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Asthma is a heterogeneous inflammatory disease and eosinophilic, non-eosinophilic and neutrophilic forms are recognised. While clinically similar to eosinophilic asthma, patients with non-eosinophilic asthma have different responses to treatment and little is known about the triggers of symptoms and inflammation.
This study sought to characterise a...
Contexts in source publication
Context 1
... with eosinophilic asthma had poorest asthma control with a higher ACQ score (P =0.029, Table 2) and a lower prevalence of controlled asthma (32%, P =0.011). ...
Context 2
... frequencies of severe exacerbations (defined by requirement of a course of oral corticosteroids in the previous 12 months) were similar across inflammatory subtypes (Table 2). However participants with paucigranulocytic asthma and neutrophilic asthma had more than double the amount of primary care visits for uncontrolled asthma in the past year (Table 2, P =0.015) and in particular those with neutrophilic asthma had 4.5 times the odds of requiring a visit to their general practice physician for their asthma compared to those with eosinophilic asthma (Table 4). ...
Context 3
... frequencies of severe exacerbations (defined by requirement of a course of oral corticosteroids in the previous 12 months) were similar across inflammatory subtypes (Table 2). However participants with paucigranulocytic asthma and neutrophilic asthma had more than double the amount of primary care visits for uncontrolled asthma in the past year (Table 2, P =0.015) and in particular those with neutrophilic asthma had 4.5 times the odds of requiring a visit to their general practice physician for their asthma compared to those with eosinophilic asthma (Table 4). No participant had a hospital admission in the past year. ...
Context 4
... infections were more common in those with neutrophilic asthma. More than 70% reported a chest infection in the previous 12 months, and a higher prevalence of bacterial pathogens was detected when asthma was stable (Table 2). Overall there was a low rate of positive culture with a bacterial pathogen identified in five participants (10%), one each with Moraxella catarrhalis, Haemophilus influenzae, Pseudomonas aeruginosa and 2 with Staphylococcus aureus. ...
Citations
... Notably, a prominent airway neutrophil inflammation is often associated with the asthma severity and insensitivity to treatment with ICS [6,7]. External factors like smoking, air pollution, and persistent infection with pathogenic microorganisms have been implicated in driving neutrophilic inflammation in asthma [8][9][10][11]. The underlying inflammatory mechanism of asthma aggravation caused by these exogenous factors are intricately tied to cell membrane receptors and the innate immune system. Pattern recognition receptors (PRRs), including toll-like receptors (TLRs) and so on, which mainly express on innate immune cells, play a pivotal role in recognizing external allergens [12], cigarette smoke [13], pathogenic microorganisms [14] and other stimuli. ...
Background
The pattern recognition receptor Dectin-1 was initially discovered to play a pivotal role in mediating pulmonary antifungal immunity and promoting neutrophil-driven inflammation. Recent studies have revealed that Dectin-1 is overexpressed in asthma, but the specific mechanism remains elusive. Additionally, Dectin-1 has been implicated in promoting pyroptosis, a hallmark of severe asthma airway inflammation. Nevertheless, the involvement of the non-classical pyroptosis signal caspase-11/4 and its upstream regulatory mechanisms in asthma has not been completely explored.
Methods
House dust mite (HDM)-induced mice was treated with Dectin-1 agonist Curdlan, Dectin-1 inhibitor Laminarin, and caspase-11 inhibitor wedelolactone separately. Subsequently, inflammatory cells in bronchoalveolar lavage fluid (BALF) were analyzed. Western blotting was performed to measure the protein expression of caspase-11 and gasdermin D (GSDMD). Cell pyroptosis and the expression of chemokine were detected in vitro. The correlation between Dectin-1 expression, pyroptosis factors and neutrophils in the induced sputum of asthma patients was analyzed.
Results
Curdlan appeared to exacerbate neutrophil airway inflammation in asthmatic mice, whereas wedelolactone effectively alleviated airway inflammation aggravated by Curdlan. Moreover, Curdlan enhanced the release of caspase-11 activation fragments and N-terminal fragments of gasdermin D (GSDMD-N) stimulated by HDM both in vivo or in vitro. In mouse alveolar macrophages (MH-S cells), Curdlan/HDM stimulation resulted in vacuolar degeneration and elevated lactate dehydrogenase (LDH) release. In addition, there was an upregulation of neutrophil chemokines CXCL1, CXCL3, CXCL5 and their receptor CXCR2, which was suppressed by wedelolactone. In asthma patients, a positive correlation was observed between the expression of Dectin-1 on macrophages and caspase-4 (the human homology of caspase-11), and the proportion of neutrophils in induced sputum.
