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1.
Cir Cir ; 88(5): 569-575, 2020.
Article in English | MEDLINE | ID: covidwho-836484

ABSTRACT

Objective: To describe the clinical characteristics and management of severe COVID-19 patients. Method: Observational, descriptive, longitudinal, and retrospective study. Results: 56 patients were admitted, of whom 80.3% (n = 45) were males with a mean age of 58 years [46-67]. The main comorbidities were obesity, high blood pressure, and diabetes. Symptoms onset time at admittance to the ICU was 9 [7-14] days, of which the most frequent were dyspnea, fever, and dry cough. Laboratory data were lymphopenia; elevation of LDH, fibrinogen, D-dimer, ferritin and CRP. 100% of the patients required mechanical ventilation, the median mechanical ventilation time was 12 [6-17] days, and 66% (n= 37) required a prone position. The pharmacological treatment was mainly based on azithromycin, hydroxychloroquine, tocilizumab and steroids. The most frequent complications were acute kidney injury, venous thromboembolism and acute myocardial infarction. Mortality rate was 17.8% (n = 10). Conclusion: The characteristics of the critically ill patients in our hospital were mostly elderly and obese, with the variables of higher SOFA score and acute kidney injury associated with higher mortality.


Subject(s)
Betacoronavirus , Coronavirus Infections/therapy , Critical Care/methods , Intensive Care Units , Pandemics , Pneumonia, Viral/therapy , Acute Kidney Injury/epidemiology , Acute Kidney Injury/etiology , Adrenal Cortex Hormones/therapeutic use , Aged , Antibodies, Monoclonal, Humanized/therapeutic use , Antiviral Agents/therapeutic use , Azithromycin/therapeutic use , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/etiology , Combined Modality Therapy , Comorbidity , Coronavirus Infections/blood , Coronavirus Infections/complications , Coronavirus Infections/drug therapy , Coronavirus Infections/epidemiology , Female , Hospital Mortality , Hospitals, University/organization & administration , Humans , Hydroxychloroquine/therapeutic use , Male , Mexico/epidemiology , Middle Aged , Organ Dysfunction Scores , Pneumonia, Viral/blood , Pneumonia, Viral/complications , Pneumonia, Viral/epidemiology , Respiration, Artificial , Symptom Assessment
3.
Chest ; 158(4): 1397-1408, 2020 10.
Article in English | MEDLINE | ID: covidwho-805858

ABSTRACT

BACKGROUND: Tocilizumab, an IL-6 receptor antagonist, can be used to treat cytokine release syndrome (CRS), with observed improvements in a coronavirus disease 2019 (COVID-19) case series. RESEARCH QUESTION: The goal of this study was to determine if tocilizumab benefits patients hospitalized with COVID-19. STUDY DESIGN AND METHODS: This observational study of consecutive COVID-19 patients hospitalized between March 10, 2020, and March 31, 2020, and followed up through April 21, 2020, was conducted by chart review. Patients were treated with tocilizumab using an algorithm that targeted CRS. Survival and mechanical ventilation (MV) outcomes were reported for 14 days and stratified according to disease severity designated at admission (severe, ≥ 3 L supplemental oxygen to maintain oxygen saturation > 93%). For tocilizumab-treated patients, pre/post analyses of clinical response, biomarkers, and safety outcomes were assessed. Post hoc survival analyses were conducted for race/ethnicity. RESULTS: Among the 239 patients, median age was 64 years; 36% and 19% were black and Hispanic, respectively. Hospital census increased exponentially, yet MV census did not. Severe disease was associated with lower survival (78% vs 93%; P < .001), greater proportion requiring MV (44% vs 5%; P < .001), and longer median MV days (5.5 vs 1.0; P = .003). Tocilizumab-treated patients (n = 153 [64%]) comprised 90% of those with severe disease; 44% of patients with nonsevere disease received tocilizumab for evolving CRS. Tocilizumab-treated patients with severe disease had higher admission levels of high-sensitivity C-reactive protein (120 vs 71 mg/L; P < .001) and received tocilizumab sooner (2 vs 3 days; P < .001), but their survival was similar to that of patients with nonsevere disease (83% vs 91%; P = .11). For tocilizumab-treated patients requiring MV, survival was 75% (95% CI, 64-89). Following tocilizumab treatment, few adverse events occurred, and oxygenation and inflammatory biomarkers (eg, high-sensitivity C-reactive protein, IL-6) improved; however, D-dimer and soluble IL-2 receptor (also termed CD25) levels increased significantly. Survival in black and Hispanic patients, after controlling for age, was significantly higher than in white patients (log-rank test, P = .002). INTERPRETATION: A treatment algorithm that included tocilizumab to target CRS may influence MV and survival outcomes. In tocilizumab-treated patients, oxygenation and inflammatory biomarkers improved, with higher than expected survival. Randomized trials must confirm these findings.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Betacoronavirus , Coronavirus Infections/complications , Coronavirus Infections/therapy , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/virology , Pneumonia, Viral/complications , Pneumonia, Viral/therapy , Adult , Aged , Aged, 80 and over , Algorithms , Coronavirus Infections/mortality , Cytokine Release Syndrome/mortality , Female , Hospitalization , Humans , Male , Middle Aged , Pandemics , Pneumonia, Viral/mortality , Respiration, Artificial , Survival Rate , Treatment Outcome , Young Adult
4.
Crit Care ; 24(1): 589, 2020 09 29.
Article in English | MEDLINE | ID: covidwho-802272

