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3.
Clin Infect Dis ; 2021 Nov 28.
Article in English | MEDLINE | ID: covidwho-2017777

ABSTRACT

BACKGROUND: Multisystem inflammatory syndrome in adults (MIS-A) was reported in association with the COVID-19 pandemic. MIS-A was included in the list of adverse events to be monitored as part of the emergency use authorizations issued for COVID-19 vaccines. METHODS: Reports of MIS-A patients received by the Centers for Disease Control and Prevention (CDC) after COVID-19 vaccines became available were assessed. Data collected on the patients included clinical and demographic characteristics and their vaccine status. The Vaccine Adverse Events Reporting System (VAERS) was also reviewed for possible cases of MIS-A. RESULTS: From December 14, 2020 to April 30, 2021, 20 patients who met the case definition for MIS-A were reported to CDC. Their median age was 35 years (range, 21-66 years), and 13 (65%) were male. Overall, 16 (80%) patients had a preceding COVID-19-like illness a median of 26 days (range 11-78 days) before MIS-A onset. All 20 patients had laboratory evidence of SARS-CoV-2 infection. Seven MIS-A patients (35%) received COVID-19 vaccine a median of 10 days (range, 6-45 days) before MIS-A onset; 3 patients received a second dose of COVID-19 vaccine 4, 17, and 22 days before MIS-A onset. Patients with MIS-A predominantly had gastrointestinal and cardiac manifestations and hypotension or shock. CONCLUSIONS: Although 7 patients were reported to have received COVID-19 vaccine, all had evidence of prior SARS-CoV-2 infection. Given the widespread use of COVID-19 vaccines, the lack of reporting of MIS-A associated with vaccination alone, without evidence of underlying SARS-CoV-2 infection, is reassuring.

4.
PLoS One ; 17(3): e0261508, 2022.
Article in English | MEDLINE | ID: covidwho-1793546

ABSTRACT

BACKGROUND: Accurate methods of identifying patients with COVID-19 who are at high risk of poor outcomes has become especially important with the advent of limited-availability therapies such as monoclonal antibodies. Here we describe development and validation of a simple but accurate scoring tool to classify risk of hospitalization and mortality. METHODS: All consecutive patients testing positive for SARS-CoV-2 from March 25-October 1, 2020 within the Intermountain Healthcare system were included. The cohort was randomly divided into 70% derivation and 30% validation cohorts. A multivariable logistic regression model was fitted for 14-day hospitalization. The optimal model was then adapted to a simple, probabilistic score and applied to the validation cohort and evaluated for prediction of hospitalization and 28-day mortality. RESULTS: 22,816 patients were included; mean age was 40 years, 50.1% were female and 44% identified as non-white race or Hispanic/Latinx ethnicity. 6.2% required hospitalization and 0.4% died. Criteria in the simple model included: age (0.5 points per decade); high-risk comorbidities (2 points each): diabetes mellitus, severe immunocompromised status and obesity (body mass index≥30); non-white race/Hispanic or Latinx ethnicity (2 points), and 1 point each for: male sex, dyspnea, hypertension, coronary artery disease, cardiac arrythmia, congestive heart failure, chronic kidney disease, chronic pulmonary disease, chronic liver disease, cerebrovascular disease, and chronic neurologic disease. In the derivation cohort (n = 16,030) area under the receiver-operator characteristic curve (AUROC) was 0.82 (95% CI 0.81-0.84) for hospitalization and 0.91 (0.83-0.94) for 28-day mortality; in the validation cohort (n = 6,786) AUROC for hospitalization was 0.8 (CI 0.78-0.82) and for mortality 0.8 (CI 0.69-0.9). CONCLUSION: A prediction score based on widely available patient attributes accurately risk stratifies patients with COVID-19 at the time of testing. Applications include patient selection for therapies targeted at preventing disease progression in non-hospitalized patients, including monoclonal antibodies. External validation in independent healthcare environments is needed.


