Systemic Inflammation In Asthma Research Articles

Inflammasome-Mediated Mechanisms Of Systemic Inflammation In COVID-19 And Asthma

The review examines the formation of inflammasome-mediated mechanisms of systemic inflammation in asthma after COVID-19. It provides insight into the clinical and pathophysiological relationship between asthma and COVID-19. The review summarizes information about the role of the NLRP3 inflammasome in the pathogenesis of asthma and describes in detail its manifestations in various asthma phenotypes. Emphasizing the significance of the inflammatory-mediated immune response during coronavirus infection in patients with bronchopulmonary pathology, the review outlines the consequences of hyperactivation of the NLRP3 pathway, leading to increased production of cytokines, the appearance of neutrophil and monocyte-derived traps, induction of pyroptosis and the development of complications.

Systemic Inflammation in Asthma: What Are the Risks and Impacts Outside the Airway?

Airway inflammation in asthma has been well recognized for several decades, with general agreement on its role in asthma pathogenesis, symptoms, propensity toward exacerbation, and decline in lung function. This has led to universal recommendation in asthma management guidelines to incorporate the use of inhaled corticosteroid as an anti-inflammatory therapy for all patients with persistent asthma symptoms. However, there has been limited attention paid to the presence and potential impact of systemic inflammation in asthma. Accumulating evidence from epidemiological observations and cohort studies points to a host of downstream organ dysfunction in asthma especially among patients with longstanding or more severe disease, frequent exacerbations, and underlying risk factors for organ dysfunction. Most studies to date have focused on cognitive impairment, depression/anxiety, metabolic syndrome, and cardiovascular abnormalities. In this review, we summarize some of the evidence demonstrating these abnormalities, highlight the proposed mechanisms and potential benefits of treatment in limiting these extrapulmonary abnormalities in patients with asthma. The goal of this commentary is to raise awareness of the importance of recognizing potential extra-pulmonary conditions associated with systemic inflammation of asthma. This area of treatment of patients with asthma is a large unmet need.

Asthma and comorbidities: recent advances.

Asthma is usually associated with pulmonary and extrapulmonary comorbidities that are more common in patients with severe asthma than in those with mild‑to‑moderate illness or in the general population. These comorbidities may affect the clinical intensity and severity of asthma and, as a result, increase health care costs related to its therapy. On the other hand, their recognition and appropriate treatment appear to improve asthma outcomes while optimizing therapy by preventing overtreatment. Comorbid conditions such as gastroesophageal reflux disease, allergic rhinitis, obesity, depression, diabetes mellitus, and cardiovascular disease are commonly known, though their prevalence varies significantly between studies; however, many more comorbidities may remain undiagnosed and only be discovered in an experienced specialized environment. Unfortunately, the pathogenetic pathways linking asthma and many comorbidities are still unknown, which explains why they may often be misdiagnosed as diseases related to asthma treatment. Nevertheless, asthma and comorbid conditions often have common risk factors, and some evidence suggests that they share inflammatory pathways which exacerbate asthma. Inflammation was shown to play an essential role in the onset and development of various comorbidities. The role of systemic inflammation in asthma, on the other hand, remains unknown. Understanding the mechanism(s) that link(s) asthma and its concomitant disorders is critical for developing an effective treatment strategy. This review examines the epidemiology, pathophysiology, treatment suggestions, and significant knowledge gaps of these comorbidities.

Transcriptomic Profiling of Adult-Onset Asthma Related to Damp and Moldy Buildings and Idiopathic Environmental Intolerance.

A subset of adult-onset asthma patients attribute their symptoms to damp and moldy buildings. Symptoms of idiopathic environmental intolerance (IEI) may resemble asthma and these two entities overlap. We aimed to evaluate if a distinct clinical subtype of asthma related to damp and moldy buildings can be identified, to unravel its corresponding pathomechanistic gene signatures, and to investigate potential molecular similarities with IEI. Fifty female adult-onset asthma patients were categorized based on exposure to building dampness and molds during disease initiation. IEI patients (n = 17) and healthy subjects (n = 21) were also included yielding 88 study subjects. IEI was scored with the Quick Environmental Exposure and Sensitivity Inventory (QEESI) questionnaire. Inflammation was evaluated by blood cell type profiling and cytokine measurements. Disease mechanisms were investigated via gene set variation analysis of RNA from nasal biopsies and peripheral blood mononuclear cells. Nasal biopsy gene expression and plasma cytokine profiles suggested airway and systemic inflammation in asthma without exposure to dampness (AND). Similar evidence of inflammation was absent in patients with dampness-and-mold-related asthma (AAD). Gene expression signatures revealed a greater degree of similarity between IEI and dampness-related asthma than between IEI patients and asthma not associated to dampness and mold. Blood cell transcriptome of IEI subjects showed strong suppression of immune cell activation, migration, and movement. QEESI scores correlated to blood cell gene expression of all study subjects. Transcriptomic analysis revealed clear pathomechanisms for AND but not AAD patients. Furthermore, we found a distinct molecular pathological profile in nasal and blood immune cells of IEI subjects, including several differentially expressed genes that were also identified in AAD samples, suggesting IEI-type mechanisms.

