Treatment of uncontrolled asthma with dupilumab, an anti–interleukin-4 and anti–interleukin-13 receptor monoclonal antibody, in addition to usual therapy, led to a rate of severe exacerbations that ...was approximately 50% lower than the rate with placebo.
Asthma is a heterogeneous disease with considerable variability noted in disease severity, patterns of airway inflammation, and achievement of disease control on current medications. An absence of ...disease control is most frequently noted in patients with severe asthma, and is defined as a lack of control while on high dose inhaled corticosteroids (ICS) plus a second controller medication. In part, this lack of control may relate to a diminished effect of current guideline-directed care on the existing pattern of airway inflammation in severe asthma.
Airway inflammation in severe asthma has been arbitrarily divided into T (type) 2 high and T2 low. T2 high is characterized by the generation of key cytokines, interleukin (IL)-4, −5 and −13, which generate and regulate airway inflammation. Biomarkers to mark the presence of T2-high inflammation include eosinophils, fractional exhaled nitric oxide (FeNO) and immunoglobulin (Ig) E, whose presence arises from the action of IgE, IL-5, IL-4, and IL-13. In this review, treatment of severe asthma with monoclonal antibodies, i.e. biologics, which are directed against these inflammation generated pathways are reviewed. The available monoclonal antibodies include omalizumab (anti-IgE); mepolizumab, reslizumab and benralizumab (anti-IL-5 pathways), and dupilumab (anti-IL-4/IL-13).
The use of these T2-high interventions has led to significant reductions in asthma symptoms, a decreased frequency of exacerbations, and improved lung function in many patients. Not only has the use of these monoclonal antibodies led to improved asthma control in patients with severe disease, their use has provided insight into mechanisms of severe asthma.
1 DSMZ-Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH, Inhoffenstraße 7B, D-38124 Braunschweig, Germany
2 Grup de Microbiologia Marina, Departament d'Ecologia I Recursos Marins, IMEDEA ...(CSIC-UIB), C/Miquel Marqués 21, E-07190, Esporles, Spain
3 Institut für Bakteriologie, Mykologie und Hygiene, University of Veterinary Medicine Vienna, Veterinärplatz 1, A-1210 Vienna, Austria
4 Lehrstuhl für Mikrobiologie, Technische Universität München, Am Hochanger 4, D-85354 Freising-Weihenstephan, Germany
5 Institut für Angewandte Mikrobiologie, Justus-Liebig-Universität Giessen, Heinrich-Buff-Ring 26-32 (IFZ), D-35392 Giessen, Germany
Correspondence Brian J. Tindall bti{at}dsmz.de
Taxonomy relies on three key elements: characterization, classification and nomenclature. All three elements are dynamic fields, but each step depends on the one which precedes it. Thus, the nomenclature of a group of organisms depends on the way they are classified, and the classification (among other elements) depends on the information gathered as a result of characterization. While nomenclature is governed by the Bacteriological Code, the classification and characterization of prokaryotes is an area that is not formally regulated and one in which numerous changes have taken place in the last 50 years. The purpose of the present article is to outline the key elements in the way that prokaryotes are characterized, with a view to providing an overview of some of the pitfalls commonly encountered in taxonomic papers.
Abbreviations: AFLP, amplified fragment-length polymorphism; DDH, DNA–DNA hybridization; LPS, lipopolysaccharides; MLSA, multilocus sequence analysis; MLST, multilocus sequence typing
Vasoplegic syndrome is a common occurrence following cardiothoracic surgery and is characterized as a high-output shock state with poor systemic vascular resistance. The pathophysiology is complex ...and includes dysregulation of vasodilatory and vasoconstrictive properties of smooth vascular muscle cells. Specific bypass machine and patient factors play key roles in occurrence. Research into treatment of this syndrome is limited and extrapolated primarily from that pertaining to septic shock, but is evolving with the expanded use of catecholamine-sparing agents. Recent reports demonstrate potential benefit in novel treatment options, but large clinical trials are needed to confirm.
Chronic noncancer pain includes any painful condition that persists for at least three months and is not associated with malignant disease. According to seven national surveys conducted between ...1994-2008, 15%-19% of Canadian adults live with chronic noncancer pain. Chronic noncancer pain interferes with activities of daily living, has a major negative impact on quality of life and physical function, and is the leading cause of health resource utilization and disability among working-age adults. Here, Busse et al inform the prescribing of opioids for adults with chronic noncancer pain.