Subject(s)
SARS-CoV-2
5.
BMJ Open ; 12(3): e053864, 2022 03 24.
Article in English | MEDLINE | ID: covidwho-1765122

ABSTRACT

OBJECTIVES: The Intermountain Risk Score (IMRS), composed using published sex-specific weightings of parameters in the complete blood count (CBC) and basic metabolic profile (BMP), is a validated predictor of mortality. We hypothesised that IMRS calculated from prepandemic CBC and BMP predicts COVID-19 outcomes and that IMRS using laboratory results tested at COVID-19 diagnosis is also predictive. DESIGN: Prospective observational cohort study. SETTING: Primary, secondary, urgent and emergent care, and drive-through testing locations across Utah and in sections of adjacent US states. Viral RNA testing for SARS-CoV-2 was conducted from 3 March to 2 November 2020. PARTICIPANTS: Patients aged ≥18 years were evaluated if they had CBC and BMP measured in 2019 and tested positive for COVID-19 in 2020. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was a composite of hospitalisation or mortality, with secondary outcomes being hospitalisation and mortality separately. RESULTS: Among 3883 patients, 8.2% were hospitalised and 1.6% died. Subjects with low, mild, moderate and high-risk IMRS had the composite endpoint in 3.5% (52/1502), 8.6% (108/1256), 15.5% (152/979) and 28.1% (41/146) of patients, respectively. Compared with low-risk, subjects in mild-risk, moderate-risk and high-risk groups had HR=2.33 (95% CI 1.67 to 3.24), HR=4.01 (95% CI 2.93 to 5.50) and HR=8.34 (95% CI 5.54 to 12.57), respectively. Subjects aged <60 years had HR=3.06 (95% CI 2.01 to 4.65) and HR=7.38 (95% CI 3.14 to 17.34) for moderate and high risks versus low risk, respectively; those ≥60 years had HR=1.95 (95% CI 0.99 to 3.86) and HR=3.40 (95% CI 1.63 to 7.07). In multivariable analyses, IMRS was independently predictive and was shown to capture substantial risk variation of comorbidities. CONCLUSIONS: IMRS, a simple risk score using very basic laboratory results, predicted COVID-19 hospitalisation and mortality. This included important abilities to identify risk in younger adults with few diagnosed comorbidities and to predict risk prior to SARS-CoV-2 infection.


Subject(s)
COVID-19 , Adolescent , Adult , COVID-19/diagnosis , COVID-19/epidemiology , COVID-19 Testing , Cohort Studies , Female , Humans , Male , Middle Aged , Predictive Value of Tests , Prospective Studies , Risk Assessment/methods , Risk Factors , SARS-CoV-2
6.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-312526

ABSTRACT

Background: As the COVID-19 pandemic evolves, stratifying risk is increasingly important. The Intermountain Risk Score (IMRS) uses the complete blood count (CBC) and basic metabolic profile (BMP) as a first-line predictor of mortality and is widely validated. We hypothesized that IMRS predicts COVID-19 outcomes.Methods: Intermountain Healthcare patients aged ≥18 years were evaluated if they had CBC and BMP measured in 2019 and tested positive for COVID-19 in 2020. Viral RNA testing for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was conducted March 3 through November 2, 2020. IMRS used published sex-specific weightings and associations were evaluated for the composite of COVID-19 hospitalization or mortality.Findings: Among 3,883 patients, 8.2% were hospitalized, 1.6% died. Subjects with low, mild, moderate, and high-risk IMRS had the composite endpoint in 3.5% (52/1,502), 8.6% (108/1,256), 15.5% (152/979), and 28.1% (41/146), respectively. Versus low-risk, subjects in mild, moderate, and high-risk groups had HR=2.33 (95% CI: 1.67, 3.24), HR=4.01 (CI: 2.93, 5.50), and HR=8.34 (CI: 5.54, 12.57), respectively. Subjects aged <60 years had HR=3.06 (CI: 2.01, 4.65) and HR=7.38 (CI: 3.14, 17.34) for moderate and high versus low-risk, respectively;those ≥60 years had HR=1.95 (CI: 0.99, 3.86) and HR=3.40 (CI: 1.63, 7.07). In multivariable analyses, IMRS was independently predictive but was shown to capture substantial risk variation of comorbidities.Interpretation: IMRS, a simple risk score using very basic laboratory results, predicted COVID-19 hospitalization and mortality. This included important abilities to identify risk in younger adults with few diagnosed comorbidities and to predict risk prior to SARS-CoV-2 infection.Funding Statement: This study was funded by internal Intermountain departmental funds.Declaration of Interests: BDH, HTM, BSR, and JLA are inventors of clinical decision tools that are licensed to CareCentra and Alluceo. BDH is the PI of grants related to clinical decision tools that were funded by Intermountain Healthcare’s Foundry innovation program, the Intermountain Research and Medical Foundation, CareCentra, GlaxoSmithKline, and AstraZeneca. BDH is a member of the scientific advisory board of Labme.ai. KUK is PI of and BDH a co-investigator of a grant funded by the Patient- Centered Outcomes Research Institute (PCORI). IDP was supported by a grant from the National Institute of General Medical Sciences (K23GM129661). Outside the current work, IDP has received grant support from the National Institutes of Health, Centers for Disease Control, Janssen Pharmaceuticals, and Immunexpress Inc and funding to his institution from Regeneron Pharmaceuticals. The authors have no other potential conflicts of interest to report.Ethics Approval Statement: This study was approved as a data-only historical records review study with a waiver of consent by the Intermountain Healthcare Institutional Review Board.

