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7.
Lancet Respir Med ; 9(12): 1365-1376, 2021 12.
Article in English | MEDLINE | ID: covidwho-1472211

ABSTRACT

BACKGROUND: Functional impairment of interferon, a natural antiviral component of the immune system, is associated with the pathogenesis and severity of COVID-19. We aimed to compare the efficacy of interferon beta-1a in combination with remdesivir compared with remdesivir alone in hospitalised patients with COVID-19. METHODS: We did a double-blind, randomised, placebo-controlled trial at 63 hospitals across five countries (Japan, Mexico, Singapore, South Korea, and the USA). Eligible patients were hospitalised adults (aged ≥18 years) with SARS-CoV-2 infection, as confirmed by a positive RT-PCR test, and who met one of the following criteria suggestive of lower respiratory tract infection: the presence of radiographic infiltrates on imaging, a peripheral oxygen saturation on room air of 94% or less, or requiring supplemental oxygen. Patients were excluded if they had either an alanine aminotransferase or an aspartate aminotransferase concentration more than five times the upper limit of normal; had impaired renal function; were allergic to the study product; were pregnant or breast feeding; were already on mechanical ventilation; or were anticipating discharge from the hospital or transfer to another hospital within 72 h of enrolment. Patients were randomly assigned (1:1) to receive intravenous remdesivir as a 200 mg loading dose on day 1 followed by a 100 mg maintenance dose administered daily for up to 9 days and up to four doses of either 44 µg interferon beta-1a (interferon beta-1a group plus remdesivir group) or placebo (placebo plus remdesivir group) administered subcutaneously every other day. Randomisation was stratified by study site and disease severity at enrolment. Patients, investigators, and site staff were masked to interferon beta-1a and placebo treatment; remdesivir treatment was given to all patients without masking. The primary outcome was time to recovery, defined as the first day that a patient attained a category 1, 2, or 3 score on the eight-category ordinal scale within 28 days, assessed in the modified intention-to-treat population, defined as all randomised patients who were classified according to actual clinical severity. Safety was assessed in the as-treated population, defined as all patients who received at least one dose of the assigned treatment. This trial is registered with ClinicalTrials.gov, NCT04492475. FINDINGS: Between Aug 5, 2020, and Nov 11, 2020, 969 patients were enrolled and randomly assigned to the interferon beta-1a plus remdesivir group (n=487) or to the placebo plus remdesivir group (n=482). The mean duration of symptoms before enrolment was 8·7 days (SD 4·4) in the interferon beta-1a plus remdesivir group and 8·5 days (SD 4·3) days in the placebo plus remdesivir group. Patients in both groups had a time to recovery of 5 days (95% CI not estimable) (rate ratio of interferon beta-1a plus remdesivir group vs placebo plus remdesivir 0·99 [95% CI 0·87-1·13]; p=0·88). The Kaplan-Meier estimate of mortality at 28 days was 5% (95% CI 3-7%) in the interferon beta-1a plus remdesivir group and 3% (2-6%) in the placebo plus remdesivir group (hazard ratio 1·33 [95% CI 0·69-2·55]; p=0·39). Patients who did not require high-flow oxygen at baseline were more likely to have at least one related adverse event in the interferon beta-1a plus remdesivir group (33 [7%] of 442 patients) than in the placebo plus remdesivir group (15 [3%] of 435). In patients who required high-flow oxygen at baseline, 24 (69%) of 35 had an adverse event and 21 (60%) had a serious adverse event in the interferon beta-1a plus remdesivir group compared with 13 (39%) of 33 who had an adverse event and eight (24%) who had a serious adverse event in the placebo plus remdesivir group. INTERPRETATION: Interferon beta-1a plus remdesivir was not superior to remdesivir alone in hospitalised patients with COVID-19 pneumonia. Patients who required high-flow oxygen at baseline had worse outcomes after treatment with interferon beta-1a compared with those given placebo. FUNDING: The National Institute of Allergy and Infectious Diseases (USA).


