ABSTRACT
Background: Granulocyte-macrophage colony-stimulating factor (GM-CSF), a myeloid cell growth factor and pro-inflammatory cytokine, may drive the overactive host immune response in COVID-19. We conducted a clinical trial assessing the anti-GM-CSF monoclonal antibody gimsilumab for hyperinflammatory COVID-19 pneumonia (BREATHE). Here, we report a pre-specified subgroup analysis demonstrating a signal of benefit in patients invasively ventilated at baseline. Methods: BREATHE (NCT04351243) was a double-blind, randomized, placebo-controlled trial at 21 US locations. Patients were randomized 1:1 to receive two doses of IV gimsilumab or placebo one week apart. The study included hospitalized COVID-19 patients with hyperinflammation (CRP ≥50 mg/L or ferritin ≥1,000 ng/mL) and pre-ARDS lung injury or ARDS. The primary endpoint was all cause mortality at day 43, and key secondary outcomes assessed ventilator use and hospitalization length. Results: 225 patients were randomized and dosed. 41 patients were invasively ventilated at baseline. Steroid use and baseline characteristics were generally balanced across study arms in this subgroup. Ventilated patients treated with gimsilumab demonstrated improvements over placebo on the primary and key secondary endpoints (Table 1). Contrasting the placebo group, gimsilumabtreated patients did not experience a sharp rise in NT-proBNP, a marker of heart failure, through day 43 (Figure 1). Conclusions: GM-CSF inhibition may be therapeutic in ventilated COVID-19 patients through a neurohormonal mechanism. More studies are needed to assess the role of GM-CSF in COVID-19-associated cardiomyopathy, volume status, and ARDS.
ABSTRACT
Background: Nonalcoholic fatty liver disease (NAFLD) is characterized by macrovesicular hepatic steatosis occurring in the absence of significant alcohol consumption or identifiable secondary causes of hepatic lipid accumulation. Estimated prevalence of pediatric NAFLD in the United States has increased from 3.8% in 1988-1994 to 10% -12 % in 2007-2018. Pediatric obesity rates have also risen, with a prevalence among adolescents 12-19 years of 21% in 2018. Cognitively, recent studies have shown an association between NAFLD and deficits in executive functioning and visuospatial domains;the etiology is uncertain but may relate to increase in pro-inflammatory cytokines and microvascular changes altering neuronal functioning and cerebral perfusion. Studies associating NAFLD and decreased cerebral volume even after controlling for cardiometabolic risk factors suggest hepatic steatosis can influence brain development. Objective: To investigate the potential association between NAFLD and neurocognitive and social/emotional health in adolescents. Methods: Study of three groups comprised of a convenience-based sample of participants, 12 to 17 years of age, recruited from an outpatient pediatric gastroenterology clinic. NAFLD Group (n=15) included youth with BMI ≥ 95th% for age/sex, hepatic ultrasound with increased echogenicity compatible with hepatic steatosis, and ALT > 2 times upper limit of normal. Elevated BMI Group (n=16) included youth with BMI ≥ 95th% for age/sex and normal ALT. Non-obese Control Group (n=15) included youth with BMI <95th % for age/ and sex normal ALT. The study included subjects proficient in English and English or Spanish speaking parent/legal guardian available to participate in the consent process. Exclusion criteria included individuals with documented causes of liver disease (e.g., known hepatotoxic medications, autoimmune hepatitis, hemachromatosis, viral hepatitis, rheumatalogic diseases), or treatment with combined hormonal contraceptives, antipsychotic or diabetic medications. Using the NIH Toolbox iPad app, subjects were administered the Sadness, Emotional Support, & Anxiety self-report measures and three performance-based cognitive tasks: Picture Vocabulary Test, Flanker Inhibitory Control and Attention Test, and Dimensional Change Card Sort Test. Statistical analyses of primary outcome measures included one-way ANOVAs, unpaired Student's t-tests, and Pearson correlations to assess relationships between dependent and independent variables. Results: No significant group differences for demographics, social/emotional outcomes, vocabulary test, or dimensional card sort test were observed. ANOVA of the Flanker Test of Inhibition and Attention was significant (p= 0.047), and post-hoc t-tests revealed Elevated BMI group scored significantly lower than the non-obese controls (p=0.03). Pearson correlation analysis of the total study sample revealed a significant inverse relationship between BMI and Flanker Test (r= -0.38, p <0.001). Exploratory analysis revealed a significant increase in BMI of study subjects enrolled following onset of COVID-19 pandemic (n=22) compared to subjects enrolled pre-pandemic (n=23), p= 0.03. Conclusions: We found no significant difference in social/emotional health or cognitive functioning between adolescents with NAFLD and those without NAFLD from our pediatric GI clinic. However, adolescents with elevated BMI (without NAFLD) performed significantly below non-obese controls on a measure of attention and inhibition. We also found a significant inverse relationship between BMI and attentional processing and inhibition for our overall adolescent sample. These results are consistent with studies reporting lower cognitive function in obese adults and improved neurocognitive outcomes in adults following bariatric surgery. Studies with children and adolescents are limited but our data support findings from a previous adolescent study citing a negative correlation between elevated BMI and cognition. Our study adds to a growing body of research in pediatric populations. tudy limitations include potential impact of confounding variables, namely the environment in which the cognitive tests were administered -a busy outpatient GI clinic- as well as possible inclusion of undiagnosed NAFLD patients in the elevated BMI group, as our study included a mix of both newly referred patients and established patients. Interestingly, we must also consider and further explore the potential impact of COVID-19 pandemic, as across all three of our study groups, pre-pandemic patients had a lower BMI compared to patients enrolled during the pandemic.
ABSTRACT
A portion of those infected with SARS-CoV-2 shed the virus and its genetic material in respiratory fluids, saliva, urine, and stool, thus giving the potential to monitor for infections via wastewater. Wastewater surveillance efforts to date have largely assumed that stool shedding has been the primary source of SARS-CoV-2 RNA signal; however, there are increasing questions about the possible contribution of other shedding routes, with implications for wastewater surveillance design and feasibility. In this study we used clinical SARS-CoV-2 RNA shedding data and a Monte Carlo framework to assess the relative contribution of various shedding routes on SARS-CoV-2 RNA loads in wastewater. Stool shedding dominated total SARS-CoV-2 RNA load for community-level surveillance, with mean contributions more than two orders of magnitude greater than other shedding routes. However, RNA loads were more nuanced when considering building-level monitoring efforts designed to identify a single infected individual, where any shedding route could plausibly contribute a detectable signal. The greatest source of model variability was viral load in excreta, suggesting that future modeling efforts may be improved by incorporating specific modeling scenarios with precise SARS-CoV-2 shedding data, and beyond that wastewater surveillance must continue to account for large variability during data analysis and reporting. Importantly, the findings imply that wastewater surveillance at finer spatial scales is not entirely dependent on shedding via feces for sensitive detection of infections thus enlarging the potential use cases of wastewater as a non-intrusive surveillance methodology.