Efficacy of Tocilizumab in Patients Hospitalized with Covid-19.

BACKGROUND: The efficacy of interleukin-6 receptor blockade in hospitalized patients with coronavirus disease 2019 (Covid-19) who are not receiving mechanical ventilation is unclear. METHODS: We performed a randomized, double-blind, placebo-controlled trial involving patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, hyperinflammatory states, and at least two of the following signs: fever (body temperature >38°C), pulmonary infiltrates, or the need for supplemental oxygen in order to maintain an oxygen saturation greater than 92%. Patients were randomly assigned in a 2:1 ratio to receive standard care plus a single dose of either tocilizumab (8 mg per kilogram of body weight) or placebo. The primary outcome was intubation or death, assessed in a time-to-event analysis. The secondary efficacy outcomes were clinical worsening and discontinuation of supplemental oxygen among patients who had been receiving it at baseline, both assessed in time-to-event analyses. RESULTS: We enrolled 243 patients; 141 (58%) were men, and 102 (42%) were women. The median age was 59.8 years (range, 21.7 to 85.4), and 45% of the patients were Hispanic or Latino. The hazard ratio for intubation or death in the tocilizumab group as compared with the placebo group was 0.83 (95% confidence interval [CI], 0.38 to 1.81; P = 0.64), and the hazard ratio for disease worsening was 1.11 (95% CI, 0.59 to 2.10; P = 0.73). At 14 days, 18.0% of the patients in the tocilizumab group and 14.9% of the patients in the placebo group had had worsening of disease. The median time to discontinuation of supplemental oxygen was 5.0 days (95% CI, 3.8 to 7.6) in the tocilizumab group and 4.9 days (95% CI, 3.8 to 7.8) in the placebo group (P = 0.69). At 14 days, 24.6% of the patients in the tocilizumab group and 21.2% of the patients in the placebo group were still receiving supplemental oxygen. Patients who received tocilizumab had fewer serious infections than patients who received placebo. CONCLUSIONS: Tocilizumab was not effective for preventing intubation or death in moderately ill hospitalized patients with Covid-19. Some benefit or harm cannot be ruled out, however, because the confidence intervals for efficacy comparisons were wide. (Funded by Genentech; ClinicalTrials.gov number, NCT04356937.).

Platelet transfusion in critical care: A new method to analyze transfusion practice based on decision time intervals.

BACKGROUND: While prior studies of platelet transfusion in critical care have focused on transfusions given, proper analysis of clinical transfusion practice also requires consideration of the decision not to transfuse. STUDY DESIGN AND METHODS: We introduce a new method to assess transfusion practice based on decision time intervals (DTIs). Each patient's intensive care (ICU) stay was segmented into a series of DTIs defined by a time interval following results of a complete blood count (CBC). We studied the presence of 17 clinical factors during each DTI whether transfusion was given or not. We used a generalized linear mixed model to assess the most influential clinical triggers for platelet transfusion. RESULTS: Among 6125 ICU patients treated between October 2016 and October 2021, we analyzed 39,745 DTIs among patients (n = 2921) who had at least one DTI with thrombocytopenia (≤150,000/µL). We found no association between platelet count and two markers of bleeding: drop in hemoglobin and chest tube drainage. We found that the majority of DTIs were associated with no platelet transfusion regardless of the platelet count; that no specific platelet value triggered transfusion; but rather that multiple clinical factors in conjunction with the platelet count influenced the decision to transfuse. DISCUSSION: DTI analysis represents a new method to assess transfusion practice that considers both transfusions given and not given, and that analyzes clinical circumstances present when decisions regarding transfusion are made. The method is easily adapted to blood components other than platelet transfusions and is easily extended to other ICU and other hospital settings.

Determining the Incidence of Asymptomatic SARS-CoV-2 Among Early Recipients of COVID-19 Vaccines (DISCOVER-COVID-19): A Prospective Cohort Study of Healthcare Workers Before, During and After Vaccination.

The impact of coronavirus disease 2019 vaccination on viral characteristics of breakthrough infections is unknown. In this prospective cohort study, incidence of severe acute respiratory syndrome coronavirus 2 infection decreased following vaccination. Although asymptomatic positive tests were observed following vaccination, the higher cycle thresholds, repeat negative tests, and inability to culture virus raise questions about their clinical significance.

The Landscape of COVID-19 Research in the United States: a Cross-sectional Study of Randomized Trials Registered on ClinicalTrials.Gov.