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/therapeutic use , COVID-19 , Interferon beta-1a/therapeutic use , Adenosine Monophosphate/therapeutic use , Adult , Aged , Alanine/therapeutic use , COVID-19/drug therapy , Double-Blind Method , Female , Humans , Japan , Male , Mexico , Middle Aged , Oxygen , Republic of Korea , SARS-CoV-2 , Singapore , Treatment Outcome , United States
8.
Curr Opin Crit Care ; 27(5): 461, 2021 10 01.
Article in English | MEDLINE | ID: covidwho-1462553

Subject(s)
COVID-19 , Humans , SARS-CoV-2
10.
Semin Respir Crit Care Med ; 42(5): 639-640, 2021 10.
Article in English | MEDLINE | ID: covidwho-1447393
11.
13.
Curr Opin Crit Care ; 27(5): 493-496, 2021 10 01.
Article in English | MEDLINE | ID: covidwho-1345769

ABSTRACT

PURPOSE OF REVIEW: Janus Kinase (JAK) inhibitors have been successfully utilized in the clinical treatment of several rheumatologic (e.g. rheumatoid arthritis) and inflammatory diseases (e.g. hemophagocytic lymphohistiocytosis). Based on the growing evidence that moderate and severe COVID-19 infections are associated with a dysregulated inflammatory state, this class of medications has been repurposed as a potential therapy for COVID-19, an infection caused by Severe Acute Respiratory Syndrome Coronavirus 2. RECENT FINDINGS: Three JAK inhibitors have been evaluated in human studies of COVID-19: Baricitinib, Tofacitinib, and Ruxolitinib. Most published studies are observational, but three randomized placebo-controlled double-blind trials have been completed: two large trials (N = 2,558 patients) with baricitinb demonstrated significant faster improvement in clinical status and reduction in the recovery time, as well as, significant reduction in the progression to invasive mechanical ventilation and mortality. One smaller randomized trial (N = 289) involving tofacitinib showed significant reduction in the progression to invasive ventilation or death. Notably, these three randomized placebo-controlled trials with close to 3,000 patients did not reveal any safety concerns associated with JAK inhibitors in terms of secondary infections or venous thromboembolism. Based on this high-quality evidence, both the Infectious Diseases Society of America and the National Institutes of Health guidelines recommend using baricitinib as part of the treatment approach for hospitalized patients with COVID-19. SUMMARY: JAK inhibitors are novel treatment agents in the field of infectious diseases. One JAK inhibitor, baricitinib has demonstrated significant clinical and survival benefits in hospitalized patients with COVID-19 in phase III randomized placebo-controlled trials. Baricitinib is already recommended for clinical practice by multiple guidelines.


Subject(s)
COVID-19 , Janus Kinase Inhibitors , Venous Thromboembolism , Humans , Janus Kinase Inhibitors/therapeutic use , Randomized Controlled Trials as Topic , Respiration, Artificial , SARS-CoV-2
14.
Crit Care Explor ; 3(7): e0474, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1313893

ABSTRACT

We sought to validate prognostic scores in coronavirus disease 2019 including National Early Warning Score, Modified Early Warning Score, and age-based modifications, and define their performance characteristics. DESIGN: We analyzed prospectively collected data from the Adaptive COVID-19 Treatment Trial. National Early Warning Score was collected daily during the trial, Modified Early Warning Score was calculated, and age applied to both scores. We assessed prognostic value for the end points of recovery, mechanical ventilation, and death for score at enrollment, average, and slope of score over the first 48 hours. SETTING: A multisite international inpatient trial. PATIENTS: A total of 1,062 adult nonpregnant inpatients with severe coronavirus disease 2019 pneumonia. INTERVENTIONS: Adaptive COVID-19 Treatment Trial 1 randomized participants to receive remdesivir or placebo. The prognostic value of predictive scores was evaluated in both groups separately to assess for differential performance in the setting of remdesivir treatment. MEASUREMENTS AND MAIN RESULTS: For mortality, baseline National Early Warning Score and Modified Early Warning Score were weakly to moderately prognostic (c-index, 0.60-0.68), and improved with addition of age (c-index, 0.66-0.74). For recovery, baseline National Early Warning Score and Modified Early Warning Score demonstrated somewhat better prognostic ability (c-index, 0.65-0.69); however, National Early Warning Score+age and Modified Early Warning Score+age further improved performance (c-index, 0.68-0.71). For deterioration, baseline National Early Warning Score and Modified Early Warning Score were weakly to moderately prognostic (c-index, 0.59-0.69) and improved with addition of age (c-index, 0.63-0.70). All prognostic performance improvements due to addition of age were significant (p < 0.05). CONCLUSIONS: In the Adaptive COVID-19 Treatment Trial 1 cohort, National Early Warning Score and Modified Early Warning Score demonstrated moderate prognostic performance in patients with severe coronavirus disease 2019, with improvement in predictive ability for National Early Warning Score+age and Modified Early Warning Score+age. Area under receiver operating curve for National Early Warning Score and Modified Early Warning Score improved in patients receiving remdesivir versus placebo early in the pandemic for recovery and mortality. Although these scores are simple and readily obtainable in myriad settings, in our data set, they were insufficiently predictive to completely replace clinical judgment in coronavirus disease 2019 and may serve best as an adjunct to triage, disposition, and resourcing decisions.