ABSTRACT

BACKGROUND: The severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is extremely variable, ranging from asymptomatic patients to those who develop severe acute respiratory distress syndrome (ARDS). As for now, there are still no really effective therapies for coronavirus disease 2019 (COVID-19). Some evidences suggest that tocilizumab (TCZ) may avoid the progression of severe COVID-19. The aim of this retrospective case-control study was to analyze the efficacy and safety of TCZ in patients with COVID-19 ARDS undergoing noninvasive mechanical ventilation (NIV). METHODS: Seventy-nine consecutive patients with severe COVID-19 pneumonia and worsening acute respiratory failure (ARF) were admitted to the Pulmonology Unit of Azienda USL of Reggio Emilia-IRCCS. All patients were inflamed (elevated CRP and IL-6 levels) and received NIV at admission according to the presence of a pO2/FiO2 ratio ≤ 200 mmHg. The possibility of being treated with TCZ depended on the drug availability. The primary outcome was the in-hospital mortality rate. A secondary composite outcome of worsening was represented by the patients who died in the pulmonology unit or were intubated. RESULTS: Out of 79 patients, 41 were treated with TCZ. Twenty-eight patients received intravenous (IV) TCZ and 13 patients received subcutaneous (SC) TCZ. In-hospital overall mortality rate was 38% (30/79 patients). The probabilities of dying and being intubated during the follow-up using Kaplan-Meier method were significantly lower in total patients treated with TCZ compared to those of patients not treated with TCZ (log-rank p value = 0.006 and 0.036, respectively). However, using Cox multivariate analyses adjusted for age and Charlson comorbidity index only the association with the reduced risk of being intubated or dying maintained the significance (HR 0.44, 95%CI 0.22-0.89, p = 0.022). Two patients treated with TCZ developed cavitating lung lesions during the follow-up. CONCLUSIONS: This study shows that TCZ treatment may be effective in COVID-19 patients with severe respiratory impairment receiving NIV. More data on safety are required. Randomized controlled trials are needed to confirm these results.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Coronavirus Infections/therapy , Noninvasive Ventilation , Pneumonia, Viral/therapy , Respiratory Distress Syndrome, Adult/therapy , Respiratory Distress Syndrome, Adult/virology , Aged , Betacoronavirus , Case-Control Studies , Female , Humans , Male , Middle Aged , Pandemics , Retrospective Studies
5.
Front Immunol ; 11: 1942, 2020.
Article in English | MEDLINE | ID: covidwho-800867

ABSTRACT

Severe cases of COVID-19 present with serious lung inflammation, acute respiratory distress syndrome and multiorgan damage. SARS-CoV-2 infection is associated with high cytokine levels, including interleukin-6 and certain subsets of immune cells, in particular, NK, distinguished according to the cell surface density of CD56. Cytokine levels are inversely correlated with lymphocyte count, therefore cytokine release syndrome may be an impediment to the adaptive immune response against SARS-CoV-2 infection. Canakinumab, a monoclonal antibody targeting IL-1ß is under investigation for the treatment of severe SAR-CoV-2 infection. An 85 year old male presenting in our hospital with COVID-19, whose condition was complicated by acute respiratory distress syndrome and cardiac and renal failure (with oliguria) after 25 days of hospitalization, was intubated and received canakinumab for compassionate use. On the next day, diuresis recovered and conditions improved: high IL-6 levels and NK cells expressing CD56 bright (associated with cytokine relase) were significantly reduced giving rise to NK CD56 dim . Patient died on day 58 with pulmonary bacterial superinfection and persistent SARS-CoV-2 positivity. In conclusion, canakinumab rescued a high risk, very elderly patient, from multiorgan damage complicating COVID-19. It may represent an useful treatment in severe cases.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Betacoronavirus , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Respiratory Distress Syndrome, Adult/drug therapy , Aged, 80 and over , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/pharmacology , CD56 Antigen/metabolism , Coronavirus Infections/virology , Fatal Outcome , Humans , Interleukin-1beta/antagonists & inhibitors , Interleukin-6/blood , Killer Cells, Natural/immunology , Male , Pandemics , Pneumonia, Viral/virology , Respiratory Distress Syndrome, Adult/virology , Severity of Illness Index
6.
Arch Med Res ; 51(6): 595-597, 2020 08.
Article in English | MEDLINE | ID: covidwho-793360