7.
N Engl J Med ; 386(4): 305-315, 2022 01 27.
Article in English | MEDLINE | ID: covidwho-1585665

ABSTRACT

BACKGROUND: Remdesivir improves clinical outcomes in patients hospitalized with moderate-to-severe coronavirus disease 2019 (Covid-19). Whether the use of remdesivir in symptomatic, nonhospitalized patients with Covid-19 who are at high risk for disease progression prevents hospitalization is uncertain. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving nonhospitalized patients with Covid-19 who had symptom onset within the previous 7 days and who had at least one risk factor for disease progression (age ≥60 years, obesity, or certain coexisting medical conditions). Patients were randomly assigned to receive intravenous remdesivir (200 mg on day 1 and 100 mg on days 2 and 3) or placebo. The primary efficacy end point was a composite of Covid-19-related hospitalization or death from any cause by day 28. The primary safety end point was any adverse event. A secondary end point was a composite of a Covid-19-related medically attended visit or death from any cause by day 28. RESULTS: A total of 562 patients who underwent randomization and received at least one dose of remdesivir or placebo were included in the analyses: 279 patients in the remdesivir group and 283 in the placebo group. The mean age was 50 years, 47.9% of the patients were women, and 41.8% were Hispanic or Latinx. The most common coexisting conditions were diabetes mellitus (61.6%), obesity (55.2%), and hypertension (47.7%). Covid-19-related hospitalization or death from any cause occurred in 2 patients (0.7%) in the remdesivir group and in 15 (5.3%) in the placebo group (hazard ratio, 0.13; 95% confidence interval [CI], 0.03 to 0.59; P = 0.008). A total of 4 of 246 patients (1.6%) in the remdesivir group and 21 of 252 (8.3%) in the placebo group had a Covid-19-related medically attended visit by day 28 (hazard ratio, 0.19; 95% CI, 0.07 to 0.56). No patients had died by day 28. Adverse events occurred in 42.3% of the patients in the remdesivir group and in 46.3% of those in the placebo group. CONCLUSIONS: Among nonhospitalized patients who were at high risk for Covid-19 progression, a 3-day course of remdesivir had an acceptable safety profile and resulted in an 87% lower risk of hospitalization or death than placebo. (Funded by Gilead Sciences; PINETREE ClinicalTrials.gov number, NCT04501952; EudraCT number, 2020-003510-12.).


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Adenosine Monophosphate/adverse effects , Adenosine Monophosphate/therapeutic use , Adult , Aged , Aged, 80 and over , Alanine/adverse effects , Alanine/therapeutic use , Antiviral Agents/adverse effects , COVID-19/complications , COVID-19/mortality , Comorbidity , Disease Progression , Double-Blind Method , Female , Hospitalization/statistics & numerical data , Humans , Male , Middle Aged , Outpatients , SARS-CoV-2/drug effects , Time-to-Treatment , Viral Load
10.
Open forum infectious diseases ; 8(Suppl 1):84-84, 2021.
Article in English | EuropePMC | ID: covidwho-1564955