15.
Arthritis Rheumatol ; 73(12): 2179-2188, 2021 12.
Article in English | MEDLINE | ID: covidwho-1217345

ABSTRACT

OBJECTIVE: Rheumatoid arthritis (RA) and its treatments are associated with an increased risk of infection, but it remains unclear whether these factors have an impact on the risk or severity of COVID-19. The present study was undertaken to assess the risk and severity of COVID-19 in a US Department of Veterans Affairs (VA) cohort of patients with RA and those without RA. METHODS: A matched cohort study using national VA data was conducted. Patients diagnosed as having RA were identified among nondeceased individuals who were active in the VA health care system as of January 1, 2020 and who had received care in a VA medical center in 2019; patients for whom no RA diagnostic code was indicated were matched to the RA patients (1:1) by age, sex, and VA site (non-RA controls). Patients diagnosed as having COVID-19 and those with severe COVID-19 (defined as requiring hospitalization or leading to death) were ascertained from a national VA COVID-19 surveillance database through December 10, 2020. Multivariable Cox models were used to compare the risk of COVID-19 and COVID-19 hospitalization or death between RA patients and non-RA controls, after adjusting for demographic characteristics, comorbidities, health care utilization and access, and county-level COVID-19 incidence rates. RESULTS: This VA cohort of RA patients and non-RA controls (n = 33,886 subjects per group) predominantly comprised male patients (84.5%), and the mean age was 67.8 years. During follow-up, 1,503 patients in the cohort were diagnosed as having COVID-19; among them, 388 patients had severe COVID-19 (hospitalization or death), while in 228 patients, the deaths were not related to COVID-19. In the multivariable model, RA was associated with a higher risk of COVID-19 (adjusted hazard ratio [HR] 1.25 [95% confidence interval (95% CI) 1.13-1.39]) and a higher risk of COVID-19 hospitalization or death (adjusted HR 1.35 [95% CI 1.10-1.66]) as compared to non-RA controls. Use of disease-modifying antirheumatic drugs and prednisone, as well as self-reported Black race, self-reported Hispanic ethnicity, and presence of several chronic conditions, but not seropositivity for RA autoantibodies, were each associated with risk of COVID-19 and severe COVID-19 (hospitalization or death). CONCLUSION: Patients with RA are at higher risk of developing COVID-19 and severe COVID-19 (leading to hospitalization or death) compared to those without RA. With a risk of COVID-19 that approaches that of other recognized chronic conditions, these findings suggest that RA patients should be prioritized for COVID-19 prevention and management strategies.


