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1.
Minerva Med ; 113(2): 281-290, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1847990

ABSTRACT

BACKGROUND: The efficacy and safety of continuous positive airway pressure and respiratory physiotherapy outside the Intensive Care Unit during a pandemic. METHODS: In this cohort study performed in February-May 2020 in a large teaching hospital in Milan, COVID-19 patients with adult respiratory distress syndrome receiving continuous positive airway pressure (positive end-expiratory pressure =10 cm H2O, FiO2=0.6, daily treatment duration: 4×3h-cycles) and respiratory physiotherapy including pronation outside the Intensive Care Unit were followed-up. RESULTS: Of 90 acute respiratory distress syndrome (ARDS) patients treated with continuous positive airway pressure (45/90, 50% pronated at least once) outside the Intensive Care Unit and with a median (interquartile) follow-up of 37 (11-46) days, 45 (50%) were discharged at home, 28 (31%) were still hospitalized, and 17 (19%) died. Continuous positive airway pressure failure was recorded for 35 (39%) patients. Patient mobilization was associated with reduced failure rates (P=0.033). No safety issues were observed. CONCLUSIONS: Continuous positive airway pressure with patient mobilization (including pronation) was effective and safe in patients with ARDS due to COVID-19 managed outside the Intensive Care Unit setting during the pandemic.


Subject(s)
COVID-19 , Respiratory Distress Syndrome , Adult , COVID-19/complications , COVID-19/therapy , Cohort Studies , Continuous Positive Airway Pressure , Humans , Intensive Care Units , Pronation , Respiratory Distress Syndrome/therapy
2.
Crit Care Explor ; 2(9): e0207, 2020 Sep.
Article in English | MEDLINE | ID: covidwho-1795073

ABSTRACT

OBJECTIVES: To determine whether placental cell therapy PLacental eXpanded (PLX)-PAD (Pluristem Therapeutics, Haifa, Israel) may be beneficial to treating critically ill patients suffering from acute respiratory distress syndrome due to coronavirus disease 2019. DESIGN: Retrospective case report of critically ill coronavirus disease 2019 patients treated with PLacental eXpanded (PLX)-PAD from March 26, 2020, to April 4, 2020, with follow-up through May 2, 2020. SETTING: Four hospitals in Israel (Rambam Health Care Campus, Bnai Zion Medical Center, and Samson Assuta Ashdod University Hospital), and Holy Name Medical Center in New Jersey. PATIENTS: Eight critically ill patients on invasive mechanical ventilation, suffering from acute respiratory distress syndrome due to coronavirus disease 2019. INTERVENTIONS: Intramuscular injection of PLacental eXpanded (PLX)-PAD (300 × 106 cells) given as one to two treatments. MEASUREMENTS AND MAIN RESULTS: Mortality, time to discharge, and changes in blood and respiratory variables were monitored during hospitalization to day 17 posttreatment. Of the eight patients treated (median age 55 yr, seven males and one female), five were discharged, two remained hospitalized, and one died. By day 3 postinjection, mean C-reactive protein fell 45% (240.3-131.3 mg/L; p = 0.0019) and fell to 77% by day 5 (56.0 mg/L; p < 0.0001). Pao2/Fio2 improved in 5:8 patients after 24-hour posttreatment, with similar effects 48-hour posttreatment. A decrease in positive end-expiratory pressure and increase in pH were statistically significant between days 0 and 14 (p = 0.0032 and p = 0.00072, respectively). A decrease in hemoglobin was statistically significant for days 0-5 and 0-14 (p = 0.015 and p = 0.0028, respectively), whereas for creatinine, it was statistically significant between days 0 and 14 (p = 0.032). CONCLUSIONS: Improvement in several variables such as C-reactive protein, positive end-expiratory pressure, and Pao2/Fio2 was observed following PLacental eXpanded (PLX)-PAD treatment, suggesting possible therapeutic effect. However, interpretation of the data is limited due to the small sample size, use of concomitant investigational therapies, and the uncontrolled study design. The efficacy of PLacental eXpanded (PLX)-PAD in coronavirus disease 2019 should be further evaluated in a controlled clinical trial.