High-Sensitivity Assays for C-Reactive Protein as a Systemic Inflammatory Marker in Assessing Asthma

Asthma is a chronic inflammatory condition, and the main features include airway hyper-responsiveness and inflammation of the airway with the accumulation of inflammatory cells. Increased level of plasma fibrinogen and serum amyloid A suggests the involvement of systemic inflammation in asthma. C-reactive protein (CRP) is an acute-phase protein that produced mainly by hepatocytes and is an inflammatory marker. CRP levels monitoring is useful in the evaluation of early inflammation and efficacy of treatment in acute-phase illnesses. Several studies show that asthma alone can cause an increase in high-sensitivity CRP (hs-CRP) when compared with the healthy controls. Besides that, steroid-naïve patients have a higher mean value of hs-CRP levels compared with those on inhaled corticosteroid. Furthermore, studies have shown that an elevated hs-CRP level has a positive correlation with non-atopic asthma but not atopic asthma. Additionally, an increase in serum hs-CRP levels correlates with the severity of asthma. Therefore, serum hs-CRP is a useful surrogate marker to predict the severity of inflammation of the bronchus in asthma and assess the asthma status.

Impact of sinus surgery on type 2 airway and systemic inflammation in asthma

Objective: Asthma is frequently associated with chronic rhinosinusitis with nasal polyps (CRSwNP). Although endoscopic sinus surgery (ESS) improves asthma control in CRSwNP patients with asthma, the mechanism that underlies the response to surgical treatment is still unclear. We evaluated the relevance of changes in asthma control and changes in airway/systemic inflammation in eosinophilic CRSwNP patients with not well controlled asthma who underwent ESS.Methods: We prospectively assessed changes in the asthma control questionnaire (ACQ) score, blood eosinophil counts (B-Eos), forced expiratory volume in 1 s (FEV1), and fraction of exhaled nitric oxide (FeNO) levels at 1-week before and 8 and 52 weeks after ESS.Results: Twenty-five subjects were analyzed. The ACQ score, B-Eos, and FeNO decreased, and FEV1 increased significantly after ESS. In the period from baseline to 52 weeks after ESS, changes in ACQ were significantly correlated with the changes in blood eosinophil counts (r = 0.58, p<.01) and FeNO (r = 0.45, p<.05). Ten subjects (40%) showed consistently improved asthma control at 52-weeks after ESS. In the remaining subjects, although the ACQ score temporarily improved at 8-weeks after ESS, but eventually deteriorated at 52-weeks. Higher levels of total immunoglobulin E were associated with long-term improved asthma control after ESS.Conclusions: In eosinophilic CRSwNP patients with asthma, sinus surgery impacts asthma control through the suppression of airway/systemic type 2 inflammation. The present study reinforced the common pathophysiology of type 2 inflammation between the upper and lower airways.

Dietary inflammatory index is related to asthma risk, lung function and systemic inflammation in asthma

Asthma prevalence has increased in recent years, and evidence suggests that diet may be a contributing factor. Increased use of processed foods has led to a decrease in diet quality, which may be creating a pro-inflammatory environment, thereby leading to the development and/or progression of various chronic inflammatory diseases and conditions. Recently, the dietary inflammatory index (DII) has been developed and validated to assess the inflammatory potential of individual diets. This study aimed to examine the DII in subjects with asthma compared to healthy controls and to relate the DII to asthma risk, lung function and systemic inflammation. Subjects with asthma (n = 99) and healthy controls (n = 61) were recruited. Blood was collected and spirometry was performed. The DII was calculated from food frequency questionnaires administered to study subjects. The mean DII score for the asthmatics was higher than the mean DII score for healthy controls (- 1.40 vs. - 1.86, P = 0.04), indicating that their diets were more pro-inflammatory. For every 1 unit increase in DII score, the odds of having asthma increased by 70% (OR: 1.70, 95% CI: 1.03, 2.14; P = 0.040). FEV1 was significantly associated with DII score (β = - 3.44, 95% CI: - 6.50, - 0.39; P = 0.020), indicating that for every 1 unit increase in DII score, FEV1 decreased by 3.44 times. Furthermore, plasma IL-6 concentrations were positively associated with DII score (β = 0.13, 95% CI: 0.05, 0.21; P = 0.002). As assessed using the DII score, the usual diet consumed by asthmatics in this study was pro-inflammatory relative to the diet consumed by the healthy controls. The DII score was associated with increased systemic inflammation and lower lung function. Hence, consumption of pro-inflammatory foods may contribute to worse asthma status, and targeting an improvement in DII in asthmatics, as an indicator of suitable dietary intake, might be a useful strategy for improving clinical outcomes in the disease.

