Urinary leukotriene E4 and prostaglandin D2 metabolites increase in adult and childhood severe asthma characterized by type-2 inflammation

RATIONALE: New approaches are needed to guide personalized treatment of asthma. OBJECTIVE: To test if urinary eicosanoid metabolites can direct asthma phenotyping. METHODS: Urinary metabolites of prostaglandins (PGs), cysteinyl-leukotrienes (LTs) and isoprostanes were quantified in the Unbiased Biomarkers for the Prediction of Respiratory Diseases Outcomes (U-BIOPRED) study including 86 adults with mild-to-moderate asthma (MMA), 411 with severe asthma (SA), and 100 healthy controls (HC). Validation was performed internally in 302 SA subjects followed-up after 12-18 months, and externally in 95 adolescents with asthma. MEASUREMENT AND MAIN RESULTS: Metabolite levels in HC were unrelated to age, BMI and sex, except for the PGE2-pathway. Eicosanoid levels were generally greater in MMA relative to HC, with further elevations in SA. However, PGE2-metabolite levels were either the same or lower in male non-smoking asthmatics as in HC. Metabolite levels were unchanged in asthmatics adherent to oral corticosteroid treatment as documented by urinary prednisolone detection, whereas SA treated with omalizumab had lower levels of LTE4 and the PGD2 metabolite 2,3-dinor-11β-PGF2α. High levels of LTE4 and PGD2-metabolites were associated with lower lung-function, and increased levels of exhaled nitric oxide and eosinophil markers in blood, sputum and urine in U-BIOPRED and in adolescents with asthma. These type-2 (T2) asthma associations were reproduced in the follow-up visit of the U-BIOPRED study, and found to be as sensitive to detect T2 inflammation as the established biomarkers. CONCLUSIONS: Monitoring of urinary eicosanoids can identify T2 asthma and introduces a new non-invasive approach for molecular phenotyping of adult and adolescent asthma. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)

A Randomized Trial of a Composite T2-Biomarker Strategy Adjusting Corticosteroid Treatment in Severe Asthma: A <em>Post Hoc</em> Analysis by Sex

\ua9 2023 The AuthorsBackground: Approximately 5% to 10% of patients with asthma have severe disease, with a consistent preponderance in females. Current asthma guidelines recommend stepwise treatment to achieve symptom control with no differential treatment considerations for either sex. Objective: To examine whether patient sex affects outcomes when using a composite T2-biomarker score to adjust corticosteroid (CS) treatment in patients with severe asthma compared with standard care. Methods: This is a post hoc analysis, stratifying patient outcomes by sex, of a 48-week, multicenter, randomized controlled clinical trial comparing a biomarker-defined treatment algorithm with standard care. The primary outcome was the proportion of patients with a reduction in CS treatment (inhaled and oral corticosteroids). Secondary outcomes included exacerbation rates, hospital admissions, and lung function. Results: Of the 301 patients randomized, 194 (64.5%) were females and 107 (35.5%) were males. The biomarker algorithm led to a greater proportion of females being on a lower CS dose versus standard care, which was not seen in males (effect estimate: females, 3.57; 95% CI, 1.14-11.18 vs males, 0.54; 95% CI, 0.16-1.80). In T2-biomarker–low females, reducing CS dose was not associated with increased exacerbations. Females scored higher in all domains of the 7-item Asthma Control Questionnaire, apart from FEV1, but with no difference when adjusted for body mass index/anxiety and/or depression. Dissociation between symptoms and T2 biomarkers were noted in both sexes, with a higher proportion of females being symptom high/T2-biomarker low (22.8% vs 15.6%; P = .0002), whereas males were symptom low/T2-biomarker high (22.3% vs 11.4%; P &lt; .0001). Conclusions: This exploratory post hoc analysis identified that females achieved a greater benefit from biomarker-directed CS optimization versus symptom-directed treatment

A randomised trial of a T2-composite-biomarker strategy adjusting corticosteroidtreatment in severe asthma, a post- hoc analysis by sex.

Background Approximately 5–10% of patients with asthma have severe disease with a consistent preponderance in females. Current asthma guidelines recommend stepwise treatment to achieve symptom control with no differential treatment considerations for either sex. Objectives To examine whether patient sex affects outcomes when using a composite T2-biomarker score to adjust corticosteroid treatment in patients with severe asthma compared to standard care. Methods Post-hoc analysis stratifying patient outcomes by sex of a 48-week, multicentre, randomised controlled clinical trial comparing a biomarker-defined treatment algorithm with standard care. The primary outcome was the proportion of patients with a reduction in corticosteroid treatment (inhaled (ICS) and oral (OCS) corticosteroids). Secondary outcomes included exacerbation rates, hospital admissions and lung function. Results Of 301 patients randomised; 194 (64.5%) were females and 107 (35.5%) were males. The biomarker algorithm led to a greater proportion of females being on a lower corticosteroid dose vs standard care which was not seen in males (effects estimate females: 3.57, 95% CI: 1.14, 11.18 vs. males 0.54, 95% CI: 0.16, 1.80). In T2-biomarker low females, reducing corticosteroid dose was not associated with increased exacerbations. Females scored higher in all ACQ-7 domains, but with no difference when adjusted for BMI/ anxiety and/or depression. Dissociation between symptoms and T2-biomarkers were noted in both sexes, with a higher proportion of females being symptom high/T2-biomarker low (22.8% vs. 15.6%; p=0.0002), whereas males were symptom low/T2-biomarker high (11.4% vs. 22.3%; p Conclusion This exploratory post-hoc analysis identified females achieved a greater benefit from biomarker-directed corticosteroid optimisation versus symptom-directed treatment.</p

Myocardial Gene Expression Profiling to Predict and Identify Cardiac Allograft Acute Cellular Rejection: The GET-Study

Serial invasive endomyocardial biopsies (EMB) remain the gold standard for acute cellular rejection (ACR) diagnosis. However histological grading has several limitations. We aimed to explore the value of myocardial Gene Expression Profiling (GEP) for diagnosing and identifying predictive biomarkers of ACR.A case-control study nested within a retrospective heart transplant patients cohort included 126 patients with median (IQR) age 50 (41-57) years and 111 (88%) males. Among 1157 EMB performed, 467 were eligible (i.e, corresponding to either ISHLT grade 0 or ≥3A), among which 36 were selected for GEP according to the grading: 0 (CISHLT, n = 13); rejection ≥3A (RISHLT, n = 13); 0 one month before ACR (BRISHLT, n = 10).We found 294 genes differentially expressed between CISHLT and RISHLT, mainly involved in immune activation, and inflammation. Hierarchical clustering showed a clear segregation of CISHLT and RISHLT groups and heterogeneity of GEP within RISHLT. All EMB presented immune activation, but some RISHLT EMB were strongly subject to inflammation, whereas others, closer to CISHLT, were characterized by structural modifications with lower inflammation level. We identified 15 probes significantly different between BRISHLT and CISHLT, including the gene of the muscular protein TTN. This result suggests that structural alterations precede inflammation in ACR. Linear Discriminant Analysis based on these 15 probes was able to identify the histological status of every 36 samples.Myocardial GEP is a helpful method to accurately diagnose ACR, and predicts rejection one month before its histological occurrence. These results should be considered in cardiac allograft recipients' care