ABSTRACT

Background Early bacterial co-infection is rare in hospitalized COVID-19 patients, yet antibiotics are commonly prescribed. Antibiotic stewardship (AS) intervention is needed, especially in small community hospitals (SCHs), which often lack access to AS expertise. Methods We implemented daily remote multidisciplinary tele-COVID rounds (synchronous case review between SCH providers and ID clinicians) and tele-stewardship surveillance (ID pharmacist review of COVID patients on antibiotics) on 6/24/2020 in 17 SCHs. We retrospectively included adult symptomatic COVID-19 admissions between 3/2020 and 4/2021. The primary outcome was early use of antibiotics for pneumonia (started within 48 hours of admission);mean monthly days of therapy per 1,000 patient days (DOT) were compared pre- (3/2020-6/2020) and post-intervention (7/2020-4/2021). Secondary outcomes were early use of antibiotics for any indication, estimated days of antibiotics avoided (comparing pre- and post-intervention DOT), and in-hospital mortality. Analyses were conducted using a two-tailed unpaired t-test (antibiotic use) or Fisher’s exact test (mortality). Results Of the 1,976 patients included (124 pre- vs. 1852 post-intervention), 55.4% were male and 85.5% were white. Patients in the pre-intervention group were more likely to require hospital transfer [21.8% vs 8.8% (p< 0.001)] and ICU admission [18.5% vs. 9.7% (p=0.003)]. We observed a significant decrease in mean use of early antibiotics for pneumonia [656.9 vs. 240.1 DOT (p< 0.001)], including among non-ICU patients only [603.6 vs 240.2 DOT (p< 0.001)]. Early antibiotic use for any indication also decreased [686.2 vs. 359.3 DOT (p< 0.001)]. An estimated 3,697 days of unnecessary antibiotics for pneumonia were avoided in the 10-months post-intervention [370 days per month (95% CI 304 – 435)]. Unadjusted in-hospital mortality was not different pre- vs post-intervention (0.8% vs. 2.0%, p=0.511), but was higher among those prescribed early antibiotics (4.4% vs 0.5%, p< 0.001). Conclusion A significant, sustained reduction in antibiotic use among COVID-19 patients at 17 SCHs was observed after implementation of tele-COVID rounds and tele-stewardship surveillance without an observed difference in mortality. Disclosures All Authors: No reported disclosures

