Randomized trial of the safety and efficacy of anti-SARS-CoV-2 mAb in the treatment of patients with nosocomial COVID-19 (CATCO-NOS).

Background: Patients with nosocomial acquisition of COVID-19 have poor outcomes but have not been included in therapeutic trials to date. Methods: A pragmatic open-label randomized controlled trial of anti-SARS-CoV-2 monoclonal antibodies (mAb) was performed in hospitalized patients with nosocomial COVID-19 infection in acute care hospitals spanning a provincial health care network. Participants within 5 days of first positive test or symptom onset were randomized to standard of care (SOC) plus a single dose intravenous mAb treatment (bamlanivimab or casirivimab/imdevimab) or SOC alone on a 2:1 basis. The primary study endpoint was the need for invasive mechanical ventilation (IMV) or inpatient mortality by day 60 after randomization. Results: Forty-six participants were enrolled from 13 hospitals between February 14 and October 8, 2021: 31 in the mAb and 15 in the SOC arm. IMV or inpatient mortality up to day 60 occurred in 4 (12.9%) participants in the mAb versus 3 in the SOC arm (20.0%), difference of -7.1% (95% CI -22.5 to 13.4, p = 0.67). The study was terminated early due to lack of equipoise as effectiveness of anti-viral therapies and mAb was published in similar high-risk patient populations. Conclusions: The trial was underpowered to detect meaningful differences given its early termination. The study does highlight the feasibility of undertaking trials in this patient population using a pragmatic approach allowing for trial participation and treatment access across a large health care network and may serve as a template for future designs.

Historique: Les patients qui contractent une COVID-19 nosocomiale ont de mauvais résultats cliniques, mais n'ont pas fait partie des études thérapeutiques jusqu'à présent. Méthodologie: Les chercheurs ont mené une étude randomisée et contrôlée ouverte et pragmatique des anticorps monoclonaux (AcM) anti-SRAS-CoV-2 auprès de patients hospitalisés qui ont contracté une COVID-19 nosocomiale dans les hôpitaux de soins aigus d'un réseau de santé provincial. Dans les cinq jours suivant un premier test positif ou l'apparition des symptômes, les participants ont été divisés de manière randomisée entre la norme des soins (NdS) combinée à une monodose de traitement aux AcM par voie intraveineuse (bamlanivimab ou casirivimab-imdevimab) ou la NdS seule sur une base de deux pour un. Le critère d'évaluation primaire de l'étude était la ventilation mécanique invasive (VMI) ou la mortalité en milieu hospitalier le 60e jour après la randomisation. Résultats: Au total, 46 participants de 13 hôpitaux ont été inclus entre le 14 février et le 8 octobre 2021, soit 31 patients du volet des AcM et 15 du volet de la NdS. La VMI ou la mortalité en milieu hospitalier jusqu'au 60e jour a été observée chez quatre participants au volet des AcM (12,9 %) et trois participants du volet de la NdS (20,0 %), soit une différence de −7,1 % (IC à 95 %, −22,5 à 13,4, p = 0,67). L'étude a été interrompue précocement à cause de l'absence d'équilibre clinique, car des données sur l'efficacité des traitements antiviraux et des AcM ont été publiées au sujet de populations semblables de patients à haut risque. Conclusions: L'échantillon à l'étude était insuffisant pour déceler des différences significatives compte tenu de son interruption précoce. Cette recherche fait ressortir la faisabilité d'études auprès de cette population de patients au moyen d'une approche pragmatique pour y inclure des participants et accéder au traitement dans un vaste réseau de soins et pourrait servir de modèle pour concevoir d'autres études.

Cost-effectiveness of remdesivir plus usual care versus usual care alone for hospitalized patients with COVID-19: an economic evaluation as part of the Canadian Treatments for COVID-19 (CATCO) randomized clinical trial.