IMPORTANCE: SARS-CoV-2 has infected over 200 million people worldwide, resulting in more than 4 million deaths. Randomized controlled trials are the single best tool to identify effective treatments against this novel pathogen. OBJECTIVE: To describe the characteristics of randomized controlled trials of treatments for COVID-19 in the United States launched in the first 9 months of the pandemic. Design, Setting, and Participants We conducted a cross-sectional study of all completed or actively enrolling randomized, interventional, clinical trials for the treatment of COVID-19 in the United States registered on www.clinicaltrials.gov as of August 10, 2020. We excluded trials of vaccines and other interventions intended to prevent COVID-19. Main Outcomes and Measures We used descriptive statistics to characterize the clinical trials and the statistical power for the available studies. For the late-phase trials (i.e., phase 3 and 2/3 studies), we compared the geographic distribution of the clinical trials with the geographic distribution of people diagnosed with COVID-19. RESULTS: We identified 200 randomized controlled trials of treatments for people with COVID-19. Across all trials, 87 (43.5%) were single-center, 64 (32.0%) were unblinded, and 80 (40.0%) were sponsored by industry. The most common treatments included monoclonal antibodies (N=46 trials), small molecule immunomodulators (N=28), antiviral medications (N=24 trials), and hydroxychloroquine (N=20 trials). Of the 9 trials completed by August 2020, the median sample size was 450 (IQR 67-1113); of the 191 ongoing trials, the median planned sample size was 150 (IQR 60-400). Of the late-phase trials (N=54), the most common primary outcome was a severity scale (N=23, 42.6%), followed by a composite of mortality and ventilation (N=10, 18.5%), and mortality alone (N=6, 11.1%). Among these late-phase trials, all trials of antivirals, monoclonal antibodies, or chloroquine/hydroxychloroquine had a power of less than 25% to detect a 20% relative risk reduction in mortality. Had the individual trials for a given class of treatments instead formed a single trial, the power to detect that same reduction in mortality would have been greater than 98%. There was large variability in access to trials with the highest number of trials per capita in the Northeast and the lowest in the Midwest. CONCLUSIONS AND RELEVANCE: A large number of randomized trials were launched early in the pandemic to evaluate treatments for COVID-19. However, many trials were underpowered for important clinical endpoints and substantial geographic disparities were observed, highlighting the importance of improving national clinical trial infrastructure.

Lung function and atherosclerosis: a cross-sectional study of multimorbidity in rural Uganda.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a leading cause of global mortality. In high-income settings, the presence of cardiovascular disease among people with COPD increases mortality and complicates longitudinal disease management. An estimated 26 million people are living with COPD in sub-Saharan Africa, where risk factors for co-occurring pulmonary and cardiovascular disease may differ from high-income settings but remain uncharacterized. As non-communicable diseases have become the leading cause of death in sub-Saharan Africa, defining multimorbidity in this setting is critical to inform the required scale-up of existing healthcare infrastructure. METHODS: We measured lung function and carotid intima media thickness (cIMT) among participants in the UGANDAC Study. Study participants were over 40 years old and equally divided into people living with HIV (PLWH) and an age- and sex-similar, HIV-uninfected control population. We fit multivariable linear regression models to characterize the relationship between lung function (forced expiratory volume in one second, FEV1) and pre-clinical atherosclerosis (cIMT), and evaluated for effect modification by age, sex, smoking history, HIV, and socioeconomic status. RESULTS: Of 265 participants, median age was 52 years, 125 (47%) were women, and 140 (53%) were PLWH. Most participants who met criteria for COPD were PLWH (13/17, 76%). Median cIMT was 0.67 mm (IQR: 0.60 to 0.74), which did not differ by HIV serostatus. In models adjusted for age, sex, socioeconomic status, smoking, and HIV, lower FEV1 was associated with increased cIMT (ß = 0.006 per 200 mL FEV1 decrease; 95% CI 0.002 to 0.011, p = 0.01). There was no evidence that age, sex, HIV serostatus, smoking, or socioeconomic status modified the relationship between FEV1 and cIMT. CONCLUSIONS: Impaired lung function was associated with increased cIMT, a measure of pre-clinical atherosclerosis, among adults with and without HIV in rural Uganda. Future work should explore how co-occurring lung and cardiovascular disease might share risk factors and contribute to health outcomes in sub-Saharan Africa.

Utility of Hypertonic Saline and Diazepam in COVID-19-Related Hydroxychloroquine Toxicity.