11.
Open forum infectious diseases ; 8(Suppl 1):S806-S807, 2021.
Article in English | EuropePMC | ID: covidwho-1564252

ABSTRACT

Background Remdesivir (RDV) is a potent nucleotide prodrug inhibitor of the SARS-CoV-2 RNA-dependent RNA polymerase that has demonstrated efficacy in the treatment of patients hospitalized with moderate to severe COVID-19. This Phase 3 (GS-US-540–9012) double-blind, placebo-controlled study compared the efficacy and safety of 3 days of RDV to standard of care in non-hospitalized, high-risk participants with confirmed COVID-19. Table 1. COVID-19 related hospitalization or death, COVID-19 related medically attended visits or death, and Treatment Emergent Adverse Events Methods Participants were randomly assigned 1:1 to receive intravenous (IV) RDV (200 mg on day 1, 100 mg on days 2 to 3) or placebo. The primary efficacy endpoint was composite COVID-19 hospitalization or all-cause death by day 28 and compared using Cox proportional hazards model with baseline stratification factors as covariates. The primary safety endpoint was proportion of participants with treatment-emergent adverse events. Study enrollment was terminated early for administrative reasons in light of the evolving pandemic. Results 562 patients underwent randomization and started their assigned treatment (279, RDV;283, placebo). Baseline demographics and characteristics were balanced across arms. Overall, 52% were male, 44% were Hispanic/Latino ethnicity and 30% were ≥ 60 years old. The most common comorbidities were diabetes mellitus (62%), obesity (56%;median BMI, 30.7), and hypertension (48%). Median baseline SARS-CoV-2 RNA nasopharyngeal viral load was 6.2 log10 copies/mL. Treatment with RDV significantly reduced COVID-19 hospitalization or all-cause death by day 28 (HR, 0.13;95% CI, 0.03 – 0.59;p = 0.008;Table 1) compared to placebo. Participants receiving RDV also had significantly lower risk for COVID-19-related medically attended visits or all-cause death by day 28 compared to placebo (HR, 0.19;95% CI, 0.07 – 0.56;p = 0.002;Table 1). No deaths occurred in either arm by day 28. There was no difference between arms in time-weighted average change in nasopharyngeal viral loads from baseline up to day 7. The proportion of patients with AEs was similar between arms (Table 1);the most common AEs in the RDV arm were nausea (11%), headache (6%), and diarrhea (4%). Conclusion A 3-day course of IV RDV was safe, well tolerated and highly effective at preventing COVID-19 related hospitalization or death in high-risk non-hospitalized COVID-19 patients. Disclosures Joshua A. Hill, MD, Allogene (Individual(s) Involved: Self): Consultant;Allovir (Individual(s) Involved: Self): Consultant, Grant/Research Support;Amplyx (Individual(s) Involved: Self): Consultant;Covance/CSL (Individual(s) Involved: Self): Consultant;CRISPR (Individual(s) Involved: Self): Consultant;Gilead (Individual(s) Involved: Self): Consultant, Grant/Research Support;Karius: Grant/Research Support, Scientific Research Study Investigator;Medscape (Individual(s) Involved: Self): Consultant;Octapharma (Individual(s) Involved: Self): Consultant;OptumHealth (Individual(s) Involved: Self): Consultant;Takeda (Individual(s) Involved: Self): Consultant, Grant/Research Support, Scientific Research Study Investigator Roger Paredes, MD, PhD, Gilead Sciences, Inc (Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member) Carlos Vaca, MD, Gilead Sciences, Inc (Scientific Research Study Investigator) Jorge Mera, MD, Gilead Sciences, Inc (Consultant, Study Investigator (payment to employer not self)) Gilberto Perez, MD, Gilead Sciences, Inc (Scientific Research Study Investigator) Godson Oguchi, MD, Gilead Sciences, Inc (Scientific Research Study Investigator) Pablo Ryan, MD PhD, Gilead Sciences, Inc (Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member) Jan Gerstoft, MD, Gilead Sciences, Inc (Other Financial or Material Support, Study Investigator (payment to employer)) Michael Brown, FRCP PhD, Gilead Sciences, Inc (Scientific Research Study Inve tigator, Investigator for numerous remdesivir trials (employer received compensation)) Morgan Katz, MD, MHS, Roche (Individual(s) Involved: Self): Advisor or Review Panel member;Skinclique (Individual(s) Involved: Self): Consultant Gregory Camus, PhD, Gilead Sciences (Employee, Shareholder) Danielle P. Porter, PhD, Gilead Sciences (Employee, Shareholder) Robert H. Hyland, DPhil, Gilead Sciences, Inc (Shareholder, Other Financial or Material Support, Employee during the conduct of this trial) Shuguang Chen, PhD, Gilead Sciences, Inc (Employee, Shareholder) Kavita Juneja, MD, Gilead Sciences, Inc (Employee) Anu Osinusi, MD, Gilead Sciences, Inc (Employee, Shareholder) Frank Duff, MD, Gilead Sciences, Inc (Employee, Shareholder) Robert L. Gottlieb, MD, Eli Lilly (Scientific Research Study Investigator, Advisor or Review Panel member)Gilead Sciences (Scientific Research Study Investigator, Advisor or Review Panel member, Other Financial or Material Support, Gift in kind to Baylor Scott and White Research Institute for NCT03383419)GSK (Advisor or Review Panel member)Johnson and Johnson (Scientific Research Study Investigator)Kinevant (Scientific Research Study Investigator)Roche/Genentech (Scientific Research Study Investigator)

12.
Lancet Rheumatol ; 3(9): e609-e611, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1392684
13.
Open Forum Infect Dis ; 8(7): ofab331, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1334239