3.
Trials ; 22(1): 172, 2021 Mar 01.
Article in English | MEDLINE | ID: covidwho-1622253

ABSTRACT

OBJECTIVES: The primary objective of this study is to test the hypothesis that administration of dexamethasone 20 mg is superior to a 6 mg dose in adult patients with moderate or severe ARDS due to confirmed COVID-19. The secondary objective is to investigate the efficacy and safety of dexamethasone 20 mg versus dexamethasone 6 mg. The exploratory objective of this study is to assess long-term consequences on mortality and quality of life at 180 and 360 days. TRIAL DESIGN: REMED is a prospective, phase II, open-label, randomised controlled trial testing superiority of dexamethasone 20 mg vs 6 mg. The trial aims to be pragmatic, i.e. designed to evaluate the effectiveness of the intervention in conditions that are close to real-life routine clinical practice. PARTICIPANTS: The study is multi-centre and will be conducted in the intensive care units (ICUs) of ten university hospitals in the Czech Republic. INCLUSION CRITERIA: Subjects will be eligible for the trial if they meet all of the following criteria: 1. Adult (≥18 years of age) at time of enrolment; 2. Present COVID-19 (infection confirmed by RT-PCR or antigen testing); 3. Intubation/mechanical ventilation or ongoing high-flow nasal cannula (HFNC) oxygen therapy; 4. Moderate or severe ARDS according to Berlin criteria: • Moderate - PaO2/FiO2 100-200 mmHg; • Severe - PaO2/FiO2 < 100 mmHg; 5. Admission to ICU in the last 24 hours. EXCLUSION CRITERIA: Subjects will not be eligible for the trial if they meet any of the following criteria: 1. Known allergy/hypersensitivity to dexamethasone or excipients of the investigational medicinal product (e.g. parabens, benzyl alcohol); 2. Fulfilled criteria for ARDS for ≥14 days at enrolment; 3. Pregnancy or breastfeeding; 4. Unwillingness to comply with contraception measurements from enrolment until at least 1 week after the last dose of dexamethasone (sexual abstinence is considered an adequate contraception method); 5. End-of-life decision or patient is expected to die within next 24 hours; 6. Decision not to intubate or ceilings of care in place; 7. Immunosuppression and/or immunosuppressive drugs in medical history: a) Systemic immunosuppressive drugs or chemotherapy in the past 30 days; b) Systemic corticosteroid use before hospitalization; c) Any dose of dexamethasone during the present hospital stay for COVID-19 for ≥5 days before enrolment; d) Systemic corticosteroids during present hospital stay for conditions other than COVID-19 (e.g. septic shock); 8. Current haematological or generalized solid malignancy; 9. Any contraindication for corticosteroid administration, e.g. • intractable hyperglycaemia; • active gastrointestinal bleeding; • adrenal gland disorders; • presence of superinfection diagnosed with locally established clinical and laboratory criteria without adequate antimicrobial treatment; 10. Cardiac arrest before ICU admission; 11. Participation in another interventional trial in the last 30 days. INTERVENTION AND COMPARATOR: Dexamethasone solution for injection/infusion is the investigational medicinal product as well as the comparator. The trial will assess two doses, 20 mg (investigational) vs 6 mg (comparator). Patients in the intervention group will receive dexamethasone 20 mg intravenously once daily on day 1-5, followed by dexamethasone 10 mg intravenously once daily on day 6-10. Patients in the control group will receive dexamethasone 6 mg day 1-10. All authorized medicinal products containing dexamethasone in the form of solution for i.v. injection/infusion can be used. MAIN OUTCOMES: Primary endpoint: Number of ventilator-free days (VFDs) at 28 days after randomisation, defined as being alive and free from mechanical ventilation. SECONDARY ENDPOINTS: a) Mortality from any cause at 60 days after randomisation; b) Dynamics of inflammatory marker (C-Reactive Protein, CRP) change from Day 1 to Day 14; c) WHO Clinical Progression Scale at Day 14; d) Adverse events related to corticosteroids (new infections, new thrombotic complications) until Day 28 or hospital discharge; e) Independence at 90 days after randomisation assessed by Barthel Index. The long-term outcomes of this study are to assess long-term consequences on mortality and quality of life at 180 and 360 days through telephone structured interviews using the Barthel Index. RANDOMISATION: Randomisation will be carried out within the electronic case report form (eCRF) by the stratified permuted block randomisation method. Allocation sequences will be prepared by a statistician independent of the study team. Allocation to the treatment arm of an individual patient will not be available to the investigators before completion of the whole randomisation process. The following stratification factors will be applied: • Age <65 and ≥ 65; • Charlson Comorbidity index (CCI) <3 and ≥3; • CRP <150 mg/L and ≥150 mg/L • Trial centre. Patients will be randomised in a 1 : 1 ratio into one of the two treatment arms. Randomisation through the eCRF will be available 24 hours every day. BLINDING (MASKING): This is an open-label trial in which the participants and the study staff will be aware of the allocated intervention. Blinded pre-planned statistical analysis will be performed. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The sample size is calculated to detect the difference of 3 VFDs at 28 days (primary efficacy endpoint) between the two treatment arms with a two-sided type I error of 0.05 and power of 80%. Based on data from a multi-centre randomised controlled trial in COVID-19 ARDS patients in Brazil and a multi-centre observational study from French and Belgian ICUs regarding moderate to severe ARDS related to COVID-19, investigators assumed a standard deviation of VFD at 28 days as 9. Using these assumptions, a total of 142 patients per treatment arm would be needed. After adjustment for a drop-out rate, 150 per treatment arm (300 patients per study) will be enrolled. TRIAL STATUS: This is protocol version 1.1, 15.01.2021. The trial is due to start on 2 February 2021 and recruitment is expected to be completed by December 2021. TRIAL REGISTRATION: The study protocol was registered on EudraCT No.:2020-005887-70, and on December 11, 2020 on ClinicalTrials.gov (Title: Effect of Two Different Doses of Dexamethasone in Patients With ARDS and COVID-19 (REMED)) Identifier: NCT04663555 with a last update posted on February 1, 2021. FULL PROTOCOL: The full protocol (version 1.1) is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the standard formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Subject(s)
COVID-19/therapy , Dexamethasone/administration & dosage , Glucocorticoids/administration & dosage , Respiration, Artificial , Respiratory Distress Syndrome/therapy , COVID-19/complications , Clinical Trials, Phase II as Topic , Disease Progression , Dose-Response Relationship, Drug , Equivalence Trials as Topic , Humans , Length of Stay , Multicenter Studies as Topic , Randomized Controlled Trials as Topic , Respiratory Distress Syndrome/etiology , SARS-CoV-2
4.
Ann Med ; 53(1): 410-412, 2021 12.
Article in English | MEDLINE | ID: covidwho-1573909

