The Effect of Baricitinib and Corticosteroid Compared to that of Corticosteroid Monotherapy in Severely and Critically ill Patients with COVID-19: A Japanese Multicenter Inpatient Database Study.

Imoto W., Ihara Y., Imai T., Tamoto M., Ibuki T., Yamada K., Kaneko Y., Shintani A., Kakeya H.

Obesity is a risk factor for aggravation of and mortality from coronavirus disease 2019 (COVID-19). We aimed to investigate the relationship between COVID-19 and Body Mass Index (BMI) in the Japanese population.We used administrative claims data from an advanced treatment hospital in Japan and extracted data from patients hospitalized for COVID-19. The exposure variable was BMI measured at the time of admission, and the study outcomes were progression to critical illness and death. Analyses were performed for each age group.Overall, 58,944 patients met the inclusion criteria. The risk of critical illness increased monotonically with higher BMI. In contrast, the relationship between BMI and mortality follows a J-shaped curve; being underweight and obese are risk factors for mortality. When stratified by age, similar trends were observed for both critical illness and mortality.A higher BMI is a risk factor for the progression of COVID-19 severity, whereas both lower and higher BMIs are risk factors for mortality in the Japanese population.

Suzuki J., Endo S., Suzuki T., Sasahara T., Hatakeyama S., Morisawa Y., Hayakawa M., Yamakawa K., Endo A., Ogura T., Hirayama A., Yasunaga H., Tagami T.

Abstract Background Coronavirus disease 2019 (COVID-19) is an ongoing global pandemic. Although systemic steroids play an important role in treating patients with severe COVID-19, the role of inhaled corticosteroids in non-critically ill, hospitalized patients with COVID-19 remains unclear. Methods We analyzed non-critically ill, hospitalized patients with COVID-19 who were older than 18 years and were admitted to 64 Japanese hospitals between January and September 2020. We performed propensity score matching analysis to evaluate 28-day mortality and in-hospital mortality with or without inhaled ciclesonide within two days of admission. Sensitivity analyses using inverse probability weighting analysis and the generalized estimating equation method were also performed. Results Eligible patients (n = 3,638) were divided into ciclesonide (n = 290) and control (n = 3, 393) groups. One-to-four propensity score matching analysis included 271 ciclesonide users and 1,084 non-users. There were no significant differences between the two groups for 28-day mortality (3.3% vs. 2.3%, risk difference: 1.0%, 95% CI: -1.2 to 3.3), in-hospital mortality (4.8% vs. 2.6%, risk difference: 2.2, 95% CI: -0.5 to 4.9). The sensitivity analysis showed similar outcomes. Conclusions From this multicenter observational study in Japan, inhaled ciclesonide did not decrease 28-day mortality and in-hospital mortality in non-critically ill, hospitalized patients with COVID-19. Future large, multinational, randomized trials are required to confirm our results.

Xie Y., Choi T., Al-Aly Z.

This study uses data from the US Department of Veterans Affairs to assess whether SARS-CoV-2 remains associated with higher risk of death compared with seasonal influenza in fall-winter 2022-2023.

Krause T.M., Greenberg R., Ghosh L., Wozny J.S., Hansen R.M., Schaefer C.

Abstract Objective To create and validate a methodology to assign a severity level to an episode of COVID-19 for retrospective analysis in claims data. Data Source Secondary data obtained by license agreement from Optum provided claims records nationally for 19,761,754 persons, of which, 692,094 persons had COVID-19 in 2020. Study Design The World Health Organization (WHO) COVID-19 Progression Scale was used as a model to identify endpoints as measures of episode severity within claims data. Endpoints used included symptoms, respiratory status, progression to levels of treatment and mortality. Data Collection/Extraction methods The strategy for identification of cases relied upon the February 2020 guidance from the Centers for Disease Control and Prevention (CDC). Principal Findings A total of 709,846 persons (3.6%) met the criteria for one of the nine severity levels based on diagnosis codes with 692,094 having confirmatory diagnoses. The rates for each level varied considerably by age groups, with the older age groups reaching higher severity levels at a higher rate. Mean and median costs increased as severity level increased. Statistical validation of the severity scales revealed that the rates for each level varied considerably by age group, with the older ages reaching higher severity levels (p < 0.001). Other demographic factors such as race and ethnicity, geographic region, and comorbidity count had statistically significant associations with severity level of COVID-19. Conclusion A standardized severity scale for use with claims data will allow researchers to evaluate episodes so that analyses can be conducted on the processes of intervention, effectiveness, efficiencies, costs and outcomes related to COVID-19.