BACKGROUND: The role of remdesivir in the treatment of hospitalized patients with COVID-19 remains ill-defined. We conducted a cost-effectiveness analysis alongside the Canadian Treatments for COVID-19 (CATCO) open-label, randomized clinical trial evaluating remdesivir. METHODS: Patients with COVID-19 in Canadian hospitals from Aug. 14, 2020, to Apr. 1, 2021, were randomly assigned to receive remdesivir plus usual care versus usual care alone. Taking a public health care payer's perspective, we collected in-hospital outcomes and health care resource utilization alongside estimated unit costs in 2020 Canadian dollars over a time horizon from randomization to hospital discharge or death. Data from 1281 adults admitted to 52 hospitals in 6 Canadian provinces were analyzed. RESULTS: The total mean cost per patient was $37 918 (standard deviation [SD] $42 413; 95% confidence interval [CI] $34 617 to $41 220) for patients randomly assigned to the remdesivir group and $38 026 (SD $46 021; 95% CI $34 480 to $41 573) for patients receiving usual care (incremental cost -$108 [95% CI -$4953 to $4737], p > 0.9). The difference in proportions of in-hospital deaths between remdesivir and usual care groups was -3.9% (18.7% v. 22.6%, 95% CI -8.3% to 1.0%, p = 0.09). The difference in proportions of incident invasive mechanical ventilation events between groups was -7.0% (8.0% v. 15.0%, 95% CI -10.6% to -3.4%, p = 0.006), whereas the difference in proportions of total mechanical ventilation events between groups was -5.7% (16.4% v. 22.1%, 95% CI -10.0% to -1.4%, p = 0.01). Remdesivir was the dominant intervention (but only marginally less costly, with mildly lower mortality) with an incalculable incremental cost effectiveness ratio; we report results of incremental costs and incremental effects separately. For willingness-to-pay thresholds of $0, $20 000, $50 000 and $100 000 per death averted, a strategy using remdesivir was cost-effective in 60%, 67%, 74% and 79% of simulations, respectively. The remdesivir costs were the fifth highest cost driver, offset by shorter lengths of stay and less mechanical ventilation. INTERPRETATION: From a health care payer perspective, treating patients hospitalized with COVID-19 with remdesivir and usual care appears to be preferrable to treating with usual care alone, albeit with marginal incremental cost and small clinical effects. The added cost of remdesivir was offset by shorter lengths of stay in the intensive care unit and less need for ventilation. STUDY REGISTRATION: ClinicalTrials. gov, no. NCT04330690.

Dysregulation of ACE (Angiotensin-Converting Enzyme)-2 and Renin-Angiotensin Peptides in SARS-CoV-2 Mediated Mortality and End-Organ Injuries.

ACE (angiotensin-converting enzyme)-2 as the target for SARS-CoV-2 also negatively regulates the renin-angiotensin system. Pathological activation of ADAM17 (A disintegrin and metalloproteinase-17) may potentiate inflammation and diminish ACE2-mediated tissue protection through proteolytic shedding, contributing to SARS-CoV-2 pathogenesis. We aim to examine plasma soluble ACE2 and angiotensin profiles in relation to outcomes by enrolling consecutive patients admitted for COVID-19 with baseline blood collection at admission and repeated sampling at 7 days. The primary outcome was 90-day mortality, and secondary outcomes were the incidence of end-organ injuries. Overall, 242 patients were included, the median age was 63 (52-74) years, 155 (64.0%) were men, and 57 (23.6%) patients reached the primary end point. Baseline soluble ACE2 was elevated in COVID-19 but was not associated with disease severity or mortality. In contrast, an upward trajectory of soluble ACE2 at repeat sampling was independently associated with an elevated risk of mortality and incidence of acute myocardial injury and circulatory shock. Similarly, an increase in soluble tumor necrosis factor receptor levels was also associated with adverse outcomes. Plasma Ang I, Ang 1-7 (angiotensin 1-7) levels, and the Ang 1-7/Ang II (angiotensin II) ratio were elevated during SARS-CoV-2 infection related to downregulation of ACE activity at baseline. Moreover, patients having an upward trajectory of soluble ACE2 were characterized by an imbalance in the Ang 1-7/Ang II ratio. The observed dysregulation of ACE2 and angiotensin peptides with disease progression suggest a potential role of ADAM17 inhibition and enhancing the beneficial Ang 1-7/Mas axis to improve outcomes against SARS-CoV-2 infection.