Conclusion
Dectin-1 activation in asthma induced caspase-11/4 mediated macrophage pyroptosis, which subsequently stimulated the secretion of chemokines, leading to the exacerbation of airway neutrophil inflammation.
Graphical Abstract
... The causative events of airways neutrophilic inflammation comprise bacterial and viral infections, the latter being a trigger for asthma exacerbations. SIMPSON et al. [66] observed higher exacerbation frequency and a greater incidence of CRS and viral infections in patients with neutrophilic inflammation. A subgroup of these patients also showed airway colonisation of Moraxella catarrhalis, Haemophilus influenzae, Pseudomonas aeruginosa and Staphylococcus aureus. ...
The heterogeneity of asthma makes it challenging to unravel the pathophysiologic mechanisms of the disease. Despite the wealth of research identifying diverse phenotypes, many gaps still remain in our knowledge of the disease's complexity. A crucial aspect is the impact of airborne factors over a lifetime, which often results in a complex overlap of phenotypes associated with type 2 (T2), non-T2 and mixed inflammation. Evidence now shows overlaps between the phenotypes associated with T2, non-T2 and mixed T2/non-T2 inflammation. These interconnections could be induced by different determinants such as recurrent infections, environmental factors, T-helper plasticity and comorbidities, collectively resulting in a complex network of distinct pathways generally considered as mutually exclusive. In this scenario, we need to abandon the concept of asthma as a disease characterised by distinct traits grouped into static segregated categories. It is now evident that there are multiple interplays between the various physiologic, cellular and molecular features of asthma, and the overlap of phenotypes cannot be ignored.
... GERD is often accompanied by mixed eosinophilic and neutrophilic inflammation (reviewed in [177]). Simpson et al. found that patients with neutrophilic asthma had a high prevalence of rhinosinusitis and symptoms of GERD as compared with patients with eosinophilic asthma [178]. The mechanism through which GERD induces or enhances airway inflammation in asthma has not been determined, but GERD is associated with obesity [179], which may lead to neutrophilic inflammation, as mentioned above. ...
Although eosinophilic inflammation is characteristic of asthma pathogenesis, neutrophilic inflammation is also marked, and eosinophils and neutrophils can coexist in some cases. Based on the proportion of sputum cell differentiation, asthma is classified into eosinophilic asthma, neutrophilic asthma, neutrophilic and eosinophilic asthma, and paucigranulocytic asthma. Classification by bronchoalveolar lavage is also performed. Eosinophilic asthma accounts for most severe asthma cases, but neutrophilic asthma or a mixture of the two types can also present a severe phenotype. Biomarkers for the diagnosis of neutrophilic asthma include sputum neutrophils, blood neutrophils, chitinase-3-like protein, and hydrogen sulfide in sputum and serum. Thymic stromal lymphoprotein (TSLP)/T-helper 17 pathways, bacterial colonization/microbiome, neutrophil extracellular traps, and activation of nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3 pathways are involved in the pathophysiology of neutrophilic asthma and coexistence of obesity, gastroesophageal reflux disease, and habitual cigarette smoking have been associated with its pathogenesis. Thus, targeting neutrophilic asthma is important. Smoking cessation, neutrophil-targeting treatments, and biologics have been tested as treatments for severe asthma, but most clinical studies have not focused on neutrophilic asthma. Phosphodiesterase inhibitors, anti-TSLP antibodies, azithromycin, and anti-cholinergic agents are promising drugs for neutrophilic asthma. However, clinical research targeting neutrophilic inflammation is required to elucidate the optimal treatment.
... Past analyses explored the correlated risks using as a classification of inflammation a F E NO threshold of [35][36][37][38][39][40] ppb [4,10,16]. However, according to the American Thoracic Society (ATS) guidelines, in adults, such F E NO concentrations define an intermediate level that should be considered with caution [12]. ...
