scholarly journals Treatment options in type-2 low asthma

2020 ◽  
pp. 2000528 ◽  
Author(s):  
Timothy SC Hinks ◽  
Stewart J Levine ◽  
Guy G Brusselle
Keyword(s):  
Severe Asthma ◽  
Bacterial Infections ◽  
Current Knowledge ◽  
Treatment Options ◽  
Occupational Exposures ◽  
Evidence Base ◽  
Type I ◽  
Eosinophilic Asthma ◽  
Ongoing Research

Monoclonal antibodies targeting IgE or the type-2 cytokines IL-4, IL-5 and IL-13 are proving highly effective in reducing exacerbations and symptoms in people with severe allergic and eosinophilic asthma respectively. However, these therapies are not appropriate for 30–50% of patients in severe asthma clinics who present with non-allergic, non-eosinophilic, “type-2 low” asthma. These patients constitute an important and common clinical asthma phenotype, driven by distinct, though poorly understood pathobiological mechanisms. In this review we describe the heterogeneity and clinical characteristics of type-2 low asthma and summarise current knowledge on the underlying pathobiological mechanisms, which includes neutrophilic airway inflammation often associated with smoking, obesity, occupational exposures and may be driven by persistent bacterial infections and by activation of a recently-described IL-6 pathway. We review the evidence base underlying existing treatment options for specific treatable traits which can be identified and addressed. We particularly focus on severe asthma as opposed to difficult-to-treat asthma, on emerging data on the identification of airway bacterial infection, on the increasing evidence base for the use of long-term low-dose macrolides, a critical appraisal of bronchial thermoplasty, and evidence for the use of biologics in type-2 low disease. Finally we review ongoing research into other pathways including TNF, IL-17, resolvins, apolipoproteins, type I interferons, IL-6 and mast cells. We suggest that type-2 low disease frequently presents opportunities for identification and treatment of tractable clinical problems and is currently a rapidly evolving field with potential for the development of novel targeted therapeutics.

scholarly journals Precision medicine applications for severe asthma

2019 ◽  
Vol 6 (4) ◽  
pp. 117-135
Author(s):  
Orit Gourgy Hacohen ◽  
Shai Cohen
Keyword(s):  
Precision Medicine ◽  
Severe Asthma ◽  
Oral Corticosteroid ◽  
Treatment Options ◽  
Current Evidence ◽  
Blood Eosinophil ◽  
Eosinophilic Asthma ◽  
Severe Eosinophilic Asthma ◽  
Beneficial Effects ◽  
New Treatment

Asthma is a heterogeneous condition in which multiple pathological pathways manifest with similar symptoms. Severe asthma (SA) is challenging to manage and comprises a significant health and economic burden. Many studies have been conducted in an attempt to define different clinical phenotypes that translate into biological endotypes, with the goal of tailoring treatment based on precision medicine. This review summarizes the current evidence for the treatments of SA, and in particular, the biologic treatments that are currently available: omalizumab, mepolizumab, reslizumab, benralizumab and dupilumab. We found only limited high-quality direct evidence regarding treatment with anti-IgE (omalizumab) in SA patients. Data regarding anti-interleukin (IL)-5 (mepolizumab, reslizumab and benralizumab) showed beneficial effects in severe eosinophilic asthma (SEA) with different levels of blood eosinophils used in clinical trials. Dupilumab, anti-IL-4/IL-13, was shown to be effective in SEA and is the only agent currently FDA-approved for the indication of oral corticosteroid dependent asthma, regardless of the blood eosinophil level. This review also summarizes the existing knowledge regarding the characteristics of the patient who may respond to the different therapies. As of today, more studies are needed to better understand the diverse mechanisms that underlie SA phenotypes. We have not yet adequately reached the goal of precision medicine. Additional studies are necessary in order to find novel surrogate markers that can predict the response to a specific biologic therapy, especially in patients who are oral corticosteroid dependent. In addition, efforts must be invested into research looking for new treatment options for patients with non-type-2 inflammation SA. Statement of novelty: we review the current evidence regarding tailored treatment therapies in SA, with a particular focus on the knowledge regarding patient selection for specific biologic treatments.

scholarly journals Versatility of USP18 in physiology and pathophysiology

2019 ◽  
Author(s):  
Paulina Dziamałek-Macioszczyk ◽  
Joanna Haraźna ◽  
Tomasz Stompór
Keyword(s):  
Bacterial Infections ◽  
Current Knowledge ◽  
Cell Signalling ◽  
Signalling Pathways ◽  
Type I ◽  
Multifunctional Protein ◽  
Enzymatic Function ◽  
Multiple Processes ◽  
Specific Protease ◽  
Interferon Stimulated Gene 15

