contribute to the cytokine storm, endothelial inflammation (endotheliitis) and thrombosis. No antiviral drug has yet been shown to be effective in COVID-19. Therefore, immunotherapies represent a promising therapeutic in the immunopathological phase (following the viral phase) of the disease. Complement blockade, mostly C5a-C5aR axis blockade, may prevent acute respiratory distress syndrome (ARDS) from worsening or progression to death. Clinical trials are underway.


Subject(s)
COVID-19/pathology , Complement C5a/antagonists & inhibitors , Cytokine Release Syndrome/pathology , Cytokines/immunology , Immunotherapy/methods , Receptor, Anaphylatoxin C5a/antagonists & inhibitors , COVID-19/drug therapy , COVID-19/immunology , Complement Activation/immunology , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/immunology , Humans , Inflammation/immunology , Inflammation/pathology , Respiratory Distress Syndrome/prevention & control , SARS-CoV-2/immunology , Signal Transduction/immunology , Thrombosis/immunology , Thrombosis/pathology
13.
Pharmacol Res ; 167: 105548, 2021 05.
Article in English | MEDLINE | ID: covidwho-1135540

ABSTRACT

Acute Respiratory Distress Syndrome (ARDS) is triggered by a variety of agents, including Staphylococcal Enterotoxin B (SEB). Interestingly, a significant proportion of patients with COVID-19, also develop ARDS. In the absence of effective treatments, ARDS results in almost 40% mortality. Previous studies from our laboratory demonstrated that resveratrol (RES), a stilbenoid, with potent anti-inflammatory properties can attenuate SEB-induced ARDS. In the current study, we investigated the role of RES-induced alterations in the gut and lung microbiota in the regulation of ARDS. Our studies revealed that SEB administration induced inflammatory cytokines, ARDS, and 100% mortality in C3H/HeJ mice. Additionally, SEB caused a significant increase in pathogenic Proteobacteria phylum and Propionibacterium acnes species in the lungs. In contrast, RES treatment attenuated SEB-mediated ARDS and mortality in mice, and significantly increased probiotic Actinobacteria phylum, Tenericutes phylum, and Lactobacillus reuteri species in both the colon and lungs. Colonic Microbiota Transplantation (CMT) from SEB-injected mice that were treated with RES as well as the transfer of L. reuteri into recipient mice inhibited the production of SEB-mediated induction of pro-inflammatory cytokines such as IFN-γ and IL-17 but increased that of anti-inflammatory IL-10. Additionally, such CMT and L. reuteri recipient mice exposed to SEB, showed a decrease in lung-infiltrating mononuclear cells, cytotoxic CD8+ T cells, NKT cells, Th1 cells, and Th17 cells, but an increase in the population of regulatory T cells (Tregs) and Th3 cells, and increase in the survival of mice from SEB-mediated ARDS. Together, the current study demonstrates that ARDS induced by SEB triggers dysbiosis in the lungs and gut and that attenuation of ARDS by RES may be mediated, at least in part, by alterations in microbiota in the lungs and the gut, especially through the induction of beneficial bacteria such as L. reuteri.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Colon/drug effects , Enterotoxins , Fecal Microbiota Transplantation , Gastrointestinal Microbiome/drug effects , Lung/drug effects , Respiratory Distress Syndrome/prevention & control , Resveratrol/pharmacology , Superantigens , Animals , Cell Line , Colon/immunology , Colon/metabolism , Colon/microbiology , Cytokines/metabolism , Disease Models, Animal , Dysbiosis , Female , Inflammation Mediators/metabolism , Lactobacillus reuteri/drug effects , Lactobacillus reuteri/growth & development , Lung/immunology , Lung/metabolism , Lung/microbiology , Mice, Inbred C3H , Respiratory Distress Syndrome/immunology , Respiratory Distress Syndrome/metabolism , Respiratory Distress Syndrome/microbiology
14.
Biomed Pharmacother ; 134: 111143, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-1071107

