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1.
EBioMedicine ; 85: 104299, 2022 Nov.
Article in English | MEDLINE | ID: covidwho-2061075

ABSTRACT

A hyperinflammatory response during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection crucially worsens clinical evolution of coronavirus disease 2019 (COVID-19). The interaction between SARS-CoV-2 and angiotensin-converting enzyme 2 (ACE2) triggers the activation of the NACHT, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome. Enhanced inflammasome activity has been associated with increased disease severity and poor prognosis. Evidence suggests that inflammasome activation and interleukin-1ß (IL-1ß) release aggravate pulmonary injury and induce hypercoagulability, favoring progression to respiratory failure and widespread thrombosis eventually leading to multiorgan failure and death. Observational studies with the IL-1 blockers anakinra and canakinumab provided promising results. In the SAVE-MORE trial, early treatment with anakinra significantly shortened hospital stay and improved survival in patients with moderate-to-severe COVID-19. In this review, we summarize current evidence supporting the pathogenetic role of the NLRP3 inflammasome and IL-1ß in COVID-19, and discuss clinical trials testing IL-1 inhibition in COVID-19.


Subject(s)
COVID-19 , Inflammasomes , Humans , Inflammasomes/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , COVID-19/complications , COVID-19/drug therapy , Interleukin 1 Receptor Antagonist Protein , SARS-CoV-2 , Interleukin-1beta/metabolism
2.
J Clin Invest ; 131(24)2021 12 15.
Article in English | MEDLINE | ID: covidwho-1495792

ABSTRACT

Acute COVID-19, caused by SARS-CoV-2, is characterized by diverse clinical presentations, ranging from asymptomatic infection to fatal respiratory failure, and often associated with varied longer-term sequelae. Over the past 18 months, it has become apparent that inappropriate immune responses contribute to the pathogenesis of severe COVID-19. Researchers working at the intersection of COVID-19 and autoimmunity recently gathered at an American Autoimmune Related Diseases Association Noel R. Rose Colloquium to address the current state of knowledge regarding two important questions: Does established autoimmunity predispose to severe COVID-19? And, at the same time, can SARS-CoV-2 infection trigger de novo autoimmunity? Indeed, work to date has demonstrated that 10% to 15% of patients with critical COVID-19 pneumonia exhibit autoantibodies against type I interferons, suggesting that preexisting autoimmunity underlies severe disease in some patients. Other studies have identified functional autoantibodies following infection with SARS-CoV-2, such as those that promote thrombosis or antagonize cytokine signaling. These autoantibodies may arise from a predominantly extrafollicular B cell response that is more prone to generating autoantibody-secreting B cells. This Review highlights the current understanding, evolving concepts, and unanswered questions provided by this unique opportunity to determine mechanisms by which a viral infection can be exacerbated by, and even trigger, autoimmunity. The potential role of autoimmunity in post-acute sequelae of COVID-19 is also discussed.


Subject(s)
Autoantibodies/chemistry , Autoimmunity/immunology , COVID-19/immunology , COVID-19/physiopathology , Signal Transduction , Animals , Autoimmune Diseases , B-Lymphocytes/cytology , Cytokines/metabolism , Disease Progression , Female , Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Humans , Inflammation , Interleukin-1/metabolism , Interleukin-6/metabolism , Macrophage Activation , Male , Mice , Phospholipids/metabolism , SARS-CoV-2
3.
Nat Med ; 27(10): 1674-1675, 2021 10.
Article in English | MEDLINE | ID: covidwho-1392878
4.
JAMA ; 326(3): 230-239, 2021 07 20.
Article in English | MEDLINE | ID: covidwho-1338164