Differential Signature of the Microbiome and Neutrophils in the Oral Cavity of HIV-Infected Individuals.

HIV infection is associated with a wide range of changes in microbial communities and immune cell components of the oral cavity. The purpose of this study was to evaluate the oral microbiome in relationship to oral neutrophils in HIV-infected compared to healthy individuals. We evaluated oral washes and saliva samples from HIV-infected individuals (n=52) and healthy controls (n=43). Using 16S-rRNA gene sequencing, we found differential ß-diversity using Principal Coordinate Analysis (PCoA) with Bray-Curtis distances. The α-diversity analysis by Faith's, Shannon, and observed OTUs indexes indicated that the saliva samples from HIV-infected individuals harbored significantly richer bacterial communities compared to the saliva samples from healthy individuals. Notably, we observed that five species of Spirochaeta including Spirochaetaceae, Spirochaeta, Treponema, Treponema amylovorum, and Treponema azotonutricum were significantly abundant. In contrast, Helicobacter species were significantly reduced in the saliva of HIV-infected individuals. Moreover, we found a significant reduction in the frequency of oral neutrophils in the oral cavity of HIV-infected individuals, which was positively related to their CD4+ T cell count. In particular, we noted a significant decline in CD44 expressing neutrophils and the intensity of CD44 expression on oral neutrophils of HIV-infected individuals. This observation was supported by the elevation of soluble CD44 in the saliva of HIV-infected individuals. Overall, the core oral microbiome was distinguishable between HIV-infected individuals on antiretroviral therapy compared to the HIV-negative group. The observed reduction in oral neutrophils might likely be related to the low surface expression of CD44, resulting in a higher bacterial diversity and richness in HIV-infected individuals.

Galectin-9, a Player in Cytokine Release Syndrome and a Surrogate Diagnostic Biomarker in SARS-CoV-2 Infection.

The outbreak of SARS-CoV-2 infection has enormously impacted our lives. Clinical evidence has implicated the emergence of cytokine release syndrome as the prominent cause of mortality in COVID-19 patients. In this study, we observed massive elevation of plasma Galectin-9 (Gal-9) in COVID-19 patients compared to healthy controls (HCs). By using the receiver operating characteristic (ROC) curve, we found that a baseline of 2,042 pg/ml plasma Gal-9 can differentiate SARS-CoV-2-infected from noninfected individuals with high specificity/sensitivity (95%). Analysis of 30 cytokines and chemokines detected a positive correlation of the plasma Gal-9 with C-reactive protein (CRP) and proinflammatory cytokines/chemokines such as interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), IP-10, MIP-1α, and MCP-1 but an inverse correlation with transforming growth factor ß (TGF-ß) in COVID-19 patients. In agreement, we found enhanced production of IL-6 and TNF-α by monocytes and NK cells of COVID-19 patients once treated with the recombinant human Gal-9 in vitro Also, we observed that although the cell-membrane expression of Gal-9 on monocytes does not change in COVID-19 patients, those with higher Gal-9 expression exhibit an activated phenotype. Furthermore, we noted significant downregulation of surface Gal-9 in neutrophils from COVID-19 patients compared to HCs. Our further investigations indicated that immune activation following SARS-CoV-2 infection results in Gal-9 shedding from neutrophils. The strong correlation of Gal-9 with proinflammatory mediators suggests that inhibition of Gal-9 may severe as a therapeutic approach in COVID-19 infection. Besides, the plasma Gal-9 measurement may be used as a surrogate diagnostic biomarker in COVID-19 patients.IMPORTANCE The outbreak of SARS-CoV-2 infection has enormously impacted our lives. Clinical evidence has implicated the emergence of cytokine release syndrome as the prominent cause of mortality in COVID-19 patients. We observed substantial elevation of the plasma Galectin-9 (Gal-9) in COVID-19 patients compared to healthy controls. Gal-9 is an abundant protein in many immune and nonimmune cells. We found that Gal-9 detection assay can differentiate SARS-CoV-2-infected from noninfected individuals with a specificity/sensitivity of 95%. Importantly, we found a positive correlation of the plasma Gal-9 with a wide range of proinflammatory biomarkers in COVID-19 patients. In agreement, we found enhanced expression and production of such proinflammatory molecules by immune cells of COVID-19 patients once treated with Gal-9 in vitro Our results propose Gal-9 as an important contributing factor in cytokine release syndrome; therefore, Gal-9 inhibition may serve as a beneficial therapeutic approach by suppressing the hyperimmune activation in COVID-19 patients.