ABSTRACT

OBJECTIVE: Cytokine release syndrome is suggested to be the most important mechanism triggering acute respiratory distress syndrome and end organ damage in COVID-19. The severity of disease may be measured by different biomarkers. METHODS: We studied markers of inflammation and coagulation as recorded in 29 patients on admission to the hospital in order to identify markers of severe COVID-19 and need of ICU. RESULTS: Patients who were eventually admitted to ICU displayed significantly higher serum levels of interleukin-6 (IL-6), C-reactive protein (CRP), and procalcitonin. No statistical differences were found between the groups in median levels of lymphocytes, D-dimer or ferritin. CONCLUSIONS: IL-6 and CRP were the strongest predictors of severity in hospitalized patients with COVID-19.


Subject(s)
COVID-19/blood , COVID-19/diagnosis , Interleukin-6/blood , Adolescent , Adult , Aged , Aged, 80 and over , Biomarkers/blood , Female , Humans , Male , Middle Aged , Severity of Illness Index , Young Adult
5.
Clin Infect Dis ; 73(11): e4005-e4011, 2021 12 06.
Article in English | MEDLINE | ID: covidwho-1562130

ABSTRACT

BACKGROUND: Racial disparities are central in the national conversation about coronavirus disease 2019 (COVID-19) , with Black/African Americans being disproportionately affected. We assessed risk factors for death from COVID-19 among Black inpatients at an urban hospital in Detroit, Michigan. METHODS: This was a retrospective, single-center cohort study. We reviewed the electronic medical records of patients positive for severe acute respiratory syndrome coronavirus 2 (the COVID-19 virus) on qualitative polymerase chain reaction assay who were admitted between 8 March 2020 and 6 May 2020. The primary outcome was in-hospital mortality. RESULTS: The case fatality rate was 29.1% (122/419). The mean duration of symptoms prior to hospitalization was 5.3 (3.9) days. The incidence of altered mental status on presentation was higher among patients who died than those who survived, 43% vs 20.0%, respectively (P < .0001). From multivariable analysis, the odds of death increased with age (≥60 years), admission from a nursing facility, Charlson score, altered mental status, higher C-reactive protein on admission, need for mechanical ventilation, presence of shock, and acute respiratory distress syndrome. CONCLUSIONS: These demographic, clinical, and laboratory factors may help healthcare providers identify Black patients at highest risk for severe COVID-19-associated outcomes. Early and aggressive interventions among this at-risk population may help mitigate adverse outcomes.


Subject(s)
COVID-19 , African Americans , Cohort Studies , Hospital Mortality , Hospitalization , Humans , Middle Aged , Retrospective Studies , Risk Factors , SARS-CoV-2
6.
Curr Opin Organ Transplant ; 26(3): 302-308, 2021 06 01.
Article in English | MEDLINE | ID: covidwho-1526214

ABSTRACT

PURPOSE OF REVIEW: Over the past two decades, lung transplant has become the mainstay of treatment for several end-stage lung diseases. As the field continues to evolve, the criteria for referral and listing have also changed. The last update to these guidelines was in 2014 and several studies since then have changed how patients are transplanted. Our article aims to briefly discuss these updates in lung transplantation. RECENT FINDINGS: This article discusses the importance of early referral of patients for lung transplantation and the concept of the 'transplant window'. We review the referral and listing criteria for some common pulmonary diseases and also cite the updated literature surrounding the absolute and relative contraindications keeping in mind that they are a constantly moving target. Frailty and psychosocial barriers are difficult to assess with the current assessment tools but continue to impact posttransplant outcomes. Finally, we discuss the limited data on transplantation in acute respiratory distress syndrome (ARDS) due to COVID19 as well as extracorporeal membrane oxygenation bridge to transplantation. SUMMARY: The findings discussed in this article will strongly impact, if not already, how we select candidates for lung transplantation. It also addresses some aspects of lung transplant such as frailty and ARDS, which need better assessment tools and clinical data.


Subject(s)
Lung Diseases , Lung Transplantation , COVID-19 , Humans , Lung Diseases/surgery , Lung Transplantation/adverse effects , Patient Selection , SARS-CoV-2
7.
Phytother Res ; 35(9): 4988-5006, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1432473

ABSTRACT

The SARS-CoV-2 virus, responsible for COVID-19, spread rapidly worldwide and became a pandemic in 2020. In some patients, the virus remains in the respiratory tract, causing pneumonia, respiratory failure, acute respiratory distress syndrome (ARDS), and sepsis, leading to death. Natural flavonoids (aglycone and glycosides) possess broad biological activities encompassing antiinflammatory, antiviral, antitumoral, antiallergic, antiplatelet, and antioxidant effects. While many studies have focused on the effects of natural flavonoids in experimental models, reports based on clinical trials are still insufficient. In this review, we highlight the effects of flavonoids in controlling pulmonary diseases, particularly the acute respiratory distress syndrome, a consequence of COVID-19, and their potential use in coronavirus-related diseases. Furthermore, we also focus on establishing a relationship between biological potential and chemical aspects of related flavonoids and discuss several possible mechanisms of action, pointing out some possible effects on COVID-19.