Subject(s)
Arthritis, Rheumatoid/complications , COVID-19/etiology , Aged , COVID-19/epidemiology , Cohort Studies , Female , Hospitalization/statistics & numerical data , Humans , Male , Middle Aged , Retrospective Studies , Risk Assessment , Severity of Illness Index , Veterans Health
17.
CJC Open ; 3(7): 965-975, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1174145

ABSTRACT

BACKGROUND: Angiotensin receptor blockers (ARBs) and/or angiotensin-converting enzyme (ACE) inhibitors could alter mortality from coronavirus disease 2019 (COVID-19), but existing meta-analyses that combined crude and adjusted results may be confounded by the fact that comorbidities are more common in ARB/ACE inhibitor users. METHODS: We searched PubMed/MEDLINE/Embase for cohort studies and meta-analyses reporting mortality by preexisting ARB/ACE inhibitor treatment in hospitalized COVID-19 patients. Random effects meta-regression was used to compute pooled odds ratios for mortality adjusted for imbalance in age, sex, and prevalence of cardiovascular disease, hypertension, diabetes mellitus, and chronic kidney disease between users and nonusers of ARBs/ACE inhibitors at the study level during data synthesis. RESULTS: In 30 included studies of 17,281 patients, 22%, 68%, 25%, and 11% had cardiovascular disease, hypertension, diabetes mellitus, and chronic kidney disease. ARB/ACE inhibitor use was associated with significantly lower mortality after controlling for potential confounding factors (odds ratio 0.77 [95% confidence interval: 0.62, 0.96]). In contrast, meta-analysis of ARB/ACE inhibitor use was not significantly associated with mortality when all studies were combined with no adjustment made for confounders (0.87 [95% confidence interval: 0.71, 1.08]). CONCLUSIONS: ARB/ACE inhibitor use was associated with decreased mortality in cohorts of COVID-19 patients after adjusting for age, sex, cardiovascular disease, hypertension, diabetes, and chronic kidney disease. Unadjusted meta-analyses may not be appropriate for determining whether ARBs/ACE inhibitors are associated with mortality from COVID-19 because of indication bias.


INTRODUCTION: Les antagonistes des récepteurs de l'angiotensine (ARA) et/ou les inhibiteurs de l'enzyme de conversion de l'angiotensine (IECA) feraient varier la mortalité liée à la COVID-19, mais il est possible que les méta-analyses actuelles qui combinaient les résultats bruts et ajustés soient invalidées du fait que les comorbidités sont plus fréquentes chez les utilisateurs d'ARA/IECA. MÉTHODES: Nous avons effectué des recherches dans les bases de données PubMed/MEDLINE/Embase pour trouver des études de cohorte et des méta-analyses qui portent sur la mortalité associée à un traitement préexistant par ARA/IECA chez les patients hospitalisés atteints de la COVID-19. Nous avons utilisé la métarégression à effets aléatoires pour calculer les rapports de cotes regroupés de mortalité ajustés en fonction du déséquilibre de l'âge, du sexe, et de la prévalence des maladies cardiovasculaires, de l'hypertension, du diabète sucré et de l'insuffisance rénale chronique entre les utilisateurs et les non-utilisateurs d'ARA/IECA dans le cadre de l'étude durant la synthèse des données. RÉSULTATS: Dans les 30 études portant sur 17 281 patients, 22 %, 68 %, 25 % et 11 % avaient respectivement une maladie cardiovasculaire, de l'hypertension, le diabète sucré et de l'insuffisance rénale chronique. L'utilisation des ARA/IECA a été associée à une mortalité significativement plus faible après avoir tenu compte des facteurs confusionnels potentiels (rapport de cotes 0,77 [intervalle de confiance à 95 % : 0,62, 0,96]). En revanche, la méta-analyse sur l'utilisation des ARA/IECA n'a pas été associée de façon significative à la mortalité lorsque toutes les études ont été combinées sans ajustement sur les facteurs confusionnels (0,87 [intervalle de confiance à 95 % : 0,71, 1,08]). CONCLUSIONS: L'utilisation des ARA/IECA a été associée à la diminution de la mortalité au sein des cohortes de patients atteints de la COVID-19 après l'ajustement en fonction de l'âge, du sexe, des maladies cardiovasculaires, de l'hypertension, du diabète et de l'insuffisance rénale chronique. Les méta-analyses non ajustées peuvent ne pas permettre de déterminer si les ARA/IECA sont associés à la mortalité liée à la COVID-19 en raison du biais d'indication.