ABSTRACT

Presently, we need more therapeutic molecules for this COVID-19 outbreak. The severity and mortality of the disease is associated with a high level of release of cytokine in the patients which is known as CRS (cytokine release syndrome) or cytokine storm syndrome. IL-6 is a type of pro-inflammatory cytokine which release in the severe COVID-19 patients. This cytokine initiates CRS the JAK-STAT or MAPK/NF-κB-IL-6 pathway. Tocilizumab, a humanized monoclonal antibody, is designed to bind both mIL-6R (membrane bound receptor for IL-6) and sIL-6R (soluble receptor for IL-6) and inhibit the JAK-STAT or MAPK/NF-κB-IL-6 signaling pathway. It finally stops the cytokine storm syndrome. However, we need to understand that how tocilizumab is bound with mIL-6R or sIL-6R. Similarly, we also need to understand more about the real molecular mechanism of activity of tocilizumab.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Coronavirus Infections/drug therapy , Cytokine Release Syndrome/drug therapy , Pneumonia, Viral/drug therapy , Receptors, Interleukin-6/antagonists & inhibitors , Betacoronavirus , Humans , Interleukin-6/immunology , Pandemics , Protein Binding , Signal Transduction
7.
Front Immunol ; 11: 2132, 2020.
Article in English | MEDLINE | ID: covidwho-782002

ABSTRACT

In December 2019, a novel coronavirus, COVID-19, was discovered to be the causal agent of a severe respiratory infection named SARS-CoV-2, and it has since been recognized worldwide as a pandemic. There are still numerous doubts concerning its pathogenesis and particularly the underlying causes of the various clinical courses, ranging from severe manifestations to asymptomatic forms, including acute respiratory distress syndrome. The major factor responsible for acute respiratory distress syndrome is the so-called "cytokine storm," which is an aberrant response from the host immune system that induces an exaggerated release of proinflammatory cytokines/chemokines. In this review, we will discuss the role of cytokine storm in COVID-19 and potential treatments with which counteract this aberrant response, which may be valuable in the clinical translation.


Subject(s)
Betacoronavirus/immunology , Chemokines/blood , Chemokines/immunology , Coronavirus Infections/immunology , Pneumonia, Viral/immunology , Respiratory Distress Syndrome, Adult/immunology , Animals , Antibodies, Monoclonal, Humanized/pharmacology , Antibodies, Monoclonal, Humanized/therapeutic use , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Glucocorticoids/therapeutic use , Humans , Hydroxychloroquine/therapeutic use , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Pandemics , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , Receptors, Interleukin-6/antagonists & inhibitors , Respiratory Distress Syndrome, Adult/drug therapy
9.
Rheumatol Int ; 40(9): 1353-1360, 2020 09.
Article in English | MEDLINE | ID: covidwho-640396

ABSTRACT

As of June 10th 2020 about 7.2 million individuals have tested positive for, and more than 410,000 have died due to COVID-19. In this review we outline the pathophysiology that underpins the potential use of anti-rheumatic therapies for severe COVID-19 infection and summarize the current evidence regarding the risk and outcome of COVID-19 in patients with systemic autoimmune diseases. Thus far there is no convincing evidence that any disease-modifying anti-rheumatic drug (conventional synthetic, biologic or targeted synthetic) including hydroxychloroquine, may protect against severe COVID-19 infection; answers about their possible usefulness in the management of the cytokine storm associated with severe COVID-9 infection will only arise from ongoing randomized controlled trials. Evidence on COVID-19 risk and outcome in patients with systemic autoimmune diseases is extremely limited; thus, any conclusions would be unsafe and should be seen with great caution. At present, the risk and severity (hospitalization, intensive care unit admission and death) of COVID-19 infection in people with autoimmune diseases do not appear particularly dissimilar to the general population, with the possible exception of hospitalization in patients exposed to high glucocorticoid doses. At this stage it is impossible to draw any conclusions for differences in COVID-19 risk and outcome between different autoimmune diseases and between the various immunomodulatory therapies used for them. More research in the field is obviously required, including as a minimum careful and systematic epidemiology and appropriately controlled clinical trials.