ABSTRACT

BACKGROUND: Neutralizing monoclonal antibodies (MAbs) are a promising therapy for early coronavirus disease 2019 (COVID-19), but their effectiveness has not been confirmed in a real-world setting. METHODS: In this quasi-experimental pre-/postimplementation study, we estimated the effectiveness of MAb treatment within 7 days of symptom onset in high-risk ambulatory adults with COVID-19. The primary outcome was a composite of emergency department visits or hospitalizations within 14 days of positive test. Secondary outcomes included adverse events and 14-day mortality. The average treatment effect in the treated for MAb therapy was estimated using inverse probability of treatment weighting and the impact of MAb implementation using propensity-weighted interrupted time series analysis. RESULTS: Pre-implementation (July-November 2020), 7404 qualifying patients were identified. Postimplementation (December 2020-January 2021), 594 patients received MAb treatment and 5536 did not. The primary outcome occurred in 75 (12.6%) MAb recipients, 1018 (18.4%) contemporaneous controls, and 1525 (20.6%) historical controls. MAb treatment was associated with decreased likelihood of emergency care or hospitalization (odds ratio, 0.69; 95% CI, 0.60-0.79). After implementation, the weighted probability that a given patient would require an emergency department visit or hospitalization decreased significantly (0.7% per day; 95% CI, 0.03%-0.10%). Mortality was 0.2% (n = 1) in the MAb group compared with 1.0% (n = 71) and 1.0% (n = 57) in pre- and postimplementation controls, respectively. Adverse events occurred in 7 (1.2%); 2 (0.3%) were considered serious. CONCLUSIONS: MAb treatment of high-risk ambulatory patients with early COVID-19 was well tolerated and likely effective at preventing the need for subsequent emergency department or hospital care.

14.
PLoS One ; 16(5): e0251214, 2021.
Article in English | MEDLINE | ID: covidwho-1215147

ABSTRACT

BACKGROUND: SARS-CoV-2 reinfection and reactivation has mostly been described in case reports. We therefore investigated the epidemiology of recurrent COVID-19 SARS-CoV-2. METHODS: Among patients testing positive for SARS-CoV-2 between March 11 and July 31, 2020 within an integrated healthcare system, we identified patients with a recurrent positive SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR) assay ≥60 days after an initial positive test. To assign an overall likelihood of COVID-19 recurrence, we combined quantitative data from initial and recurrent positive RT-PCR cycle thresholds-a value inversely correlated with viral RNA burden- with a clinical recurrence likelihood assigned based on independent, standardized case review by two physicians. "Probable" or "possible" recurrence by clinical assessment was confirmed as the final recurrence likelihood only if a cycle threshold value obtained ≥60 days after initial testing was lower than its preceding cycle threshold or if the patient had an interval negative RT-PCR. RESULTS: Among 23,176 patients testing positive for SARS-CoV-2, 1,301 (5.6%) had at least one additional SARS-CoV-2 RT-PCRs assay ≥60 days later. Of 122 testing positive, 114 had sufficient data for evaluation. The median interval to the recurrent positive RT-PCR was 85.5 (IQR 74-107) days. After combining clinical and RT-PCR cycle threshold data, four patients (3.5%) met criteria for probable COVID-19 recurrence. All four exhibited symptoms at recurrence and three required a higher level of medical care compared to their initial diagnosis. After including six additional patients (5.3%) with possible recurrence, recurrence incidence was 4.3 (95% CI 2.1-7.9) cases per 10,000 COVID-19 patients. CONCLUSIONS: Only 0.04% of all COVID-19 patients in our health system experienced probable or possible recurrence; 90% of repeat positive SARS-CoV-2 RT-PCRs were not consistent with true recurrence. Our pragmatic approach combining clinical and quantitative RT-PCR data could aid assessment of COVID-19 reinfection or reactivation by clinicians and public health personnel.


Subject(s)
COVID-19/diagnosis , Adult , COVID-19/virology , COVID-19 Testing , Female , Humans , Male , Middle Aged , RNA, Viral/analysis , RNA, Viral/metabolism , Recurrence , Reverse Transcriptase Polymerase Chain Reaction/standards , SARS-CoV-2/genetics , SARS-CoV-2/isolation & purification , Time Factors , Viral Load
15.
Ann Am Thorac Soc ; 2020 Nov 09.
Article in English | MEDLINE | ID: covidwho-1175439

