Exploring Definitions and Predictors of Severe Asthma Clinical Remission Post-Biologic in Adults.

RATIONALE: There is no consensus on criteria to include in an asthma remission definition in real-life. Factors associated with achieving remission post-biologic-initiation remain poorly understood. OBJECTIVES: To quantify the proportion of adults with severe asthma achieving multi-domain-defined remission post-biologic-initiation and identify pre-biologic characteristics associated with achieving remission which 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 pre- and post-biologic-initiation. A priori-defined remission cut-offs were: 0 exacerbations/year, no long-term oral corticosteroid (LTOCS), partly/well-controlled asthma, and percent predicted forced expiratory volume in one second ≥80%. Remission was defined using 2 (exacerbations + LTOCS), 3 (+control or +lung function) and 4 of these domains. The association between pre-biologic characteristics and post-biologic remission was assessed by multivariable analysis. MEASUREMENTS AND MAIN RESULTS: 50.2%, 33.5%, 25.8% and 20.3% of patients met criteria for 2, 3 (+control), 3 (+lung function) and 4-domain-remission, respectively. The odds of achieving 4-domain remission decreased by 15% for every additional 10-years asthma duration (odds ratio: 0.85; 95% CI: 0.73, 1.00). The odds of remission increased in those with fewer exacerbations/year, lower LTOCS daily dose, better control and better lung function pre-biologic-initiation. CONCLUSIONS: One in 5 patients achieved 4-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 post-biologic, indicating that biologic treatment should not be delayed if remission is the goal. 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/).

Overcoming Barriers to Remission in Severe Eosinophilic Asthma: Two-Year Real-World Data With Benralizumab.

BACKGROUND: Benralizumab 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. METHODS: Clinical 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. RESULTS: In 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). CONCLUSIONS: In 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.

Impact of pre-biologic impairment on meeting domain-specific biologic responder definitions in patients with severe asthma.

BACKGROUND: There is little agreement on clinically useful criteria for identifying real-world responders to biologic treatments for asthma. OBJECTIVE: To investigate the impact of pre-biologic impairment on meeting domain-specific biologic responder definitions in adults with severe asthma. METHODS: This was a longitudinal, cohort study across 22 countries participating in the International Severe Asthma Registry (https://isaregistries.org/) between May 2017 and January 2023. Change in 4 asthma domains (exacerbation rate, asthma control, long-term oral corticosteroid [LTOCS] dose, and lung function) was assessed from biologic initiation to 1 year post-treatment (minimum 24 weeks). Pre- to post-biologic changes for responders and nonresponders were described along a categorical gradient for each domain derived from pre-biologic distributions (exacerbation rate: 0 to 6+/y; asthma control: well controlled to uncontrolled; LTOCS: 0 to >30 mg/d; percent-predicted forced expiratory volume in 1 second [ppFEV1]: <50% to ≥80%). RESULTS: Percentage of biologic responders (ie, those with a category improvement pre- to post-biologic) varied by domain and increased with greater pre-biologic impairment, increasing from 70.2% to 90.0% for exacerbation rate, 46.3% to 52.3% for asthma control, 31.1% to 58.5% for LTOCS daily dose, and 35.8% to 50.6% for ppFEV1. The proportion of patients having improvement post-biologic tended to be greater for anti-IL-5/5R compared with for anti-IgE for exacerbation, asthma control, and ppFEV1 domains, irrespective of pre-biologic impairment. CONCLUSION: Our results provide realistic outcome-specific post-biologic expectations for both physicians and patients, will be foundational to inform future work on a multidimensional approach to define and assess biologic responders and response, and may enhance appropriate patient selection for biologic therapies. TRIAL REGISTRATION: The ISAR database has ethical approval from the Anonymous Data Ethics Protocols and Transparency (ADEPT) committee (ADEPT0218) and is registered with the European Union Electronic Register of Post-Authorization studies (ENCEPP/DSPP/23720). The study was designed, implemented, and reported in compliance with the European Network Centres for Pharmacoepidemiology and Pharmacovigilance (ENCEPP) Code of Conduct (EUPAS38288) and with all applicable local and international laws and regulation, and registered with ENCEPP (https://www.encepp.eu/encepp/viewResource.htm?id=38289). Governance was provided by ADEPT (registration number: ADEPT1220).