The effects of trained observers (dofficers) and audits during a facility-wide COVID-19 outbreak: A mixed-methods quality improvement analysis.

BACKGROUND: In response to a facility-wide COVID-19 outbreak, our tertiary acute care hospital implemented an evidence-based bundle of infection control practices including the use of audits and trained observers "dofficers" to provide real-time constructive feedback. METHODS: We trained furloughed staff to perform the role of dofficer. They offered support and corrective feedback on proper PPE use and completed 21-point audits during a 4-week intervention period. Audits tracked appropriate signage, placement and availability of supplies (equipment), correct PPE use, enhanced environmental cleaning, along with cohorting and social distancing rates. Audit data was used to provide weekly quality improvement reports to units. RESULTS: Nine hundred and sixty two separate audits recorded 36,948 observations, over 7,696 observer-hours. The most common errors were with environmental cleaning and PPE use; the least common were with regards to equipment availability and cohorting and social distancing. Mean error rates decreased from 9.81% to 2.88% (P < .001). The largest reduction, 22.57%, occurred in the category of PPE doffing errors. CONCLUSIONS: Dofficer led audits effectively identified areas for improvement. Feedback through weekly reports and real-time correction of PPE errors by dofficers led to statistically significant improvements; however, error rates remained high. Further research is needed establish if these relationships are causal.

Achievement of hepatitis C cascade of care milestones: a population-level analysis in Alberta, Canada.

OBJECTIVES: Despite highly effective directly acting antiviral (DAA) therapy for hepatitis C virus (HCV), many patients do not receive treatment. We characterized the achievement of cascade of care milestones within 2 years of diagnosis among the Alberta population and evaluated variables associated with engagement at each stage. METHODS: All Albertans with a first-time positive HCV antibody between 2009 and 2014 were included in this retrospective study. We determined which patients received follow-up testing (HCV RNA and HCV genotype), referral to hepatitis specialty care, and antiviral prescription, and achieved SVR within 2 years of diagnosis. Factors associated with achieving cascade milestones were identified by multivariable logistic regression analysis. RESULTS: Of 6154 patients with HCV antibody and complete follow-up, 4238 (68.9%) had HCV RNA testing, 2360 (38.3%) had HCV genotyping, 2096 (34.1%) were assessed by a specialist, 711 (11.6%) were prescribed treatment and 207 (3.4%) achieved SVR within 2 years of diagnosis. Independent variables associated with reduced likelihood of achieving cascade milestones were Indigenous heritage (adjusted odds ratio (AOR) 0.53 (0.41-0.68) for HCV RNA testing), unstable housing (AOR 0.50 (0.32-0.79) for specialist assessment) and alcohol misuse (AOR 0.61 (0.38-0.99) for antiviral prescription). Men, older patients, patients with a higher income and patients with more advanced liver disease were more likely to achieve cascade of care milestones. CONCLUSION: At each stage of patient engagement, opportunities for improvement were identified. Understanding the local cascade of care and factors associated with achieving cascade milestones will help prioritize initiatives to facilitate access to DAA therapy in Alberta.