ABSTRACT

RATIONALE: The COVID-19 pandemic struck an immunologically naïve, globally interconnected population. In the face of a new infectious agent causing acute respiratory failure for which there were no known effective therapies, rapid, often pragmatic trials were necessary to evaluate potential treatments, frequently starting with medications that are already marketed for other indications. Early in the pandemic, hydroxychloroquine and azithromycin were two such candidates. OBJECTIVE: Assess the relative efficacy of hydroxychloroquine and azithromycin among hospitalized patients with COVID-19. METHODS: We performed a randomized clinical trial of hydroxychloroquine vs. azithromycin among hospitalized patients with COVID-19. Treatment was 5 days of study medication. The primary endpoint was the COVID Ordinal Outcomes scale at day 14. Secondary endpoints included hospital-, ICU-, and ventilator-free days at day 28. The trial was stopped early after enrollment of 85 patients when a separate clinical trial concluded that a clinically important effect of hydroxychloroquine over placebo was definitively excluded. Comparisons were made a priori using a proportional odds model from a Bayesian perspective. RESULTS: We enrolled 85 patients at 13 hospitals over 11 weeks. Adherence to study medication was high. The estimated odds ratio for less favorable status on the ordinal scale for hydroxychloroquine vs. azithromycin from the primary analysis was 1.07, with a 95% credible interval from 0.63 to 1.83 with a posterior probability of 60% that hydroxychloroquine was worse than azithryomycin. Secondary outcomes displayed a similar, slight preference for azithromycin over hydroxychloroquine. QTc prolongation was rare and did not differ between groups. The twenty safety outcomes were similar between arms with the possible exception of post-randomization onset acute kidney injury, which was more common with hydroxychloroquine (15% vs. 0%). Patients in the hydroxychloroquine arm received remdesivir more often than in the azithromycin arm (19% vs. 2%). There was no apparent association between remdesivir use and acute kidney injury. CONCLUSIONS: While early termination limits the precision of our results, we found no suggestion of substantial efficacy for hydroxychloroquine over azithromycin. Acute kidney injury may be more common with hydroxychloroquine than azithromycin, although this may be due to the play of chance. Differential use of remdesivir may have biased our results in favor of hydroxychloroquine. Our results are consistent with conclusions from other trials that hydroxychloroquine cannot be recommended for inpatients with COVID-19; azithromycin may merit additional investigation. CLINICAL TRIAL REGISTRATION: This trial was prospectively registered (NCT04329832) before enrollment of the first patient.

16.
Am J Health Syst Pharm ; 78(8): 732-735, 2021 03 31.
Article in English | MEDLINE | ID: covidwho-1041993

ABSTRACT

PURPOSE: This report describes our process of 4 health systems coming together to agree on standard use criteria for remdesivir as a coronavirus disease 2019 (COVID-19) treatment for patients in Utah. We hope our process provides a framework for remdesivir use in other states and insights on future use of other therapeutic agents that may also be in short supply, such as vaccines and monoclonal antibodies. SUMMARY: Emergency use authorization (EUA) criteria for COVID-19 treatments often allow for broad use of a treatment relative to limited supplies. Without national criteria, each health system must develop further rationing criteria. Health systems in Utah worked together as part of the state's crisis standards of care workgroup to develop a framework for how to limit the EUA criteria for remdesivir to match available supplies. The 4 largest health systems were represented by infectious diseases specialists, chief medical officers, and pharmacists. The group met several times online and communicated via email over a 9-day period to develop the criteria. The clinicians agreed to use this framework to develop criteria for future therapeutics such as monoclonal antibodies. CONCLUSION: The unique collaboration of the 4 health systems in Utah led to statewide criteria for use of remdesivir for patients with COVID-19, ensuring similar access to this limited resource for all patients in Utah.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Pharmacy Service, Hospital/standards , Practice Guidelines as Topic , SARS-CoV-2 , Adenosine Monophosphate/administration & dosage , Adenosine Monophosphate/therapeutic use , Alanine/administration & dosage , Alanine/therapeutic use , Antiviral Agents/administration & dosage , Humans , Utah
17.
Lancet Rheumatol ; 2(12): e754-e763, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-1003184