ABSTRACT

BACKGROUND: The ARDS (Acute Respiratory Distress Syndrome) is a severe respiratory syndrome that was recently associated as the main death cause in the COVID-19 pandemic outbreak. Hence, in order to prevent ARDS, the pulmonary function maintenance has been the target of several pharmacological approaches. However, there is a lack of reports regarding the use of effective pharmaceutical active natural products (PANPs) for early treatment and prevention of COVID-19-related ARDS. Therefore, the aim of this work was to conduct a systematic review regarding the PANPs that could be further studied as alternatives to prevent ARDS. Consequently, this work can pave the way to spread the use of PANPs on the prevention of ARDS in COVID-19-confirmed or -suspected patients. METHODS: The search strategy included scientific studies published in English from 2015 to 2020 that promoted the elucidation of anti-inflammatory pathways targeting ARDS by in vitro and/or in vivo experiments using PANPs. Then, 74 studies regarding PANPs, able to maintain or improve the pulmonary function, were reported. CONCLUSIONS: The PANPs may present different pulmonary anti-inflammatory pathways, wherein (i) reduction/attenuation of pro-inflammatory cytokines, (ii) increase of the anti-inflammatory mediators' levels, (iii) pulmonary edema inhibition and (iv) attenuation of lung injury were the most observed biological effects of such products in in vitro experiments or in clinical studies. Finally, this work highlighted the PANPs with promising potential to be used on respiratory syndromes, allowing their possible use as alternative treatment at the prevention of ARDS in COVID-19-infected or -suspected patients.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Biological Products/therapeutic use , COVID-19/drug therapy , Inflammation Mediators/antagonists & inhibitors , Respiratory Distress Syndrome/prevention & control , Animals , Anti-Inflammatory Agents/pharmacology , Biological Products/pharmacology , COVID-19/diagnosis , COVID-19/metabolism , Humans , Inflammation Mediators/metabolism , Respiratory Distress Syndrome/diagnosis , Respiratory Distress Syndrome/metabolism
15.
Int J Environ Res Public Health ; 18(2)2021 01 16.
Article in English | MEDLINE | ID: covidwho-1067729

ABSTRACT

The foremost mortality-causing symptom associated with COVID-19 is acute respiratory distress syndrome (ARDS). A significant correlation has been identified between the deficiency in vitamin D and the risk of developing ARDS. It has been suggested that if we can reduce or modify ARDS in COVID-19 patients, we may significantly reduce the severity of COVID-19 symptoms and associated mortality rates. The increased mortality of dark-skinned people, who have a reduced UV absorption capacity, may be consistent with diminished vitamin D status. The factors associated with COVID-19 mortality, such as old age, ethnicity, obesity, hypertension, cardiovascular diseases, and diabetes, are all found to be linked with vitamin D deficiency. Based on this review and as a precautionary measure, it is suggested that the adoption of appropriate and safe solar exposure and vitamin D enriched foods and supplements should be considered to reduce the possible severity of COVID-19 symptoms. Safe sun exposure is deemed beneficial globally, specifically in low and middle-income countries, as there is no cost involved. It is also noted that improved solar exposure and vitamin D levels can reduce the impact of other diseases as well, thus assisting in maintaining general human well-being.


Subject(s)
COVID-19/therapy , Sunlight , Vitamin D/therapeutic use , COVID-19/prevention & control , Humans , Respiratory Distress Syndrome/prevention & control , Respiratory Distress Syndrome/therapy , Vitamin D Deficiency/epidemiology , Vitamin D Deficiency/prevention & control
16.
Int J Environ Res Public Health ; 18(2)2021 01 16.
Article in English | MEDLINE | ID: covidwho-1031135

ABSTRACT

The foremost mortality-causing symptom associated with COVID-19 is acute respiratory distress syndrome (ARDS). A significant correlation has been identified between the deficiency in vitamin D and the risk of developing ARDS. It has been suggested that if we can reduce or modify ARDS in COVID-19 patients, we may significantly reduce the severity of COVID-19 symptoms and associated mortality rates. The increased mortality of dark-skinned people, who have a reduced UV absorption capacity, may be consistent with diminished vitamin D status. The factors associated with COVID-19 mortality, such as old age, ethnicity, obesity, hypertension, cardiovascular diseases, and diabetes, are all found to be linked with vitamin D deficiency. Based on this review and as a precautionary measure, it is suggested that the adoption of appropriate and safe solar exposure and vitamin D enriched foods and supplements should be considered to reduce the possible severity of COVID-19 symptoms. Safe sun exposure is deemed beneficial globally, specifically in low and middle-income countries, as there is no cost involved. It is also noted that improved solar exposure and vitamin D levels can reduce the impact of other diseases as well, thus assisting in maintaining general human well-being.


Subject(s)
COVID-19/therapy , Sunlight , Vitamin D/therapeutic use , COVID-19/prevention & control , Humans , Respiratory Distress Syndrome/prevention & control , Respiratory Distress Syndrome/therapy , Vitamin D Deficiency/epidemiology , Vitamin D Deficiency/prevention & control
17.
Am J Physiol Lung Cell Mol Physiol ; 320(3): L331-L338, 2021 03 01.
Article in English | MEDLINE | ID: covidwho-1011023

