There are limited data regarding the real-world impact of benralizumab on exacerbations among subspecialist-treated patients with severe asthma (SA) in the United States (US).

Disease severity in atopic dermatitis (AD) is negatively influenced by S. aureus (SA). SA can be inhibited by antimicrobial molecules made by some strains of coagulase-negative Staphylococcus (AM+CoNS). A lack of AM+CoNS correlates with SA abundance and disease severity in AD. A previous clinical trial showed autologous AM+CoNS could reduce SA on AD skin within 24 hrs. Recently, some CoNS were also found to inhibit expression of SA toxins by blocking quorum sensing through production of autoinducing peptides (AIPs). For this reason, a single strain of S. hominis(SHA9) that produces both AMs and an AIPwas selected for further testing of safety and potential therapeutic efficacy in mice and humans. Application ofSHA9 to OVA-sensitized Balb/c FLGft/ftmice reduced SA survival by >99% (P<.05). In these mice, SHA9 was also a potent anti-inflammatory agent and suppressedIL-4 by 89.6%, IL-13 by 84.6% and TSLP by 87.3% (P<.05). SHA9 also increased skin cathelicidin expression by 9.2 fold (P<.01) to provide enhanced host defense. Efficacy was in part due to the action of AIP; genetic deletion of AMs from SHA9 did not completely eliminate the anti-inflammatory activity but did diminish the capacity to eliminate SA. SHA9 was also evaluated in a double-blind, vehicle-controlled phase 1 clinical trial on 54 moderate to severe SA-positive AD adult subjects. SHA9 or vehicle was applied BID to upper extremities for 7 days and skin swabs were obtained for up to 11 days. No difference in adverse events was observed between active and vehicle groups. Compared to vehicle, SHA9 reduced SA abundance on lesional skin by 99% at day-7 (P<.001). This reduction persisted up to day-11 (99%, P<.001) and correlated with a decrease in local EASI at day-9 (P=.001) and day-11 (P=.007). These data show the safety and efficacy of a highly-defined and rationally selected member of the skin microbiome to manage AD.

Patients with atopic dermatitis (AD) are commonly colonized with Staphylococcus aureus (AD S. aureus thorn), but what differentiates this group from noncolonized AD patients (AD S. aureus e) has not been well studied. To evaluate whether these two groups have unique phenotypic or endotypic features, we performed a multicenter, cross-sectional study enrolling AD S. aureus thorn (n = 51) and AD S. aureus e (n = 45) participants defined by the presence or absence of S. aureus by routine culture techniques and nonatopic, noncolonized control individuals (NA S. aureus e) (n = 46). Filaggrin (FLG) genotypes were determined, and disease severity (Eczema Area and Severity Index, Rajka-Langeland Severity Score, Investigator's Global Assessment score, Numerical Rating Scale, and Dermatology Life Quality Index) was captured. Skin physiology was assessed (transepidermal water loss [TEWL], stratum corneum integrity, hydration, and pH), and serum biomarkers were also measured. We found that AD S. aureus thorn patients had more severe disease based on all scoring systems except itch (Numerical Rating Scale), and they had higher levels of type 2 biomarkers (eosinophil count, tIgE, CCL17, and periostin). Additionally, AD S. aureus thorn patients had significantly greater allergen sensitization (Phadiatop and tIgE), barrier dysfunction (TEWL and stratum corneum integrity), and serum lactate dehydrogenase (LDH) than both the AD S. aureus e and NA S. aureus e groups. FLG mutations did not associate with S. aureus thorn colonization. In conclusion, adult patients with AD who are colonized on their skin with S. aureus have more severe disease, greater type 2 immune deviation, allergen sensitization, barrier disruption, and LDH level elevation than noncolonized patients with AD.