Subject(s)
Antirheumatic Agents/therapeutic use , Autoimmune Diseases/drug therapy , Coronavirus Infections/drug therapy , Cytokine Release Syndrome/drug therapy , Pneumonia, Viral/drug therapy , Antibodies, Monoclonal, Humanized/therapeutic use , Autoimmune Diseases/epidemiology , Autoimmune Diseases/immunology , Betacoronavirus , Comorbidity , Coronavirus Infections/epidemiology , Coronavirus Infections/immunology , Cytokine Release Syndrome/immunology , Humans , Janus Kinase Inhibitors/therapeutic use , Pandemics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/immunology , Risk Factors , Severity of Illness Index , Tumor Necrosis Factor Inhibitors/therapeutic use
10.
Front Immunol ; 11: 1844, 2020.
Article in English | MEDLINE | ID: covidwho-742725

ABSTRACT

With the onset of the global pandemic in 2020 of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), there has been increasing research activity around certain disease-modifying drugs that are used for the management of inflammatory disorders such as rheumatoid arthritis, spondyloarthrosis, psoriatic arthritis, systemic lupus erythematosus, and inflammatory bowel disease for managing coronavirus symptoms. In the conditions mentioned, many people are on long-term treatment with agents including hydroxychloroquine, tumor necrosis factor alpha (TNFα) inhibitor drugs, other biologic agents such as monoclonal antibodies to IL-6 and Janus kinase inhibitors including baricitinib and tofacitinib, which are used to control inflammatory responses in their respective auto-immune condition. There is emerging data that immunomodulatory drugs could be protective at reducing certain features of SARS-CoV-2 and improving recovery. In addition, it is important to understand if subjects being treated with the immunomodulatory agents described have a less severe SARS-CoV-2 infection, as they are deemed some protection from their immunomodulatory treatment, or if they develop infections similar to non-immunocompromised patients. There is a huge unmet clinical need to advise patients responsibly about whether they should remain on their immunomodulatory treatment or not in light of Covid-19 infection. In this article we will discuss potential treatment options for SARS-CoV-2 using immunomodulatory drugs and at what stage of the condition they may be beneficial. Viable treatment options during the global coronavirus pandemic are a much-needed and an intensely active area of research.


Subject(s)
Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Immunomodulation/drug effects , Pneumonia, Viral/drug therapy , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Colchicine/therapeutic use , Cytokine Release Syndrome/drug therapy , Cytokines/blood , Female , Humans , Hydroxychloroquine/therapeutic use , Janus Kinase Inhibitors/therapeutic use , Middle Aged , Pandemics , Risk Factors , Tumor Necrosis Factor-alpha/antagonists & inhibitors
12.
J Int Med Res ; 48(8): 300060520949077, 2020 Aug.
Article in English | MEDLINE | ID: covidwho-737978

ABSTRACT

The emergence of coronavirus disease 2019 (COVID-19) in December 2019 has resulted in over 20 million cases and 741,808 deaths globally, affecting more than 200 countries. COVID-19 was declared a pandemic on 11 March 2020 by the World Health Organization. The disease is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). There is limited information on COVID-19, and treatment has so far focused on supportive care and use of repurposed drugs. COVID-19 can be transmitted via person-to-person contact through droplet spread. Some of the recommended precautionary measures to reduce the rate of disease spread include social distancing, good hygiene practices, and avoidance of crowded areas. These measures are effective because the droplets are heavy and can only travel approximately 1 meter in the air, settling quickly on fixed surfaces. Promising strategies to combat SARS-CoV-2 include discovery of therapeutic targets/drugs and vaccines. In this review, we summarize the epidemiology, pathophysiology, and diagnosis of COVID-19. We also address the mechanisms of action of approved repurposed drugs for therapeutic management of the disease.