Subject(s)
COVID-19 , Flavonoids , Lung Injury , COVID-19/complications , Flavonoids/pharmacology , Humans , Lung Injury/drug therapy , Lung Injury/virology , Pandemics
8.
Curr Cardiol Rev ; 17(4): e230421189016, 2021.
Article in English | MEDLINE | ID: covidwho-1435702

ABSTRACT

In December 2019, a novel COVID-19 infection caused by SARS-CoV-2 has emerged as a global emergency. In a few months, the pathogen has infected millions of people in the world. Primarily SARS-CoV-2 infects the pulmonary system which ultimately leads to ARDS and lung failure. The majority of patients develop milder symptoms but the infection turns severe in a huge number of people, which ultimately results in enhanced mortality in COVID-19 patients. Co-morbid conditions, primarily cardiovascular complications and diabetes, have been reported to show a strong correlation with COVID-19 severity. Further, the onset of myocardial injury secondary to pulmonary damage has been observed in critically ill patients who have never reported heart-related ailments before. Due to drastic health risks associated with virus infection, the unprecedented disruption in normal business throughout the world has caused economic misery. Apparently, newer treatments are urgently needed to combat the virus particularly to reduce the severity burden. Therefore, understanding the crosstalk between lung and heart during COVID-19 might give us better clarity for early diagnosis followed by appropriate treatment in patients with the likelihood of developing severe symptoms. Accordingly, the present review highlights the potential mechanisms that may explain the crosstalk between lung and heart so that effective treatment/management strategies can be evolved swiftly in this direction.


Subject(s)
COVID-19 , Heart Diseases , Heart , Heart Diseases/virology , Humans , Lung/pathology , Lung/virology , SARS-CoV-2
9.
Clin Hemorheol Microcirc ; 78(2): 199-207, 2021.
Article in English | MEDLINE | ID: covidwho-1352794

ABSTRACT

INTRODUCTION: Coronavirus disease-19 (COVID-19) is a new type of epidemic pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The population is generally susceptible to COVID-19, which mainly causes lung injury. Some cases may develop severe acute respiratory distress syndrome (ARDS). Currently, ARDS treatment is mainly mechanical ventilation, but mechanical ventilation often causes ventilator-induced lung injury (VILI) accompanied by hypercapnia in 14% of patients. Extracorporeal carbon dioxide removal (ECCO2R) can remove carbon dioxide from the blood of patients with ARDS, correct the respiratory acidosis, reduce the tidal volume and airway pressure, and reduce the incidence of VILI. CASE REPORT: Two patients with critical COVID-19 combined with multiple organ failure undertook mechanical ventilation and suffered from hypercapnia. ECCO2R, combined with continuous renal replacement therapy (CRRT), was conducted concomitantly. In both cases (No. 1 and 2), the tidal volume and positive end-expiratory pressure (PEEP) were down-regulated before the treatment and at 1.5 hours, one day, three days, five days, eight days, and ten days after the treatment, together with a noticeable decrease in PCO2 and clear increase in PO2, while FiO2 decreased to approximately 40%. In case No 2, compared with the condition before treatment, the PCO2 decreased significantly with down-regulation in the tidal volume and PEEP and improvement in the pulmonary edema and ARDS after the treatment. CONCLUSION: ECCO2R combined with continuous blood purification therapy in patients with COVID-19 who are criti-cally ill and have ARDS and hypercapnia might gain both time and opportunity in the treatment, down-regulate the ventilator parameters, reduce the incidence of VILI and achieve favorable therapeutic outcomes.


Subject(s)
COVID-19/complications , Carbon Dioxide/isolation & purification , Extracorporeal Circulation/methods , Hemofiltration/methods , Hypercapnia/therapy , Respiratory Distress Syndrome/therapy , SARS-CoV-2/isolation & purification , Aged , COVID-19/transmission , COVID-19/virology , Humans , Hypercapnia/physiopathology , Hypercapnia/virology , Male , Positive-Pressure Respiration , Respiration, Artificial , Respiratory Distress Syndrome/physiopathology , Respiratory Distress Syndrome/virology
10.
Cancer Cytopathol ; 129(8): 632-641, 2021 08.
Article in English | MEDLINE | ID: covidwho-1342873