BACKGROUND: Hydroxychloroquine (HCQ) poisoning is a life-threatening but treatable toxic ingestion. The scale of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (COVID-19) and the controversial suggestion that HCQ is a treatment option have led to a significant increase in HCQ use. HCQ poisoning should be at the top-of-mind for emergency providers in cases of toxic ingestion. Treatment for HCQ poisoning includes sodium bicarbonate, epinephrine, and aggressive electrolyte repletion. We highlight the use of hypertonic saline and diazepam. CASE REPORT: We describe the case of a 37-year-old man who presented to the emergency department after the ingestion of approximately 16 g of HCQ tablets (initial serum concentration 4270 ng/mL). He was treated with an epinephrine infusion, hypertonic sodium chloride, high-dose diazepam, sodium bicarbonate, and aggressive potassium repletion. Persistent altered mental status necessitated intubation, and he was managed in the medical intensive care unit until his QRS widening and QTc prolongation resolved. After his mental status improved and it was confirmed that his ingestion was not with the intent to self-harm, he was discharged home with outpatient follow-up. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: For patients presenting with HCQ overdose and an unknown initial serum potassium level, high-dose diazepam and hypertonic sodium chloride should be started immediately for the patient with widened QRS. The choice of hypertonic sodium chloride instead of sodium bicarbonate is to avoid exacerbating underlying hypokalemia which may in turn potentiate unstable dysrhythmia. In addition, early intubation should be a priority in vomiting patients because both HCQ toxicity and high-dose diazepam cause profound sedation.

Female sex and cardiovascular disease risk in rural Uganda: a cross-sectional, population-based study.

BACKGROUND: Sex-based differences in cardiovascular disease (CVD) burden are widely acknowledged, with male sex considered a risk factor in high-income settings. However, these relationships have not been examined in sub-Saharan Africa (SSA). We aimed to apply the American Heart Association (AHA) ideal cardiovascular health (CVH) tool modified by the addition of C-reactive protein (CRP) to examine potential sex-based differences in the prevalence of CVD risk in rural Uganda. METHODS: In a cross-sectional study nested within a population-wide census, 857 community-living adults completed physical and laboratory-based assessments to calculate individual ideal CVH metrics including an eight category for CRP levels. We summarized sex-specific ideal CVH indices, fitting ordinal logistic regression models to identify correlates of improving CVH. As secondary outcomes, we assessed subscales of ideal CVH behaviours and factors. Models included inverse probability of sampling weights to determine population-level estimates. RESULTS: The weighted-population mean age was 39.2 (1.2) years with 52.0 (3.7) % females. Women had ideal scores in smoking (80.4% vs. 68.0%; p < 0.001) and dietary intake (26.7% vs. 16.8%; p = 0.037) versus men, but the opposite in body mass index (47.3% vs. 84.4%; p < 0.001), glycated hemoglobin (87.4% vs. 95.2%; p = 0.001), total cholesterol (80.2% vs. 85.0%; p = 0.039) and CRP (30.8% vs. 49.7%; p = 0.009). Overall, significantly more men than women were classified as having optimal cardiovascular health (6-8 metrics attaining ideal level) (39.7% vs. 29.0%; p = 0.025). In adjusted models, female sex was correlated with lower CVH health factors sub-scales but higher ideal CVH behaviors. CONCLUSIONS: Contrary to findings in much of the world, female sex in rural SSA is associated with worse ideal CVH profiles, despite women having better indices for ideal CVH behaviors. Future work should assess the potential role of socio-behavioural sex-specific risk factors for ideal CVH in SSA, and better define the downstream consequences of these differences.

Personal carbon monoxide exposure, respiratory symptoms, and the potentially modifying roles of sex and HIV infection in rural Uganda: a cohort study.