Subject(s)
Antiviral Agents/therapeutic use , Betacoronavirus/pathogenicity , Communicable Disease Control/organization & administration , Coronavirus Infections/epidemiology , Coronavirus Infections/therapy , Pandemics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/therapy , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/therapeutic use , Age Factors , Alanine/analogs & derivatives , Alanine/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Betacoronavirus/drug effects , Betacoronavirus/genetics , Chloroquine/therapeutic use , Communicable Disease Control/methods , Coronavirus Infections/diagnosis , Coronavirus Infections/physiopathology , Drug Repositioning , Humans , Incidence , Personal Protective Equipment/supply & distribution , Pneumonia, Viral/diagnosis , Pneumonia, Viral/physiopathology , Quarantine/methods , Quarantine/organization & administration , Severity of Illness Index , Social Distance , Survival Analysis
13.
Orv Hetil ; 161(26): 1070-1077, 2020 06.
Article in Hungarian | MEDLINE | ID: covidwho-736545

ABSTRACT

During the past few months, a pandemic originating from China named new coronavirus disease (COVID-19) has shown how vulnerable the world is. To date, no medication supported by randomized clinical trials has been approved for the treatment of COVID-19. At the time of writing of this paper, severe acute respiratory syndrome caused by coronavirus-2 (SARS-CoV-2) has been responsible - according to modest estimations - for around 4 million of infections and 300 000 deaths. Unveiling details of patomechanism, in fatal cases the role of immune dysregulation, namely cytokine release syndrome (CRS) has been discovered. Based on the current knowledge, interleukin-6 (IL6) plays a pivotal role in COVID-19 associated CRS. Case reports and result of small case series suggest efficacy of an IL6 inhibitor monoclonal antibody (tocilizumab) in treating CRS. Authors describe a case and review recent knowledge on the treatment of COVID-19. To our knowledge, the first case of severe COVID-19-associated cytokine storm syndrome - treated succesfully with IL6 monoclocal antibody at a Hungarian department of infectology - is presented here. Orv Hetil. 2020; 161(26): 1070-1077.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Coronavirus Infections/drug therapy , Cytokine Release Syndrome/drug therapy , Pneumonia, Viral/drug therapy , Coronavirus Infections/complications , Coronavirus Infections/epidemiology , Cytokine Release Syndrome/virology , Humans , Hungary/epidemiology , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/epidemiology , Severity of Illness Index , Treatment Outcome
14.
BMJ Open Respir Res ; 7(1)2020 08.
Article in English | MEDLINE | ID: covidwho-733150

ABSTRACT

Invasive mechanical has been associated with high mortality in COVID-19. Alternative therapy of high flow nasal therapy (HFNT) has been greatly debated around the world for use in COVID-19 pandemic due to concern for increased healthcare worker transmission.This was a retrospective analysis of consecutive patients admitted to Temple University Hospital in Philadelphia, Pennsylvania, from 10 March 2020 to 24 April 2020 with moderate-to-severe respiratory failure treated with HFNT. Primary outcome was prevention of intubation. Of the 445 patients with COVID-19, 104 met our inclusion criteria. The average age was 60.66 (+13.50) years, 49 (47.12 %) were female, 53 (50.96%) were African-American, 23 (22.12%) Hispanic. Forty-three patients (43.43%) were smokers. Saturation to fraction ratio and chest X-ray scores had a statistically significant improvement from day 1 to day 7. 67 of 104 (64.42%) were able to avoid invasive mechanical ventilation in our cohort. Incidence of hospital-associated/ventilator-associated pneumonia was 2.9%. Overall, mortality was 14.44% (n=15) in our cohort with 13 (34.4%) in the progressed to intubation group and 2 (2.9%) in the non-intubation group. Mortality and incidence of pneumonia was statistically higher in the progressed to intubation group. CONCLUSION: HFNT use is associated with a reduction in the rate of invasive mechanical ventilation and overall mortality in patients with COVID-19 infection.


Subject(s)
Coronavirus Infections/therapy , Healthcare-Associated Pneumonia/epidemiology , Hypoxia/therapy , Intubation, Intratracheal/statistics & numerical data , Oxygen Inhalation Therapy/methods , Pneumonia, Viral/therapy , Respiratory Insufficiency/therapy , Adrenal Cortex Hormones/therapeutic use , African Americans , Aged , Anti-Bacterial Agents/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Antirheumatic Agents/therapeutic use , Azithromycin/therapeutic use , Betacoronavirus , Cannula , Comorbidity , Coronavirus Infections/epidemiology , Diabetes Mellitus/epidemiology , European Continental Ancestry Group , Female , Heart Diseases/epidemiology , Hispanic Americans , Humans , Hydroxychloroquine/therapeutic use , Hypertension/epidemiology , Immunoglobulins, Intravenous/therapeutic use , Immunologic Factors/therapeutic use , Lung Diseases/epidemiology , Male , Middle Aged , Pandemics , Philadelphia/epidemiology , Pneumonia, Ventilator-Associated/epidemiology , Pneumonia, Viral/epidemiology , Pulse Therapy, Drug , Renal Insufficiency, Chronic/epidemiology , Retrospective Studies , Severity of Illness Index , Smoking/epidemiology
16.
PLoS One ; 15(8): e0237831, 2020.
Article in English | MEDLINE | ID: covidwho-725099