ABSTRACT

BACKGROUND: Bronchoalveolar lavage (BAL) in patients with severe coronavirus disease 2019 (COVID-19) may provide additional and complementary findings for the management of these patients admitted to intensive care units (ICUs). This study addresses the cytological features of the infection and highlights the more influential inflammatory components. The correlation between pathological variables and clinical data is also analyzed. METHODS: The authors performed a retrospective analysis of the cytopathological features of BAL in 20 COVID-19 patients and 20 members of a matched cohort from a critical ICU who had acute respiratory distress syndrome caused by other pulmonary conditions. RESULTS: A comparison of the controls (n = 20) and the COVID-19 patients (n = 20) revealed that the latter had a higher neutrophil count (median, 63.8% of the cell count) with lower percentages of macrophages and lymphocytes. An increase in the expression of CD68-positive, monocytic multinucleated giant cells (MGCs) was reported; megakaryocytes were not detected on CD61 staining. Perls staining showed isolated elements. In situ RNA analysis demonstrated scattered chromogenic signals in type II pneumocytes. An ultrastructural analysis confirmed the presence of intracytoplasmic vacuoles containing rounded structures measuring 140 nm in diameter (putative viral particles). In COVID-19 patients, the clinicopathological correlation revealed a positive correlation between lactate dehydrogenase values and MGCs (r = 0.54). CONCLUSIONS: The analysis of BAL samples might be implemented as a routine practice for the evaluation of COVID-19 patients in ICUs in the appropriate clinical scenario. Additional studies using a larger sample size of patients who developed COVID-19 during the second wave of the epidemic in the autumn of 2020 are needed to further support our findings.


Subject(s)
Bronchoalveolar Lavage Fluid/cytology , Bronchoalveolar Lavage Fluid/immunology , COVID-19/diagnosis , COVID-19/immunology , COVID-19/pathology , Adult , Aged , Female , Humans , Male , Middle Aged , Pilot Projects , Pneumonia, Viral/diagnosis , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , Retrospective Studies , SARS-CoV-2
11.
Thromb Haemost ; 121(8): 1031-1042, 2021 08.
Article in English | MEDLINE | ID: covidwho-1324458

ABSTRACT

Hemostatic changes induced by extracorporeal membrane oxygenation (ECMO) support have been yet poorly documented in coronavirus-19 (COVID-19) patients who have a baseline complex hypercoagulable state. In this prospective monocentric study of patients with severe acute respiratory distress syndrome (ARDS) rescued by ECMO, we performed longitudinal measurements of coagulation and fibrinolysis markers throughout the course of ECMO support in 20 COVID-19 and 10 non-COVID-19 patients. Blood was sampled before and then 24 hours, 7, and 14 days after ECMO implantation. Clinical outcomes were prospectively assessed until discharge from the intensive care unit or death. The median age of participants was 47 (35-56) years, with a median body mass index of 30 (27-35) kg/m2, and a Sepsis-related Organ Failure Assessment score of 12 (8-16). Baseline levels of von Willebrand factor, fibrinogen, factor VIII, prothrombin F1 + 2, thrombin-antithrombin, D-dimer, and plasminogen activator inhibitor-1 (PAI-1) were elevated in both COVID-19 and non-COVID-19 ARDS patients, indicating that endothelial activation, endogenous thrombin generation, and fibrinolysis shutdown occur in all ARDS patients before ECMO implantation. From baseline to day 7, thrombin generation (prothrombin F1 + 2, p < 0.01) and fibrin formation markers (fibrin monomers, p < 0.001) significantly increased, further resulting in significant decreases in platelet count (p < 0.0001) and fibrinogen level (p < 0.001). PAI-1 levels significantly decreased from baseline to day 7 (p < 0.0001) in all ARDS patients. These changes were more marked in COVID-19 patients, resulting in 14 nonfatal and 3 fatal bleeding. Additional studies are warranted to determine whether monitoring of thrombin generation and fibrinolysis markers might help to early predict bleeding complications in COVID-19 patients supported by ECMO.


Subject(s)
Blood Coagulation , COVID-19/therapy , Extracorporeal Membrane Oxygenation/adverse effects , Fibrinolysis , Respiratory Distress Syndrome/therapy , Adult , COVID-19/blood , COVID-19/complications , Female , Hemorrhage/etiology , Humans , Male , Middle Aged , Prospective Studies , Respiratory Distress Syndrome/blood , Respiratory Distress Syndrome/complications , von Willebrand Factor/analysis
12.
Exp Clin Transplant ; 19(7): 744-748, 2021 07.
Article in English | MEDLINE | ID: covidwho-1323413

ABSTRACT

Acute respiratory distress syndrome remains the main cause of death among people with COVID-19. Although many immunomodulatory and antiviral drug therapies have been tested, the only effective therapy against severe COVID-19 pneumonia among the general population is a regimen of high-dose corticosteroids for cases of severe associated inflammation. In solid-organ transplant recipients with long-term immunosuppression, data on disease presentation and evolution are scarce, and the benefit of high-dose corticosteroids remains uncertain for cases of severe COVID-19 pneumonia. Here, we report 2 cases of COVID-19-related acute respiratory distress syndrome that occurred in lung transplant recipients in March and April 2020, respectively. Both cases of acute respiratory distress syndrome occurred in patients with long-term azithromycin treatment prescribed to prevent chronic allograft dysfunction. Acute respiratory distress syndrome was associated with severe inflammation and was cured after early administration of high-dose corticosteroids in both cases, with progressive and complete resolution of lung lesions evidenced on thoracic computed tomography scan. Our findings support the benefit of early high-dose corticosteroids in COVID-19-related acute respiratory distress syndrome with hyperinflammation in patients with long-term immunosuppression such as lung transplant recipients.