ABSTRACT

BACKGROUND: A subset of patients with COVID-19 develops a hyperinflammatory syndrome that has similarities with other hyperinflammatory disorders. However, clinical criteria specifically to define COVID-19-associated hyperinflammatory syndrome (cHIS) have not been established. We aimed to develop and validate diagnostic criteria for cHIS in a cohort of inpatients with COVID-19. METHODS: We searched for clinical research articles published between Jan 1, 1990, and Aug 20, 2020, on features and diagnostic criteria for secondary haemophagocytic lymphohistiocytosis, macrophage activation syndrome, macrophage activation-like syndrome of sepsis, cytokine release syndrome, and COVID-19. We compared published clinical data for COVID-19 with clinical features of other hyperinflammatory or cytokine storm syndromes. Based on a framework of conserved clinical characteristics, we developed a six-criterion additive scale for cHIS: fever, macrophage activation (hyperferritinaemia), haematological dysfunction (neutrophil to lymphocyte ratio), hepatic injury (lactate dehydrogenase or asparate aminotransferase), coagulopathy (D-dimer), and cytokinaemia (C-reactive protein, interleukin-6, or triglycerides). We then validated the association of the cHIS scale with in-hospital mortality and need for mechanical ventilation in consecutive patients in the Intermountain Prospective Observational COVID-19 (IPOC) registry who were admitted to hospital with PCR-confirmed COVID-19. We used a multistate model to estimate the temporal implications of cHIS. FINDINGS: We included 299 patients admitted to hospital with COVID-19 between March 13 and May 5, 2020, in analyses. Unadjusted discrimination of the maximum daily cHIS score was 0·81 (95% CI 0·74-0·88) for in-hospital mortality and 0·92 (0·88-0·96) for mechanical ventilation; these results remained significant in multivariable analysis (odds ratio 1·6 [95% CI 1·2-2·1], p=0·0020, for mortality and 4·3 [3·0-6·0], p<0·0001, for mechanical ventilation). 161 (54%) of 299 patients met two or more cHIS criteria during their hospital admission; these patients had higher risk of mortality than patients with a score of less than 2 (24 [15%] of 138 vs one [1%] of 161) and for mechanical ventilation (73 [45%] vs three [2%]). In the multistate model, using daily cHIS score as a time-dependent variable, the cHIS hazard ratio for worsening from low to moderate oxygen requirement was 1·4 (95% CI 1·2-1·6), from moderate oxygen to high-flow oxygen 2·2 (1·1-4·4), and to mechanical ventilation 4·0 (1·9-8·2). INTERPRETATION: We proposed and validated criteria for hyperinflammation in COVID-19. This hyperinflammatory state, cHIS, is commonly associated with progression to mechanical ventilation and death. External validation is needed. The cHIS scale might be helpful in defining target populations for trials and immunomodulatory therapies. FUNDING: Intermountain Research and Medical Foundation.

19.
Ann Am Thorac Soc ; 17(8): 1008-1015, 2020 08.
Article in English | MEDLINE | ID: covidwho-724110

ABSTRACT

Coronavirus disease (COVID-19) is a potentially fatal illness with no proven therapy beyond excellent supportive care. Treatments are urgently sought. Adaptations to traditional trial logistics and design to allow rapid implementation, evaluation of trials within a global trials context, flexible interim monitoring, and access outside traditional research hospitals (even in settings where formal placebos are unavailable) may be helpful. Thoughtful adaptations to traditional trial designs, especially within the global context of related studies, may also foster collaborative relationships among government, community, and the research enterprise. Here, we describe the protocol for a pragmatic, active comparator trial in as many as 300 patients comparing two current "off-label" treatments for COVID-19-hydroxychloroquine and azithromycin-in academic and nonacademic hospitals in Utah. We developed the trial in response to local pressures for widespread, indiscriminate off-label use of these medications. We used a hybrid Bayesian-frequentist design for interim monitoring to allow rapid, contextual assessment of the available evidence. We also developed an inference grid for interpreting the range of possible results from this trial within the context of parallel trials and prepared for a network meta-analysis of the resulting data. This trial was prospectively registered (ClinicalTrials.gov Identifier: NCT04329832) before enrollment of the first patient.Clinical trial registered with www.clinicaltrials.gov (NCT04329832).


Subject(s)
Azithromycin , Coronavirus Infections , Hydroxychloroquine , Pandemics , Pneumonia, Viral , Adult , Anti-Infective Agents/administration & dosage , Anti-Infective Agents/adverse effects , Azithromycin/administration & dosage , Azithromycin/adverse effects , Betacoronavirus/drug effects , Betacoronavirus/isolation & purification , COVID-19 , Coronavirus Infections/diagnosis , Coronavirus Infections/drug therapy , Coronavirus Infections/epidemiology , Drug Monitoring/methods , Female , Humans , Hydroxychloroquine/administration & dosage , Hydroxychloroquine/adverse effects , Male , Pneumonia, Viral/diagnosis , Pneumonia, Viral/drug therapy , Pneumonia, Viral/epidemiology , Randomized Controlled Trials as Topic , SARS-CoV-2 , Treatment Outcome , Utah
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