Adjei S., Hong K., Molinari N.M., Bull-Otterson L., Ajani U.A., Gundlapalli A.V., Harris A.M., Hsu J., Kadri S.S., Starnes J., Yeoman K., Boehmer T.K.

The risk for COVID-19-associated mortality increases with age, disability, and underlying medical conditions (1). Early in the emergence of the Omicron variant of SARS-CoV-2, the virus that causes COVID-19, mortality among hospitalized COVID-19 patients was lower than that during previous pandemic peaks (2-5), and some health authorities reported that a substantial proportion of COVID-19 hospitalizations were not primarily for COVID-19-related illness,* which might account for the lower mortality among hospitalized patients. Using a large hospital administrative database, CDC assessed in-hospital mortality risk overall and by demographic and clinical characteristics during the Delta (July-October 2021), early Omicron (January-March 2022), and later Omicron (April-June 2022) variant periods† among patients hospitalized primarily for COVID-19. Model-estimated adjusted mortality risk differences (aMRDs) (measures of absolute risk) and adjusted mortality risk ratios (aMRRs) (measures of relative risk) for in-hospital death were calculated comparing the early and later Omicron periods with the Delta period. Crude mortality risk (cMR) (deaths per 100 patients hospitalized primarily for COVID-19) was lower during the early Omicron (13.1) and later Omicron (4.9) periods than during the Delta (15.1) period (p

Bhimraj A., Morgan R.L., Shumaker A.H., Baden L., Cheng V.C., Edwards K.M., Gallagher J.C., Gandhi R.T., Muller W.J., Nakamura M.M., O’Horo J.C., Shafer R.W., Shoham S., Murad M.H., Mustafa R.A., et. al.

Abstract Background There are many pharmacologic therapies that are being used or considered for treatment of coronavirus disease 2019 (COVID-19), with rapidly changing efficacy and safety evidence from trials. Objective Develop evidence-based, rapid, living guidelines intended to support patients, clinicians, and other healthcare professionals in their decisions about treatment and management of patients with COVID-19. Methods In March 2020, the Infectious Diseases Society of America (IDSA) formed a multidisciplinary guideline panel of infectious disease clinicians, pharmacists, and methodologists with varied areas of expertise to regularly review the evidence and make recommendations about the treatment and management of persons with COVID-19. The process used a living guideline approach and followed a rapid recommendation development checklist. The panel prioritized questions and outcomes. A systematic review of the peer-reviewed and grey literature was conducted at regular intervals. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess the certainty of evidence and make recommendations. Results Based on the most recent search conducted on May 31, 2022, the IDSA guideline panel has made 30 recommendations for the treatment and management of the following groups/populations: pre- and post-exposure prophylaxis, ambulatory with mild-to-moderate disease, hospitalized with mild-to-moderate, severe but not critical, and critical disease. As these are living guidelines, the most recent recommendations can be found online at: https://idsociety.org/COVID19guidelines. Conclusions At the inception of its work, the panel has expressed the overarching goal that patients be recruited into ongoing trials. Since then, many trials were done which provided much needed evidence for COVID-19 therapies. There still remain many unanswered questions as the pandemic evolved which we hope future trials can answer.

Wolfe C.R., Tomashek K.M., Patterson T.F., Gomez C.A., Marconi V.C., Jain M.K., Yang O.O., Paules C.I., Palacios G.M., Grossberg R., Harkins M.S., Mularski R.A., Erdmann N., Sandkovsky U., Almasri E., et. al.