Long-Term Follow-up and Quantitative Hepatitis B Surface Antigen Monitoring in North American Chronic HBV Carriers.

INTRODUCTION: Quantitative hepatitis B surface antigen (qHBsAg) combined with HBV DNA may be useful for predicting chronic hepatitis B (CHB) activity and nucleoside analogue (NA) response. MATERIAL AND METHODS: In this retrospective cohort study we evaluated qHBsAg levels according to CHB disease phase and among patients on treatment. Random effect logistic regression analysis was used to analyze qHBsAg change with time in the NA-treated cohort. RESULTS: 545 CHB carriers [56% M, median age 48 y (IQR 38-59), 73% Asian] had qHBsAg testing. In the untreated group (44%), 8% were classified as immune tolerant, 10% immune clearance, 40% inactive, and 43% had HBeAg- CHB and the median HBsAg levels were 4.6 (IQR 3.4-4.9), 4.0 (IQR 3.4-4.5), 2.9 (IQR 1.4-3.8), and 3.2 log IU/mL (IQR 2.6-4.0), respectively; p < 0.001. In the NA-treated group (28% entecavir, 68% tenofovir, 4% lamivudine), no significant change in qHBsAg levels occured with time. However, 19% of patients on long-term NA had sustained qHBsAg < 2 log10 IU/mL. CONCLUSION: qHBsAg titers were associated with CHB phase and remained stable in those on long-term NA. A significant number of treated patients had low-level qHBsAg, of which some may be eligible for treatment discontinuation without risk of flare.

One lab finding, 2 vastly different causes.

While both of these patients had eosinophilia, their diagnoses ended up being quite different. What is the best approach to the diagnosis and management of eosinophilia in the ambulatory care setting?

Bone and Joint Infections due to Haemophilus parainfluenzae: Case Report and Review of the Literature.

Haemophilus parainfluenzae is a normal inhabitant of the human respiratory tract. However it is an increasingly recognized pathogen in invasive infections, particularly in the immunocompromised host and where there is disruption of the normal skin or mucosal barriers. We present a case of a 56-year-old female with a history of asplenia who developed H. parainfluenzae septic arthritis of the hip following an intra-articular steroid injection. We also summarize previously reported cases of bone and joint infections caused by H. parainfluenzae.

Factors associated with antiretroviral medication adherence among HIV-positive adults accessing highly active antiretroviral therapy (HAART) in British Columbia, Canada.

BACKGROUND: Among those accessing treatment, highly active antiretroviral therapy (HAART) has transformed HIV into a chronic and manageable condition. However, high levels of adherence are required to derive a sustained, long-term clinical benefit. The aim of this study was to examine the predictors of adherence based on prescription refill among persons on HAART in British Columbia, Canada. METHODS: This study utilizes data collected between July 2007 and January 2010, as part of the Longitudinal Investigations into Supportive and Ancillary health services (LISA) cohort, which is a study of HIV-positive persons who have accessed antiretroviral therapy (ART) in British Columbia. Participants were considered optimally adherent if they were dispensed ≥95% of their prescribed antiretrovirals. RESULTS: Of a total of 566 participants, only 316 (55.8%) were optimally adherent to HAART. Independent predictors of optimal adherence were increasing age (adjusted odds ratio [AOR] = 1.84, 95% confidence interval [CI]: 1.44-2.33), male gender (AOR = 1.68, 95% CI: 1.07-2.64), and being enrolled in a comprehensive adherence assistance program (AOR = 4.26, 95% CI: 2.12-8.54). Having an annual income <$15 000 (AOR = 0.47, 95% CI: 0.31-0.72) and both former and current injection drug use (AOR = 0.46, 95% CI: 0.29-0.73 and AOR = 0.35, 95% CI: 0.20-0.58, respectively) were independently associated with suboptimal (<95%) adherence. CONCLUSIONS: We found that women and people who inject drugs are at increased risk of being suboptimally adherent to HAART. Optimal adherence remains a significant public health and clinical goal in the context of rapidly expanding access to HAART.