... Moreover, they had a higher incidence of arterial hypertension and myocardial infarction than those with very high F E NO. These comorbidities are associated with neutrophilic inflammation [37,38], which could also be the reason for the higher incidence of obstructive sleep apnoea syndrome and GERD [39] in low F E NO group. ...
Background:
In asthma, exhaled nitric oxide (FENO) is a clinically established biomarker of airway T2 inflammation and an indicator for anti-inflammatory therapy.
Objectives:
The aim of the study was to identify, in an observational real-world cross-sectional study, the main characteristics of patients with asthma as classified by their FENO level.
Method:
We stratified 398 patients with stable mild-to-severe asthma according to FENO level as low (≤25 ppb) versus elevated (>25 ppb), subdividing the latter into two subgroups: moderately elevated (26-50 ppb) versus very high FENO (>50 ppb). Clinical, functional, and blood parameters were extrapolated from patients' chart data and compared with the FENO stratification. Predictors of low and elevated FENO asthma were detected by logistic regression model.
Results:
Low BMI, higher blood eosinophilia, allergen poly-sensitization, the severest airflow obstruction (FEV1/FVC), and anti-leukotriene use are predictors of elevated FENO values in asthma, as well as persistent rhinitis and chronic rhinosinusitis with or without nasal polyps. Beyond these, younger age, more than 2 asthma exacerbations/year, higher airflow reversibility (post-bronchodilator ∆FEV1), and oral corticosteroid dependence are predictors of very high FENO values. In contrast, obesity, obstructive sleep apnoea syndrome, gastroesophageal reflux disease, arterial hypertension, and myocardial infarction are predictors of low FENO asthma. In our population, FENO correlated with blood eosinophils, airflow obstruction, and reversibility and negatively correlated with age and BMI.
Conclusions:
Stratifying patients by FENO level can identify specific asthma phenotypes with distinct clinical features and predictors useful in clinical practice to tailor treatment and improve asthmatic patients' outcomes.
... However, treatments centered on inhaled steroids and long-acting inhaled b2 agonists are currently used. In the case of severe asthma, oral steroids are used as a therapeutic approach, but the symptoms sometimes cannot be properly managed (Simpson et al., 2014;Uddin et al., 2010Uddin et al., , 2013. Exacerbation of asthma results in reduced lung function, markedly reduced quality of life, and financial burdens. ...
Respiratory syncytial virus (RSV) infection often exacerbates bronchial asthma, but there is no licensed RSV vaccine or specific treatments. Here we show that RSV-induced alveolar macrophages, which produce high levels of matrix metalloproteinase-12 (MMP-12), exacerbate allergic airway inflammation with increased neutrophil infiltration. When mice subjected to allergic airway inflammation via exposure to the house dust mite antigen (HDM) were infected with RSV (HDM/RSV), MMP-12 expression, viral load, neutrophil infiltration, and airway hyperresponsiveness (AHR) were increased compared to those in the HDM and RSV groups. These exacerbations in the HDM/RSV group were attenuated in MMP-12-deficient mice and mice treated with MMP408, a selective MMP-12 inhibitor, but not in mice treated with dexamethasone. Finally, M2-like macrophages produced MMP-12, and its production was promoted by increase of IFN-β-induced IL-4 receptor expression with RSV infection. Thus, targeting MMP-12 represents a potentially novel therapeutic strategy for the exacerbation of asthma.
... All rights reserved respiratory viral infections, such as rhinovirus (RV), are a frequent cause of asthma exacerbations and concomitant increases in airway neutrophilia, whilst fungal pathogens also associate with neutrophilic, severe asthma 88 . Other factors have also been associated with the appearance of a neutrophilic endotype of asthma, including environmental factors such as cigarette smoke and pollution [89][90][91] , and comorbid factors such as obesity and gastroesophageal reflux disease 92,93 . ...
