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Refractory asthma (RA) remains poorly controlled, resulting in high health care utilization despite guideline-based therapies. Patients with RA manifest higher neutrophilia as a result of increased airway inflammation and subclinical infection, the underlying mechanisms of which remain unclear.We sought to characterize and clinically correlate gene expression differences between refractory and nonrefractory (NR) asthma to uncover molecular mechanisms driving group distinctions.Microarray gene expression of paired airway epithelial brush and endobronchial biopsy samples was compared between 60 RA and 30 NR subjects. Subjects were hierarchically clustered to identify subgroups of RA, and biochemical and clinical traits (airway inflammatory molecules, respiratory pathogens, chest imaging) were compared between groups. Weighted gene correlation network analysis was used to identify coexpressed gene modules. Module expression scores were compared between groups using linear regression, controlling for age, sex, and body mass index.Differential gene expression analysis showed upregulation of proneutrophilic and downregulation of ciliary function genes/pathways in RA compared to NR. A subgroup of RA with downregulated ciliary gene expression had increased levels of subclinical infections, airway neutrophilia, and eosinophilia as well as higher chest imaging mucus burden compared to other RA, the dominant differences between RA and NR. Weighted gene correlation network analysis identified gene modules related to ciliary function, which were downregulated in RA and were associated with lower pulmonary function and higher airway wall thickness/inflammation, markers of poorer asthma control.Identification of a novel ciliary-deficient subgroup of RA suggests that diminished mucociliary clearance may underlie repeated asthma exacerbations despite adequate treatment, necessitating further exploration of function, mechanism, and therapeutics.

Asthma is a heterogeneous disease, with multiple underlying inflammatory pathways and structural airway abnormalities that impact disease persistence and severity. Recent progress has been made in developing targeted asthma therapeutics, especially for subjects with eosinophilic asthma. However, there is an unmet need for new approaches to treat patients with severe and exacerbation-prone asthma, who contribute disproportionately to disease burden. Extensive deep phenotyping has revealed the heterogeneous nature of severe asthma and identified distinct disease subtypes. Acurrent challenge in the field is to translate new and emerging knowledge about different pathobiologic mechanisms in asthma into patient-specific therapies, with the ultimate goal of modifying the natural history of disease. Here, we describe the Precision Interventions for Severe and/or Exacerbation-Prone Asthma (PrecISE) Network, a groundbreaking collaborative effort of asthma researchers and biostatisticians from around the United States. The PrecISE Network was designed to conduct phase II/proof-of-concept clinical trials of precision interventions in the population with severe asthma, and is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health. Using an innovative adaptive platform trial design, the PrecISE Network will evaluate up to 6 interventions simultaneously in biomarker-defined subgroups of subjects. We review the development and organizational structure of the PrecISE Network, and choice of interventions being studied. We hope that the PrecISE Network will enhance our understanding of asthma subtypes and accelerate the development of therapeutics for severe asthma.

SARS-CoV-2 continues to cause a global pandemic and management of COVID-19 in outpatient settings remains challenging.We sought to describe characteristics of patients with chronic respiratory disease (CRD) experiencing symptoms consistent with COVID-19, who were seen in a novel Acute Respiratory Clinic, prior to widely available testing, emergence of variants, COVID-19 vaccination, and post-vaccination (breakthrough) SARS-CoV-2 infections.Retrospective electronic medical record data were analyzed from 907 adults with presumed COVID-19 seen between March 16, 2020 and January 7, 2021. Data included demographics, comorbidities, medications, vital signs, laboratory tests, pulmonary function tests, patient disposition, and co-infections. The overdispersed data (aod) R package was used to create a logit model using COVID-19 diagnosis by PCR as the dichotomous outcome variable. Univariate, conventional multivariate and elastic net machine learning were used to analyze data.Male gender, elevated baseline temperature, and respiratory rate predicted COVID-19 diagnosis. Eosinopenia, neutrophilia, and lymphocytosis were also associated with COVID-19 diagnosis. However, asthma and COPD diagnoses were not associated with SARS-CoV-2 PCR positive test. Male gender, low oxygen saturation, and lower forced expiratory volume in 1 s (FEVCRD patients with acute respiratory symptoms in the ambulatory setting were more likely to have COVID-19 if male, febrile and tachypneic. Patients with lower pre-morbid FEV

Eosinophilic granulomatosis with polyangiitis (EGPA), a rare vasculitis with substantial morbidity, is characterized by asthma, eosinophilia, sinusitis, pulmonary infiltrates, neuropathy, positivity for antineutrophil cytoplasmic antibody, and multiorgan vasculitis. Although treatment options previously included corticosteroids and immunosuppressants, anti-interleukin 5 therapies have gained interest in EGPA treatment. Mepolizumab was approved for and recently benralizumab was found to have safety and efficacy in EGPA.To determine the safety and efficacy of reslizumab in EGPA.In this open-label, pilot study, we evaluated the safety and efficacy of intravenous reslizumab (3 mg/kg) in EGPA in 10 subjects. Oral corticosteroid dose, adverse events, exacerbations, symptom control, disease activity, blood markers, and lung function were evaluated before, during, and after 7 monthly reslizumab treatments.Reslizumab was tolerated and resulted in a significant reduction in daily oral corticosteroid (P.05). Of the 10 subjects, 3 experienced an EGPA exacerbation during the treatment. One had a severe adverse event, requiring removal from the study.Yielding similar results to other anti-interleukin 5 biologic medications, reslizumab is generally a safe and effective treatment for EGPA that warrants further study.ClinicalTrials.gov Identifier: NCT02947945.