SummaryBackground Baricitinib and dexamethasone have randomised trials supporting their use for the treatment of patients with COVID-19. We assessed the combination of baricitinib plus remdesivir versus dexamethasone plus remdesivir in preventing progression to mechanical ventilation or death in hospitalised patients with COVID-19. Methods In this randomised, double-blind, double placebo-controlled trial, patients were enrolled at 67 trial sites in the USA (60 sites), South Korea (two sites), Mexico (two sites), Singapore (two sites), and Japan (one site). Hospitalised adults (≥18 years) with COVID-19 who required supplemental oxygen administered by low-flow (≤15 L/min), high-flow (>15 L/min), or non-invasive mechanical ventilation modalities who met the study eligibility criteria (male or non-pregnant female adults ≥18 years old with laboratory-confirmed SARS-CoV-2 infection) were enrolled in the study. Patients were randomly assigned (1:1) to receive either baricitinib, remdesivir, and placebo, or dexamethasone, remdesivir, and placebo using a permuted block design. Randomisation was stratified by study site and baseline ordinal score at enrolment. All patients received remdesivir (≤10 days) and either baricitinib (or matching oral placebo) for a maximum of 14 days or dexamethasone (or matching intravenous placebo) for a maximum of 10 days. The primary outcome was the difference in mechanical ventilation-free survival by day 29 between the two treatment groups in the modified intention-to-treat population. Safety analyses were done in the as-treated population, comprising all participants who received one dose of the study drug. The trial is registered with ClinicalTrials.gov, NCT04640168. Findings Between Dec 1, 2020, and April 13, 2021, 1047 patients were assessed for eligibility. 1010 patients were enrolled and randomly assigned, 516 (51%) to baricitinib plus remdesivir plus placebo and 494 (49%) to dexamethasone plus remdesivir plus placebo. The mean age of the patients was 58·3 years (SD 14·0) and 590 (58%) of 1010 patients were male. 588 (58%) of 1010 patients were White, 188 (19%) were Black, 70 (7%) were Asian, and 18 (2%) were American Indian or Alaska Native. 347 (34%) of 1010 patients were Hispanic or Latino. Mechanical ventilation-free survival by day 29 was similar between the study groups (Kaplan-Meier estimates of 87·0% [95% CI 83·7 to 89·6] in the baricitinib plus remdesivir plus placebo group and 87·6% [84·2 to 90·3] in the dexamethasone plus remdesivir plus placebo group; risk difference 0·6 [95% CI −3·6 to 4·8]; p=0·91). The odds ratio for improved status in the dexamethasone plus remdesivir plus placebo group compared with the baricitinib plus remdesivir plus placebo group was 1·01 (95% CI 0·80 to 1·27). At least one adverse event occurred in 149 (30%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 179 (37%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·5% [1·6 to 13·3]; p=0·014). 21 (4%) of 503 patients in the baricitinib plus remdesivir plus placebo group had at least one treatment-related adverse event versus 49 (10%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 6·0% [2·8 to 9·3]; p=0·00041). Severe or life-threatening grade 3 or 4 adverse events occurred in 143 (28%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 174 (36%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·7% [1·8 to 13·4]; p=0·012). Interpretation In hospitalised patients with COVID-19 requiring supplemental oxygen by low-flow, high-flow, or non-invasive ventilation, baricitinib plus remdesivir and dexamethasone plus remdesivir resulted in similar mechanical ventilation-free survival by day 29, but dexamethasone was associated with significantly more adverse events, treatment-related adverse events, and severe or life-threatening adverse events. A more individually tailored choice of immunomodulation now appears possible, where side-effect profile, ease of administration, cost, and patient comorbidities can all be considered. Funding National Institute of Allergy and Infectious Diseases.

Forsberg J., Bedard E., Mahmoud S.H.

Critically ill patients managed in the Intensive Care Unit (ICU) suffer from several pathophysiological alterations due to critical illness resulting in potential changes in the pharmacokinetics of drugs including systemic absorption. Nevertheless, these patients are still given some medications in unadjusted doses thereby putting the patients at a risk for therapy failure. The objective for this study was to summarize the available evidence regarding oral drug absorption in the ICU. A literature search of the databases MEDLINE, EMBASE, and PubMed was conducted on (February 24, 2020). Articles discussing the rate and/or extent of orally administered drugs in critically ill patients were included. A total of 58 studies were found: 17 interventional studies, 33 observational studies (30 prospective, 3 retrospective) and 8 case reports. A total of 43 articles reported altered drug absorption in critically ill patients suggesting the need for alternative measures to facilitate treatment success. The absorption of orally administered drugs may be altered in critically ill patients. Measures for altered drug absorption in critically ill patients were suggested such as holding tube feeding before and after medication administration, increasing doses of orally administrated drugs and using alternate routes of administration.

