Background:Chronic disease in young adults is associated with poor healthcare engagement, poor health-related outcomes and high-risk behaviours. However, there are minimal data regarding the outcomes of young adults with severe asthma. In this study we aimed to assess asthma characteristics and outcomes in young adults aged 16-25 years compared to older age groups. Methods:Using the UK Severe Asthma Registry, we undertook a retrospective observational analysis comparing baseline assessment and annual follow-up data in young adults against other age groups. We investigated differences in medication use, healthcare utilisation, exacerbation rates, lung function, airway inflammation, quality of life and comorbidities using univariate and multivariable analysis. Results:Registry data from 2812 participants was included, including 236 (8.4%) young adults. This age group had the lowest levels of adherence and highest fractional exhaled nitric oxide, highest rates of emergency department attendance and hospitalisation, the second highest rate of intubation, and most frequently reported anxiety and depression. Data from the first annual review confirmed this age group still had the highest rate of emergency department attendance, hospitalisation and the smallest improvement in asthma control. Conclusion:In this cohort, young adults with severe asthma were at a higher risk of poor clinical outcomes when compared to other age groups. The higher rates of emergency treatment and admission and higher levels of airway inflammation suggest that they may experience more severe exacerbations, the reasons for which require further investigation. If a causative link is supported by further work, these findings suggest that age-specific management strategies should be explored towards improving clinical outcomes.

BACKGROUND:Benralizumab, an interleukin-5 receptor α antagonist, depletes blood eosinophils, reducing exacerbations of severe asthma by approximately 50% versus placebo. In this study, we aimed to characterise mechanisms underlying exacerbations occurring on benralizumab. METHODS:BenRex, a multicentre, prospective cohort study, recruited participants meeting national licensing criteria for benralizumab for asthma. The study was conducted in 15 UK severe asthma centres. After collecting baseline data, open-label benralizumab was administered for 12-18 months. At exacerbation, participants attended for medical review before initiating treatment, fractional exhaled nitric oxide (FeNO), spirometry, asthma control questionnaire, and blood and sputum sampling. FINDINGS:Between Sept 30, 2019, and April 23, 2024, 121 exacerbation events were assessed in 156 individuals. 90 participants (58%) were female and 66 (42%) were male; 147 (94%) of participants identified as White. Median blood eosinophil counts at exacerbation were 0 (IQR 0-0) cells per μL. Airway neutrophilia was present in 55% of exacerbations where sputum was available (27/49). Median C-reactive protein (CRP) increased from 3·00 mg/L (1·00-6·00) at baseline to 9·00 mg/L (3·00-17·00) at exacerbation (p=0·0067). Clinically relevant viral pathogens were seen in eight (20·5%) of 39 sputum samples; although viruses were detected in 22 (56·4%) of 39 samples. Influenza A, metapneumovirus, and rhinovirus were the most common viral pathogens (each found in 2 [5·1%] of 39 samples). New acquisition of Moraxella catarrhalis (3 [13·6%] of 22), Haemophilus influenzae (4 [18·2%] of 22), and Streptococcus pneumoniae (2 [9·1%] of 22) occurred. DNA-neutrophil elastase complexes (p=0·0080) and azurocidin-1 (p=0·012) concentrations rose from baseline to exacerbation. FeNO was ≥50 parts per billion in 56 (50·5%) of 111 assessed exacerbations and was associated with reduced odds of bacterial detection. FeNO did not correlate with CRP or sputum neutrophils. INTERPRETATION:Our findings suggested that eosinophilic inflammation is not involved in exacerbations when a patient is being treated with benralizumab. Airway neutrophilia, viral pathogens, and alteration of the sputum microbiome point to infection as the most prominent causes of exacerbations. This observation should improve precision management of asthma exacerbations occurring despite treatment with benralizumab. FUNDING:AstraZeneca.