Ubiquitin-specific peptidase 18 (USP18) is a multifunctional protein and its roles are still being investigated. This enzyme removes ubiquitin-like molecules from their substrates and the only known interferon-stimulated gene 15 (ISG15) specific protease. Apart from its enzymatic function, it also inhibits interferon type I and III signalling pathways. USP18 is known to regulate multiple processes, such as: cell cycle, cell signalling and response to viral and bacterial infections. Moreover, it contributes to the development of several autoimmune diseases and carcinogenesis, and recently was described as a cardiac remodelling inhibitor. This review summarizes the current knowledge on USP18 functions, highlighting its contribution to the development of heart failure, given the fact that this disease’s etiology is now considered to be inflammatory in nature.

scholarly journals Stating the obvious: intravenous magnesium sulphate should be the first parenteral bronchodilator in paediatric asthma exacerbations unresponsive to first-line therapy

Breathe ◽  
2021 ◽  
Vol 17 (4) ◽  
pp. 210113
Author(s):  
Gokul Erumbala ◽  
Sabu Anzar ◽  
Amjad Tonbari ◽  
Ramadan Salem ◽  
Colin Powell
Keyword(s):  
Magnesium Sulphate ◽  
Current Knowledge ◽  
Treatment Options ◽  
Asthma Management ◽  
Evidence Base ◽  
Second Line ◽  
First Line Therapy ◽  
Line Therapy ◽  
Asthma Attack ◽  
Bronchodilator Treatment

What is the most appropriate second-line intravenous bronchodilator treatment when a child with a severe asthma attack is not responsive to initial inhaled therapy? The second-line treatment options for acute asthma include parenteral β2-agonists, methylxanthine and magnesium sulphate (MgSO4). There is a poor evidence-base to inform this decision. This review argues that intravenous MgSO4 is the obvious treatment of choice for this situation as the initial treatment based on current knowledge.  We describe the mode of action, scope and limitations of MgSO4, safety profile, economic impact, comparisons of the alternatives, and finally, what the guidelines say.  This review explores the suitability of intravenous MgSO4 as a pragmatic and safe initial second-line therapy for children unresponsive to initial asthma management.

scholarly journals Understanding Diabetic Neuropathy: Focus on Oxidative Stress

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Lei Pang ◽  
Xin Lian ◽  
Huanqiu Liu ◽  
Yuan Zhang ◽  
Qian Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Diabetic Neuropathy ◽  
Current Knowledge ◽  
Treatment Options ◽  
Specific Treatment ◽  
Diagnostic Procedures ◽  
Type I ◽  
Foot Care ◽  
Clinical Syndromes ◽  
Poor Outcomes

Diabetic neuropathy is one of the clinical syndromes characterized by pain and substantial morbidity primarily due to a lesion of the somatosensory nervous system. The burden of diabetic neuropathy is related not only to the complexity of diabetes but also to the poor outcomes and difficult treatment options. There is no specific treatment for diabetic neuropathy other than glycemic control and diligent foot care. Although various metabolic pathways are impaired in diabetic neuropathy, enhanced cellular oxidative stress is proposed as a common initiator. A mechanism-based treatment of diabetic neuropathy is challenging; a better understanding of the pathophysiology of diabetic neuropathy will help to develop strategies for the new and correct diagnostic procedures and personalized interventions. Thus, we review the current knowledge of the pathophysiology in diabetic neuropathy. We focus on discussing how the defects in metabolic and vascular pathways converge to enhance oxidative stress and how they produce the onset and progression of nerve injury present in diabetic neuropathy. We discuss if the mechanisms underlying neuropathy are similarly operated in type I and type II diabetes and the progression of antioxidants in treating diabetic neuropathy.

scholarly journals A Novel Insight on Endotyping Heterogeneous Severe Asthma Based on Endoplasmic Reticulum Stress: Beyond the “Type 2/Non-Type 2 Dichotomy”

2019 ◽  
Vol 20 (3) ◽  
pp. 713 ◽  
Author(s):  
Jae Seok Jeong ◽  
So Ri Kim ◽  
Seong Ho Cho ◽  
Yong Chul Lee
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Severe Asthma ◽  
Current Knowledge ◽  
Current System ◽  
Clinical Syndrome ◽  
Eosinophilic Inflammation ◽  
Corticosteroid Resistance ◽  
Asthma Patients