ABSTRACT

INTRODUCTION: Coronavirus disease 2019 (COVID-19) can lead to respiratory failure due to severe immune response. Treatment targeting this immune response might be beneficial but there is limited evidence on its efficacy. The aim of this study was to determine if early treatment of patients with COVID-19 pneumonia with tocilizumab and/or steroids was associated with better outcome. METHODS: This observational single-center study included patients with COVID-19 pneumonia who were not intubated and received either standard of care (SOC, controls) or SOC plus early (within 3 days from hospital admission) anti-inflammatory treatment. SOC consisted of hydroxychloroquine 400mg bid plus, in those admitted before March 24th, also darunavir/ritonavir. Anti-inflammatory treatment consisted of either tocilizumab (8mg/kg intravenously or 162mg subcutaneously) or methylprednisolone 1 mg/kg for 5 days or both. Failure was defined as intubation or death, and the endpoints were failure-free survival (primary endpoint) and overall survival (secondary) at day 30. Difference between the groups was estimated as Hazard Ratio by a propensity score weighted Cox regression analysis (HROW). RESULTS: Overall, 196 adults were included in the analyses. They were mainly male (67.4%), with comorbidities (78.1%) and severe COVID-19 pneumonia (83.7%). Median age was 67.9 years (range, 30-100) and median PaO2/FiO2 200 mmHg (IQR 133-289). Among them, 130 received early anti-inflammatory treatment with: tocilizumab (n = 29, 22.3%), methylprednisolone (n = 45, 34.6%), or both (n = 56, 43.1%). The adjusted failure-free survival among tocilizumab/methylprednisolone/SOC treated patients vs. SOC was 80.8% (95%CI, 72.8-86.7) vs. 64.1% (95%CI, 51.3-74.0), HROW 0.48, 95%CI, 0.23-0.99; p = 0.049. The overall survival among tocilizumab/methylprednisolone/SOC patients vs. SOC was 85.9% (95%CI, 80.7-92.6) vs. 71.9% (95%CI, 46-73), HROW 0.41, 95%CI: 0.19-0.89, p = 0.025. CONCLUSION: Early adjunctive treatment with tocilizumab, methylprednisolone or both may improve outcomes in non-intubated patients with COVID-19 pneumonia.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Coronavirus Infections/drug therapy , Methylprednisolone/therapeutic use , Pneumonia, Viral/drug therapy , Adult , Aged , Aged, 80 and over , Anti-Inflammatory Agents/administration & dosage , Antibodies, Monoclonal, Humanized/administration & dosage , Antimalarials/administration & dosage , Antimalarials/therapeutic use , Betacoronavirus , Coronavirus Infections/virology , Darunavir/therapeutic use , Female , Follow-Up Studies , HIV Protease Inhibitors/therapeutic use , Humans , Hydroxychloroquine/administration & dosage , Hydroxychloroquine/therapeutic use , Male , Methylprednisolone/administration & dosage , Middle Aged , Pandemics , Pneumonia, Viral/virology , Ritonavir/therapeutic use , Treatment Outcome
17.
PLoS One ; 15(8): e0237903, 2020.
Article in English | MEDLINE | ID: covidwho-724760

ABSTRACT

AIM: To identify investigated interventions for COVID-19 prevention or treatment via trial registry entries on planned or ongoing randomised clinical trials. To assess these registry entries for recruitment status, planned trial size, blinding and reporting of mortality. METHODS: We identified trial registry entries systematically via the WHO International Clinical Trials Registry Platform and 33 trial registries up to June 23, 2020. We included relevant trial registry entries for randomized clinical trials investigating medical preventive, adjunct or supportive therapies and therapeutics for treatment of COVID-19. Studies with non-random and single-arm design were excluded. Trial registry entries were screened by two authors independently and data were systematically extracted. RESULTS: We included 1303 trial registry entries from 71 countries investigating 381 different single interventions. Blinding was planned in 47% of trials. Sample size was >200 participants in 40% of trials and a total of 611,364 participants were planned for inclusion. Mortality was listed as an outcome in 57% of trials. Recruitment was ongoing in 54% of trials and completed in 8%. Thirty-five percent were multicenter trials. The five most frequent investigational categories were immune modulating drugs (266 trials (20%)), unconventional medicine (167 trials (13%)), antimalarial drugs (118 trials (9%)), antiviral drugs (100 trials (8%)) and respiratory adjuncts (78 trials (6%)). The five most frequently tested uni-modal interventions were: chloroquine/hydroxychloroquine (113 trials with 199,841 participants); convalescent plasma (64 trials with 11,840 participants); stem cells (51 trials with 3,370 participants); tocilizumab (19 trials with 4,139 participants) and favipiravir (19 trials with 3,210 participants). CONCLUSION: An extraordinary number of randomized clinical trials investigating COVID-19 management have been initiated with a multitude of medical preventive, adjunctive and treatment modalities. Blinding will be used in only 47% of trials, which may have influence on future reported treatment effects. Fifty-seven percent of all trials will assess mortality as an outcome facilitating future meta-analyses.