Clinical remission in severe asthma with biologic therapy: an analysis from the UK Severe Asthma Registry.

BACKGROUND: Novel biologic therapies have revolutionised the management of severe asthma with more ambitious treatment aims. Here we analyse the definition of clinical remission as a suggested treatment goal and consider the characteristics associated with clinical remission in a large, real-world severe asthma cohort. METHODS: This was a retrospective analysis of severe asthma patients registered in the UK Severe Asthma Registry (UKSAR) who met strict national access criteria for biologics. Patients had a pre-biologics baseline assessment and annual review. The primary definition of clinical remission applied included Asthma Control Questionnaire (ACQ)-5 <1.5 and no oral corticosteroids for disease control and forced expiratory volume in 1 s above lower limit of normal or no more than 100 mL less than baseline. RESULTS: 18.3% of patients achieved the primary definition of remission. The adjusted odds of remission on biologic therapy were 7.44 (95% CI 1.73-31.95)-fold higher in patients with type 2 (T2)-high biomarkers. The adjusted odds of remission were lower in patients who were female (OR 0.61, 95% CI 0.45-0.93), obese (OR 0.49, 95% CI 0.24-0.65) or had ACQ-5 ≥1.5 (OR 0.19, 95% CI 0.12-0.31) pre-biologic therapy. The likelihood of remission reduced by 14% (95% CI 0.76-0.97) for every 10-year increase in disease duration. 12-21% of the cohort attained clinical remission depending on the definition applied; most of those who did not achieve remission failed to meet multiple criteria. CONCLUSIONS: 18.3% of patients achieved the primary definition of clinical remission. Remission was more likely in T2-high biomarker patients with shorter duration of disease and less comorbidity. Further research on the optimum time to commence biologics in severe asthma is required.

Subfertility and reduced progestin synthesis in Pgrmc2 knockout zebrafish.

Progestin receptor membrane component (Pgrmc1 & 2) is a heme-binding protein. Studies on Pgrmc1 have suggested possible roles in heme binding, activation of steroid-synthesizing P450s, along with binding and transferring of membrane proteins. However, the studies of Pgrmc1's paralog, Pgrmc2 are still lacking. In order to determine the physiologic function(s) of Pgrmc2, we generated a zebrafish mutant line (pgrmc2-/-). We found a reduction in both spawning frequency and the number of embryos produced in female pgrmc2-/-. This subfertility is caused by reduced oocyte maturation (germinal vesicle breakdown, GVBD) in pgrmc2-/- in vivo. Nonetheless, oocytes from pgrmc2-/- had similar sensitivity to 17α,20ß-dihydroxy-4-pregnen-3-one (DHP, a maturation induced progestin in zebrafish) compared with wildtype (wt) in vitro. Therefore, we hypothesized that oocyte maturation tardiness found in vivo, could be due to lack of progestin in pgrmc2-/-. Interestingly, we found significant reduced expression of hormones, receptors, and steroid synthesizing enzymes including lhcgr, egfra, ar, and esr2, cyp11a1 and hsd3b1. In addition, DHP levels in pgrmc2-/- ovaries showed a significant decrease compared to those in wt. In summary, we have provided a plausible molecular mechanism for the physiological functions of Pgrmc2 in the regulation of female fertility, likely via regulation of receptors and steroids in the ovary, which in turn regulates oocyte maturation in zebrafish.

Prion-Protein-interacting Amyloid-ß Oligomers of High Molecular Weight Are Tightly Correlated with Memory Impairment in Multiple Alzheimer Mouse Models.

Alzheimer disease (AD) is characterized by amyloid-ß accumulation, with soluble oligomers (Aßo) being the most synaptotoxic. However, the multivalent and unstable nature of Aßo limits molecular characterization and hinders research reproducibility. Here, we characterized multiple Aßo forms throughout the life span of various AD mice and in post-mortem human brain. Aßo exists in several populations, where prion protein (PrP(C))-interacting Aßo is a high molecular weight Aß assembly present in multiple mice and humans with AD. Levels of PrP(C)-interacting Aßo match closely with mouse memory and are equal or superior to other Aß measures in predicting behavioral impairment. However, Aßo metrics vary considerably between mouse strains. Deleting PrP(C) expression in mice with relatively low PrP(C)-interacting Aßo (Tg2576) results in partial rescue of cognitive performance as opposed to complete recovery in animals with a high percentage of PrP(C)-interacting Aßo (APP/PSEN1). These findings highlight the relative contributions and interplay of Aßo forms in AD.