ABSTRACT

Importance: Effective treatments for patients with severe COVID-19 are needed. Objective: To evaluate the efficacy of canakinumab, an anti-interleukin-1ß antibody, in patients hospitalized with severe COVID-19. Design, Setting, and Participants: This randomized, double-blind, placebo-controlled phase 3 trial was conducted at 39 hospitals in Europe and the United States. A total of 454 hospitalized patients with COVID-19 pneumonia, hypoxia (not requiring invasive mechanical ventilation [IMV]), and systemic hyperinflammation defined by increased blood concentrations of C-reactive protein or ferritin were enrolled between April 30 and August 17, 2020, with the last assessment of the primary end point on September 22, 2020. Intervention: Patients were randomly assigned 1:1 to receive a single intravenous infusion of canakinumab (450 mg for body weight of 40-<60 kg, 600 mg for 60-80 kg, and 750 mg for >80 kg; n = 227) or placebo (n = 227). Main Outcomes and Measures: The primary outcome was survival without IMV from day 3 to day 29. Secondary outcomes were COVID-19-related mortality, measurements of biomarkers of systemic hyperinflammation, and safety evaluations. Results: Among 454 patients who were randomized (median age, 59 years; 187 women [41.2%]), 417 (91.9%) completed day 29 of the trial. Between days 3 and 29, 198 of 223 patients (88.8%) survived without requiring IMV in the canakinumab group and 191 of 223 (85.7%) in the placebo group, with a rate difference of 3.1% (95% CI, -3.1% to 9.3%) and an odds ratio of 1.39 (95% CI, 0.76 to 2.54; P = .29). COVID-19-related mortality occurred in 11 of 223 patients (4.9%) in the canakinumab group vs 16 of 222 (7.2%) in the placebo group, with a rate difference of -2.3% (95% CI, -6.7% to 2.2%) and an odds ratio of 0.67 (95% CI, 0.30 to 1.50). Serious adverse events were observed in 36 of 225 patients (16%) treated with canakinumab vs 46 of 223 (20.6%) who received placebo. Conclusions and Relevance: Among patients hospitalized with severe COVID-19, treatment with canakinumab, compared with placebo, did not significantly increase the likelihood of survival without IMV at day 29. Trial Registration: ClinicalTrials.gov Identifier: NCT04362813.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19/drug therapy , Interleukin-1beta/antagonists & inhibitors , Respiration, Artificial/statistics & numerical data , Aged , Antibodies, Monoclonal, Humanized/adverse effects , C-Reactive Protein/analysis , COVID-19/mortality , COVID-19/therapy , Combined Modality Therapy , Double-Blind Method , Female , Ferritins/blood , Fibrin Fibrinogen Degradation Products/analysis , Hospitalization , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Survival Rate , Treatment Outcome
5.
Minerva Med ; 2021 Jul 16.
Article in English | MEDLINE | ID: covidwho-1316063

ABSTRACT

The ongoing coronavirus disease 2019 (COVID-19) pandemic has placed tremendous strain on health systems throughout the world. This has led to many clinical trials being launched in order to try to find ways to combat the disease. The unprecedented nature of the pandemic has been reflected in the methods used in some of these trials. Placebo-controlled randomized trials are considered the gold-standard, however, there are inherent challenges in the use of placebo, especially during COVID-19. We herein review the pros, cons, challenges and limitations of using placebo in clinical trials investigating treatments for COVID-19. We also discuss the importance of viewing research critically, examining the potential impact of placebo use or lack thereof, on blinding and possible biases. This becomes important as we assess the responses to the pandemic in preparation for a future pandemic. Although placebo-controlled clinical trials are the gold standard for clinical research, they may not be practically or ethically feasible during a pandemic. Choices accomplished to design many COVID-19 trials might reflect the unprecedently trying environment in which they were made. However, critical evaluation of the methodology and practice of scientific research remains a crucial part of the scientific process. Even when conducted as randomized double-blinded studies, residual biases may exist and interfere with the study conduct and interpretation of the data. A critical review of all data, remains essential to thoroughly assess the impact of a research study.

6.
Chest ; 159(4): 1679, 2021 04.
Article in English | MEDLINE | ID: covidwho-1275201
7.
Chest ; 159(1): e7-e11, 2021 01.
Article in English | MEDLINE | ID: covidwho-1064922

ABSTRACT

Coronavirus disease 2019 (COVID-19) has resulted in significant morbidity and mortality because of a lack of effective therapies. Therapeutic strategies under investigation target the overactive cytokine response with anti-cytokine or immunomodulators therapies. We present a unique case of severe cytokine storm resistant to multiple anti-cytokine therapies, but eventually responsive to etoposide. Thus, etoposide may have a role as salvage therapy in treatment of cytokine storm in COVID-19. To our knowledge, this is the first reported case of use of etoposide in COVID-19.


Subject(s)
COVID-19/complications , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/etiology , Etoposide/therapeutic use , Aged , Female , Humans , Salvage Therapy/methods , Severity of Illness Index
9.
J Vasc Surg Venous Lymphat Disord ; 9(3): 585-591.e2, 2021 05.
Article in English | MEDLINE | ID: covidwho-813723