IntroductionObesity is a major pediatric health concern affecting almost 20% of American children and adolescents. Obesity is a risk factor for the development of asthma and is associated with increased asthma severity. Children with obesity and asthma have reduced responsiveness to inhaled corticosteroids, increased use of systemic corticosteroids during exacerbations, and a reduced FEV1/FVC ratio. The mechanisms underlying the influence of obesity on asthma pathogenesis remain poorly understood.MethodsChildren (ages 6-17 years) with a priori defined exacerbation-prone asthma and blood eosinophils ≥150/mm3 had repeated nasal lavage sampling during a one-week period following reported URI symptoms. Nasal cell differentials were determined by cytospin and nasal gene expression assessed by RNA-sequencing. Differential gene expression was assessed by cell deconvolution and modular analysis.Results154 URI events from 106 participants were captured and 47 of those events resulted in asthma exacerbation. 42/106 participants were obese defined by a BMI ≥95th percentile. Children with obesity had higher expression levels of 7 geneset modules when compared to those without obesity. These modules were associated with the airway epithelium and represent molecular functions including keratinization, tissue kallikrein induction, extracellular matrix production, and EGFR signaling. Measured effect sizes ranged from 1.24-2.05 fold higher.ConclusionsWe identified several airway epithelial associated gene networks upregulated in children with obesity and asthma. Previous studies of obesity and asthma have focused largely on metabolic and inflammatory alterations. Our results highlight the relevance of epithelial response pathways, which may serve as novel targets for biomarkers or therapies for obesity associated asthma.

It is not well-understood how leukopenia affects the synovial white blood cell (WBC) and percent neutrophils (%PMNs) in the setting of septic arthritis. We sought to determine 1. Do synovial WBC and %PMNs differ between patients with culture positive septic arthritis with or without leukopenia? And 2. Are traditional thresholds of synovial fluid studies for accurately diagnosing septic arthritis still applicable in the leukopenic patient population?A retrospective cohort study was performed at a single institution of 79 non-leukopenic and 11 leukopenic patients diagnosed with culture-positive septic arthritis. Demographic data, serum laboratory values, synovial laboratory values, and culture results were recorded. Significant differences in synovial laboratory values were evaluated using the Wilcoxon-Mann-Whitney test. Results are reported as median, interquartile range, and p values.There was a significant difference in synovial WBC in leukopenic patients compared to non-leukopenic patients with culture positive septic arthritis (p = 0.01). No significant difference was found in the synovial %PMNs between two cohorts (p = 0.33).Leukopenic patients with culture positive septic arthritis have significantly lower synovial WBCs compared to non-leukopenic patients. Traditional thresholds for synovial WBC are not reliable for excluding diagnosis of septic arthritis in leukopenic patients.

OBJECTIVE To evaluate the reasons that complete remission is not achieved or maintained with original treatment in some patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) treated with rituximab (RTX) or with cyclophosphamide/azathioprine (CYC/AZA). METHODS The Rituximab in AAV trial was a randomized, double-blind, placebo-controlled trial comparing the rate of remission induction among patients treated with RTX (n = 99) and patients treated with CYC followed by AZA (n = 98). Glucocorticoids were tapered over a period of 5 months. The primary outcome measure was lack of disease activity without glucocorticoid treatment at 6 months. To determine the most important reason for failure to achieve the primary outcome, 7 hierarchical categories of reasons were defined retrospectively (uncontrolled disease, adverse event leading to therapy discontinuation, severe flare, limited flare, Birmingham Vasculitis Activity Score for Wegener's Granulomatosis >0, prednisone treatment at any dosage, and other). RESULTS Although remission (lack of disease activity) was achieved in 170 of the 197 patients (86%) in the first 6 months, the primary outcome measure was not achieved in 42%. There were 3 deaths. Twenty-four percent of the patients failed to achieve the primary end point due to active disease: 10 (5%) experienced uncontrolled disease in the first month and 37 (19%) experienced flares after initial improvement. In the majority of such patients, treatment with blinded crossover or according to best medical judgment led to disease control. Ninety-one percent of patients who had uncontrolled disease or experienced a severe flare had proteinase 3 (PR3)-ANCA. When patients with uncontrolled disease were excluded from analysis, those who were PR3-ANCA positive were found to experience fewer flares when treated with RTX compared to CYC/AZA (8 of 59 [14%] versus 20 of 62 [32%]; P = 0.02). Neither ANCA titers nor B cell counts predicted disease flare. CONCLUSION Current treatment regimens are largely successful in controlling AAV, but in approximately one-fourth of patients, active disease persists or recurs in the first 6 months despite treatment. PR3-ANCA positivity is a risk factor for recurrence or persistence of severe disease. ANCA titers and B cell detectability are poor predictors of both disease relapse and disease quiescence in the first 6 months.