Background: Recent studies have demonstrated that Th2 responses have the ability to antagonize Th17 responses. In mouse models of allergic asthma, blockade of Th2-effector cytokines results in elaboration of Th17 responses and associated increases in pulmonary neutrophilia. While these can be controlled by simultaneous blockade of Th17associated effector cytokines, clinical trials of anti-IL-17/IL-17RA blocking therapies have demonstrated increased of risk of bacterial and fungal infections. Identification of minimally effective doses of cytokine-blocking therapies with the goal of reducing the potential emergence of infection-related complications is a translationally relevant goal.Objective: In the current report, we examine whether combined blockade of IL-13 and IL-17A, at individually sub-therapeutic levels, can limit the development of allergic asthma while sparing expression of IL-17A-associated anti-microbial effectors.Methods: House dust mite was given intratracheally to A/J mice. Anti-IL-13 and anti-IL-17A antibodies were administered individually, or concomitantly at sub-therapeutic doses. Airway hyper-reactivity, lung inflammation, magnitude of Th2-and Th17-associated cytokine production and expression of IL-13-and IL-17A-induced genes in the lungs was assessed.Results: Initial dosing studies identified sub-therapeutic levels of IL-13 and IL-17A blocking mAbs that have a limited effect on asthma parameters and do not impair responses to microbial products or infection. Subsequent studies demonstrated that combined sub-therapeutic dosing with IL-13 and IL-17A blocking mAbs resulted in significant improvement in airway hyperresponsiveness (AHR) and expression of IL-13-induced gene expression. Importantly, these doses neither exacerbated nor inhibited production of Th17-associated cytokines, or IL-17A-associated gene expression.
Conclusion: This study suggests that combining blockade of individual Th2 andTh17 effector cytokines, even at individually sub-therapeutic levels, may be sufficient to limit disease development while preserving important anti-microbial pathways. Such a strategy may therefore have reduced potential for adverse events associated with blockade of these pathways.
Background
The COVID-19 pandemic response may unintendedly disrupt multiple public health services, including tuberculosis control programs. We aimed to assess the cascade of care of latent tuberculosis infection (LTBI) in an urban US city during the COVID-19 pandemic response.
Methods
We conducted a retrospective cohort study of adult patients who presented for LTBI evaluation at the Hamilton County Public Health Tuberculosis Clinic in Ohio between 2019 and 2020. We defined 01/2019 to 02/2020 as the pre-COVID-19 response period, and 04/2020 to 12/2020 as the COVID-19 pandemic response period. We reviewed electronic medical records and extracted sociodemographic information, medical history, and follow-up and treatment data to define steps within the LTBI cascade of care. Logistic regressions were used to assess factors associated with LTBI treatment acceptance and completion, adjusted by potential confounders and COVID-19 period.
Results
Data from 312 patients were included. There was a significant decrease in the number of monthly LTBI referrals (median, 18 vs. 8, p=0.02) and LTBI evaluations (median, 17.5 vs. 7, p< 0.01) during COVID-19. There was a decrease in the proportion of immigrants as indication for LTBI testing (30% vs. 9%; p< 0.01), and an increase in LTBI diagnoses based on interferon-gamma release assay (IGRA; 30% vs. 49%; p< 0.01) during COVID-19. The proportion of people who were recommended LTBI treatment was similar before and during COVID-19 (76% vs. 81%, p=0.41), as well as the LTBI treatment acceptance rates (56% vs. 64%, p=0.28), and LTBI treatment completion rates (65% vs. 63%, p=0.85). In multivariate analysis, LTBI treatment acceptance was associated with Hispanic ethnicity, younger age, male sex, IGRA use, no comorbidities, and non-healthcare occupation, independent of COVID-19 period. LTBI treatment completion was associated with taking a rifamycin-containing regimen, independent of COVID-19 period.
Conclusion
We observed a significant decline in the number of monthly LTBI referrals and evaluations during COVID-19. Our findings indicate an unintended negative impact of the COVID-19 response in LTBI screening efforts in our region. LTBI treatment acceptance and completion rates were not affected during COVID-19.
Disclosures
All Authors: No reported disclosures
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