Horby P.W., Emberson J.R., Mafham M., Campbell M., Peto L., Pessoa-Amorim G., Spata E., Staplin N., Lowe C., Chadwick D.R., Brightling C., Stewart R., Collini P., Ashish A., Green C.A., et. al.

SUMMARYBackgroundWe evaluated the use of baricitinib, a Janus kinase (JAK) 1/2 inhibitor, for the treatment of patients admitted to hospital because of COVID-19.MethodsThis randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple possible treatments in patients hospitalised for COVID-19. Eligible and consenting patients were randomly allocated (1:1) to either usual standard of care alone (usual care group) or usual care plus baricitinib 4 mg once daily by mouth for 10 days or until discharge if sooner (baricitinib group). The primary outcome was 28-day mortality assessed in the intention-to-treat population. A meta-analysis was conducted that included the results from the RECOVERY trial and all previous randomised controlled trials of baricitinib or other JAK inhibitor in patients hospitalised with COVID-19. The RECOVERY trial is registered with ISRCTN (50189673) and clinicaltrials.gov (NCT04381936).FindingsBetween 2 February 2021 and 29 December 2021, 8156 patients were randomly allocated to receive usual care plus baricitinib versus usual care alone. At randomisation, 95% of patients were receiving corticosteroids and 23% receiving tocilizumab (with planned use within the next 24 hours recorded for a further 9%). Overall, 513 (12%) of 4148 patients allocated to baricitinib versus 546 (14%) of 4008 patients allocated to usual care died within 28 days (age-adjusted rate ratio 0·87; 95% CI 0·77-0·98; p=0·026). This 13% proportional reduction in mortality was somewhat smaller than that seen in a meta-analysis of 8 previous trials of a JAK inhibitor (involving 3732 patients and 425 deaths) in which allocation to a JAK inhibitor was associated with a 43% proportional reduction in mortality (rate ratio 0.57; 95% CI 0.45-0.72). Including the results from RECOVERY into an updated meta-analysis of all 9 completed trials (involving 11,888 randomised patients and 1484 deaths) allocation to baricitinib or other JAK inhibitor was associated with a 20% proportional reduction in mortality (rate ratio 0.80; 95% CI 0.71-0.89; p<0.001). In RECOVERY, there was no significant excess in death or infection due to non-COVID-19 causes and no excess of thrombosis, or other safety outcomes.InterpretationIn patients hospitalised for COVID-19, baricitinib significantly reduced the risk of death but the size of benefit was somewhat smaller than that suggested by previous trials. The total randomised evidence to date suggests that JAK inhibitors (chiefly baricitinib) reduce mortality in patients hospitalised for COVID-19 by about one-fifth.FundingUK Research and Innovation (Medical Research Council) and National Institute of Health Research (Grant ref: MC_PC_19056).

Bartoletti M., Azap O., Barac A., Bussini L., Ergonul O., Krause R., Paño-Pardo J.R., Power N.R., Sibani M., Szabo B.G., Tsiodras S., Verweij P.E., Zollner-Schwetz I., Rodríguez-Baño J.