BACKGROUND: Most of the global burden of pollution-related morbidity and mortality is believed to occur in resource-limited settings, where HIV serostatus and sex may influence the relationship between air pollution exposure and respiratory morbidity. The lack of air quality monitoring networks in these settings limits progress in measuring global disparities in pollution-related health. Personal carbon monoxide monitoring may identify sub-populations at heightened risk for air pollution-associated respiratory morbidity in regions of the world where the financial cost of air quality monitoring networks is prohibitive. METHODS: From September 2015 through May 2017, we measured 48-h ambulatory carbon monoxide (CO) exposure in a longitudinal cohort of HIV-infected and uninfected adults in rural southwestern Uganda. We fit generalized mixed effects models to identify correlates of CO exposure exceeding international air quality thresholds, quantify the relationship between CO exposure and respiratory symptoms, and explore potential effect modification by sex and HIV serostatus. RESULTS: Two hundred and sixty study participants completed 419 sampling periods. Personal CO exposure exceeded international thresholds for 50 (19%) participants. In covariate-adjusted models, living in a home where charcoal was the main cooking fuel was associated with CO exposure exceeding international thresholds (adjusted odds ratio [AOR] 11.3, 95% confidence interval [95%CI] 4.7-27.4). In sex-stratified models, higher CO exposure was associated with increased odds of respiratory symptoms among women (AOR 3.3, 95%CI 1.1-10.0) but not men (AOR 1.3, 95%CI 0.4-4.4). In HIV-stratified models, higher CO exposure was associated with increased odds of respiratory symptoms among HIV-infected (AOR 2.5, 95%CI 1.01-6.0) but not HIV-uninfected (AOR 1.4, 95%CI 0.1-14.4) participants. CONCLUSIONS: In a cohort in rural Uganda, personal CO exposure frequently exceeded international thresholds, correlated with biomass exposure, and was associated with respiratory symptoms among women and people living with HIV. Our results provide support for the use of ambulatory CO monitoring as a low-cost, feasible method to identify subgroups with heightened vulnerability to pollution-related respiratory morbidity in resource-limited settings and identify subgroups that may have increased susceptibility to pollution-associated respiratory morbidity.

Smoking cessation after engagement in HIV care in rural Uganda.

People living with HIV (PLWH) are more likely to smoke compared to HIV-uninfected counterparts, but little is known about smoking behaviors in sub-Saharan Africa. To address this gap in knowledge, we characterized smoking cessation patterns among people living with HIV (PLWH) compared to HIV-uninfected individuals in rural Uganda. PLWH were at least 40 years of age and on antiretroviral therapy for at least three years, and HIV-uninfected individuals were recruited from the clinical catchment area. Our primary outcome of interest was smoking cessation, which was assessed using an adapted WHO STEPS smoking questionnaire. We fit Cox proportional hazards models to compare time to smoking cessation between PLWH pre-care, PLWH in care, and HIV-uninfected individuals. We found that, compared to HIV-uninfected individuals, PLWH in care were less likely to have ever smoked (40% vs. 49%, p = 0.04). The combined sample of 267 ever-smokers had a median age of 56 (IQR 49-68), 56% (n = 150) were male, and 26% (n = 70) were current smokers. In time-to-event analyses, HIV-uninfected individuals and PLWH prior to clinic enrollment ceased smoking at similar rates (HR 0.8, 95% CI 0.5-1.2). However, after enrolling in HIV care, PLWH had a hazard of smoking cessation over twice that of HIV-uninfected individuals and three times that of PLWH prior to enrollment (HR 2.4, 95% CI 1.3-4.6, p = 0.005 and HR 3.0, 95% CI 1.6-5.5, p = 0.001, respectively). In summary, we observed high rates of smoking cessation among PLWH after engagement in HIV care in rural Uganda. While we hypothesize that greater access to primary care services and health counseling might contribute, future studies should better investigate the mechanism of this association.

HIV Infection, Pulmonary Tuberculosis, and COPD in Rural Uganda: A Cross-Sectional Study.

PURPOSE: HIV is associated with chronic obstructive pulmonary disease (COPD) in high resource settings. Similar relationships are less understood in low resource settings. We aimed to estimate the association between HIV infection, tuberculosis, and COPD in rural Uganda. METHODS: The Uganda Non-communicable Diseases and Aging Cohort study observes people 40 years and older living with HIV (PLWH) on antiretroviral therapy, and population-based HIV-uninfected controls in rural Uganda. Participants completed respiratory questionnaires and post-bronchodilator spirometry. RESULTS: Among 269 participants with spirometry, median age was 52 (IQR 48-55), 48% (n = 130) were ever-smokers, and few (3%, n = 9) reported a history of COPD or asthma. All participants with prior tuberculosis (7%, n = 18) were PLWH. Among 143 (53%) PLWH, median CD4 count was 477 cells/mm3 and 131 (92%) were virologically suppressed. FEV1 was lower among older individuals (- 0.5%pred/year, 95% CI 0.2-0.8, p < 0.01) and those with a history of tuberculosis (- 14.4%pred, 95% CI - 23.5 to - 5.3, p < 0.01). COPD was diagnosed in 9 (4%) participants, eight of whom (89%) were PLWH, six of whom (67%) had a history of tuberculosis, and all of whom (100%) were men. Among 287 participants with complete symptom questionnaires, respiratory symptoms were more likely among women (AOR 3.9, 95% CI 2.0-7.7, p < 0.001) and those in homes cooking with charcoal (AOR 3.2, 95% CI 1.4-7.4, p = 0.008). CONCLUSION: In rural Uganda, COPD may be more prevalent among PLWH, men, and those with prior tuberculosis. Future research is needed to confirm these findings and evaluate their broader impacts on health.