ABSTRACT

BACKGROUND: Infection with the novel severe acute respiratory syndrome coronavirus 2 has been associated with a hypercoagulable state. Emerging data from China and Europe have consistently shown an increased incidence of venous thromboembolism (VTE). We aimed to identify the VTE incidence and early predictors of VTE at our high-volume tertiary care center. METHODS: We performed a retrospective cohort study of 147 patients who had been admitted to Temple University Hospital with coronavirus disease 2019 (COVID-19) from April 1, 2020 to April 27, 2020. We first identified the VTE (pulmonary embolism [PE] and deep vein thrombosis [DVT]) incidence in our cohort. The VTE and no-VTE groups were compared by univariable analysis for demographics, comorbidities, laboratory data, and treatment outcomes. Subsequently, multivariable logistic regression analysis was performed to identify the early predictors of VTE. RESULTS: The 147 patients (20.9% of all admissions) admitted to a designated COVID-19 unit at Temple University Hospital with a high clinical suspicion of acute VTE had undergone testing for VTE using computed tomography pulmonary angiography and/or extremity venous duplex ultrasonography. The overall incidence of VTE was 17% (25 of 147). Of the 25 patients, 16 had had acute PE, 14 had had acute DVT, and 5 had had both PE and DVT. The need for invasive mechanical ventilation (adjusted odds ratio, 3.19; 95% confidence interval, 1.07-9.55) and the admission D-dimer level ≥1500 ng/mL (adjusted odds ratio, 3.55; 95% confidence interval, 1.29-9.78) were independent markers associated with VTE. The all-cause mortality in the VTE group was greater than that in the non-VTE group (48% vs 22%; P = .007). CONCLUSIONS: Our study represents one of the earliest reported from the United States on the incidence rate of VTE in patients with COVID-19. Patients with a high clinical suspicion and the identified risk factors (invasive mechanical ventilation, admission D-dimer level ≥1500 ng/mL) should be considered for early VTE testing. We did not screen all patients admitted for VTE; therefore, the true incidence of VTE could have been underestimated. Our findings require confirmation in future prospective studies.


Subject(s)
COVID-19 , Fibrin Fibrinogen Degradation Products/analysis , Pulmonary Embolism , Respiration, Artificial/methods , Venous Thrombosis , COVID-19/blood , COVID-19/complications , COVID-19/epidemiology , Computed Tomography Angiography/methods , Female , Humans , Incidence , Male , Middle Aged , Philadelphia/epidemiology , Prognosis , Pulmonary Embolism/diagnosis , Pulmonary Embolism/epidemiology , Pulmonary Embolism/etiology , Retrospective Studies , Risk Factors , SARS-CoV-2 , Thrombophilia/blood , Thrombophilia/diagnosis , Thrombophilia/etiology , Ultrasonography, Doppler, Duplex/methods , Venous Thrombosis/diagnosis , Venous Thrombosis/epidemiology , Venous Thrombosis/etiology
10.
Ann Rheum Dis ; 80(1): 88-95, 2021 01.
Article in English | MEDLINE | ID: covidwho-797474

ABSTRACT

OBJECTIVES: To develop predictive criteria for COVID-19-associated cytokine storm (CS), a severe hyperimmune response that results in organ damage in some patients infected with COVID-19. We hypothesised that criteria for inflammation and cell death would predict this type of CS. METHODS: We analysed 513 hospitalised patients who were positive for COVID-19 reverse transcriptase PCR and for ground-glass opacity by chest high-resolution CT. To achieve an early diagnosis, we analysed the laboratory results of the first 7 days of hospitalisation. We implemented logistic regression and principal component analysis to determine the predictive criteria. We used a 'genetic algorithm' to derive the cut-offs for each laboratory result. We validated the criteria with a second cohort of 258 patients. RESULTS: We found that the criteria for macrophage activation syndrome, haemophagocytic lymphohistiocytosis and the HScore did not identify the COVID-19 cytokine storm (COVID-CS). We developed new predictive criteria, with sensitivity and specificity of 0.85 and 0.80, respectively, comprising three clusters of laboratory results that involve (1) inflammation, (2) cell death and tissue damage, and (3) prerenal electrolyte imbalance. The criteria identified patients with longer hospitalisation and increased mortality. These results highlight the relevance of hyperinflammation and tissue damage in the COVID-CS. CONCLUSIONS: We propose new early predictive criteria to identify the CS occurring in patients with COVID-19. The criteria can be readily used in clinical practice to determine the need for an early therapeutic regimen, block the hyperimmune response and possibly decrease mortality.


Subject(s)
COVID-19/complications , COVID-19/immunology , Cytokine Release Syndrome/diagnosis , Cytokine Release Syndrome/virology , Aged , Cohort Studies , Female , Humans , Male , Middle Aged , Risk Factors , SARS-CoV-2 , Sensitivity and Specificity
12.
Arthritis Rheumatol ; 72(7): 1059-1063, 2020 07.
Article in English | MEDLINE | ID: covidwho-60433

ABSTRACT

Poor outcomes in COVID-19 correlate with clinical and laboratory features of cytokine storm syndrome. Broad screening for cytokine storm and early, targeted antiinflammatory therapy may prevent immunopathology and could help conserve limited health care resources. While studies are ongoing, extrapolating from clinical experience in cytokine storm syndromes may benefit the multidisciplinary teams caring for patients with severe COVID-19.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Coronavirus Infections/immunology , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/virology , Pneumonia, Viral/immunology , Betacoronavirus , Biomarkers , COVID-19 , Coronavirus Infections/complications , Coronavirus Infections/therapy , Cytokine Release Syndrome/diagnosis , Early Medical Intervention , Humans , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/therapy , SARS-CoV-2
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