A pilot optical coherence tomography angiography classification of retinal neovascularization in retinopathy of prematurity.

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.

Clinical and Economic Burden of Severe Asthma With Low Blood Eosinophil Counts.

BACKGROUND: Type 2 low-severe asthma phenotype is often a result of corticosteroid-overtreated type 2 disease owing to persistent symptoms, often unrelated to asthma and unlikely to respond to high-dose corticosteroid treatment. OBJECTIVE: This study aimed to characterize patients with severe asthma with low eosinophil counts (<300 cells/µL) and describe their disease burden and treatment across health care settings in the United Kingdom. METHODS: A retrospective cohort study of patients with severe asthma using linked Clinical Practice Research Datalink (CPRD) Aurum-Hospital Episode Statistics (HES) and UK Severe Asthma Registry (UKSAR) data indexed patients according to the latest blood eosinophil count (BEC). Clinical characteristics, treatment patterns, outcomes, and health care resource use were described by baseline BEC (≤150 and >150 to <300 cells/µL). RESULTS: Analysis included 701 (CPRD-HES) and 1,546 (UKSAR) patients; 60.5% and 59.4% had BECs 150 cells/µL or less at baseline, respectively. Across BEC groups, the proportion with uncontrolled asthma (two or more exacerbations) at follow-up (12 months after the index) was 5.4% in CPRD-HES and 45.2% in UKSAR. Maintenance oral corticosteroid use remained high across BEC groups (CPRD-HES: 29.4%; UKSAR: 51.7%), symptom control remained poor (>200 µg short-acting ß2 agonist or >500 µg terbutaline/d in CPRD-HES: 48.8%; median Asthma Control Questionnaire-6 score in UKSAR: 2.0 [range, 1.0-3.3]). Health care resource use was similar across BEC groups. CONCLUSIONS: Most patients managed in primary care experienced infrequent exacerbations, whereas UKSAR patients had frequent exacerbations. Large proportions of both patient groups had poor symptom control and continued to receive high levels of maintenance oral corticosteroids, increasing the risk of corticosteroid-induced morbidity. These data highlight the need for rigorous assessment of underlying disease pathology to guide appropriate treatment.

Defining Suicidal Thought and Behavior Phenotypes for Genetic Studies.

Background: Standardized definitions of suicidality phenotypes, including suicidal ideation (SI), attempt (SA), and death (SD) are a critical step towards improving understanding and comparison of results in suicide research. The complexity of suicidality contributes to heterogeneity in phenotype definitions, impeding evaluation of clinical and genetic risk factors across studies and efforts to combine samples within consortia. Here, we present expert and data-supported recommendations for defining suicidality and control phenotypes to facilitate merging current/legacy samples with definition variability and aid future sample creation. Methods: A subgroup of clinician researchers and experts from the Suicide Workgroup of the Psychiatric Genomics Consortium (PGC) reviewed existing PGC definitions for SI, SA, SD, and control groups and generated preliminary consensus guidelines for instrument-derived and international classification of disease (ICD) data. ICD lists were validated in two independent datasets (N = 9,151 and 12,394). Results: Recommendations are provided for evaluated instruments for SA and SI, emphasizing selection of lifetime measures phenotype-specific wording. Recommendations are also provided for defining SI and SD from ICD data. As the SA ICD definition is complex, SA code list recommendations were validated against instrument results with sensitivity (range = 15.4% to 80.6%), specificity (range = 67.6% to 97.4%), and positive predictive values (range = 0.59-0.93) reported. Conclusions: Best-practice guidelines are presented for the use of existing information to define SI/SA/SD in consortia research. These proposed definitions are expected to facilitate more homogeneous data aggregation for genetic and multisite studies. Future research should involve refinement, improved generalizability, and validation in diverse populations.