Neutrophils are critical components of the body’s immune response to infection, being loaded with a potent arsenal of toxic mediators and displaying immense destructive capacity. Given the potential of neutrophils to impart extensive tissue damage, it is perhaps not surprising that when augmented these cells are also implicated in the pathology of inflammatory diseases. Prominent neutrophilic inflammation is a hallmark feature of patients with chronic lung diseases such as chronic obstructive pulmonary disease, severe asthma, bronchiectasis and cystic fibrosis, with their numbers frequently associating with worse prognosis. Accordingly, it is anticipated that neutrophils are central to the pathology of these diseases and represent an attractive therapeutic target. However, in many instances, evidence directly linking neutrophils to the pathology of disease has remained somewhat circumstantial and strategies that have looked to reduce neutrophilic inflammation in the clinic have proved largely disappointing. We have classically viewed neutrophils as somewhat crude, terminally differentiated, insular and homogenous protagonists of pathology. However, it is now clear that this does not do the neutrophil justice, and we now recognize that these cells exhibit heterogeneity, a pronounced awareness of the localized environment and a remarkable capacity to interact with and modulate the behaviour of a multitude of cells, even exhibiting anti‐inflammatory, pro‐resolving and pro‐repair functions. In this review, we discuss evidence for the role of neutrophils in chronic lung disease and how our evolving view of these cells may impact upon our perceived assessment of their contribution to disease pathology and efforts to target them therapeutically.
... Also Haemophilus Influenza is often detected in sputum of asthmatics with increased neutrophil numbers and the diversity of the sputum microbiome is reduced [43,44]. Neutrophilic asthma patients have a higher frequency of asthma exacerbations and a higher prevalence of chest infections compared to eosinophilic asthma [45]. Also fungal infections play a role. ...
... Some comorbidities are more frequent in neutrophilic asthma, such as rhinosinusitis and increased gastroesophageal reflux [45]. Obstructive sleep apnea occurs more in asthma and is associated with the presence of neutrophilic inflammation [61]. ...
Suppression of airway inflammation with inhaled corticosteroids has been the key therapeutic approach for asthma for many years. Identification of inflammatory phenotypes in asthma has moreover led to important breakthroughs, e.g. with specific targeting of the IL-5 pathway as add-on treatment in difficult-to-treat eosinophilic asthma. However, the impact of interfering with the neutrophilic component in asthma is less documented and understood.
This review provides an overview of established and recent insights with regard to the role of neutrophils in asthma, focusing on research in humans. We will describe the main drivers of neutrophilic responses in asthma, the heterogeneity in neutrophils and how they could contribute to asthma pathogenesis. Moreover we will describe findings from clinical trials, in which neutrophilic inflammation was targeted. It is clear that neutrophils are important actors in asthma development and play a role in exacerbations. However, more research is required to fully understand how modulation of neutrophil activity could lead to a significant benefit in asthma patients with airway neutrophilia.
... 55 However, patient with neutrophilic asthma have an increased prevalence of rhinosunisitis (>64%) compared to those with eosinophilic asthma. 56 Sinupulmonary infection is also reported to be high in patient with neutrophilic asthma. 7 Patients with asthma should be investigated for chronic rhinosinusitis and nasal polyps. ...
... 93 Patients with GERD and neutrophilic asthma have severe refractory disease, lower lung function, and poor symptom control. 7,56,86 Several reports have documented that medical treatment with prokinetics and H2antagonists, proton-pump inhibitors, and antireflux surgery improve asthma symptom and reduce exacerbations in asthmatic patients with GERD. 95 Prokinetics and H2-receptor antagonists have been reported to reduce symptoms, 96 and nocturnal asthma in patients with GERD. ...
Asthma is a common chronic airway disease affecting about 334 million people worldwide, and an estimated 7 million children globally. Approximately 10% of patients with asthma have severe refractory disease, which is difficult to control on high doses of inhaled corticosteroids and other modifiers. Among these, are patients with severe neutrophilic asthma. Neutrophilic asthma is a phenotype of asthma that is very severe and persistent, with frequent exacerbations, and characterized by fixed airway obstruction. It is associated with comorbidities such as respiratory infections, obesity, gastroeosophageal reflux disease, and obstructive sleep apnoea. Immunopathologically, it is characterized by the presence of high levels of neutrophils in the lungs and airways. Neutrophils and the interleukin-17 family of cytokines play a pivotal role in the pathogenesis of severe neutrophilic asthma. Most patients with the disease do not achieve control with high dose inhaled corticosteroids, and probably to novel IgE, interleukin and interleukin monoclonal antibodies.