BACKGROUND:The aim of biologic therapies in severe asthma is inhibition of type 2 (T2) inflammatory pathways. OBJECTIVE:We hypothesized that patients who achieve complete suppression of IL-5 and IL-4/IL-13 pathways with biologic therapy (FeNO <20 ppb and blood eosinophil count <0.15 × 109, considered biological remission) would have better outcomes than patients with incomplete suppression of T2 biology. METHODS:This was a retrospective analysis of patients with severe asthma in the United Kingdom Severe Asthma Registry who met strict national access criteria for biologics. Characteristics before the biologic and at annual review were compared across biologic remission (BR) and non-BR. RESULTS:Of 778 patients, 148 (19%) had BR and 630 (81%) non-BR. Biologic remission did not confer additional benefit in exacerbation reduction, oral steroid exposure, lung function improvement, symptom improvement, or T2 biomarker reduction. The BR cohort was less T2 high before commencing biologics. Long disease duration (adjusted odds ratio [adjOR] = 1.96; 95% CI, 1.17-3.28), macrolide therapy (adjOR = 2.08; 95% CI, 1.17-3.71), and smoking history (adjOR = 1.63; 95% CI, 1.11-2.39) were positive predictors of BR, whereas higher T2 biomarkers predicted non-BR. However, blood eosinophil count and FeNO both had a negative correlation with lung function. CONCLUSION:Patients who achieve BR do not have superior outcomes compared with those who do not achieve BR. Biologic remission denotes a cohort of patients with a lower burden of T2 disease and additional factors driving disease severity. However, suppression of T2 biology is important for lung function gain. Prospective evaluation of treatment strategies that completely suppress IL-5 and IL-4/IL-13 pathways in T2 composite-high patients is needed.

BACKGROUND:Obesity is a common comorbidity associated with poor outcomes in severe asthma. OBJECTIVE:We aimed to determine whether obesity is associated with an altered response to severe asthma biologic agents. METHODS:We analyzed data from the UK Severe Asthma Registry, a large UK-wide cohort of patients attending regional severe asthma services. We analyzed the change in clinical outcomes between baseline and first annual review visit by body mass index (BMI) category (healthy range [18.50-24.99], overweight [25.00-29.99], obese [30.00-39.99], and severely obese [≥40]) and biologic treatment status. RESULTS:The study cohort comprised 1956 patients, of whom 1477 (75.5%) commenced a biologic agent during the follow-up. Baseline Asthma Control Questionnaire-6 (ACQ-6) scores and rates of exacerbations, emergency department attendances, and hospital admissions were higher with increasing BMI category. Biologic treatment was associated with significant additional improvement in ACQ-6, compared with patients not receiving biologics, in overweight, obese, and severely obese patients. However, the ACQ-6 score after biologic treatment remained significantly different across BMI categories, with the mean score being 1.3 in the healthy weight group and 2.8 in the severely obese group (P < .001). Biologic treatment was associated with significant additional reductions in exacerbation rates in all BMI groups except for the severely obese group. CONCLUSIONS:Asthma biologic agents appear to have important clinical benefits across the spectrum of BMI. However, because patients with obesity start at a worse baseline with respect to symptoms and exacerbations, they are still more likely to remain uncontrolled after treatment.

The baroreflex system is involved in modulating several physiological functions of the cardiovascular system and can modulate cardiac output, blood pressure, and cardiac electrophysiology directly and indirectly. In addition, it is involved in regulating neurohormonal pathways involved in the cardiovascular function, such as the renin-angiotensin-aldosterone system and vasopressin release. Baroreflex dysfunction is characterized by sympathetic overactivation and parasympathetic withdrawal and is associated with several cardiovascular diseases, such as hypertension, heart failure, and coronary artery disease. Targeting the baroreflex system via invasive (eg, baroreflex activation therapy and endovascular baroreceptor amplification) and noninvasive approaches (eg, slow breathing exercises and exercise training) has emerged as a novel pathway to manage cardiovascular diseases. Studies examining the long-term safety and efficacy of such interventions in various cardiovascular diseases are needed.