Exploring Definitions and Predictors of Response to Biologics for Severe Asthma.

BACKGROUND: Biologic effectiveness is often assessed as response, a term that eludes consistent definition. Identifying those most likely to respond in real-life has proven challenging. OBJECTIVE: To explore definitions of biologic responders in adults with severe asthma and investigate patient characteristics associated with biologic response. METHODS: This was a longitudinal cohort study using data from 21 countries, which shared data with the International Severe Asthma Registry. Changes in four asthma outcome domains were assessed in the 1-year period before and after biologic initiation in patients with a predefined level of prebiologic impairment. Responder cutoffs were 50% or greater reduction in exacerbation rate, 50% or greater reduction in long-term oral corticosteroid daily dose, improvement in one or more category in asthma control, and 100 mL or greater improvement in FEV1. Responders were defined using single and multiple domains. The association between prebiologic characteristics and postbiologic initiation response was examined by multivariable analysis. RESULTS: A total of 2,210 patients were included. Responder rate ranged from 80.7% (n = 566 of 701) for exacerbation response to 10.6% (n = 9 of 85) for a four-domain response. Many responders still exhibited significant impairment after biologic initiation: 46.7% (n = 206 of 441) of asthma control responders with uncontrolled asthma before the biologic still had incompletely controlled disease postbiologic initiation. Predictors of response were outcome-dependent. Lung function responders were more likely to have higher prebiologic FeNO (odds ratio = 1.20 for every 25-parts per billion increase), and shorter asthma duration (odds ratio = 0.81 for every 10-year increase in duration). Higher blood eosinophil count and the presence of type 2-related comorbidities were positively associated with higher odds of meeting long-term oral corticosteroid, control, and lung function responder criteria. CONCLUSIONS: Our findings underscore the multimodal nature of response, showing that many responders experience residual symptoms after biologic initiation and that predictors of response vary according to the outcome assessed.

Feasibility and value of a domiciliary spirometry programme in the assessment of severe asthma: a real-world evaluation.

Background: Domiciliary spirometry (DS) is a novel tool that is widely employed in the assessment of respiratory disease. We assessed real-world feasibility, effectiveness and value of a physiologist-led home spirometry programme in patients with treatment-refractory severe asthma. Methods: Patients were referred and provided with a hand-held DS device. Patients completed baseline measurements in a physiologist-led virtual clinic and were instructed to provide further values during any periods of respiratory symptoms. Outcome measures included prevalence of new obstructed events, DS adherence and uptake of this approach. Results: 112 patients were enrolled from November 2020 to January 2023. 102 individuals, mean±sd age 44±13 years (86% female) with median (IQR) forced expiratory volume in 1 s % predicted 88% (77-97%), successfully recorded baseline spirometry values. During follow-up (24 months), 11 (11%) were identified with new obstructive spirometry and were subsequently able to be commenced on biologic therapy. Patient engagement was poor with median (IQR) of 4 (2-6) attempts of contact made before baseline values were recorded, and 2 (1-3) attempts required to record technically acceptable values. Continued DS use was suboptimal; 34% failed to use their device after baseline and only 10% continued at the end of the study period. The cost of DS measurements was greater than a single hospital-based visit but enables multiple event capture. Conclusion: Overall, DS measurement uptake was poor, with a minority of patients continuing to use the device at the end of the study period. However, for those that engage, DS provides an alternative approach to traditional hospital-based spirometry measurements that can alter clinical management.

MACULAR NEUROVASCULAR ABNORMALITIES IN A CHILD WITH INCONTINENTIA PIGMENTI ON HANDHELD OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY.

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.

A pilot study of lymphoscintigraphy with tracer injection into the human brain.