Subject(s)
COVID-19/drug therapy , Lung Transplantation , Methylprednisolone/therapeutic use , Postoperative Complications/drug therapy , Respiratory Distress Syndrome/drug therapy , COVID-19/complications , Female , Humans , Male , Middle Aged , Postoperative Complications/virology , Remission Induction , Respiratory Distress Syndrome/virology
13.
J Thromb Haemost ; 18(7): 1752-1755, 2020 07.
Article in English | MEDLINE | ID: covidwho-1317980

ABSTRACT

A prothrombotic coagulopathy is commonly found in critically ill COVID-19 patients with acute respiratory distress syndrome (ARDS). A unique feature of COVID-19 respiratory failure is a relatively preserved lung compliance and high Alveolar-arterial oxygen gradient, with pathology reports consistently demonstrating diffuse pulmonary microthrombi on autopsy, all consistent with a vascular occlusive etiology of respiratory failure rather than the more classic findings of low-compliance in ARDS. The COVID-19 pandemic is overwhelming the world's medical care capacity with unprecedented needs for mechanical ventilators and high rates of mortality once patients progress to needing mechanical ventilation, and in many environments including in parts of the United States the medical capacity is being exhausted. Fibrinolytic therapy has previously been used in a Phase 1 clinical trial that led to reduced mortality and marked improvements in oxygenation. Here we report a series of three patients with severe COVID-19 respiratory failure who were treated with tissue plasminogen activator. All three patients had a temporally related improvement in their respiratory status, with one of them being a durable response.


Subject(s)
Betacoronavirus/pathogenicity , Blood Coagulation Disorders/drug therapy , Coronavirus Infections/drug therapy , Fibrinolysis/drug effects , Fibrinolytic Agents/administration & dosage , Pneumonia, Viral/drug therapy , Thrombolytic Therapy , Tissue Plasminogen Activator/administration & dosage , Aged , Blood Coagulation Disorders/blood , Blood Coagulation Disorders/diagnosis , Blood Coagulation Disorders/virology , COVID-19 , Coronavirus Infections/blood , Coronavirus Infections/diagnosis , Coronavirus Infections/virology , Fatal Outcome , Female , Fibrinolytic Agents/adverse effects , Host-Pathogen Interactions , Humans , Male , Middle Aged , Pandemics , Pneumonia, Viral/blood , Pneumonia, Viral/diagnosis , Pneumonia, Viral/virology , Recovery of Function , SARS-CoV-2 , Thrombolytic Therapy/adverse effects , Tissue Plasminogen Activator/adverse effects , Treatment Outcome
14.
Ann Am Thorac Soc ; 18(7): 1202-1210, 2021 07.
Article in English | MEDLINE | ID: covidwho-1305584

ABSTRACT

Rationale: There is an urgent need for improved understanding of the mechanisms and clinical characteristics of acute respiratory distress syndrome (ARDS) due to coronavirus disease (COVID-19).Objectives: To compare key demographic and physiologic parameters, biomarkers, and clinical outcomes of COVID-19 ARDS and ARDS secondary to direct lung injury from other etiologies of pneumonia.Methods: We enrolled 27 patients with COVID-19 ARDS in a prospective, observational cohort study and compared them with a historical, pre-COVID-19 cohort of patients with viral ARDS (n = 14), bacterial ARDS (n = 21), and ARDS due to culture-negative pneumonia (n = 30). We recorded clinical demographics; measured respiratory mechanical parameters; collected serial peripheral blood specimens for measurement of plasma interleukin (IL)-6, IL-8, and IL-10; and followed patients prospectively for patient-centered outcomes. We conducted between-group comparisons with nonparametric tests and analyzed time-to-event outcomes with Kaplan-Meier and Cox proportional hazards models.Results: Patients with COVID-19 ARDS had higher body mass index and were more likely to be Black, or residents of skilled nursing facilities, compared with those with non-COVID-19 ARDS (P < 0.05). Patients with COVID-19 had lower delivered minute ventilation compared with bacterial and culture-negative ARDS (post hoc P < 0.01) but not compared with viral ARDS. We found no differences in static compliance, hypoxemic indices, or carbon dioxide clearance between groups. Patients with COVID-19 had lower IL-6 levels compared with bacterial and culture-negative ARDS at early time points after intubation but no differences in IL-6 levels compared with viral ARDS. Patients with COVID-19 had longer duration of mechanical ventilation but similar 60-day mortality in both unadjusted and adjusted analyses.Conclusions: COVID-19 ARDS bears several similarities to viral ARDS but demonstrates lower minute ventilation and lower systemic levels of IL-6 compared with bacterial and culture-negative ARDS. COVID-19 ARDS was associated with longer dependence on mechanical ventilation compared with non-COVID-19 ARDS. Such detectable differences of COVID-19 do not merit deviation from evidence-based management of ARDS but suggest priorities for clinical research to better characterize and treat this new clinical entity.