Summary Viral respiratory tract infections are common and usually selflimited illnesses. For patients at risk of asthma, or with existing asthma, viral respiratory tract infections can have a ...profound effect on the expression of disease or loss of control. New evidence has shown that wheezing episodes early in life due to human rhinoviruses are a major risk factor for the later diagnosis of asthma at age 6 years. For those with existing asthma, exacerbations are a major cause of morbidity, can need acute care, and can, albeit rarely, result in death. Viral respiratory tract infections, predominantly those caused by human rhinoviruses, are associated with asthma exacerbations. There is also evidence that deficiencies in antiviral activity and the integrity of the airway epithelial barrier could make individuals with asthma more likely to have severe viral respiratory infections of the lower airway, and thus increase the risk of exacerbation. In view of the effect of respiratory viruses on many aspects of asthma, efforts to understand the mechanisms and risk factors by which these airway infections cause changes in airway pathophysiology are a first step towards improved treatment.
Background
Genome‐wide association studies (GWASs) have identified various genes associated with asthma, yet, causal genes or single nucleotide polymorphisms (SNPs) remain elusive. We sought to ...dissect functional genes/SNPs for asthma by combining expression quantitative trait loci (eQTLs) and GWASs.
Methods
Cis‐eQTL analyses of 34 asthma genes were performed in cells from human bronchial epithelial biopsy (BEC, n = 107) and from bronchial alveolar lavage (BAL, n = 94).
Results
For TSLP‐WDR36 region, rs3806932 (G allele protective against eosinophilic esophagitis) and rs2416257 (A allele associated with lower eosinophil counts and protective against asthma) were correlated with decreased expression of TSLP in BAL (P = 7.9 × 10−11 and 5.4 × 10−4, respectively) and BEC, but not WDR36. Surprisingly, rs1837253 (consistently associated with asthma) showed no correlation with TSLP expression levels. For ORMDL3‐GSDMB region, rs8067378 (G allele protective against asthma) was correlated with decreased expression of GSDMB in BEC and BAL (P = 1.3 × 10−4 and 0.04) but not ORMDL3. rs992969 in the promoter region of IL33 (A allele associated with higher eosinophil counts and risk for asthma) was correlated with increased expression of IL33 in BEC (P = 1.3 × 10−6) but not in BAL.
Conclusions
Our study illustrates cell‐type‐specific regulation of the expression of asthma‐related genes documenting SNPs in TSLP, GSDMB, IL33, HLA‐DQB1, C11orf30, DEXI, CDHR3, and ZBTB10 affect asthma risk through cis‐regulation of its gene expression. Whenever possible, disease‐relevant tissues should be used for transcription analysis. SNPs in TSLP may affect asthma risk through up‐regulating TSLP mRNA expression or protein secretion. Further functional studies are warranted.
IL-17 signaling has been implicated in development and persistence of asthma. Cytokine-targeted strategies blocking IL-17 receptor signaling may be beneficial in asthma treatment.
To determine ...efficacy and safety of brodalumab, a human anti-IL-17 receptor A monoclonal antibody, in subjects with inadequately controlled moderate to severe asthma taking regular inhaled corticosteroids.
Three hundred two subjects were randomized to brodalumab (140, 210, or 280 mg) or placebo. Primary endpoint was change in Asthma Control Questionnaire (ACQ) score from baseline to Week 12. Secondary endpoints included FEV1, symptom scores, and symptom-free days. Prespecified subgroup analyses were conducted to identify potential responsive subpopulations. Analyses included randomized subjects receiving one or more doses of investigational product using last-observation-carried-forward imputation.
Demographics and baseline characteristics were generally balanced among groups (n = 302; n = 226 brodalumab). For the overall study population, no treatment differences were observed. Nine prespecified subgroups were examined without corrections for multiple testing. In only the high-reversibility subgroup (post-bronchodilator FEV1 improvement ≥ 20%; n = 112) was an ACQ change with nominal significance noted; ACQ responses were nominally significant in the 210-mg group (estimated treatment difference, 0.53) but not significant in the higher 280-mg group (estimated treatment difference, 0.38). Adverse events, generally balanced among groups, were most commonly asthma, upper respiratory tract infection, and injection site reaction.
Inhibition of IL-17 receptor A did not produce a treatment effect in subjects with asthma. The results of the high-reversibility subgroup analysis are of uncertain significance, requiring further study of brodalumab in this asthma subpopulation. Clinical trial registered with www.clinicaltrials.gov (NCT01199289).
Guideline-based management of asthma focuses on disease severity and choosing the appropriate medical therapy to control symptoms and reduce the risk of exacerbations. However, irrespective of asthma ...severity and often despite optimal medical therapy, patients may experience acute exacerbations of symptoms and a loss of disease control. Asthma exacerbations are most commonly triggered by viral respiratory infections, particularly with human rhinovirus. Given the importance of these events to asthma morbidity and health care costs, we will review common inciting factors for asthma exacerbations and approaches to prevent and treat these events.
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