Many groups have reported lymphatic and glymphatic structures in animal and human brains, but tracer injection into the human brain to demonstrate real-time lymphatic drainage and mapping has not been described. We enrolled patients undergoing standard-of-care resection or stereotactic biopsy for suspected intracranial tumors. Patients received peritumoral injections of 99mTc-tilmanocept followed by planar or tomographic imaging. Fourteen patients with suspected brain tumors were enrolled. One was excluded from analysis because of tracer leakage during injection. There was no drainage of 99mTc-tilmanocept to regional lymph nodes in any of the patients. On average, after correcting for radioactive decay, 70.7% (95% CI: 59.9%, 81.6%) of the tracer in the injection site and 78.1% (95% CI: 71.1%, 85.1%) in the whole-head on the day of surgery remained the morning after, with variable radioactivity in the subarachnoid space. The retained fraction was much greater than expected based on the clearance rate from non-brain injection sites. In this pilot study, the lymphatic tracer 99mTc-tilmanocept was injected into the brain parenchyma, and there was no drainage outside the brain to the cervical lymph nodes. Our work demonstrates an inefficiency of drainage from peritumoral brain parenchyma and highlights a therapeutic opportunity to improve immunosurveillance of the brain.

Bilateral anterior and posterior scleritis in a patient with acute myelogenous leukemia.

Purpose: To report a novel case of bilateral anterior and posterior scleritis in a patient with acute myelogenous leukemia (AML). Observations: A 69-year-old African American man was admitted to the hospital for relapse of AML. After admission, but prior to induction of chemotherapy, the patient developed ocular redness and proptosis. The diagnosis of bilateral anterior and posterior scleritis was made following an ophthalmic examination, infectious and autoimmune lab work-up, and neuroimaging. The patient was administered immunosuppressive therapy, clinically monitored, and initiated on chemotherapy for AML relapse. About one week later, the patient showed clinical improvement and resolution of the scleritis and proptosis. Conclusion: Scleritis may present during AML relapse, and it may be due to a paraneoplastic syndrome or a reactive anti-leukemic inflammatory response. Clinicians should monitor patients with AML relapse for symptoms such as ocular redness, proptosis, pain, photophobia, and decreased vision, which may indicate development of scleritis.

Expert-level detection of pathologies from unannotated chest X-ray images via self-supervised learning.

In tasks involving the interpretation of medical images, suitably trained machine-learning models often exceed the performance of medical experts. Yet such a high-level of performance typically requires that the models be trained with relevant datasets that have been painstakingly annotated by experts. Here we show that a self-supervised model trained on chest X-ray images that lack explicit annotations performs pathology-classification tasks with accuracies comparable to those of radiologists. On an external validation dataset of chest X-rays, the self-supervised model outperformed a fully supervised model in the detection of three pathologies (out of eight), and the performance generalized to pathologies that were not explicitly annotated for model training, to multiple image-interpretation tasks and to datasets from multiple institutions.

Characteristics, phenotypes, mechanisms and management of severe asthma.

ABSTRACT: Severe asthma is "asthma which requires treatment with high dose inhaled corticosteroids (ICS) plus a second controller (and/or systemic corticosteroids) to prevent it from becoming 'uncontrolled' or which remains 'uncontrolled' despite this therapy." The state of control was defined by symptoms, exacerbations and the degree of airflow obstruction. Therefore, for the diagnosis of severe asthma, it is important to have evidence for a diagnosis of asthma with an assessment of its severity, followed by a review of comorbidities, risk factors, triggers and an assessment of whether treatment is commensurate with severity, whether the prescribed treatments have been adhered to and whether inhaled therapy has been properly administered. Phenotyping of severe asthma has been introduced with the definition of a severe eosinophilic asthma phenotype characterized by recurrent exacerbations despite being on high dose ICS and sometimes oral corticosteroids, with a high blood eosinophil count and a raised level of nitric oxide in exhaled breath. This phenotype has been associated with a Type-2 (T2) inflammatory profile with expression of interleukin (IL)-4, IL-5, and IL-13. Molecular phenotyping has also revealed non-T2 inflammatory phenotypes such as Type-1 or Type-17 driven phenotypes. Antibody treatments targeted at the T2 targets such as anti-IL5, anti-IL5Rα, and anti-IL4Rα antibodies are now available for treating severe eosinophilic asthma, in addition to anti-immunoglobulin E antibody for severe allergic asthma. No targeted treatments are currently available for non-T2 inflammatory phenotypes. Long-term azithromycin and bronchial thermoplasty may be considered. The future lies with molecular phenotyping of the airway inflammatory process to refine asthma endotypes for precision medicine.