Subject(s)
COVID-19 , Respiratory Distress Syndrome , Biomarkers , Demography , Humans , Prospective Studies , Respiration, Artificial , Respiratory Distress Syndrome/epidemiology , SARS-CoV-2
15.
Mol Cell Proteomics ; 20: 100113, 2021.
Article in English | MEDLINE | ID: covidwho-1275575

ABSTRACT

Severe coronavirus disease 2019 (COVID-19) can result in pneumonia and acute respiratory failure. Accumulation of mucus in the airways is a hallmark of the disease and can result in hypoxemia. Here, we show that quantitative proteome analysis of the sputum from severe patients with COVID-19 reveal high levels of neutrophil extracellular trap (NET) components, which was confirmed by microscopy. Extracellular DNA from excessive NET formation can increase sputum viscosity and lead to acute respiratory distress syndrome. Recombinant human DNase (Pulmozyme; Roche) has been shown to be beneficial in reducing sputum viscosity and improve lung function. We treated five patients pwith COVID-19 resenting acute symptoms with clinically approved aerosolized Pulmozyme. No adverse reactions to the drug were seen, and improved oxygen saturation and recovery in all severely ill patients with COVID-19 was observed after therapy. Immunofluorescence and proteome analysis of sputum and blood plasma samples after treatment revealed a marked reduction of NETs and a set of statistically significant proteome changes that indicate reduction of hemorrhage, plasma leakage and inflammation in the airways, and reduced systemic inflammatory state in the blood plasma of patients. Taken together, the results indicate that NETs contribute to acute respiratory failure in COVID-19 and that degrading NETs may reduce dependency on external high-flow oxygen therapy in patients. Targeting NETs using recombinant human DNase may have significant therapeutic implications in COVID-19 disease and warrants further studies.


Subject(s)
COVID-19/drug therapy , Deoxyribonuclease I/pharmacology , Extracellular Traps/metabolism , Proteome/analysis , Aged , Blood Proteins/analysis , COVID-19/metabolism , COVID-19/therapy , Female , Fluorescent Antibody Technique , Humans , Male , Middle Aged , Recombinant Proteins/pharmacology , Severity of Illness Index , Sputum/drug effects , Sputum/metabolism , Sputum/virology , Systemic Inflammatory Response Syndrome/drug therapy , Systemic Inflammatory Response Syndrome/metabolism , Systemic Inflammatory Response Syndrome/virology
16.
Acta Pharmacol Sin ; 41(12): 1539-1546, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-1269381

ABSTRACT

The pandemic of coronavirus disease 2019 (COVID-19) and its pathogen, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have become the greatest current threat to global public health. The highly infectious SARS-CoV-2 virus primarily attacks pulmonary tissues and impairs gas exchange leading to acute respiratory distress syndrome (ARDS) and systemic hypoxia. The current pharmacotherapies for COVID-19 largely rely on supportive and anti-thrombi treatment and the repurposing of antimalarial and antiviral drugs such as hydroxychloroquine and remdesivir. For a better mechanistic understanding of COVID-19, our present review focuses on its primary pathophysiologic features: hypoxia and cytokine storm, which are a prelude to multiple organ failure and lethality. We discussed a possible link between the activation of hypoxia inducible factor 1α (HIF-1α) and cell entry of SARS-CoV-2, since HIF-1α is shown to suppress the angiotensin-converting enzyme 2 (ACE2) receptor and transmembrane protease serine 2 (TMPRSS2) and upregulate disintegrin and metalloproteinase domain-containing protein 17 (ADAM17). In addition, the protein targets of HIF-1α are involved with the activation of pro-inflammatory cytokine expression and the subsequent inflammatory process. Furthermore, we hypothesized a potential utility of so-called "hypoxic conditioning" to activate HIF-1α-induced cytoprotective signaling for reduction of illness severity and improvement of vital organ function in patients with COVID-19. Taken together, we would propose further investigations into the hypoxia-related molecular mechanisms, from which novel targeted therapies can be developed for the improved management of COVID-19.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Animals , COVID-19/physiopathology , COVID-19/virology , Cytokine Release Syndrome/virology , Drug Development , Drug Repositioning , Humans , Hypoxia/drug therapy , Hypoxia/virology , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Molecular Targeted Therapy , SARS-CoV-2/isolation & purification , SARS-CoV-2/pathogenicity
17.
J Cancer Res Ther ; 17(2): 295-302, 2021.
Article in English | MEDLINE | ID: covidwho-1268380

ABSTRACT

The world is fighting the onslaught of COVID 19 for the last 10 months, ever since the first case was reported in December 2019 in Wuhan, China. Now, it has spread to over 200 countries. COVID 19-associated respiratory syndrome is causing a lot of mortality and morbidity. There are reports suggesting that the complications and ARDS associated with COVID 19 is an immune response reaction. The cytokine storm associated with severe cases of COVID 19 acts as a cause of death in many sick patients. It has been shown that COVID 19 is associated with a peculiar immune profile: Decrease in CD3, CD4, CD8, natural killer cell and B-cells; Rise in interleukin (IL)-4, IL-6 and tumor necrosis factor (TNF) alpha; Decrease in IL-10; Decrease in interferon-gamma. Low-dose radiotherapy (LDRT) immunosuppressive features resulting from M2 macrophage phenotype activation, increase in IL-10, transforming growth factor beta, a decrease in IL-6, TNF alpha and an increase in CD3, CD4, and CD8 T cell counts may negate the harmful effects of cytokine release syndrome. Literature review shows that radiation was previously used to treat viral pneumonia with a good success rate. This practice was discontinued in view of the availability of effective antibiotics and antivirals. As there are no scientifically proven treatment for severe COVID 19-associated respiratory distress today, it is prudent that we understand the benefits of LDRT at this critical juncture and take rational decisions to treat the same. This article provides an radioimmunological rationale for the treatment of immune crisis mediated complications in severe cases of COVID 19.