Aeroallergen and food IgE sensitization and local and systemic inflammation in asthma

We recently reported an independent association between IgE sensitization to food allergens and increased airway inflammation, assessed by fraction of exhaled nitric oxide (FeNO), in a population-based study (J Allergy Clin Immunol, 130, 2012, 397). Similar studies have not been performed in populations with asthma. The aim of the present study was to investigate the allergic sensitization profile in asthmatics and examine FeNO, airway responsiveness and blood eosinophilia in relation to type and degree of IgE sensitization. FeNO, airway responsiveness, blood eosinophil count (B-Eos) and IgE sensitization to food allergens and aeroallergens were determined in 408 subjects with asthma, aged 10-34 years. Asthmatics had higher prevalence of IgE sensitization against all allergens than controls (P < 0.001). Mite, pollen, furry animal, mould and food sensitizations were each associated with increased FeNO, airway responsiveness and B-Eos in asthmatics. IgE sensitization to mould, furry animals and food allergens was independently related to FeNO (all P < 0.05) after adjustment for age, sex, height, smoking history and medication. IgE sensitization to mould (P < 0.001) and furry animals (P = 0.02) was related to airway responsiveness in a similar model. Finally, IgE sensitization to mould (P = 0.001), furry animals (P < 0.001) and food allergens (P < 0.001) was independently related to B-Eos. Independent effects of IgE sensitization to aeroallergens (furry animals and mould) and food allergens were found on both local and systemic markers of inflammation in asthma. The finding regarding food IgE sensitization is novel, and a clinical implication might be that even food sensitization must be assessed to fully understand inflammation patterns in asthma.

Effect of inhaled corticosteroids on systemic inflammation in asthma.

Background:Recent research using serum high sensitivity C-reactive protein (hs-CRP) has evidenced existence of low grade systemic inflammation in asthmatics whose correlation with various clinical indices is not fully studied.Objective:To investigate the relationship between systemic inflammation and various clinical and treatment characteristics of asthma.Materials and Methods:Forty asthmatics (22 steroid inhaling and 18 steroid naïve) and 40 healthy subjects matched for age and sex were examined cross-sectionally. Along with clinical assessment, serum hs-CRP levels were measured for all subjects using latex enhanced immunoturbidometry method.Results:Serum hs CRP levels were significantly higher in steroid naïve asthmatics when compared to normal subjects (0.93 ± 1.18 vs 0.24 ± 0.31 mg/dL, respectively; Mann-Whitney U test, P < 0.001). This association persisted after adjusting for age, gender, body mass index (BMI), and socioeconomic status (adjusted odds ratio 10.47; 95% CI 1.88-58.3; P < 0.01). Steroid inhaling asthmatics had serum hs-CRP levels comparable with control group (0.17 ± 0.18 vs 0.24 ± 0.31 mg/dL respectively, P > 0.05). Among the clinical and treatment related variables, duration of inhaled steroids usage alone correlated significantly with serum hs-CRP levels (Pearson correlation coefficient r = 0.449, P < 0.05), which was independent of age, BMI, duration of illness, and frequency of emergency visits.Conclusion:This study confirms the existence of low grade systemic inflammation in asthma which is effectively controlled by inhaled steroids. Such an effect of inhaled steroids appears to be more pronounced in recent users than that of long-term users, possibly due to lower adherence rate among the latter.