Severe asthma is an extremely heterogeneous clinical syndrome in which diverse cellular and molecular pathobiologic mechanisms exist, namely endotypes. The current system for endotyping severe asthma is largely based on inflammatory cellular profiles and related pathways, namely the dichotomy of type 2 response (resulting in eosinophilic inflammation) and non-type 2 response (reinforcing non-eosinophilic inflammation involving neutrophils or less inflammatory cells), forming the basis of a development strategy for novel therapies. Although specific subgroups of type 2 severe asthma patients may derive benefit from modern precision medicine targeting type 2 cytokines, there is no approved and effective therapeutic agent for non-type 2 severe asthma, which comprises nearly 50% of all asthma patients. Importantly, the critical implication of endoplasmic reticulum (ER) stress and unfolded protein response—in close relation with several pivotal cellular immune/inflammatory platforms including mitochondria, NLRP3 inflammasome, and phosphoinositide 3-kinase-δ—in the generation of corticosteroid resistance is now being increasingly demonstrated in numerous experimental settings of severe asthma. Consistent with these findings, recent clinical data from a large European severe asthma cohort, in which molecular phenotyping as well as diverse clinical and physiological parameters from severe asthmatic patients were incorporated, suggest a brand new framework for endotyping severe asthma in relation to ER-associated mitochondria and inflammasome pathways. These findings highlight the view that ER stress-associated molecular pathways may serve as a unique endotype of severe asthma, and thus present a novel insight into the current knowledge and future development of treatment to overcome corticosteroid resistance in heterogeneous severe asthma

scholarly journals Polymyxins–Curcumin Combination Antimicrobial Therapy: Safety Implications and Efficacy for Infection Treatment

Antioxidants ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 506 ◽  
Author(s):  
Chongshan Dai ◽  
Yang Wang ◽  
Gaurav Sharma ◽  
Jianzhong Shen ◽  
Tony Velkov ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Current Knowledge ◽  
Treatment Options ◽  
Inhibitory Effect ◽  
Limiting Factors ◽  
Therapeutic Window ◽  
Limiting Factor ◽  
Gram Negative Bacteria ◽  
Gram Negative

The emergence of antimicrobial resistance in Gram-negative bacteria poses a huge health challenge. The therapeutic use of polymyxins (i.e., colistin and polymyxin B) is commonplace due to high efficacy and limiting treatment options for multidrug-resistant Gram-negative bacterial infections. Nephrotoxicity and neurotoxicity are the major dose-limiting factors that limit the therapeutic window of polymyxins; nephrotoxicity is a complication in up to ~60% of patients. The emergence of polymyxin-resistant strains or polymyxin heteroresistance is also a limiting factor. These caveats have catalyzed the search for polymyxin combinations that synergistically kill polymyxin-susceptible and resistant organisms and/or minimize the unwanted side effects. Curcumin—an FDA-approved natural product—exerts many pharmacological activities. Recent studies showed that polymyxins–curcumin combinations showed a synergistically inhibitory effect on the growth of bacteria (e.g., Gram-positive and Gram-negative bacteria) in vitro. Moreover, curcumin co-administration ameliorated colistin-induced nephrotoxicity and neurotoxicity by inhibiting oxidative stress, mitochondrial dysfunction, inflammation and apoptosis. In this review, we summarize the current knowledge-base of polymyxins–curcumin combination therapy and discuss the underlying mechanisms. For the clinical translation of this combination to become a reality, further research is required to develop novel polymyxins–curcumin formulations with optimized pharmacokinetics and dosage regimens.

Clusters of Severe Eosinophilic Asthma in a Korean Asthma Cohort

Respiration ◽  
2021 ◽  
pp. 1-11
Author(s):  
Ji-Hyang Lee ◽  
Jin An ◽  
Ha-Kyeong Won ◽  
Bomi Seo ◽  
Jung-Hyun Kim ◽  
...  
Keyword(s):  
Cluster Analysis ◽  
Lung Function ◽  
Severe Asthma ◽  
Treatment Options ◽  
Clinical Importance ◽  
Forced Expiratory Volume ◽  
Blood Eosinophil ◽  
Eosinophilic Asthma ◽  
Severe Eosinophilic Asthma ◽  
Patient Subgroups

<b><i>Background:</i></b> Targeted therapies have broadened the available treatment options for patients with severe eosinophilic asthma (SEA). However, differences in the magnitude of treatment responses among patients indicate the presence of various underlying pathophysiological processes and patient subgroups. <b><i>Objectives:</i></b> We aimed to describe the characteristics of SEA and identify its patient subgroups. <b><i>Methods:</i></b> Clinical data from the Cohort for Reality and Evolution of Adult Asthma in Korea were analyzed. Cluster analysis was performed among those with SEA using 5 variables, namely, prebronchodilator forced expiratory volume in 1 s, body mass index, age at symptom onset, smoking amount, and blood eosinophil counts. <b><i>Results:</i></b> Patients with SEA showed prevalent sensitization to aeroallergens, decreased lung function, and poor asthma control status. Cluster analysis revealed 3 distinctive subgroups among patients with SEA. Cluster 1 (<i>n</i> = 177) consisted of patients reporting the lowest blood eosinophils (median, 346.8 cells/μL) and modest severe asthma with preserved lung function during the 12-month treatment period. Cluster 2 (<i>n</i> = 42) predominantly included smoking males with severe persistent airway obstruction and moderate eosinophilia (median, 451.8 cells/μL). Lastly, cluster 3 (<i>n</i> = 95) included patients with the most severe asthma, the highest eosinophil levels (median, 817.5 cells/μL), and good treatment response in terms of improved lung function and control status. <b><i>Conclusions:</i></b> Three subgroups were identified in SEA through the cluster analysis. The distinctive features of each cluster may help physicians predict patients who will respond to biologics with greater magnitude of clinical improvement. Further research regarding the underlying pathophysiology and clinical importance of each subgroup is warranted.