Subject(s)
Betacoronavirus , Coronavirus Infections/drug therapy , Coronavirus Infections/prevention & control , Pandemics/prevention & control , Pneumonia, Viral/drug therapy , Pneumonia, Viral/prevention & control , Randomized Controlled Trials as Topic , Registries , Anti-Bacterial Agents/therapeutic use , Anti-Inflammatory Agents/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Antimalarials/therapeutic use , Antiviral Agents/therapeutic use , Coronavirus Infections/mortality , Coronavirus Infections/virology , Drug Therapy, Combination , Humans , Hydroxychloroquine/therapeutic use , Interleukin-6/antagonists & inhibitors , Pneumonia, Viral/mortality , Pneumonia, Viral/virology , Treatment Outcome
18.
Proc Natl Acad Sci U S A ; 117(36): 22351-22356, 2020 09 08.
Article in English | MEDLINE | ID: covidwho-724752

ABSTRACT

Cytokine release syndrome (CRS) is a life-threatening complication induced by systemic inflammatory responses to infections, including bacteria and chimeric antigen receptor T cell therapy. There are currently no immunotherapies with proven clinical efficacy and understanding of the molecular mechanisms of CRS pathogenesis is limited. Here, we found that patients diagnosed with CRS from sepsis, acute respiratory distress syndrome (ARDS), or burns showed common manifestations: strikingly elevated levels of the four proinflammatory cytokines interleukin (IL)-6, IL-8, monocyte chemotactic protein-1 (MCP-1), and IL-10 and the coagulation cascade activator plasminogen activator inhibitor-1 (PAI-1). Our in vitro data indicate that endothelial IL-6 trans-signaling formed an inflammation circuit for robust IL-6, IL-8, and MCP-1 production and promoted PAI-1 production; additionally, an IL-6 signaling blockade by the human monoclonal antibody tocilizumab blunted endothelial cell activation. Plasma from severe COVID-19 patients similarly exhibited increased IL-6, IL-10, and MCP-1 levels, but these levels were not as high as those in patients with CRS from other causes. In contrast, the PAI-1 levels in COVID-19 patients were as highly elevated as those in patients with bacterial sepsis or ARDS. Tocilizumab treatment decreased the PAI-1 levels and alleviated critical illness in severe COVID-19 patients. Our findings suggest that distinct levels of cytokine production are associated with CRS induced by bacterial infection and COVID-19, but both CRS types are accompanied by endotheliopathy through IL-6 trans-signaling. Thus, the present study highlights the crucial role of IL-6 signaling in endothelial dysfunction during bacterial infection and COVID-19.


Subject(s)
Cytokine Release Syndrome/metabolism , Endothelial Cells/metabolism , Interleukin-6/metabolism , Plasminogen Activator Inhibitor 1/metabolism , Signal Transduction , Adult , Aged , Antibodies, Monoclonal, Humanized/therapeutic use , Betacoronavirus , Burns/metabolism , Burns/pathology , Cells, Cultured , Coronavirus Infections/drug therapy , Coronavirus Infections/metabolism , Coronavirus Infections/pathology , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/pathology , Cytokines/blood , Cytokines/metabolism , Endothelial Cells/drug effects , Female , Humans , Inflammation , Interleukin-6/blood , Male , Middle Aged , Pandemics , Plasminogen Activator Inhibitor 1/blood , Pneumonia, Viral/drug therapy , Pneumonia, Viral/metabolism , Pneumonia, Viral/pathology , Receptors, Interleukin-6/antagonists & inhibitors , Receptors, Interleukin-6/metabolism , Respiratory Distress Syndrome, Adult/metabolism , Respiratory Distress Syndrome, Adult/pathology , Sepsis/metabolism , Sepsis/pathology
19.
Int J Rheum Dis ; 23(8): 1030-1039, 2020 Aug.
Article in English | MEDLINE | ID: covidwho-721094