Ambient PM2.5 temporal variation and source apportionment in Mbarara, Uganda.

Air pollution is the leading environmental cause of death globally, and most mortality occurs in resource-limited settings such as sub-Saharan Africa. The African continent experiences some of the worst ambient air pollution in the world, yet there are relatively little African data characterizing ambient pollutant levels and source admixtures. In Uganda, ambient PM2.5 levels exceed international health standards. However, most studies focus only on urban environments and do not characterize pollutant sources. We measured daily ambient PM2.5 concentrations and sources in Mbarara, Uganda from May 2018 through February 2019 using Harvard impactors fitted with size-selective inlets. We compared our estimates to publicly available levels in Kampala, and to World Health Organization (WHO) air quality guidelines. We characterized the leading PM2.5 sources in Mbarara using x-ray fluorescence and positive matrix factorization. Daily PM2.5 concentrations were 26.7 µg m-3 and 59.4 µg m-3 in Mbarara and Kampala, respectively (p<0.001). PM2.5 concentrations exceeded WHO guidelines on 58% of days in Mbarara and 99% of days in Kampala. In Mbarara, PM2.5 was higher in the dry as compared to the rainy season (30.8 vs 21.3, p<0.001), while seasonal variation was not observed in Kampala. PM2.5 concentrations did not vary on weekdays versus weekends in either city. In Mbarara, the six main ambient PM2.5 sources identified included (in order of abundance): traffic-related, biomass and secondary aerosols, industry and metallurgy, heavy oil and fuel combustion, fine soil, and salt aerosol. Our findings confirm that air quality in southwestern Uganda is unsafe and that mitigation efforts are urgently needed. Ongoing work focused on improving air quality in the region may have the greatest impact if focused on traffic and biomass-related sources.

A SMART Approach to Retention in HIV Care.

The Joint United Nation Programme on HIV/AIDS (UNAIDS) has aims that, by 2025, 95% of people with HIV should know their HIV status, 95% of people who receive a diagnosis should be receiving antiretroviral therapy (ART), and 95% of people with HIV and receiving ART should be virally suppressed.1 The challenge and opportunity of the UNAIDS 95-95-95 goal are to reach people outside standard clinic-based services.2 However, after ART is initiated, retention in care is a challenge, with only 67% of persons continuing to receive ART after 5 years.3.

COPD in People with HIV: Epidemiology, Pathogenesis, Management, and Prevention Strategies.

Chronic obstructive pulmonary disease (COPD) is a progressive respiratory disorder characterized by airflow limitation and persistent respiratory symptoms. People with HIV (PWH) are particularly vulnerable to COPD development; PWH have demonstrated both higher rates of COPD and an earlier and more rapid decline in lung function than their seronegative counterparts, even after accounting for differences in cigarette smoking. Factors contributing to this HIV-associated difference include chronic immune activation and inflammation, accelerated aging, a predilection for pulmonary infections, alterations in the lung microbiome, and the interplay between HIV and inhalational toxins. In this review, we discuss what is known about the epidemiology and pathobiology of COPD among PWH and outline screening, diagnostic, prevention, and treatment strategies.

Factors Associated with Chronic Obstructive Pulmonary Disease: A Hospital-Based Case-Control Study.

Purpose: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. In this paper, we determined risk factors for COPD among patients presenting to pulmonology and medical outpatients' clinics of Mbarara Regional Referral Hospital (MRRH). Methods: In this case-control study, cases were patients with COPD confirmed by spirometry and controls were those with normal spirometry. The two groups were matched by age and gender. Results: We enrolled 123 participants, of whom 41 were cases and 82 controls. A total of 51 women (41.5%) and 72 men (58.5%), of whom 25 were male cases (61%) and 47 were male controls (57%), were included. The results of our study suggest that the variables associated with the presence of COPD among participants attending MRRH were a history of having ever smoked and a prior history of atopy. This brings to our attention the fact that smoking remains a major risk factor for COPD in this setting, just as it is in developed countries. Conclusion: Our study has shown that the factors associated with COPD are smoking and a history of atopy. Patients with a history of asthma and tuberculosis are also probably more likely to develop COPD than those without similar disease conditions.