scholarly journals Interferon-Inducible Myxovirus Resistance Proteins: Potential Biomarkers for Differentiating Viral from Bacterial Infections

2019 ◽  
Vol 65 (6) ◽  
pp. 739-750 ◽  
Author(s):  
Vladimir P Zav'yalov ◽  
Heli Hämäläinen-Laanaya ◽  
Timo K Korpela ◽  
Tony Wahlroos
Keyword(s):  
Viral Infection ◽  
Bacterial Infections ◽  
Viral Infections ◽  
Current Knowledge ◽  
World Health ◽  
Diagnostic Tools ◽  
Specific Marker ◽  
Type I ◽  
Resistance Proteins ◽  
Potential Biomarkers

Abstract BACKGROUND In 2015, the 68th World Health Assembly declared that effective, rapid, low-cost diagnostic tools were needed for guiding optimal use of antibiotics in medicine. This review is devoted to interferon-inducible myxovirus resistance proteins as potential biomarkers for differentiating viral from bacterial infections. CONTENT After viral infection, a branch of the interferon (IFN)-induced molecular reactions is triggered by the binding of IFNs with their receptors, a process leading to the activation of mx1 and mx2, which produce antiviral Mx proteins (MxA and MxB). We summarize current knowledge of the structures and functions of type I and III IFNs. Antiviral mechanisms of Mx proteins are discussed in reference to their structural and functional data to provide an in-depth picture of protection against viral attacks. Knowing such a mechanism may allow the development of countermeasures and the specific detection of any viral infection. Clinical research data indicate that Mx proteins are biomarkers for many virus infections, with some exceptions, whereas C-reactive protein (CRP) and procalcitonin have established positions as general biomarkers for bacterial infections. SUMMARY Mx genes are not directly induced by viruses and are not expressed constitutively; their expression strictly depends on IFN signaling. MxA protein production in peripheral blood cells has been shown to be a clinically sensitive and specific marker for viral infection. Viral infections specifically increase MxA concentrations, whereas viruses have only a modest increase in CRP or procalcitonin concentrations. Therefore, comparison of MxA and CRP and/or procalcitonin values can be used for the differentiation of infectious etiology.

scholarly journals Host Immune Responses to Clostridioides difficile: Toxins and Beyond

2021 ◽  
Vol 12 ◽  
Author(s):  
Britt Nibbering ◽  
Dale N. Gerding ◽  
Ed J. Kuijper ◽  
Romy D. Zwittink ◽  
Wiep Klaas Smits
Keyword(s):  
Immune Responses ◽  
Bacterial Infections ◽  
Plasma Cells ◽  
Current Knowledge ◽  
Treatment Options ◽  
T Cell Response ◽  
Medical Community ◽  
Future Research ◽  
Host Immune Responses ◽  
Clostridioides Difficile

Clostridioides difficile is often resistant to the actions of antibiotics to treat other bacterial infections and the resulting C. difficile infection (CDI) is among the leading causes of nosocomial infectious diarrhea worldwide. The primary virulence mechanism contributing to CDI is the production of toxins. Treatment failures and recurrence of CDI have urged the medical community to search for novel treatment options. Strains that do not produce toxins, so called non-toxigenic C. difficile, have been known to colonize the colon and protect the host against CDI. In this review, a comprehensive description and comparison of the immune responses to toxigenic C. difficile and non-toxigenic adherence, and colonization factors, here called non-toxin proteins, is provided. This revealed a number of similarities between the host immune responses to toxigenic C. difficile and non-toxin proteins, such as the influx of granulocytes and the type of T-cell response. Differences may reflect genuine variation between the responses to toxigenic or non-toxigenic C. difficile or gaps in the current knowledge with respect to the immune response toward non-toxigenic C. difficile. Toxin-based and non-toxin-based immunization studies have been evaluated to further explore the role of B cells and reveal that plasma cells are important in protection against CDI. Since the success of toxin-based interventions in humans to date is limited, it is vital that future research will focus on the immune responses to non-toxin proteins and in particular non-toxigenic strains.

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