In January 2021, the ESCMID Executive Committee decided to launch a new initiative to develop ESCMID guidelines on several COVID-19-related issues, including treatment of COVID-19.An ESCMID COVID-19 guidelines task force was established by the ESCMID Executive Committee. A small group was established, half appointed by the chair, and the remaining selected with an open call. Each panel met virtually once a week. For all decisions, a simple majority vote was used. A long list of clinical questions using the PICO (population, intervention, comparison, outcome) format was developed at the beginning of the process. For each PICO, two panel members performed a literature search with a third panellist involved in case of inconsistent results. Voting was based on the GRADE approach.A synthesis of the available evidence and recommendations is provided for each of the 15 PICOs, which cover use of hydroxychloroquine, bamlanivimab alone or in combination with etesevimab, casirivimab combined with imdevimab, ivermectin, azithromycin and empirical antibiotics, colchicine, corticosteroids, convalescent plasma, favipiravir, remdesivir, tocilizumab and interferon β-1a, as well as the utility of antifungal prophylaxis and enoxaparin. In general, the panel recommended against the use of hydroxychloroquine, ivermectin, azithromycin, colchicine and interferon β-1a. Conditional recommendations were given for the use of monoclonal antibodies in high-risk outpatients with mild-moderate COVID-19, and remdesivir. There was insufficient evidence to make a recommendation for use of favipiravir and antifungal prophylaxis, and it was recommended that antibiotics should not be routinely prescribed in patients with COVID-19 unless bacterial coinfection or secondary infection is suspected or confirmed. Tocilizumab and corticosteroids were recommended for treatment of severe COVID-19 but not in outpatients with non-severe COVID-19.The aim of the present guidance is to provide evidence-based recommendations for management of adults with coronavirus disease 2019 (COVID-19). More specifically, the goal is to aid clinicians managing patients with COVID-19 at various levels of severity including outpatients, hospitalized patients, and those admitted to intensive care unit. Considering the composition of the panel, mostly clinical microbiologists or infectious disease specialists with no pulmonology or intensive care background, we focus only on pharmacological treatment and do not give recommendations on oxygen supplement/support. Similarly, as no paediatricians were included in the panel; the recommendations are only for adult patients with COVID-19. Considering the current literature, no guidance was given for special populations such as the immunocompromised.

So J.M., Umeh C., Noriega S., Stratton E., Aseri M., Gupta R.C.

Marconi V.C., Ramanan A.V., de Bono S., Kartman C.E., Krishnan V., Liao R., Piruzeli M.L., Goldman J.D., Alatorre-Alexander J., de Cassia Pellegrini R., Estrada V., Som M., Cardoso A., Chakladar S., Crowe B., et. al.

Baricitinib is an oral selective Janus kinase 1/2 inhibitor with known anti-inflammatory properties. This study evaluates the efficacy and safety of baricitinib in combination with standard of care for the treatment of hospitalised adults with COVID-19.In this phase 3, double-blind, randomised, placebo-controlled trial, participants were enrolled from 101 centres across 12 countries in Asia, Europe, North America, and South America. Hospitalised adults with COVID-19 receiving standard of care were randomly assigned (1:1) to receive once-daily baricitinib (4 mg) or matched placebo for up to 14 days. Standard of care included systemic corticosteroids, such as dexamethasone, and antivirals, including remdesivir. The composite primary endpoint was the proportion who progressed to high-flow oxygen, non-invasive ventilation, invasive mechanical ventilation, or death by day 28, assessed in the intention-to-treat population. All-cause mortality by day 28 was a key secondary endpoint, and all-cause mortality by day 60 was an exploratory endpoint; both were assessed in the intention-to-treat population. Safety analyses were done in the safety population defined as all randomly allocated participants who received at least one dose of study drug and who were not lost to follow-up before the first post-baseline visit. This study is registered with ClinicalTrials.gov, NCT04421027.Between June 11, 2020, and Jan 15, 2021, 1525 participants were randomly assigned to the baricitinib group (n=764) or the placebo group (n=761). 1204 (79·3%) of 1518 participants with available data were receiving systemic corticosteroids at baseline, of whom 1099 (91·3%) were on dexamethasone; 287 (18·9%) participants were receiving remdesivir. Overall, 27·8% of participants receiving baricitinib and 30·5% receiving placebo progressed to meet the primary endpoint (odds ratio 0·85 [95% CI 0·67 to 1·08], p=0·18), with an absolute risk difference of -2·7 percentage points (95% CI -7·3 to 1·9). The 28-day all-cause mortality was 8% (n=62) for baricitinib and 13% (n=100) for placebo (hazard ratio [HR] 0·57 [95% CI 0·41-0·78]; nominal p=0·0018), a 38·2% relative reduction in mortality; one additional death was prevented per 20 baricitinib-treated participants. The 60-day all-cause mortality was 10% (n=79) for baricitinib and 15% (n=116) for placebo (HR 0·62 [95% CI 0·47-0·83]; p=0·0050). The frequencies of serious adverse events (110 [15%] of 750 in the baricitinib group vs 135 [18%] of 752 in the placebo group), serious infections (64 [9%] vs 74 [10%]), and venous thromboembolic events (20 [3%] vs 19 [3%]) were similar between the two groups.Although there was no significant reduction in the frequency of disease progression overall, treatment with baricitinib in addition to standard of care (including dexamethasone) had a similar safety profile to that of standard of care alone, and was associated with reduced mortality in hospitalised adults with COVID-19.Eli Lilly and Company.For the French, Japanese, Portuguese, Russian and Spanish translations of the abstract see Supplementary Materials section.