Persistent asthma increases the risk of chronic kidney disease: a retrospective cohort study of 2354 patients with asthma

Background Chronic kidney disease (CKD) is a growing public health problem with well-established risk factors. Other contributing factors, however, remain to be identified. Systemic inflammation in asthma plays a significant role in the development of other diseases. We therefore initiated a study to assess whether the growing prevalence of asthma is associated with an increase in the risk of CKD. Methods We conducted a retrospective cohort study using data from 3015 patients with asthma aged 14 years and older who were registered and followed up in Asthma Control Study at the Department of Respiratory Medicine of three medical centers from 2005 to 2011. History, asthma control test (ACT), and asthma stage were used to assess the traits of asthma. CKD was defined as proteinuria and/or reduced estimated glomerular filtration rate (eGFR) (&lt;60 ml·min−1·1.73 m−2) in two consecutive follow-up surveys. We used logistic regression models, adjusting for age, sex, and other confounding factor to determine associations between the traits of asthma and CKD. Kaplan-Meier curves were used to analyze patient outcomes. Results A total of 2354 subjects with complete data were recruited for this study with mean age (45.4±10.4) years. After 6 years of follow-up, 9.6% (n=227) of the analytic cohort developed proteinuria and 3.1% (n=72) progressed to eGFR &lt;60 ml·min−1·1.73 m−2. The patients with &gt;20 years asthma history, not well-controlled or persistent asthma patients had higher incidence of proteinuria and reduced eGFR compared with patients with ≤20 years asthma history, at least well-controlled or remission asthma, respectively. The multivariable adjusted OR for proteinuria and reduced eGFR in participants with persistent asthma was 1.49; (95% confidence interval (CI) 1.17-1.91) and 2.07 (95% CI 1.34-4.42). Compared to patients with no asthma traits, there was a significant risk (OR, 3.39; 95% CI 1.36-8.73) for those who met all three traits, including asthma history &gt;20 years, not well-controlled and persistent stage, after adjusting for potential confounding factors. Conclusions In this retrospective cohort study, we found that persistent asthma was associated with an increased risk of CKD, which was independent of obesity, diabetes, hypertension, and other well-established risk factors. Future studies should be directed to elucidate the mechanisms underlying the association between asthma and CKD.

Systemic Inflammation Is Associated with Differential Gene Expression and Airway Neutrophilia in Asthma

Systemic inflammation is reported to be associated with neutrophilic airway inflammation in asthma, but mechanisms underlying this finding are not well understood. This study aimed to examine the molecular mechanisms of the airway neutrophilia that are associated with systemic inflammation in asthma. Fifty stable nonsmoking adults with asthma had plasma high sensitivity C-reactive protein (hsCRP) and interleukin 6 (IL-6) assayed. Subjects with an elevation of both hsCRP and IL-6 were grouped as asthmatics with systemic inflammation, and those with both hsCRP and IL-6 within the normal ranges were grouped as asthmatics without systemic inflammation. Clinical characteristics and sputum inflammatory cell counts were compared between the two groups. Gene expression profiles from sputum were analyzed and altered expression of four genes (CCL8, IL8RA, SELL, and PI3) was confirmed using quantitative PCR. Asthmatics with systemic inflammation (n=18, 36%) had a higher BMI, greater history of cigarette smoking, lower FVC% predicted, and increased sputum neutrophils compared to those without systemic inflammation (n=16, 32%). Microarray analysis identified 449 genes that were significantly altered in sputum between the two groups. Altered genes were involved in IL-1, TNF-α/nuclear factor-κB, and Kit receptor pathways, and were related to innate immune response, defense and inflammatory response, in particular neutrophilic inflammation. Systemic inflammation was associated with airway neutrophilia in asthma, and was related to a group of differentially expressed genes in the lung involving multiple cytokine pathways. Our findings suggest that targeting systemic inflammation might provide a novel therapeutic strategy for neutrophilic asthma.

Comorbidities of asthma

Asthma is often associated with different comorbidities, mainly gastro-oesophageal reflux disease and allergic rhinitis, but also obesity, depression, diabetes mellitus and cardiovascular disease, which may affect its clinical intensity and severity. The prevalence of these comorbidities varies tremendously between studies. Nevertheless, it imposes a significant reflection on the need to explore the phenomenon in depth. Both clinical and basic studies have established that inflammation plays a vital role in the initiation and progression of several comorbidities. However, the role of systemic inflammation in asthma is still unclear. Understanding mechanism(s) that link(s) asthma and its comorbid diseases is essential to design an effective therapeutic approach. In the future, researchers must identify the weight of any comorbidity in patients with asthma, find the true mechanism(s) that link(s) it to asthma and act on these mechanisms that probably create a vicious circle. Conversely, we do not think it reasonable that the generalization of treatment with a holistic approach might affect the link(s) between asthma and its comorbidities.