... sputum culture Briefly, serial dilutions of homogenised sputum samples were prepared in phosphate buffered saline and used to inoculate chocolate bacitracin and blood agar plates that were examined for bacterial growth after 24 and 48 hours by trained microbiologists at Pathology North, John Hunter Hospital. 28 Open Access sputum colour assessment Sputum colour was assessed by laboratory staff using a 5-point sputum colour chart (BronkoTest; Heredilab Inc, Salt Lake City, Utah, USA) as soon as the sample was received in the lab and prior to sputum processing. The presence of opaque clumps in the sputum sample was also considered while recording sputum colour. ...
Introduction
Sputum colour is associated with neutrophilic inflammation in chronic bronchitis and chronic obstructive pulmonary disease (COPD). Neutrophilia and sputum expectoration is notable in asthma, but whether sputum colour is associated with and predicts the presence of neutrophilic inflammation in asthma is unknown. The objective of the study is to assess the ability of sputum colour in distinguishing asthma inflammatory phenotypes.
Methods
Induced sputum samples collected from 271 adults with stable asthma were retrospectively assessed. Sputum colour was determined using the BronkoTest sputum colour chart and correlated to differential cell counts and CXCL-8 concentration. Neutrophilic inflammation was defined as an age-corrected sputum neutrophil proportion (≥61.6% for age 20–40 years; ≥63.2% for age 40–60 and ≥67.2% for age >60 years), whereas neutrophilic bronchitis (NB) was defined as high total cell count (≥5.1×10⁶ cells/mL) plus an increased age-corrected neutrophil proportion. The optimal cut-off for sputum colour to predict neutrophilic inflammation and NB was determined using receiver operator characteristic curve analysis.
Results
A sputum colour score of ≥3 represented and predicted neutrophilic inflammation with modest accuracy (area under the curve (AUC)=0.64; p<0.001, specificity=78.4%, sensitivity=49.2%). Participants with a sputum colour score of ≥3 had significantly (p<0.05) higher CXCL-8, total cells and neutrophil number and proportion. Sputum colour score was also positively correlated with these factors. Sputum colour score ≥3 predicted NB with reasonably good accuracy (AUC=0.79, p<0.001, specificity=79.3%, sensitivity=70.7%).
Conclusions
Visual gradation of sputum colour in asthma relates to high total cell count and neutrophilic inflammation. Assessment of sputum colour can identify adults with asthma who are likely to have NB without the need for sputum processing and differential cell count, which may facilitate asthma management.
... Therefore, this could be another reason for the low prevalence in Asia, that is, low recognition because of misunderstanding of GERD symptoms by people and community physicians. Based on the impacts of GERD on the quality of life [10,11], timely accurate diagnosis and adequate treatments should improve the quality of life of patients with GERD and reduce medical expenses from GERD for patients in non-English-speaking countries. In addition, in China, outpatient clinics are overburdened [12,13], highlighting the need for fast recognition of the symptoms of GERD. ...
Objective
To explore whether pictograms could help people understand reflux symptoms.
Methods
Gastroenterologists (n = 28), non-GI physicians (n = 30), healthy people without medical education (n = 34), patients with gastrointestinal reflux disease (GERD) (n = 45), and general people (n = 100) were included. Pictograms denoting classic reflux symptoms (sour regurgitation, heartburn, retrosternal pain, and regurgitation) were created by the joint efforts of an artist and a gastroenterologist. The subjects were asked to tell the meaning of each card within 30 s.
Results
Compared with the physicians, healthy people without medical education tended to make mistakes in the understanding of the terms of reflux symptoms. Among GERD patients, all the terms of reflux symptoms could be understood accurately. Compared with that of non-GI physicians, GI physician had a higher accuracy in the understanding of the term regurgitation (P < 0.05). Pictograms denoting reflux symptoms could be understood accurately in all four groups. A sample from the general population showed that the recognition of the pictogram was more accurate than the recognition of the terms.
Conclusions
Pictograms could help ordinary people who do not have medical education to understand reflux symptoms more accurately in China. Compared with abstract terms, pictograms could be useful for epidemiological studies and diagnosis of GERD in the community.