Hodgson C.L., Higgins A.M., Bailey M.J., Mather A.M., Beach L., Bellomo R., Bissett B., Boden I.J., Bradley S., Burrell A., Cooper D.J., Fulcher B.J., Haines K.J., Hopkins J., Jones A.Y., et. al.

There are few reports of new functional impairment following critical illness from COVID-19. We aimed to describe the incidence of death or new disability, functional impairment and changes in health-related quality of life of patients after COVID-19 critical illness at 6 months. In a nationally representative, multicenter, prospective cohort study of COVID-19 critical illness, we determined the prevalence of death or new disability at 6 months, the primary outcome. We measured mortality, new disability and return to work with changes in the World Health Organization Disability Assessment Schedule 2.0 12L (WHODAS) and health status with the EQ5D-5LTM. Of 274 eligible patients, 212 were enrolled from 30 hospitals. The median age was 61 (51–70) years, and 124 (58.5%) patients were male. At 6 months, 43/160 (26.9%) patients died and 42/108 (38.9%) responding survivors reported new disability. Compared to pre-illness, the WHODAS percentage score worsened (mean difference (MD), 10.40% [95% CI 7.06–13.77]; p < 0.001). Thirteen (11.4%) survivors had not returned to work due to poor health. There was a decrease in the EQ-5D-5LTM utility score (MD, − 0.19 [− 0.28 to − 0.10]; p < 0.001). At 6 months, 82 of 115 (71.3%) patients reported persistent symptoms. The independent predictors of death or new disability were higher severity of illness and increased frailty. At six months after COVID-19 critical illness, death and new disability was substantial. Over a third of survivors had new disability, which was widespread across all areas of functioning. Clinical trial registration NCT04401254 May 26, 2020.

Pérez-Alba E., Nuzzolo-Shihadeh L., Aguirre-García G.M., Espinosa-Mora J., Lecona-Garcia J.D., Flores-Pérez R.O., Mendoza-Garza M., Camacho-Ortiz A.

We aimed to analyze clinical outcomes from patients with severe COVID-19 pneumonia that received either baricitinib plus dexamethasone or dexamethasone monotherapy.We performed a retrospective comparative study. Data from hospitalized patients with severe COVID-19 pneumonia (saturation

Block B.L., Martin T.M., Boscardin W.J., Covinsky K.E., Mourad M., Hu L.L., Smith A.K.

Some hospitals have faced a surge of patients with COVID-19, while others have not. We assessed whether COVID-19 burden (number of patients with COVID-19 admitted during April 2020 divided by hospital certified bed count) was associated with mortality in a large sample of US hospitals. Our study population included 14,226 patients with COVID-19 (median age 66 years, 45.2% women) at 117 hospitals, of whom 20.9% had died at 5 weeks of follow-up. At the hospital level, the observed mortality ranged from 0% to 44.4%. After adjustment for age, sex, and comorbidities, the adjusted odds ratio for in-hospital death in the highest quintile of burden was 1.46 (95% CI, 1.07-2.00) compared to all other quintiles. Still, there was large variability in outcomes, even among hospitals with a similar level of COVID-19 burden and after adjusting for age, sex, and comorbidities.