Subject(s)
COVID-19/radiotherapy , Cytokine Release Syndrome/radiotherapy , SARS-CoV-2/immunology , COVID-19/complications , COVID-19/immunology , COVID-19/virology , Clinical Decision-Making , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/virology , Humans , Radiotherapy Dosage , Severity of Illness Index , Treatment Outcome
19.
Elife ; 102021 06 11.
Article in English | MEDLINE | ID: covidwho-1266916

ABSTRACT

In severe viral pneumonia, including Coronavirus disease 2019 (COVID-19), the viral replication phase is often followed by hyperinflammation, which can lead to acute respiratory distress syndrome, multi-organ failure, and death. We previously demonstrated that alpha-1 adrenergic receptor (⍺1-AR) antagonists can prevent hyperinflammation and death in mice. Here, we conducted retrospective analyses in two cohorts of patients with acute respiratory distress (ARD, n = 18,547) and three cohorts with pneumonia (n = 400,907). Federated across two ARD cohorts, we find that patients exposed to ⍺1-AR antagonists, as compared to unexposed patients, had a 34% relative risk reduction for mechanical ventilation and death (OR = 0.70, p = 0.021). We replicated these methods on three pneumonia cohorts, all with similar effects on both outcomes. All results were robust to sensitivity analyses. These results highlight the urgent need for prospective trials testing whether prophylactic use of ⍺1-AR antagonists ameliorates lower respiratory tract infection-associated hyperinflammation and death, as observed in COVID-19.


Subject(s)
Adrenergic alpha-1 Receptor Antagonists/therapeutic use , Pneumonia, Viral/drug therapy , Respiration, Artificial/statistics & numerical data , Respiratory Distress Syndrome/drug therapy , Aged , Aged, 80 and over , Doxazosin/therapeutic use , Humans , Male , Middle Aged , Pneumonia, Viral/mortality , Respiratory Distress Syndrome/mortality , Retrospective Studies , Sweden/epidemiology , Tamsulosin/therapeutic use , United States/epidemiology
20.
Vasc Health Risk Manag ; 17: 273-298, 2021.
Article in English | MEDLINE | ID: covidwho-1262578

ABSTRACT

COVID-19 sepsis is characterized by acute respiratory distress syndrome (ARDS) as a consequence of pulmonary tropism of the virus and endothelial heterogeneity of the host. ARDS is a phenotype among patients with multiorgan dysfunction syndrome (MODS) due to disseminated vascular microthrombotic disease (VMTD). In response to the viral septicemia, the host activates the complement system which produces terminal complement complex C5b-9 to neutralize pathogen. C5b-9 causes pore formation on the membrane of host endothelial cells (ECs) if CD59 is underexpressed. Also, viral S protein attraction to endothelial ACE2 receptor damages ECs. Both affect ECs and provoke endotheliopathy. Disseminated endotheliopathy activates two molecular pathways: inflammatory and microthrombotic. The former releases inflammatory cytokines from ECs, which lead to inflammation. The latter initiates endothelial exocytosis of unusually large von Willebrand factor (ULVWF) multimers and FVIII from Weibel-Palade bodies. If ADAMTS13 is insufficient, ULVWF multimers activate intravascular hemostasis of ULVWF path. In activated ULVWF path, ULVWF multimers anchored to damaged endothelial cells recruit circulating platelets and trigger microthrombogenesis. This process produces "microthrombi strings" composed of platelet-ULVWF complexes, leading to endotheliopathy-associated VMTD (EA-VMTD). In COVID-19, microthrombosis initially affects the lungs per tropism causing ARDS, but EA-VMTD may orchestrate more complex clinical phenotypes, including thrombotic thrombocytopenic purpura (TTP)-like syndrome, hepatic coagulopathy, MODS and combined micro-macrothrombotic syndrome. In this pandemic, ARDS and pulmonary thromboembolism (PTE) have often coexisted. The analysis based on two hemostatic theories supports ARDS caused by activated ULVWF path is EA-VMTD and PTE caused by activated ULVWF and TF paths is macrothrombosis. The thrombotic disorder of COVID-19 sepsis is consistent with the notion that ARDS is virus-induced disseminated EA-VMTD and PTE is in-hospital vascular injury-related macrothrombosis which is not directly  related to viral pathogenesis. The pathogenesis-based therapeutic approach is discussed for the treatment of EA-VMTD with antimicrothrombotic regimen and the potential need of anticoagulation therapy for coinciding macrothrombosis in comprehensive COVID-19 care.


Subject(s)
COVID-19/epidemiology , Endothelial Cells/metabolism , Fibrinolytic Agents/therapeutic use , Hemostasis/physiology , SARS-CoV-2 , Sepsis/complications , Thrombosis/etiology , COVID-19/complications , Humans , Pandemics , Phenotype , Sepsis/metabolism , Thrombosis/drug therapy , Thrombosis/metabolism
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