Background Eosinophilic granulomatosis with polyangiitis (EGPA) is a vasculitis associated with significant morbidity and mortality that has historically been treated with systemic corticosteroids and immunosuppressants. The IL-5 antagonist mepolizumab was Food and Drug Administration approved in 2017 after demonstrating safety and efficacy in EGPA. We hypothesized that benralizumab, an IL-5 receptor antagonist approved for eosinophilic asthma, would demonstrate safety and efficacy in EGPA. Objectives To determine the safety and efficacy of benralizumab in EGPA as measured by reduction in oral corticosteroid dose and EGPA exacerbations. Methods We conducted a prospective 40-week open-label pilot study of benralizumab 30 mg administered subcutaneously in 10 patients with EGPA. Adverse events, oral corticosteroid dosing, exacerbations, and lung function were evaluated before, during, and after benralizumab treatment. Paired tests and tests derived from longitudinal models were used to compare outcome variables between phases or visits. Results Benralizumab was well tolerated and resulted in reduction of median corticosteroid dose from 15 mg at the start to 2 mg at the end of treatment. Geometric mean corticosteroid dose was reduced from 11.6 mg during pretreatment to 6.3 mg during treatment phase. Five patients were able to achieve a dose of 0 mg. Mean annualized exacerbation rate was lowest during the treatment (1.5) compared with the pre- and posttreatment phases (4.6, P = .008 for treatment vs pre- and postphases combined). Conclusions Benralizumab was well tolerated, facilitated oral corticosteroid reduction, and reduced exacerbations in EGPA. Larger controlled trials are warranted to further evaluate the role of benralizumab in EGPA.

Disseminated intravascular coagulation (DIC) is a common disorder in the ICU. It is often seen in the setting of Acute Myelocytic leukemia, and specifically Acute Promyelocytic Leukemia. The key points in care of the patient with DIC in the ICU are early diagnosis of the coagulation abnormality and treatment directed at the underlying cause. Supportive care with blood product transfusion may also be necessary.

Objective Severe asthma affects 5% to 10% of the adult asthma population and is associated with increased morbidity, mortality, and consumption of health care resources. Recently, several biologic medications have been approved for use in severe asthma. These medications target the type 2 inflammatory pathway, which is characterized by activation of cytokines, including interleukin (IL)-4, IL-5, and IL-13, which results in eosinophilia, high FeNO, and atopic features. The objective of this review was to provide clinicians with key points to assist in selecting the best biologic medication for each patient. Data Sources A comprehensive literature search was performed, and data were reviewed from basic science articles of inflammatory mediators in type 2 airway inflammation, and clinical trials of biologic medications in patients with severe asthma. Study Selections These studies analyzed outcomes of biologic medications in type 2-high severe asthma including clinical biomarkers, exacerbation rates, lung function, and quality of life measures. Results Biologic mediations in type 2-high severe asthma improve outcomes, including clinical biomarkers, exacerbation rates, lung function, and quality-of-life measures. Conclusion When choosing a biologic medication for patients with severe asthma, asthma endotype, clinical biomarkers, and patient-centered factors should be taken into account.

Allergic conditions such as asthma and atopic dermatitis have a high prevalence but represent a heterogeneous group of diseases despite similar clinical presentation and underlying pathophysiology. A better understanding of the phenotypes and endotypes of these diseases has driven rapid development of biologic medications targeting many steps of the inflammatory pathways. Areas covered: There are 2 major inflammatory pathways that drive allergic diseases: Type-2 (Th-2) inflammation and non-type 2 inflammation. All of the biologic medications currently approved for use, and most of the biologic medications under development for allergic diseases have focused on the Th-2 inflammatory pathway. Biologic targets along this pathway include Anti-Immunoglobulin E (IgE), Anti-Interleukin 5 (IL-5), Anti-IL 4, and Anti-IL 13. Although the most study has been done in the realm of severe asthma, biologic targets for other allergic diseases including atopic dermatitis, chronic rhinosinusitis with nasal polyposis, chronic idiopathic urticaria, eosinophilic esophagitis, and eosinophilic granulomatosis with polyangiitis are also discussed. Expert commentary: Novel biologic therapies have emerged over the last several years that have revolutionized the management of patients with refractory allergic disease.