Extraretinal neovascularization is a hallmark of treatment-requiring retinopathy of prematurity (ROP). Optical coherence tomography angiography (OCTA) offers vascular flow and depth information not available from indirect ophthalmoscopy and structural OCT, but OCTA is only commercially available as a tabletop device. In this study, we used an investigational handheld OCTA device to study the vascular flow in and around retinal neovascularization in seven preterm infants with treatment-requiring ROP and contrasted them to images of vascular flow in six infants of similar age without neovascular ROP. We showed stages of retinal neovascularization visible in preterm infants from 32 to 47 weeks postmenstrual age: Intraretinal neovascularization did not break through the internal limiting membrane; Subclinical neovascular buds arose from retinal vasculature with active flow through the internal limiting membrane; Flat neovascularization in aggressive ROP assumed a low-lying configuration compared to elevated extraretinal neovascular plaques; Regressed neovascularization following treatment exhibited decreased vascular flow within the preretinal tissue, but flow persisted in segments of retinal vessels elevated from their original intraretinal location. These findings enable a pilot classification of retinal neovascularization in eyes with ROP using OCTA, and may be helpful in detailed monitoring of disease progression, treatment response and predicting reactivation.

ABSTRACTBackgroundBenralizumab has been reported to lead to clinical remission of severe eosinophilic asthma (SEA) at 1 year in some patients. However, whether this is maintained over a longer term remains unclear. Additionally, the impact of pulmonary and extrapulmonary comorbidities on the ability to meet remission is poorly understood.MethodsClinical outcomes including remission of SEA with benralizumab at 1 and 2 years were assessed retrospectively in a real‐world UK multi‐centre severe asthma cohort. The presence of clinically relevant pulmonary and extrapulmonary comorbidities associated with respiratory symptoms was recorded. Analyses to identify factors associated with the ability to meet remission were performed.ResultsIn total, 276 patients with SEA treated with benralizumab including 113 patients who had switched from a previous biologic to benralizumab were included. Overall, clinical remission was met in 17% (n = 31/186) and 32% (n = 43/133) of patients at 1 and 2 years, respectively. This increased to 28% at 1 year and 49% at 2 years once patients with pulmonary and/or extrapulmonary comorbidities were excluded. Body mass index (BMI) and maintenance OCS (mOCS) use demonstrated a negative association with clinical remission at 1 (BMI: OR: 0.89, 95% CI: 0.82–0.96, p < 0.01; mOCS: OR: 0.94, 95% CI: 0.89–0.99, p < 0.05) and 2 years (BMI: OR: 0.93, 95% CI: 0.87–0.99, p < 0.05; mOCS: OR: 0.95, 95% CI: 0.89–0.99, p < 0.05).ConclusionsIn this long‐term, real‐world study, patients with SEA demonstrated the ability to meet and sustain clinical remission when treated with benralizumab. The presence of comorbidities including obesity, which are known to be independently associated with respiratory symptoms, reduced the likelihood of meeting clinical remission.

Purpose: Circulating progenitor cells (CPCs) are a measure of endogenous regenerative capacity. In younger individuals, exposure to cardiovascular risk factors is associated with higher levels of CPCs. CPCs are also mobilized in acute myocardial infarction. Patients with heart transplant (HTx) with higher grades of cardiac allograft vasculopathy (CAV) have higher levels of high-sensitivity troponin-I, suggesting chronic ischemia. We sought to determine the association between CPCs and CAV, as well as with adverse events in patients with HTx.