ABSTRACT

Acute respiratory distress syndrome and subsequent respiratory failure remains the leading cause of death (>80%) in patients severely impacted by COVID-19. The lack of clinically effective therapies for COVID-19 calls for the consideration of novel adjunct therapeutic approaches. Though novel antiviral treatments and vaccination hold promise in control and prevention of early disease, it is noteworthy that in severe cases of COVID-19, addressing "run-away" inflammatory cascades are likely more relevant for improvement of clinical outcomes. Viral loads may decrease in severe, end-stage coronavirus cases, but a systemically damaging cytokine storm persists and mediates multiple organ injury. Remote ischemic conditioning (RIC) of the limbs has shown potential in recent years to protect the lungs and other organs against pathological conditions similar to that observed in COVID-19. We review the efficacy of RIC in protecting the lungs against acute injury and current points of consideration. The beneficial effects of RIC on lung injury along with other related cardiovascular complications are discussed, as are the limitations presented by sex and aging. This adjunct therapy is highly feasible, noninvasive, and proven to be safe in clinical conditions. If proven effective in clinical trials for acute respiratory distress syndrome and COVID-19, application in the clinical setting could be immediately implemented to improve outcomes.


Subject(s)
COVID-19/complications , Ischemic Preconditioning/methods , Respiratory Distress Syndrome/prevention & control , SARS-CoV-2/isolation & purification , Humans , Respiratory Distress Syndrome/epidemiology , Respiratory Distress Syndrome/virology
18.
Cell Immunol ; 360: 104259, 2021 02.
Article in English | MEDLINE | ID: covidwho-978233

ABSTRACT

Vitamin D regulates homeostasis, anti-microbial response, and inflammation. The vitamin D receptors are expressed in the macrophages and other immune cells, regulating the transcription of many different genes, including those coding the anti-microbial peptides. One of the most severe complications of the SARS-CoV-2 infection is the acute respiratory distress syndrome (ARDS) caused by the hyperinflammatory response (commonly called cytokine storm) of the lung macrophages. Studies showed that Vitamin D deficiency increases the severity of the ARDS in COVID-19 infection. We discuss here how the vitamin D supplementation may influence macrophage and myeloid-derived suppressor cells (MDSCs) inflammatory response, subdue the hyperinflammatory response, and lessen the ARDS in COVID-19 patients.


Subject(s)
COVID-19/drug therapy , COVID-19/pathology , Lung/pathology , Vitamin D/administration & dosage , Vitamins/administration & dosage , Animals , COVID-19/complications , COVID-19/immunology , Child , Humans , Inflammation/drug therapy , Inflammation/immunology , Inflammation/pathology , Inflammation/prevention & control , Lung/immunology , Macrophages/immunology , Macrophages/metabolism , Myeloid-Derived Suppressor Cells/immunology , Myeloid-Derived Suppressor Cells/metabolism , Receptors, Calcitriol/metabolism , Respiratory Distress Syndrome/drug therapy , Respiratory Distress Syndrome/immunology , Respiratory Distress Syndrome/pathology , Respiratory Distress Syndrome/prevention & control
20.
Med Hypotheses ; 146: 110455, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-969218

ABSTRACT

SARS-CoV-2 infection generally begins in the respiratory tract where it can cause bilateral pneumonia. The disease can evolve into acute respiratory distress syndrome and multi-organ failure, due to viral spread in the blood and an excessive inflammatory reaction including cytokine storm. Antiviral and anti-cytokine drugs have proven to be poorly or in-effective in stopping disease progression, and mortality or serious chronic damage is common in severely ill cases. The low efficacy of antiviral drugs is probably due to late administration, when the virus has triggered the inflammatory reaction and is no longer the main protagonist. The relatively poor efficacy of anti-cytokine drugs is explained by the fact that they act on one or a few of the dozens of cytokines involved, and because other mediators of inflammation - reactive oxygen and nitrogen species - are not targeted. When produced in excess, reactive species cause extensive cell and tissue damage. The only drug known to inhibit the excessive production of reactive species and cytokines is methylene blue, a low-cost dye with antiseptic properties used effectively to treat malaria, urinary tract infections, septic shock, and methaemoglobinaemia. We propose testing methylene blue to contrast Covid-related acute respiratory distress syndrome, but particularly suggest testing it early in Covid infections to prevent the hyper-inflammatory reaction responsible for the serious complications of the disease.


Subject(s)
COVID-19/drug therapy , Methylene Blue/pharmacology , Models, Biological , Antiviral Agents/pharmacology , COVID-19/complications , COVID-19/physiopathology , Cytokines/antagonists & inhibitors , Endothelium, Vascular/drug effects , Endothelium, Vascular/injuries , Humans , Multiple Organ Failure/etiology , Multiple Organ Failure/prevention & control , Pandemics , Reactive Oxygen Species/antagonists & inhibitors , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/prevention & control , SARS-CoV-2 , Treatment Failure
SELECTION OF CITATIONS
SEARCH DETAIL