18.
Arthritis Rheumatol ; 72(8): 1241-1251, 2020 08.
Article in English | MEDLINE | ID: covidwho-602110

ABSTRACT

OBJECTIVE: To provide guidance to rheumatology providers on the management of adult rheumatic disease in the context of the coronavirus disease 2019 (COVID-19) pandemic. METHODS: A task force, including 10 rheumatologists and 4 infectious disease specialists from North America, was convened. Clinical questions were collated, and an evidence report was rapidly generated and disseminated. Questions and drafted statements were reviewed and assessed using a modified Delphi process. This included 2 rounds of asynchronous anonymous voting by e-mail and 3 webinars with the entire panel. Task force members voted on agreement with draft statements using a 1-9-point numerical scoring system, and consensus was determined to be low, moderate, or high based on the dispersion of votes. For approval, median votes were required to meet predefined levels of agreement (median values of 7-9, 4-6, and 1-3 defined as agreement, uncertainty, or disagreement, respectively) with either moderate or high levels of consensus. RESULTS: The task force approved 77 initial guidance statements: 36 with moderate and 41 with high consensus. These were combined, resulting in 25 final guidance statements. CONCLUSION: These guidance statements are provided to promote optimal care during the current pandemic. However, given the low level of available evidence and the rapidly evolving literature, this guidance is presented as a "living document," and future updates are anticipated.


Subject(s)
Antirheumatic Agents/therapeutic use , Coronavirus Infections/epidemiology , Glucocorticoids/therapeutic use , Immunosuppressive Agents/therapeutic use , Pneumonia, Viral/epidemiology , Rheumatic Diseases/drug therapy , Adult , Advisory Committees , Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Betacoronavirus , COVID-19 , Coronavirus Infections/complications , Coronavirus Infections/prevention & control , Delivery of Health Care , Delphi Technique , Deprescriptions , Humans , Hydroxychloroquine/therapeutic use , Infection Control , Janus Kinase Inhibitors/therapeutic use , Pandemics/prevention & control , Pneumonia, Viral/complications , Pneumonia, Viral/prevention & control , Rheumatic Diseases/complications , Rheumatology , SARS-CoV-2 , Tumor Necrosis Factor Inhibitors/therapeutic use
19.
Chest ; 158(5): 2232, 2020 11.
Article in English | MEDLINE | ID: covidwho-1023503
20.
Arthritis Rheumatol ; 73(2): e1-e12, 2021 02.
Article in English | MEDLINE | ID: covidwho-985949

ABSTRACT

OBJECTIVE: To provide guidance to rheumatology providers on the management of adult rheumatic disease in the context of the coronavirus disease 2019 (COVID-19) pandemic. METHODS: A task force, including 10 rheumatologists and 4 infectious disease specialists from North America, was convened. Clinical questions were collated, and an evidence report was rapidly generated and disseminated. Questions and drafted statements were reviewed and assessed using a modified Delphi process. This included asynchronous anonymous voting by email and webinars with the entire panel. Task force members voted on agreement with draft statements using a 1-9-point numerical scoring system, and consensus was determined to be low, moderate, or high based on the dispersion of votes. For approval, median votes were required to meet predefined levels of agreement (median values of 7-9, 4-6, and 1-3 defined as agreement, uncertainty, or disagreement, respectively) with either moderate or high levels of consensus. RESULTS: Draft guidance statements approved by the task force have been combined to form final guidance. CONCLUSION: These guidance statements are provided to promote optimal care during the current pandemic. However, given the low level of available evidence and the rapidly evolving literature, this guidance is presented as a "living document," and future updates are anticipated.


Subject(s)
Antirheumatic Agents/therapeutic use , COVID-19/prevention & control , Glucocorticoids/administration & dosage , Immunosuppressive Agents/therapeutic use , Rheumatic Diseases/therapy , Advisory Committees , COVID-19/complications , Consensus , Decision Making, Shared , Delivery of Health Care , Delphi Technique , Deprescriptions , Disease Management , Humans , Patient Education as Topic , Rheumatic Diseases/complications , Rheumatology , SARS-CoV-2 , Societies, Medical
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