Rationale: There is no consensus on criteria to include in an asthma remission definition in real life. Factors associated with achieving remission after biologic initiation remain poorly understood. Objectives: To quantify the proportion of adults with severe asthma achieving multidomain-defined remission after biologic initiation and identify prebiologic characteristics associated with achieving remission that may be used to predict it. Methods: This was a longitudinal cohort study using data from 23 countries from the International Severe Asthma Registry. Four asthma outcome domains were assessed in the 1 year before and after biologic initiation. A priori-defined remission cutoffs were: 0 exacerbations/yr, no long-term oral corticosteroid (LTOCS), partly/well-controlled asthma, and percent predicted FEV1 ⩾ 80%. Remission was defined using two (exacerbations + LTOCS), three (+control or +lung function), and four of these domains. The association between prebiologic characteristics and postbiologic remission was assessed by multivariable analysis. Measurements and Main Results: A total of 50.2%, 33.5%, 25.8%, and 20.3% of patients met criteria for two-, three- (+control), three- (+lung function), and four-domain remission, respectively. The odds of achieving four-domain remission decreased by 15% for every additional 10 years of asthma duration (odds ratio, 0.85; 95% confidence interval, 0.73-1.00). The odds of remission increased in those with fewer exacerbations per year, lower LTOCS daily dose, better control, and better lung function before biologic initiation. Conclusions: One in five patients achieved four-domain remission within 1 year of biologic initiation. Patients with less severe impairment and shorter asthma duration at initiation had a greater chance of achieving remission after biologic treatment, indicating that biologic treatment should not be delayed if remission is the goal.

Purpose: Despite initial evidence supporting the use of elevated B-type natriuretic peptide (BNP) to predict cardiac allograft vasculopathy (CAV), a recent meta-analysis questioned the diagnostic accuracy of BNP and N-terminal-pro brain natriuretic peptide (NT-proBNP) in the detection of CAV following heart transplantation (HTx). To our knowledge, no study has assessed both BNP and NT-proBNP in the prediction of CAV in HTx.

Introduction: Between 5-10% of asthmatics have severe disease and many require commencement of anti-eosinophilic biologics. Eosinophils play a pivotal role in host defence against parasite infections and thus prescribers of anti-IL5/5R biologics are cautioned against their use in patients with known or untreated helminth infections. There remains global ambiguity surrounding if, when and how, patients should be screened for this risk. Methods: A retrospective review of a protocol directed parasite screen performed from January 2019 upto January 2023 in at-risk, pre anti-IL5/5R biologic severe asthma patients was completed. Stool smear testing and serum enzyme-linked immunosorbent assays (ELISA) were used to detect parasitic antibodies. Results: A total of 479 patients were screened for parasite infection. 26 patients (5.4%) had true positive result and of these, 16 (61.5%) were for Schistosoma and 10 (38.5%) for Strongyloides. Table 1 stratifies the characteristics of these patients. No patient had a positive stool smear, or Toxocara and Filaria antibodies. Conclusions: Within a targeted population of at-risk severe eosinophilic asthma patients, just under 1 in 20 patients had a positive parasite screen. To date, this is the largest reported cohort of severe asthmatics to have undergone pre-anti-IL5/5R screening in the literature which serves to help inform global clinical practice and pre-biologic risk assessments.

Purpose: To report macular neurovascular abnormalities in a child with incontinentia pigmenti using handheld optical coherence tomography (OCT) and OCT angiography (OCT-A). Methods: An eye of a child with incontinentia pigmenti enrolled in BabySTEPS was imaged using an investigational noncontact, handheld swept-source OCT device during examination under anesthesia. Custom MATLAB scripts were used to generate depth-resolved vascular slabs, B-scans with flow overlay, and retinal thickness maps. Results: Depth-resolved OCT and OCT-A imaging demonstrated focal areas of decreased capillary flow that corresponded to areas of both inner retinal and outer retinal thinning on retinal thickness maps. Atypical diving of superficial retinal vessels occurred as they traversed from thin retina to normal-thickness retina. Conclusion: Depth-resolved OCT and OCT-A identified retinal vascular abnormalities that were not evident on fundus photography or fluorescein angiography. This case depicted concurrent, localized abnormalities in retinal thickness and microvasculature in an eye with incontinentia pigmenti.