ABSTRACT

AIM: To describe the first Australian cases of severe acute respiratory syndrome-coronavirus 2 (SARS-CoV2) disease (COVID-19) pneumonia treated with the interleukin-6 receptor antagonist tocilizumab. METHODS: Retrospective, open-label, real-world, uncontrolled, single-arm case series conducted in 2 tertiary hospitals in NSW, Australia and 1 tertiary hospital in Victoria, Australia. Five adult male patients aged between 46 and 74 years with type 1 respiratory failure due to COVID-19 pneumonia requiring intensive care unit (ICU) admission and biochemical evidence of systemic hyperinflammation (C-reactive protein greater than 100 mg/L; ferritin greater than 700 µg/L) were administered variable-dose tocilizumab. RESULTS: At between 13 and 26 days follow-up, all patients are alive and have been discharged from ICU. Two patients have been discharged home. Two patients avoided endotracheal intubation. Oxygen therapy has been ceased in three patients. Four adverse events potentially associated with tocilizumab therapy occurred in three patients: ventilator-associated pneumonia, bacteremia associated with central venous catheterization, myositis and hepatitis. All patients received broad-spectrum antibiotics, 4 received corticosteroids and 2 received both lopinavir/ritonavir and hydroxychloroquine. The time from first tocilizumab administration to improvement in ventilation, defined as a 25% reduction in fraction of inspired oxygen required to maintain peripheral oxygen saturation greater than 92%, ranged from 7 hours to 4.6 days. CONCLUSIONS: Tocilizumab use was associated with favorable clinical outcome in our patients. We recommend tocilizumab be included in randomized controlled trials of treatment for patients with severe COVID-19 pneumonia, and be considered for compassionate use in such patients pending the results of these trials.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Aged , Anti-Inflammatory Agents/adverse effects , Antibodies, Monoclonal, Humanized/adverse effects , Betacoronavirus/pathogenicity , Coronavirus Infections/diagnosis , Coronavirus Infections/virology , Host Microbial Interactions , Humans , Male , Middle Aged , New South Wales , Pandemics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/virology , Retrospective Studies , Severity of Illness Index , Time Factors , Treatment Outcome , Victoria
20.
Food Chem Toxicol ; 145: 111694, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-718753

ABSTRACT

We investigated the effects of tocilizumab on endothelial glycocalyx, a determinant of vascular permeability, and myocardial function in rheumatoid arthritis (RA). Eighty RA patients were randomized to tocilizumab (n = 40) or conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and glucocorticoids (GC) (n = 40) for 3 months. Forty healthy subjects with similar age and sex served as controls. We measured: (a)perfused boundary region (PBR) of the sublingual arterial microvessels (increased PBR indicates reduced glycocalyx thickness), (b)pulse wave velocity (PWV), (c)global LV longitudinal strain (GLS), (d)global work index (GWI) using speckle tracking echocardiography and e)C-reactive protein (CRP), malondialdehyde (MDA) and protein carbonyls (PCs) as oxidative stress markers at baseline and post-treatment. Compared to controls, RA patients had impaired glycocalyx and myocardial deformation markers (P < 0.05). Compared with baseline, tocilizumab reduced PBR(2.14 ± 0.2 versus 1.97 ± 0.2 µm; P < 0.05) while no significant differences were observed post-csDMARDs + GC(P > 0.05). Compared with csDMARDs + GC, tocilizumab achieved a greater increase of GLS, GWI and reduction of MDA, PCs and CRP(P < 0.05). The percent improvement of glycocalyx thickness (PBR) was associated with the percent decrease of PWV, MDA, PCs and the percent improvement of GLS and GWI(P < 0.05). Tocilizumab improves endothelial function leading to a greater increase of effective myocardial work than csDMARDs + GC through a profound reduction of inflammatory burden and oxidative stress. This mechanism may explain the effects of tocilizumab on COVID-19. CLINICAL TRIAL REGISTRATION: url: https://www.clinicaltrials.gov. Unique identifier: NCT03288584.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Arthritis, Rheumatoid/drug therapy , Endothelium/drug effects , Glycocalyx/drug effects , Oxidative Stress/drug effects , Aged , Betacoronavirus , Capillary Permeability/drug effects , Coronavirus Infections/drug therapy , Female , Heart/drug effects , Humans , Inflammation/drug therapy , Interleukin-6/antagonists & inhibitors , Male , Middle Aged , Pandemics , Pneumonia, Viral/drug therapy , Pulse Wave Analysis
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