The Neutrophilic Inflammatory Phenotype Is Associated With Systemic Inflammation in Asthma

The role of systemic inflammation in asthma is unclear. The aim of this study was to compare systemic inflammation in subjects with stable asthma, categorized by airway inflammatory phenotype, with healthy control subjects. Adults with stable asthma (n = 152) and healthy control subjects (n = 83) underwent hypertonic saline challenge and sputum induction. Differential leukocyte counts were performed on selected sputum. Plasma high-sensitivity C-reactive protein (CRP), IL-6, and tumor necrosis factor-α levels and sputum IL-8 and neutrophil elastase levels were determined by enzyme-linked immunosorbent assay. Sputum IL-8 receptor α (IL-8RA) and IL-8 receptor β (IL-8RB) messenger RNA expression were determined by real-time polymerase chain reaction. Subjects with asthma were classified as having nonneutrophilic asthma or neutrophilic asthma. The asthma (neutrophilic) group had increased systemic inflammation compared with the asthma (nonneutrophilic) and healthy control groups, with median (interquartile range) CRP levels of 5.0 (1.6-9.2), 1.8 (0.9-5.3), and 1.8 (0.8-4.1) mg/L (P = .011), respectively, and IL-6 levels of 2.1 (1.5-3.1), 1.4 (1.0-2.1), and 1.1 (0.8-1.5) pg/mL (P < .001), respectively. The proportion of subjects with elevated CRP and IL-6 levels was also higher in the asthma (neutrophilic) group. Sputum IL-8 and neutrophil elastase protein and IL-8RA and IL-8RB gene expression were significantly increased in the asthma (neutrophilic) group. In multiple regression analysis of subjects with asthma, sex, BMI, statin use, and percent sputum neutrophils were significant predictors of log(10)CRP. Sex, BMI, and %FEV(1) were significant predictors of log(10)IL-6. Systemic inflammation is increased in patients with asthma with neutrophilic airway inflammation and associated with worse clinical outcomes. Systemic inflammation may contribute to the pathophysiology of neutrophilic asthma.

Systemic and Local Inflammation in Asthma and Chronic Obstructive Pulmonary Disease: Is There a Connection?

Increasing evidence indicates that chronic obstructive pulmonary disease (COPD) and probably asthma are associated with low-grade systemic inflammatory changes. In patients with COPD, systemic inflammation is considered a key factor in the pathogenesis of the multicomponent disease manifestations. Spillover of inflammatory mediators into the circulation is generally considered to be the source of this systemic inflammation. Despite this attractive hypothesis, the nature of systemic inflammation in COPD and asthma remains unclear. Available scientific data challenge the spill-over hypothesis. Interventions with biologicals such as TNF-alpha do not modify local or systemic inflammation in these inflammatory respiratory diseases. Adipose tissue-mediated inflammation is discussed as a connecting link of systemic inflammation in asthma and COPD.

High-sensitivity C-reactive protein in the exhaled breath condensate and serum in stable and unstable asthma

Asthma is a chronic airway inflammatory disease. Measurement of serum high- sensitivity C-reactive protein (hs-CRP) levels has suggested the involvement of low-grade systemic inflammation in several disorders, such as cardiovascular disease and diabetes mellitus. In recent years, there have been some reports concerning hs-CRP assessment as a useful tool for detecting systemic inflammation in asthma. The study was undertaken to evaluate hs-CRP levels in the exhaled breath condensate (EBC) of asthmatics with different degrees of asthma severity and their relationship to hs-CRP levels in serum, clinical characteristics, and the intensification of airway inflammation. The study group was 62 patients with allergic asthma (20 with steroid-naïve mild asthma, 19 with ICS-treated, stable mild-to-moderate asthma, 23 with ICS-treated unstable, severe asthma) and 15 healthy volunteers. In the three groups of asthmatics hs-CRP concentrations in EBC and serum were significantly higher than in healthy volunteers. hs-CRP levels both in EBC and serum were significantly higher in patients with unstable asthma than in the two groups with stable disease. hs-CRP concentrations in EBC strongly correlated with those measured in serum. There was a significant correlation between hs-CRP levels both in EBC and serum and exhaled nitric oxide (F(ENO)) in the three groups of asthmatics or serum ECP in the group of patients with steroid-naïve mild asthma and unstable, severe asthma. The levels of hs-CRP in EBC are correlated with those measured in serum and may provide another useful diagnostic tool for detecting and monitoring low-grade inflammation in patients with asthma.